Quynh-Thu Le, MD

All Publications

• Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors. Nature biotechnology Jiang, Y., Cao, H., Deng, H., Guan, L., Langthasa, J., Colburg, D. R., Melemenidis, S., Cotton, R. M., Aleman, J., Wang, X. J., Graves, E. E., Kalbasi, A., Pu, K., Rao, J., Le, Q. T. 2024

  Abstract

  Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSCgal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.

  View details for DOI 10.1038/s41587-024-02448-0

  View details for PubMedID 39448881

  View details for PubMedCentralID 6053911

• International Recommendations on Postoperative Management for Potentially Resectable Locally Recurrent Nasopharyngeal Carcinoma. International journal of radiation oncology, biology, physics Li, J. S., Blanchard, P., Wong, C. H., Ahn, Y. C., Bonomo, P., Bresson, D., Caudell, J., Chen, M. Y., Chow, V. L., Chua, M. L., Corry, J., Dupin, C., Giralt, J., Hu, C., Kwong, D. L., Le, Q. T., Lee, A. W., Lee, N. Y., Li, Y., Lim, C. M., Lin, J. C., Mendenhall, W. M., Moya-Plana, A., O'Sullivan, B., Ozyar, E., Pan, J., Qiu, Q., Sher, D. J., Snyderman, C. H., Tao, Y., Tsang, R. K., Wang, X., Wu, P., Yom, S. S., Ng, W. T. 2024

  Abstract

  Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. While postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT.A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process.The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60Gy, and hyperfractionation has shown promise in reducing toxicity.These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for the clinical experts involved in the treatment of locally recurrent NPC.This article provides international recommendations on postoperative management for potentially resectable locally recurrent nasopharyngeal carcinoma (NPC), with a special focus on postoperative re-irradiation (re-RT). The consensus guidelines highlight the importance of achieving clear surgical margins, suggest considering re-RT for patients with positive or close margins, recommend an optimal re-RT dose of around 60Gy, and propose the use of hyperfractionation to reduce toxicity. The aim is to improve patient outcomes in the management of resectable locally recurrent NPC.

  View details for DOI 10.1016/j.ijrobp.2024.07.2143

  View details for PubMedID 39009321

• Tert-expressing cells contribute to salivary gland homeostasis and tissue regeneration after radiation therapy. Genes & development Guan, L., Viswanathan, V., Jiang, Y., Vijayakumar, S., Cao, H., Zhao, J., Colburg, D. R., Neuhöfer, P., Zhang, Y., Wang, J., Xu, Y., Laseinde, E. E., Hildebrand, R., Rahman, M., Frock, R., Kong, C., Beachy, P. A., Artandi, S., Le, Q. T. 2024

  Abstract

  Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

  View details for DOI 10.1101/gad.351577.124

  View details for PubMedID 38997156

• Large Language Model-Augmented Auto-Delineation of Treatment Target Volume in Radiation Therapy. ArXiv Rajendran, P., Yang, Y., Niedermayr, T. R., Gensheimer, M., Beadle, B., Le, Q. T., Xing, L., Dai, X. 2024

  Abstract

  Radiation therapy (RT) is one of the most effective treatments for cancer, and its success relies on the accurate delineation of targets. However, target delineation is a comprehensive medical decision that currently relies purely on manual processes by human experts. Manual delineation is time-consuming, laborious, and subject to interobserver variations. Although the advancements in artificial intelligence (AI) techniques have significantly enhanced the auto-contouring of normal tissues, accurate delineation of RT target volumes remains a challenge. In this study, we propose a visual language model-based RT target volume auto-delineation network termed Radformer. The Radformer utilizes a hierarchical vision transformer as the backbone and incorporates large language models to extract text-rich features from clinical data. We introduce a visual language attention module (VLAM) for integrating visual and linguistic features for language-aware visual encoding (LAVE). The Radformer has been evaluated on a dataset comprising 2985 patients with head-and-neck cancer who underwent RT. Metrics, including the Dice similarity coefficient (DSC), intersection over union (IOU), and 95th percentile Hausdorff distance (HD95), were used to evaluate the performance of the model quantitatively. Our results demonstrate that the Radformer has superior segmentation performance compared to other state-of-the-art models, validating its potential for adoption in RT practice.

  View details for PubMedID 39040646

  View details for PubMedCentralID PMC11261986

• The Assistant Clinical Research Coordinator Program: A Pathway for Recruitment in Radiation Oncology. Advances in radiation oncology Aboytes, M., Cody, M., Laseinde, E., Hall, J., Soltys, S., Beadle, B., Kidd, E., Qian, Y., Koong, A. C., Chang, D., Le, Q., Pollom, E. L. 2024; 9 (7): 101504

  Abstract

  Purpose: Recruiting prospective physicians to radiation oncology can be challenging, because of limited familiarity with the field. The Assistant Clinical Research Coordinator (ACRC) program can help provide trainees early exposure to radiation oncology.Methods and Materials: The ACRC program involves hiring a college graduate to provide administrative and research support for faculty members. The program was developed with our institution's clinical trials office, which provided guidance on regulatory compliance and training. A structured selection process identifies top candidates, and a rigorous onboarding process ensures smooth transitions between ACRCs. We report characteristics and outcomes of ACRC employees and surveyed them to assess their program experience using a Likert scale.Results: From 2005 to 2023, the ACRC program paired 73 ACRCs with faculty. Most faculty (68%) are currently supported by ACRCs. In 2023, 113 applications were received for 4 positions. ACRCs have contributed to research publications (293 as coauthors and 43 as first authors) and taken on leadership roles in the department. Most program alumni have attended medical school (34 of 64 program graduates; 53%). Eight have chosen to specialize in radiation oncology (13%; 2 applying into radiation oncology, 1 in residency, and 5 attendings). Of the 25% of alumni who responded to our survey, 77% responded that the mentorship provided by the ACRC program was very or extremely effective in guiding their academic development. All respondents rated the research opportunities as good or excellent, and 77% rated the clinical experience opportunities as good or excellent. Most (77%) reported that the ACRC program had substantial or significant influence on their choice of career path.Conclusions: The ACRC program provides an opportunity to address recruitment challenges in radiation oncology by offering early exposure to the field, clinical research skills, and mentorship. With the strong interest in our job posting this year, there is potential to expand this program to other institutions.

  View details for DOI 10.1016/j.adro.2024.101504

  View details for PubMedID 38846487

• Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach CANCERS Wang, D., Geng, H., Gondi, V., Lee, N. Y., Tsien, C. I., Xia, P., Chenevert, T. L., Michalski, J. M., Gilbert, M. R., Le, Q., Omuro, A. M., Men, K., Aldape, K. D., Cao, Y., Srinivasan, A., Barani, I. J., Sachdev, S., Huang, J., Choi, S., Shi, W., Battiste, J. D., Wardak, Z., Chan, M. D., Mehta, M. P., Xiao, Y. 2024; 16 (11)

  View details for DOI 10.3390/cancers16112007

  View details for Web of Science ID 001245728900001

• Optimization and Local Cost-Effectiveness of Nasopharyngeal Carcinoma Screening Strategies in Southern China: Secondary Analysis of the Guangdong Randomized Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Miller, J. A., Liu, Z., Pinsky, B. A., Le, Q., Li, T., Yu, K. J., Hildesheim, A., Cao, S. 2024

  Abstract

  BACKGROUND: Screening with anti-Epstein-Barr Virus (EBV) serology and endoscopy decreased nasopharyngeal carcinoma (NPC) mortality in Guangdong in a randomized trial. We conducted a secondary analysis of this trial using local incidence and cost data to optimize screening programs, hypothesizing that screening could be cost-effective in southern China.METHODS: Screening costs and life-years after NPC diagnosis were obtained from the Guangdong trial's intent-to-screen population (men and women age 30-69). Seropositive subjects were rescreened annually for five years. Thereafter, we evaluated 12 screening strategies in Guangdong and Guangxi using a validated model. Strategies used combinations of serology, nasopharyngeal swab PCR (NP PCR), endoscopy, and MRI from trial sub-cohorts. Incidence data and costs were obtained from local cancer registries and the provincial healthcare system.RESULTS: In the intent-to-screen population, screening with serology and endoscopy was cost-effective (42,366/life-year, 0.52 GDP per-capita). Screening for 5-15 years between ages 35-59 met a willingness-to-pay threshold of 1.5 GDP/QALY in all modeled populations. Despite doubling costs, adding MRI could be cost-effective via improved sensitivity. NP PCR triage reduced endoscopy/MRI referrals by 37%. One lifetime screen could reduce NPC mortality by pproximately 20%.CONCLUSIONS: EBV-based serologic screening for NPC is likely to be cost-effective in southern China. Among seropositive subjects, the preferred strategies use endoscopy alone or selective endoscopy triaged by MRI with or without NP PCR. These data may aid the design of screening programs in this region.IMPACT: These findings support population-based screening in southern China by defining the target population, cost effectiveness, and optimized screening approach.

  View details for DOI 10.1158/1055-9965.EPI-23-1486

  View details for PubMedID 38695706

• Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis. The Lancet. Oncology Gharzai, L. A., Morris, E., Suresh, K., Nguyen-Tân, P. F., Rosenthal, D. I., Gillison, M. L., Harari, P. M., Garden, A. S., Koyfman, S., Caudell, J. J., Jones, C. U., Mitchell, D. L., Krempl, G., Ridge, J. A., Gensheimer, M. F., Bonner, J. A., Filion, E., Dunlap, N. E., Stokes, W. A., Le, Q. T., Torres-Saavedra, P., Mierzwa, M., Schipper, M. J. 2024; 25 (3): 366-375

  Abstract

  The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy.We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy.We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival.We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints.NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

  View details for DOI 10.1016/S1470-2045(24)00016-0

  View details for PubMedID 38423050

• The lipid-binding D4 domain of perfringolysin O facilitates the active loading of exogenous cargo into extracellular vesicles. FEBS letters Opadele, A. E., Nishioka, S., Wu, P., Le, Q., Shirato, H., Nam, J., Onodera, Y. 2024

  Abstract

  Whereas extracellular vesicles (EVs) have been engineered for cargo loading, innovative strategies for it can still be developed. Here, we describe domain 4 (D4), a cholesterol-binding domain derived from perfringolysin O, as a viable candidate for EV cargo loading. D4 and its mutants localized to the plasma membrane and the membranes of different vesicular structures in the cytoplasm, and facilitate the transport of proteins of interest (POIs) into EVs. D4-EVs were internalized by recipient cells analogous to EVs engineered with CD9. Intracellular cargo discharge from D4-EVs was successfully detected with the assistance of vesicular stomatitis virus glycoprotein. This study presents a novel strategy for recruiting POIs into EVs via a lipid-binding domain that ensures content release in recipient cells.

  View details for DOI 10.1002/1873-3468.14807

  View details for PubMedID 38339784

• First-Year Experience of Stereotactic Body Radiation Therapy/Intensity Modulated Radiation Therapy Treatment Using a Novel Biology-Guided Radiation Therapy Machine. Advances in radiation oncology Shi, M., Simiele, E., Han, B., Pham, D., Palomares, P., Aguirre, M., Gensheimer, M., Vitzthum, L., Le, Q., Surucu, M., Kovalchuk, N. 2024; 9 (1): 101300

  Abstract

  Purpose: The aim of this study was to present the first-year experience of treating patients using intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) with a biology-guided radiation therapy machine, the RefleXion X1 system, installed in a clinical setting.Methods and Materials: A total of 78 patients were treated on the X1 system using IMRT and SBRT from May 2021 to May 2022. Clinical and technical data including treatment sites, number of pretreatment kilovoltage computed tomography (kVCT) scans, beam-on time, patient setup time, and imaging time were collected and analyzed. Machine quality assurance (QA) results, machine performance, and user satisfactory survey were also collected and reported.Results: The most commonly treated site was the head and neck (63%), followed by the pelvis (23%), abdomen (8%), and thorax (6%). Except for 5 patients (6%) who received SBRT treatments for bony metastases in the pelvis, all treatments were conventionally fractionated IMRT. The number of kVCT scans per fraction was 1.2 ± 0.5 (mean ± standard deviation). The beam-on time was 9.2 ± 3.5 minutes. The patient setup time and imaging time per kVCT was 4.8 ± 2.6 minutes and 4.6 ± 1.5 minutes, respectively. The daily machine output deviation was 0.4 ± 1.2% from the baseline. The patient QA had a passing rate of 97.4 ± 2.8% at 3%/2 mm gamma criteria. The machine uptime was 92% of the total treatment time. The daily QA and kVCT image quality received the highest level of satisfaction. The treatment workflow for therapists received the lowest level of satisfaction.Conclusions: One year after the installation, 78 patients were successfully treated with the X1 system using IMRT and/or SBRT. With the recent Food and Drug Administration clearance of biology-guided radiation therapy, our department is preparing to treat patients using positron emission tomography-guidance via a new product release, which will address deficiencies in the current image-guided radiation therapy workflow.

  View details for DOI 10.1016/j.adro.2023.101300

  View details for PubMedID 38260216

• A case for the study of native extracellular vesicles. Frontiers in oncology Nambiar, D., Le, Q., Pucci, F. 2024; 14: 1430971

  Abstract

  Three main areas of research revolve around extracellular vesicles (EVs): their use as early detection diagnostics for cancer prevention, engineering of EVs or other enveloped viral-like particles for therapeutic purposes and to understand how EVs impact biological processes. When investigating the biology of EVs, it is important to consider strategies able to track and alter EVs directly in vivo, as they are released by donor cells. This can be achieved by suitable engineering of EV donor cells, either before implantation or directly in vivo. Here, we make a case for the study of native EVs, that is, EVs released by cells living within a tissue. Novel genetic approaches to detect intercellular communications mediated by native EVs and profile recipient cells are discussed. The use of Rab35 dominant negative mutant is proposed for functional in vivo studies on the roles of native EVs. Ultimately, investigations on native EVs will tremendously advance our understanding of EV biology and open novel opportunities for therapy and prevention.

  View details for DOI 10.3389/fonc.2024.1430971

  View details for PubMedID 39091922

• Pulmonary interstitial lymphography: A prospective trial with potential impact on stereotactic ablative radiotherapy planning for early-stage lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Ko, R. B., Abelson, J. A., Fleischmann, D., Louie, J. D., Hwang, G. L., Sze, D. Y., Schuler, E., Kielar, K. N., Maxim, P. G., Le, Q., Hara, W. H., Diehn, M., Kothary, N., Loo, B. W. 2023: 110079

  Abstract

  This prospective feasibility trial investigated pulmonary interstitial lymphography to identify thoracic primary nodal drainage (PND). A post-hoc analysis of nodal recurrences was compared with PND for patients with early-stage lung cancer; larger studies are needed to establish correlation. Exploratory PND-inclusive stereotactic ablative radiotherapy plans were assessed for dosimetric feasibility.

  View details for DOI 10.1016/j.radonc.2023.110079

  View details for PubMedID 38163486

• Season of radiotherapy and outcomes of head & neck cancer patients in the MACH-NC & MARCH meta-analyses. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Limkin, E., Blanchard, P., Lacas, B., Bourhis, J., Parmar, M., Licitra, L., LE, Q., Yom, S., Fortpied, C., Langendijk, J., Vermorken, J. B., Bernier, J., Overgaard, J., Harris, J., Pignon, J., Auperin, A., MACH-NC* and MARCH** collaborative groups 2023: 110011

  View details for DOI 10.1016/j.radonc.2023.110011

  View details for PubMedID 37956890

• Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1. The Journal of clinical investigation Beach, C., MacLean, D., Majorova, D., Melemenidis, S., Nambiar, D. K., Kim, R. K., Valbuena, G. N., Guglietta, S., Krieg, C., Darvish-Damavandi, M., Suwa, T., Easton, A., Hillson, L. V., McCulloch, A. K., McMahon, R. K., Pennel, K., Edwards, J., O'Cathail, S. M., Roxburgh, C. S., Domingo, E., Moon, E. J., Jiang, D., Jiang, Y., Zhang, Q., Koong, A. C., Woodruff, T. M., Graves, E. E., Maughan, T., Buczacki, S. J., Stucki, M., Le, Q. T., Leedham, S. J., Giaccia, A. J., Olcina, M. M. 2023

  Abstract

  An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target which when inhibited improved radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting resulted in increased NF-kB-dependent apoptosis specifically in tumours and not normal tissues; indicating that in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 could improve radiotherapy even in tumours displaying immunosuppressive features.

  View details for DOI 10.1172/JCI168277

  View details for PubMedID 37824211

• Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial. JAMA oncology Wong, S. J., Torres-Saavedra, P. A., Saba, N. F., Shenouda, G., Bumpous, J. M., Wallace, R. E., Chung, C. H., El-Naggar, A. K., Gwede, C. K., Burtness, B., Tennant, P. A., Dunlap, N. E., Redman, R., Stokes, W. A., Rudra, S., Mell, L. K., Sacco, A. G., Spencer, S. A., Nabell, L., Yao, M., Cury, F. L., Mitchell, D. L., Jones, C. U., Firat, S., Contessa, J. N., Galloway, T., Currey, A., Harris, J., Curran, W. J., Le, Q. T. 2023

  Abstract

  Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC.To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS).This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020.Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo).The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS.Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84).In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis.ClinicalTrials.gov Identifier: NCT01711658.

  View details for DOI 10.1001/jamaoncol.2023.3809

  View details for PubMedID 37768670

• Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial. JAMA oncology Gensheimer, M. F., Gee, H., Shirato, H., Taguchi, H., Snyder, J. M., Chin, A. L., Vitzthum, L. K., Maxim, P. G., Wakelee, H. A., Neal, J., Das, M., Chang, D. T., Kidd, E., Hancock, S. L., Shultz, D. B., Horst, K. C., Le, Q. T., Wong, S., Brown, E., Nguyen, N., Liang, R., Loo, B. W., Diehn, M. 2023

  Abstract

  Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy.To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control.This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3).Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3.Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up.In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects).The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials.ClinicalTrials.gov Identifier: NCT01463423.

  View details for DOI 10.1001/jamaoncol.2023.3495

  View details for PubMedID 37707820

• Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC. Molecular & cellular proteomics : MCP Wamsley, N. T., Wilkerson, E. M., Guan, L., LaPak, K. M., Schrank, T. P., Holmes, B. J., Sprung, R. W., Gilmore, P. E., Gerndt, S. P., Jackson, R. S., Paniello, R. C., Pipkorn, P., Puram, S. V., Rich, J. T., Townsend, R. R., Zevallos, J. P., Zolkind, P., Le, Q. T., Goldfarb, D., Ben Major, M. 2023: 100647

  Abstract

  The NFE2L2(NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry (MS)-based targeted proteomics assay based on internal standard triggered parallel reaction monitoring (IS-PRM) to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing IS-PRM acquisition algorithm, called SureQuantTM, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded (FFPE) HNSCCs, NRF2 signaling intensity positively correlated with NRF2 activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus (HPV) infection status. CDKN2A (p16) protein expression positively correlated with the HPV oncogenic E7 protein, and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or FFPE archived tissues in under 90 minutes.

  View details for DOI 10.1016/j.mcpro.2023.100647

  View details for PubMedID 37716475

• Cancer Informatics for Cancer Centers: Sharing Ideas on How to Build an Artificial Intelligence-Ready Informatics Ecosystem for Radiation Oncology. JCO clinical cancer informatics Bitterman, D. S., Gensheimer, M. F., Jaffray, D., Pryma, D. A., Jiang, S. B., Morin, O., Ginart, J. B., Upadhaya, T., Vallis, K. A., Buatti, J. M., Deasy, J., Hsiao, H. T., Chung, C., Fuller, C. D., Greenspan, E., Cloyd-Warwick, K., Courdy, S., Mao, A., Barnholtz-Sloan, J., Topaloglu, U., Hands, I., Maurer, I., Terry, M., Curran, W. J., Le, Q., Nadaf, S., Kibbe, W. 2023; 7: e2300136

  Abstract

  In August 2022, the Cancer Informatics for Cancer Centers brought together cancer informatics leaders for its biannual symposium, Precision Medicine Applications in Radiation Oncology, co-chaired by Quynh-Thu Le, MD (Stanford University), and Walter J. Curran, MD (GenesisCare). Over the course of 3 days, presenters discussed a range of topics relevant to radiation oncology and the cancer informatics community more broadly, including biomarker development, decision support algorithms, novel imaging tools, theranostics, and artificial intelligence (AI) for the radiotherapy workflow. Since the symposium, there has been an impressive shift in the promise and potential for integration of AI in clinical care, accelerated in large part by major advances in generative AI. AI is now poised more than ever to revolutionize cancer care. Radiation oncology is a field that uses and generates a large amount of digital data and is therefore likely to be one of the first fields to be transformed by AI. As experts in the collection, management, and analysis of these data, the informatics community will take a leading role in ensuring that radiation oncology is prepared to take full advantage of these technological advances. In this report, we provide highlights from the symposium, which took place in Santa Barbara, California, from August 29 to 31, 2022. We discuss lessons learned from the symposium for data acquisition, management, representation, and sharing, and put these themes into context to prepare radiation oncology for the successful and safe integration of AI and informatics technologies.

  View details for DOI 10.1200/CCI.23.00136

  View details for PubMedID 38055914

• International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System. Journal of neurological surgery. Part B, Skull base Lechner, M., Takahashi, Y., Turri-Zanoni, M., Ferrari, M., Liu, J., Counsell, N., Mattavelli, D., Rampinelli, V., Vermi, W., Lombardi, D., Saade, R., Park, K. W., Schartinger, V. H., Franchi, A., Facco, C., Sessa, F., Battocchio, S., Fenton, T. R., Vaz, F. M., O'Flynn, P., Howard, D., Stimpson, P., Wang, S., Hannan, S. A., Unadkat, S., Hughes, J., Dwivedi, R., Forde, C. T., Randhawa, P., Gane, S., Joseph, J., Andrews, P. J., Dave, M., Fleming, J. C., Thomson, D., Zhu, T., Teschendorff, A., Royle, G., Steele, C., Jimenez, J. E., Laco, J., Wang, E. W., Snyderman, C., Lacy, P. D., Woods, R., O'Neill, J. P., Saraswathula, A., Kaur, R. P., Zhao, T., Ramanathan, M., Gallia, G. L., London, N. R., Le, Q. T., West, R. B., Patel, Z. M., Nayak, J. V., Hwang, P. H., Hermsen, M., Llorente, J., Facchetti, F., Nicolai, P., Bossi, P., Castelnuovo, P., Jay, A., Carnell, D., Forster, M. D., Bell, D. M., Lund, V. J., Hanna, E. Y. 2023; 84 (4): 307-319

  Abstract

  Objectives  Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods  We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results  One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p  < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p  = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p  = 0.036). Conclusions  We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

  View details for DOI 10.1055/s-0042-1750178

  View details for PubMedID 37405239

  View details for PubMedCentralID PMC10317567

• Galectin-1 mediates chronic STING activation in tumors to promote metastasis through MDSC recruitment. Cancer research Nambiar, D. K., Viswanathan, V., Cao, H., Zhang, W., Guan, L., Chamoli, M., Holmes, B., Kong, C., Hildebrand, R., Koong, A. J., von Eyben, R., Plevritis, S., Li, L., Giaccia, A., Engleman, E., Le, Q. T. 2023

  Abstract

  The immune system plays a crucial role in the regulation of metastasis. Tumor cells systemically change immune functions to facilitate metastatic progression. Through this study, we deciphered how tumoral Galectin-1 (Gal1) expression shapes the systemic immune environment to promote metastasis in head and neck cancer (HNC). In multiple preclinical models of HNC and lung cancer in immunogenic mice, Gal1 fostered the establishment of a pre-metastatic niche through polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which altered the local microenvironment to support metastatic spread. RNA sequencing of MDSCs from pre-metastatic lungs in these models demonstrated the role of PMN-MDSCs in collagen and extracellular matrix remodeling in the pre-metastatic compartment. Gal1 promoted MDSC accumulation in the pre-metastatic niche through the NF-κB signaling axis, triggering enhanced CXCL2-mediated MDSC migration. Mechanistically, Gal1 sustained NF-κB activation in tumor cells by enhancing STING protein stability, leading to prolonged inflammation-driven MDSC expansion. These findings suggest an unexpected pro-tumoral role of STING activation in metastatic progression and establish Gal1 as an endogenous positive regulator of STING in advanced-stage cancers.

  View details for DOI 10.1158/0008-5472.CAN-23-0046

  View details for PubMedID 37409887

• Lessons and Opportunities for Biomarker-Driven Radiation Personalization in Head and Neck Cancer. Seminars in radiation oncology Rahimy, E., Gensheimer, M. F., Beadle, B., Le, Q. T. 2023; 33 (3): 336-347

  Abstract

  Head and neck cancer is notoriously challenging to treat in part because it constitutes an anatomically and biologically diverse group of cancers with heterogeneous prognoses. While treatment can be associated with significant late toxicities, recurrence is often difficult to salvage with poor survival rates and functional morbidity.1,2 Thus, achieving tumor control and cure at the initial diagnosis is the highest priority. Given the differing outcome expectations (even within a specific sub-site like oropharyngeal carcinoma), there has been growing interest in personalizing treatment: de-escalation in selected cancers to decrease the risk of late toxicity without compromising oncologic outcomes, and intensification for more aggressive cancers to improve oncologic outcomes without causing undue toxicity. This risk stratification is increasingly accomplished using biomarkers, which can represent molecular, clinicopathologic, and/or radiologic data. In this review, we will focus on biomarker-driven radiotherapy dose personalization with emphasis on oropharyngeal and nasopharyngeal carcinoma. This radiation personalization is largely performed on the population level by identifying patients with good prognosis via traditional clinicopathologic factors, although there are emerging studies supporting inter-tumor and intra-tumor level personalization via imaging and molecular biomarkers.

  View details for DOI 10.1016/j.semradonc.2023.03.013

  View details for PubMedID 37331788

• Adaptive Region-Specific Loss for Improved Medical Image Segmentation. IEEE transactions on pattern analysis and machine intelligence Chen, Y., Yu, L., Wang, J., Panjwani, N., Obeid, J., Liu, W., Liu, L., Kovalchuk, N., Gensheimer, M. F., Vitzthum, L. K., Beadle, B. M., Chang, D. T., Le, Q., Han, B., Xing, L. 2023; PP

  Abstract

  Defining the loss function is an important part of neural network design and critically determines the success of deep learning modeling. A significant shortcoming of the conventional loss functions is that they weight all regions in the input image volume equally, despite the fact that the system is known to be heterogeneous (i.e., some regions can achieve high prediction performance more easily than others). Here, we introduce a region-specific loss to lift the implicit assumption of homogeneous weighting for better learning. We divide the entire volume into multiple sub-regions, each with an individualized loss constructed for optimal local performance. Effectively, this scheme imposes higher weightings on the sub-regions that are more difficult to segment, and vice versa. Furthermore, the regional false positive and false negative errors are computed for each input image during a training step and the regional penalty is adjusted accordingly to enhance the overall accuracy of the prediction. Using different public and in-house medical image datasets, we demonstrate that the proposed regionally adaptive loss paradigm outperforms conventional methods in the multi-organ segmentations, without any modification to the neural network architecture or additional data preparation.

  View details for DOI 10.1109/TPAMI.2023.3289667

  View details for PubMedID 37363838

• Hot on the trail in the TME: Clues from a trilogy of checkpoint inhibitor trials in nasopharyngeal cancer CANCER CELL Ma, B. Y., Le, Q. 2023; 41 (6): 1006-1008

  Abstract

  In this issue of Cancer Cell, Yang et al. report the third in a series of phase III trials that demonstrates the survival benefit of combining a PD-1 inhibitor with chemotherapy in nasopharyngeal cancer. A gene expression analysis identifies "hot" and "cold" tumor signatures with prognostic and predictive significance.

  View details for DOI 10.1016/j.ccell.2023.04.013

  View details for Web of Science ID 001024475200001

  View details for PubMedID 37207653

• Association between locoregional failure and NFE2L2/KEAP1/CUL3 pathway mutations in NRG/RTOG 9512: A randomized trial of hyperfractionation vs. conventional fractionation in T2N0 glottic squamous cell carcinoma (SCC). Guan, L., Torres-Saavedra, P. A., Zhao, X., Major, M. B., Holmes, B. J., Nguyen, N., Kumaravelu, P., Hodge, T., Diehn, M., Zevallos, J., Emami, B., Sagar, S. M., Morrison, W. H., Schultz, C. J., Caudell, J. J., Jones, C. U., Yom, S. S., Harris, J., Le, Q., Hayes, D. N. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003175

• Long-term Outcomes of Bevacizumab and Chemoradiation for Locoregionally Advanced Nasopharyngeal Carcinoma: A Nonrandomized Controlled Trial. JAMA network open Lee, N. Y., Harris, J., Kim, J., Garden, A., Mechalakos, J., Pfister, D. G., Chan, A. T., Hu, K., Colevas, A. D., Frank, S., Shenouda, G., Bar-Ad, V., Waldron, J. N., Harari, P. M., Raben, A., Torres-Saavedra, P., Le, Q. 2023; 6 (6): e2316094

  Abstract

  Importance: The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC).Objective: To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC.Design, Setting, and Participants: This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement.Interventions: Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d).Main Outcomes and Measures: The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation.Results: Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%).Conclusions and Relevance: In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted.Trial Registration: ClinicalTrials.gov Identifier: NCT00408694.

  View details for DOI 10.1001/jamanetworkopen.2023.16094

  View details for PubMedID 37266942

• Comparison of Real-Time PCR and Digital PCR for Detection of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma. The Journal of molecular diagnostics : JMD Miller, J. A., Huang, C., Yamamoto, F., Sahoo, M. K., Le, Q., Pinsky, B. A. 2023

  Abstract

  Plasma Epstein-Barr Virus (EBV) DNA is an established biomarker for endemic nasopharyngeal carcinoma (NPC). However, existing real-time PCR (qPCR) assays are limited by poor inter-laboratory reproducibility. This is a barrier to biomarker integration into staging systems and management. It was hypothesized that EBV digital PCR (dPCR) would have similar sensitivity but improved precision relative to qPCR. Using the WHO EBV standard and patient specimens, the NRG BamHI-W qPCR, two commercial EBNA-1 qPCR assays, and two laboratory-developed dPCR assays amplifying the BamHI-W, EBNA-1, and EBER targets were compared. Testing was conducted in the North American reference laboratory for the NRG-HN001 randomized trial. The EBV dPCR assays achieved similar performance compared with qPCR. Although dPCR does not require quantitation standards, different dPCR thresholding algorithms yielded significant qualitative and quantitative variation. This was most evident with low levels of EBV DNA. No-template control-informed thresholding (ddpcRquant) mitigated false positives/negatives. The NRG BamHI-W qPCR and laboratory-developed BamHI-W droplet dPCR offered higher sensitivity, lower limit of blank, higher precision at low plasma EBV DNA levels (≤1500 IU/mL), and higher overall agreement with clinical specimens compared to single-copy qPCR/dPCR targets (EBNA-1/EBER). These data confirm the rationale for the use of the BamHI-W target to define prognostic thresholds, and indicate that both qPCR and dPCR methods harmonized to the WHO standard can provide the necessary analytical performance.

  View details for DOI 10.1016/j.jmoldx.2023.03.007

  View details for PubMedID 37068736

• Final Report of NRG Oncology RTOG 0022: A Phase I/II Study of Conformal and Intensity. International journal of radiation oncology, biology, physics Garden, A. S., Harris, J., Eisbruch, A., Chao, K. S., Morrison, W. H., Harari, P. M., Swanson, T. A., Jones, C. U., Yom, S. S., Spencer, S. A., Scrimger, R., Shenouda, G., Shukla, M., Lau, H. Y., Mierzwa, M., Torres-Saavedra, P., Le, Q. T. 2023

  Abstract

  BACKGROUND: XXXX XXXX XXXX XXXX (XXXX) XXXX was the first clinical trial evaluating multi-institution feasibility of IMRT for head and neck cancer. The primary endpoints of 2-year local-regional failure and reduction in acute xerostomia were reported previously. This report provides secondary endpoints with long-term follow-up.METHODS: Eligibility included patients diagnosed with T1-2, N0-1 oropharyngeal cancer. Secondary endpoints included disease control and overall survival. Local-regional failure rates were estimated by the cumulative incidence method, and disease-free and overall survival rates were estimated by the Kaplan-Meier method. Late toxicities were graded by XXXX/EORTC criteria and are reported with descriptive statistics.RESULTS: Sixty-seven of 69 enrolled patients were analyzed. Fifty patients (75%) had T2 disease and 38 (57%) were node negative (N0). Median follow-up was 11.9 years. Estimated 10-year local-regional failure, disease-free survival and overall survival rates were 15% (95%CI 8-25), 50% (95%CI 38-62) and 67% (95%CI 55-78), respectively. Highest reported late toxicities were: grade 5: 0%, grade 4: 9%, grade 3: 13%, and grade 2: 63%. Grade 3-4 late toxicities involved mucous membranes (7%), bone (4%), esophagus (4%), salivary gland (4%), pain (3%), weight loss (1%), and hemorrhage (1%). Grade 2-3 salivary gland toxicity was reported in 70% but improved over time. Forty-one (74.5%) and 17 (42.5%) of surviving patients had a toxicity assessment at > 5 years and >10 years, respectively.CONCLUSIONS: This report of XXXX/XXXX XXXX, based on an early, prospectively collected dataset of head and neck IMRT treatments, provides benchmark long-term outcomes of this early version of the technology. At 10 years, 2/3 of patients were alive, with an acceptable level of grade 3-4 late toxicities.

  View details for DOI 10.1016/j.ijrobp.2023.02.057

  View details for PubMedID 36925074

• Utilizing a Culture Committee to Improve and Maintain a Positive Workplace Environment During a Global Pandemic. Practical radiation oncology Lau, B., Guo, F., Valenton, J., Chang, D., Le, Q., Horst, K. 2023

  Abstract

  Workplace culture is often overlooked in interventions to improve the delivery of healthcare efficiency. Burnout and employee morale have been long-standing issues in healthcare and can negatively affect both provider and patient health. In order to address employee wellness and promote department unity, a culture committee was established within a radiation oncology department. After the emergence of the 2019 coronavirus (COVID-19) pandemic, burnout and social isolation among healthcare workers have increased substantially, affecting job performance and stress levels. This report revisits the efficacy of a workplace culture committee five years after its establishment, while also outlining its role during the pandemic and in the transition to a peri-pandemic workplace. The initiation of a culture committee has been pivotal to identifying and improving workplace stressors that may enable burnout. We suggest healthcare environments implement initiatives that encompass tangible and actionable solutions to feedback provided by employees.

  View details for DOI 10.1016/j.prro.2023.02.003

  View details for PubMedID 36868556

• In search for optimal induction chemotherapy for advanced nasopharyngeal cancer: Standard dosing of Docetaxel, Platinum, and 5-Fluorouracil (TPF) followed by chemoradiation. PloS one Jun, M., Pinto, H., Le, Q. T., Quon, A., Hara, W., Coty, J., McMillan, A., Lu, R., Winters, E., Lira, R., Colevas, A. D. 2023; 18 (2): e0276651

  Abstract

  A phase II = design is used to evaluate the efficacy and feasibility of full dose docetaxel, platinum, and 5-fluorouracil (TPF) in a sequential chemoradiation treatment locally advanced (LA) or oligometastatic (OM) NPC patients.Twenty patients with LANPC (M0 cohort) and six patients with OMNPC (M1 cohort) received induction standard dose T (75 mg/m2) P (75 mg/m2) F (750 mg/m2 IVCI x 5days) x 3 followed by weekly cisplatin (40 mg/m2) or carboplatin (AUC 1.5) x 6 concurrent with radiation therapy of 70 Gy over 6.5-7 weeks. The first five patients received bevacizumab as part of an exploratory objective of hypoxia modification using correlative fluoromisonidasole (18F-MISO) PET CT scanning.The 18F-MISO imaging failed to reveal adequate levels of baseline hypoxia necessary to evaluate for changes with chemotherapy and bevacizumab. Ninety percent of M0 patients and 83% of M1 patients received the full-intended TPF and radiation dose. Eighty-five percent of M0 patients and all M1 patients received at least 60% of the full-intended concurrent platinum dose. The 2-year progression free survival (PFS) rate for the M0 cohort was 90% (95% CI: 77.8%- 100%), and was sustained at 5 years. The 2-year PFS rate for the M1 cohort was 66.7% (95% CI: 37.9%- 100%). The 2-year overall survival (OS) rates for the M0 and M1 cohorts were 100% and 83.3% (95% CI: 58.3%- 100%), respectively. At five years, OS was 94.4% for the M0 cohort.Administration of standard-dose TPF as induction chemotherapy in this NPC patient population is both feasible and effective when coupled with definitive concurrent chemoradiation.NCT00896181.

  View details for DOI 10.1371/journal.pone.0276651

  View details for PubMedID 36730145

• Recommendations for Epstein-Barr virus-based screening for nasopharyngeal cancer in high- and intermediate-risk regions. Journal of the National Cancer Institute Lam, W. K., King, A. D., Miller, J. A., Liu, Z., Yu, K. J., Chua, M. L., Ma, B. B., Chen, M. Y., Pinsky, B. A., Lou, P. J., Woo, J. K., Hsu, W. L., Simon, J., Doolan, D. L., Waterboer, T., Hui, E. P., Li, H., Tsang, R. K., Wong, K. C., Goh, J. P., Vlantis, A. C., Ai, Q. Y., Wong, L. M., Abdullah, V., Lin, J. C., Chen, C. J., Pfeiffer, R. M., Le, Q. T., Lee, A. W., Ji, M., Cao, S., Ma, J., Chan, A. T., Chan, K. C., Hildesheim, A. 2023

  Abstract

  A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)-based approaches to screen for early-stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.

  View details for DOI 10.1093/jnci/djad012

  View details for PubMedID 36723440

• NFE2L2 mutations enhance radioresistance in head and neck cancer by modulating intratumoral myeloid cells. Cancer research Guan, L., Nambiar, D. K., Cao, H., Viswanathan, V., Kwok, S., Hui, A. B., Hou, Y., Hildebrand, R., von Eyben, R., Holmes, B. J., Zhao, J., Kong, C. S., Wamsley, N., Zhang, W., Major, M. B., Seol, S. W., Sunwoo, J. B., Hayes, D. N., Diehn, M., Le, Q. T. 2023

  Abstract

  Radiotherapy is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, while the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. Radiotherapy increased expression of PMN-MDSC-attracting chemokines, including CXCL1, CXLC3 and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an anti-tumor phenotype, supporting clinical testing of CB-839 with radiation in HNSCC with NFE2L2 mutations.

  View details for DOI 10.1158/0008-5472.CAN-22-1903

  View details for PubMedID 36652552

• Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial. The Lancet. Oncology Sherman, E. J., Harris, J., Bible, K. C., Xia, P., Ghossein, R. A., Chung, C. H., Riaz, N., Gunn, G. B., Foote, R. L., Yom, S. S., Wong, S. J., Koyfman, S. A., Dzeda, M. F., Clump, D. A., Khan, S. A., Shah, M. H., Redmond, K., Torres-Saavedra, P. A., Le, Q., Lee, N. Y. 2023

  Abstract

  BACKGROUND: Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population.METHODS: Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete.FINDINGS: The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group).INTERPRETATION: To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated.FUNDING: National Cancer Institute and Novartis.

  View details for DOI 10.1016/S1470-2045(22)00763-X

  View details for PubMedID 36681089

• Reflections on the 2021 Accreditation Council for Graduate Medical Education and American Board of Radiology Family and Medical Leave of Absence Policies: An Opportunity to Increase Structural Support for Physicians. International journal of radiation oncology, biology, physics Baniel, C. C., Klebaner, D., Beadle, B. M., Ponce, S. E., Takiar, V., Gibbs, I. C., Soltys, S. G., Bagshaw, H. P., Chang, D. T., Le, Q. T., Pollom, E. L. 2023; 115 (1): 19-22

  View details for DOI 10.1016/j.ijrobp.2022.07.1837

  View details for PubMedID 36526381

• Long-term update of NRG/RTOG 0522: a randomized phase III trial of concurrent radiation and cisplatin with or without cetuximab in locoregionally advanced head and neck cancer. International journal of radiation oncology, biology, physics Caudell, J. J., Torres-Saavedra, P. A., Rosenthal, D. I., Axelrod, R. S., Nguyen-Tan, P. F., Sherman, E. J., Weber, R. S., Galvin, J. M., El-Naggar, A. K., Konski, A. A., Echevarria, M. I., Dunlap, N. E., Shenouda, G., Singh, A. K., Beitler, J. J., Garsa, A., Bonner, J. A., Garden, A. S., Algan, O., Harris, J., Le, Q. 2022

  Abstract

  PURPOSE/OBJECTIVE: The combination of cisplatin and radiation or cetuximab and radiation improves overall survival (OS) of patients with locoregionally advanced head and neck carcinoma (HNC). xxxx conducted a phase III trial to test the hypothesis that adding cetuximab to radiation and cisplatin would improve progression-free survival (PFS).MATERIALS/METHODS: Eligible patients with AJCC 6th edition stage T2 N2a-3 M0 or T3-4 N0-3 M0 were accrued from 11/2005 - 3/2009 and randomized to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Outcomes were correlated with patient and tumor features. Late reactions were scored using Common Terminology Criteria for Adverse Events (version 3).RESULTS: Of 891 analyzed patients, 452 with a median follow up 10.1 years were alive at analysis. The addition of cetuximab did not improve PFS [hazard ratio (HR) 1.06 (95% confidence interval (CI) 0.89 - 1.26), p=0.74], with 10-year estimates of 43.6% (95% CI 38.8 - 48.4) for Arm A and 40.2% (95% CI 35.4 - 45.0) for Arm B. Cetuximab did not reduce locoregional failure [HR 1.21 (95% CI 0.95 - 1.53), p=0.94] or distant metastasis [HR 0.79 (95% CI 0.54 - 1.14), p=0.10], or improve overall survival [HR 0.97 (95% CI 0.80 - 1.16), p=0.36]. Cetuximab did not appear to improve PFS in either p16-positive oropharynx [HR 1.30 (95% CI 0.87 - 1.93)] or p16-negative oropharynx or non-oropharyngeal primary [HR 0.94 (95% CI 0.73 - 1.21)]. Grade 3-4 late toxicity rates were 57.4% in Arm A and 61.3% in arm B (p=0.26).CONCLUSION: With a median follow-up of over 10 years, this updated report confirms the addition of cetuximab to RT and cisplatin did not improve any measured outcome in the entire cohort, or when stratifying by p16 status.

  View details for DOI 10.1016/j.ijrobp.2022.12.015

  View details for PubMedID 36549347

• International recommendations for plasma Epstein-Barr virus DNA measurement in nasopharyngeal carcinoma in resource-constrained settings: lessons from the COVID-19 pandemic. The Lancet. Oncology Lee, V. H., Adham, M., Ben Kridis, W., Bossi, P., Chen, M. Y., Chitapanarux, I., Gregoire, V., Hao, S. P., Ho, C., Ho, G. F., Kannarunimit, D., Kwong, D. L., Lam, K. O., Lam, W. K., Le, Q. T., Lee, A. W., Lee, N. Y., Leung, T. W., Licitra, L., Lim, D. W., Lin, J. C., Loh, K. S., Lou, P. J., Machiels, J. P., Mai, H. Q., Mesía, R., Ng, W. T., Ngan, R. K., Tay, J. K., Tsang, R. K., Tong, C. C., Wang, H. M., Wee, J. T. 2022; 23 (12): e544-e551

  Abstract

  The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.

  View details for DOI 10.1016/S1470-2045(22)00505-8

  View details for PubMedID 36455583

• International recommendations for plasma Epstein-Barr virus DNA measurement in nasopharyngeal carcinoma in resource-constrained settings: lessons from the COVID-19 pandemic LANCET ONCOLOGY Lee, V., Adham, M., Ben Kridis, W., Bossi, P., Chen, M., Chitapanarux, I., Gregoire, V., Hao, S., Ho, C., Ho, G., Kannarunimit, D., Kwong, D., Lam, K., Lam, W., Le, Q., Lee, A., Lee, N. Y., Leung, T., Licitra, L., Lim, D., Lin, J., Loh, K., Lou, P., Machiels, J., Mai, H., Mesia, R., Ng, W., Ngan, R., Tay, J. K., Tsang, R., Tong, C., Wang, H., Wee, J. T. 2022; 23 (12): E544-E551

  View details for Web of Science ID 000985147300015

• Improving lung cancer screening rates among patients with head and neck cancer in a radiation oncology clinic. Journal of thoracic disease Soto, L., Nesbit, S., Ramsey, M., Gensheimer, M. F., Le, Q. T., Beadle, B. M., Lui, N. S. 2022; 14 (12): 4633-4640

  Abstract

  The United States Preventive Services Task Force (USPSTF) recommends lung cancer screening via annual low dose computed tomography (LDCT) for high risk patients. Despite the strong evidence of a mortality benefit from several randomized clinical trials, rates of lung cancer screening remain low. We plan to assess how screening guidelines are implemented in a radiation oncology clinic for patients with head and neck cancer.A single institution, retrospective chart review was used to identify patients with head and neck cancer seen in a radiation oncology clinic who were potentially eligible for lung cancer screening under the current USPSTF guidelines. Patients who were potentially screening-eligible were enrolled in a phone survey to assess their knowledge about lung cancer screening and willingness to be screened.Of the 184 patients with head and neck cancer seen in the clinic, 8 (4%) patients were eligible for lung cancer screening under the previous USPSTF recommendations, including 1 (0.5%) patient already being screened. One patient (0.5%) became eligible under the expanded guidelines. All 184 patients had smoking history documented. Of the 87 current or former smokers, there were 24 (28%) who did not have pack-years documented; of the 82 former smokers, there were 8 (10%) who did not have quit date documented. Among the 16 phone survey participants (response rate: 70%) only 6 (38%) were aware there is a way to screen for lung cancer and 12 (75%) patients would be interested in screening if they are found to be eligible.These findings highlight a potential opportunity to increase rates of lung cancer screening among patients with head and neck cancer by both enhancing provider awareness as well as patient education at the community level.

  View details for DOI 10.21037/jtd-22-787

  View details for PubMedID 36647458

  View details for PubMedCentralID PMC9840013

• Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234 ADVANCES IN RADIATION ONCOLOGY Michikawa, C., Torres-Saavedra, P. A., Silver, N. L., Harari, P. M., Kies, M. S., Rosenthal, D. I., Le, Q., Jordan, R. C., Duose, D. Y., Mallampati, S., Trivedi, S., Luthra, R., Wistuba, I. I., Osman, A. A., Lichtarge, O., Foote, R. L., Parvathaneni, U., Hayes, D., Pickering, C. R., Myers, J. N. 2022; 7 (6)

  View details for DOI 10.1016/j.adro.2022.100989

  View details for Web of Science ID 000834084100001

• Improving lung cancer screening rates among patients with head and neck cancer in a radiation oncology clinic JOURNAL OF THORACIC DISEASE Soto, L., Nesbit, S., Ramsey, M., Gensheimer, M. F., Le, Q., Beadle, B. M., Lui, N. S. 2022

  View details for DOI 10.21037/jtd-22-787

  View details for Web of Science ID 000904410000001

• Safety of nivolumab added to chemoradiotherapy platforms for intermediate and high-risk local-regionally advanced head and neck squamous cell carcinoma: RTOG Foundation 3504. International journal of radiation oncology, biology, physics Gillison, M. L., Ferris, R. L., Harris, J., Colevas, A. D., Mell, L. K., Kong, C., Jordan, R. C., Moore, K. L., Truong, M., Kirsch, C., Chakravarti, A., Blakaj, D. M., Clump, D. A., Ohr, J. P., Deeken, J. F., Gensheimer, M. F., Saba, N. F., Dorth, J. A., Rosenthal, D. I., Leidner, R. S., Kimple, R. J., Machtay, M., Curran, W. J., Torres-Saavedra, P., Le, Q. T. 2022

  Abstract

  PURPOSE: Programmed death-1 immune checkpoint blockade (PD-1 ICB) improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed HNSCC patients remain unknown.METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70Gy intensity-modulated radiotherapy and weekly cisplatin (arm 1), every three-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4), in newly diagnosed intermediate or high-risk local-regionally advanced HNSCC. Patients received nivolumab from two weeks prior to three months post radiotherapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤ 2 of the first 8 evaluable patients experience a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to one year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms.RESULTS: Of 39 patients (10 in arms 1, 3, 4, and 9 in arm 2), 72% had T3-4 tumors; 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in one and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol.CONCLUSIONS: Concomitant nivolumab with the four tested regimens was safe for patients with intermediate and high-risk HNSCC and subsequent adjuvant nivolumab was feasible as defined (NCT# xxxx).

  View details for DOI 10.1016/j.ijrobp.2022.10.008

  View details for PubMedID 36228746

• Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. Journal of the National Cancer Institute Rodriguez, C. P., Kang, H., Geiger, J. L., Burtness, B., Chung, C. H., Pickering, C. R., Fakhry, C., Le, Q. T., Yom, S. S., Galloway, T. J., Golemis, E., Li, A., Shoop, J., Wong, S., Mehra, R., Skinner, H., Saba, N. F., Flores, E. R., Myers, J. N., Ford, J. M., Karchin, R., Ferris, R. L., Kunos, C., Lynn, J. M., Malik, S. 2022

  Abstract

  TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in over 80% of patients with HPV-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53 mutated tumors. The National Cancer Institute (NCI) sponsored a Clinical Trials Planning Meeting (CTPM) to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or Breakout Groups, were tasked with developing clinical studies in both the locally advanced and recurrent/metastatic disease settings as well consider signal seeking trial designs. A fourth Breakout Group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other Breakout Groups prior to the meeting to aid in study development. A total of four concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the CTPM with the goal of developing clinical trials for patients with TP53 mutant HNSCC that can be conducted within the National Clinical Trials Network.

  View details for DOI 10.1093/jnci/djac163

  View details for PubMedID 36053203

• 18F FDG PET/CT Prediction of Treatment Outcomes in HPV-positive, Locally Advanced Oropharyngeal Cancer Receiving De-intensified Therapy: Results from NRG-HN002. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Subramaniam, R. M., DeMora, L., Yao, M., Yom, S. S., Gillison, M., Caudell, J. J., Waldron, J., Xia, P., Chung, C., Truong, M. T., Echevarria, M., Chan, J. W., Geiger, J. L., Mell, L., Seaward, S., Thorstad, W. L., Beitler, J. J., Sultanem, K., Blakaj, D., Le, Q. 2022

  Abstract

  Objective: To determine the negative predictive value (NPV) of a 12-14 week post-treatment PET/CT for 2-year progression-free survival (PFS) and locoregional control (LRC) in patients with p16-positive locoregionally advanced oropharyngeal cancer (LA-OPC). Study was a secondary endpoint in NRG-HN002, a non-comparative phase II trial in p16-positive LA-OPC, stage T1-T2, N1-N2b or T3, N0-N2b (AJCC, 7th ed.) and ≤ 10 pack-year smoking. Patients were randomized in a 1:1 ratio to reduced-dose IMRT with or without cisplatin. Methods: PET/CT scans were reviewed centrally. Tumor response evaluations for the primary site, right neck, and left neck were carried out using a 5-point ordinal scale (Hopkins Criteria). Overall scores were then assigned as 'Negative,' Positive,' or 'Indeterminate'. Patients with a 'Negative' score for all three evaluation sites were given an overall score of 'Negative.' The hypotheses were NPV for PFS and LRC at two years post-treatment ≤ 90% vs >90% (1-sided alpha 0.10). Results: There were 316 patients enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a post-therapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from the end of treatment to PET/CT scan was 94 days (range 52-139). Estimated 2-year PFS and LRC rates in the analysis subgroup were 91.3% (95% confidence interval CI [84.6, 95.8%]) and 93.8% (95% CI [87.6, 97.5%]), respectively. Post-treatment scans were negative for residual tumor for 115 patients (98.3%) and positive for two patients (1.7%). NPV for 2-year PFS was 92.0% (90% lower confidence bound [LCB] 87.7%; P = 0.30) and for LRC was 94.5% (90% LCB 90.6%; P = 0.07). Conclusion: In the context of deintensification with reduced-dose radiation, the NPV of a 12-14 week post-therapy PET/CT for 2-year LRC is estimated to be > 90%, similar to that reported for patients receiving standard chemoradiation. However, there is insufficient evidence to conclude that the NPV is > 90% for PFS.

  View details for DOI 10.2967/jnumed.122.264424

  View details for PubMedID 36215572

• An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer CANCERS Amendola, B. E., Mahadevan, A., Suarez, J., Griffin, R. J., Wu, X., Perez, N. C., Hippe, D. S., Ii, C., Mohiuddin, M., Mohiuddin, M., Snider, J. W., Zhang, H., Quynh-Thu Le, Mayr, N. A. 2022; 14 (17)

  Abstract

  Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.

  View details for DOI 10.3390/cancers14174267

  View details for Web of Science ID 000851050900001

  View details for PubMedID 36077802

• Posttreatment FDG-PET/CT Hopkins criteria predict locoregional recurrence after definitive radiotherapy for oropharyngeal squamous cell carcinoma. Head & neck Miller, J. A., Moradi, F., Sundaram, V., Liang, R., Zhang, C., Nguyen, N. K., Akhtar, F., Liu, Y., Ren, Y., Harandi, N., Weng, Y., Pollom, E. L., Colevas, A. D., Divi, V., Holsinger, F. C., Beadle, B. M., Le, Q., Gensheimer, M. F. 2022

  Abstract

  BACKGROUND: Metabolic response assessment for oropharyngeal squamous cell carcinoma (OPSCC) aids in identifying locoregional persistence/recurrence (LRR). The Hopkins Criteria are a standardized qualitative response assessment system using posttreatment FDG-PET/CT.METHODS: We conducted a retrospective cohort study of patients with node-positive OPSCC treated with definitive (chemo)radiotherapy. We assessed Hopkins Criteria performance for LRR, then developed and validated a competing-risks model.RESULTS: Between 2004 and 2018, 259 patients were included with median follow-up of 43months. The Hopkins Criteria sensitivity, specificity, negative predictive value, and accuracy were 68%, 88%, 95%, and 85%. The 36-month cumulative incidence of LRR was greater with positive scores (45% vs. 5%, HR 12.60, p<0.001). PET/CTs performed ≤10weeks after radiotherapy were associated with a four-fold increase in pathologically negative biopsies/surgeries (36% vs. 9%, p=0.03). The AUC for LRR was 0.89 using a model integrating the Hopkins score.CONCLUSIONS: The Hopkins Criteria predict LRR with high accuracy for OPSCC response assessment.

  View details for DOI 10.1002/hed.27160

  View details for PubMedID 35920790

• Multiplex Epstein-Barr virus BALF2 genotyping detects high-risk variants in plasma for population screening of nasopharyngeal carcinoma. Molecular cancer Miller, J. A., Sahoo, M. K., Yamamoto, F., Huang, C., Wang, H., Zehnder, J. L., Le, Q. T., Pinsky, B. A. 2022; 21 (1): 154

  Abstract

  Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) exhibits unusual geographic restriction despite ubiquitous lifelong infection. Screening programs can detect most NPC cases at an early stage, but existing EBV diagnostics are limited by false positives and low positive predictive value (PPV), leading to excess screening endoscopies, MRIs, and repeated testing. Recent EBV genome-wide association studies (GWAS) suggest that EBV BALF2 variants account for more than 80% of attributable NPC risk. We therefore hypothesized that high-risk BALF2 variants could be readily detected in plasma for once-lifetime screening triage.We designed and validated a multiplex genotyping assay to detect EBV BALF2 polymorphisms in human plasma. Targeted next-generation sequencing was used to validate this assay, conduct association studies with clinical phenotype, and longitudinally genotype plasma to assess within-host haplotype stability. We examined the association between NPC and BALF2 haplotypes in a large non-endemic population and three prior EBV GWAS. Finally, we estimated NPC mortality reduction, resource utilization, and cost-effectiveness of BALF2 variant-informed screening using a previously-validated cohort model.Following analytical validation, the BALF2 genotyping assay had 99.3% concordance with sequencing in a cohort of 24 NPC cases and 155 non-NPC controls. BALF2 haplotype was highly associated with NPC in this non-endemic population (I613V: odds ratio [OR] 7.9; V317M: OR 178.8). No other candidate BALF2 polymorphisms were significantly associated with NPC or hematologic disorders. Longitudinal genotyping revealed 97.8% within-host haplotype concordance, indicative of lifelong latent infection. In a meta-analysis of 755 NPC cases and 981 non-NPC controls, BALF2 I613V and V317M were significantly associated with NPC in both endemic and non-endemic populations. Modeled variant-informed screening strategies achieved a 46% relative increase in PPV with 7% decrease in effective screening sensitivity, thereby averting nearly half of screening endoscopies/MRIs among endemic populations in east/southeast Asia.EBV BALF2 haplotypes are temporally stable within hosts and can be readily detected in plasma via an inexpensive multiplex genotyping assay that offers near-perfect sequencing concordance. In endemic and non-endemic populations, I613V and V317M were highly associated with NPC and could be leveraged to develop variant-informed screening programs that mitigate false positives with small reductions in screening sensitivity.

  View details for DOI 10.1186/s12943-022-01625-6

  View details for PubMedID 35902864

• Nodal Metastasis Count and Oncologic Outcomes in Head and Neck Cancer: A Secondary Analysis of NRG/RTOG 9501, NRG/RTOG 0234, and EORTC 22931 INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lu, D. J., Luu, M., Gay, C., Nguyen, A. T., Anderson, E. M., Bernier, J., Cooper, J. S., Harari, P. M., Torres-Saavedra, P. A., Le, Q., Chen, M. M., Mallen-St Clair, J., Ho, A. S., Zumsteg, Z. S. 2022; 113 (4): 787-795

  View details for DOI 10.1016/j.ijrobp.2021.03.033

  View details for Web of Science ID 000832133200015

• International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE Lechner, M., Takahashi, Y., Turri-Zanoni, M., Ferrari, M., Liu, J., Counsell, N., Mattavelli, D., Rampinelli, V., Vermi, W., Lombardi, D., Saade, R., Park, K., Schartinger, V. H., Franchi, A., Facco, C., Sessa, F., Battocchio, S., Fenton, T. R., Vaz, F. M., O'Flynn, P., Howard, D., Stimpson, P., Wang, S., Hannan, S., Unadkat, S., Hughes, J., Dwivedi, R., Forde, C. T., Randhawa, P., Gane, S., Joseph, J., Andrews, P. J., Dave, M., Fleming, J. C., Thomson, D., Zhu, T., Teschendorff, A., Royle, G., Steele, C., Jimenez, J. E., Laco, J., Wang, E. W., Snyderman, C., Lacy, P. D., Woods, R., O'Neill, J. P., Saraswathula, A., Kaur, R., Zhao, T., Ramanathan, M., Gallia, G. L., London, N. R., Le, Q., West, R. B., Patel, Z. M., Nayak, J. V., Hwang, P. H., Hermsen, M., Llorente, J., Facchetti, F., Nicolai, P., Bossi, P., Castelnuovo, P., Jay, A., Carnell, D., Forster, M. D., Bell, D. M., Lund, V. J., Hanna, E. Y. 2022

  View details for DOI 10.1055/s-0042-1750178

  View details for Web of Science ID 000822748800001

• The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer. Cancer research communications Sodji, Q. H., Nambiar, D. K., Viswanathan, V., von Eyben, R., Colburg, D., Binkley, M. S., Li, C. G., Olcina, M. M., Chang, D. T., Le, Q., Giaccia, A. J. 2022; 2 (7): 725-738

  Abstract

  Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral NK cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiation therapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell-based immunotherapy against pancreatic cancer, its combination with radiation therapy hold greater therapeutic benefit.

  View details for DOI 10.1158/2767-9764.crc-22-0069

  View details for PubMedID 35937458

• Identification of cell types in multiplexed in situ images by combining protein expression and spatial information using CELESTA. Nature methods Zhang, W., Li, I., Reticker-Flynn, N. E., Good, Z., Chang, S., Samusik, N., Saumyaa, S., Li, Y., Zhou, X., Liang, R., Kong, C. S., Le, Q., Gentles, A. J., Sunwoo, J. B., Nolan, G. P., Engleman, E. G., Plevritis, S. K. 2022

  Abstract

  Advances in multiplexed in situ imaging are revealing important insights in spatial biology. However, cell type identification remains a major challenge in imaging analysis, with most existing methods involving substantial manual assessment and subjective decisions for thousands of cells. We developed an unsupervised machine learning algorithm, CELESTA, which identifies the cell type of each cell, individually, using the cell's marker expression profile and, when needed, its spatial information. We demonstrate the performance of CELESTA on multiplexed immunofluorescence images of colorectal cancer and head and neck squamous cell carcinoma (HNSCC). Using the cell types identified by CELESTA, we identify tissue architecture associated with lymph node metastasis in HNSCC, and validate our findings in an independent cohort. By coupling our spatial analysis with single-cell RNA-sequencing data on proximal sections of the same specimens, we identify cell-cell crosstalk associated with lymph node metastasis, demonstrating the power of CELESTA to facilitate identification of clinically relevant interactions.

  View details for DOI 10.1038/s41592-022-01498-z

  View details for PubMedID 35654951

• Association of plasma tumor tissue modified viral HPV DNA (TTMV) with tumor burden, treatment type, and outcome: A translational analysis from NRG-HN002. Yom, S. S., Torres-Saavedra, P. A., Kuperwasser, C., Kumar, S., Gupta, P. B., Ha, P., Geiger, J., Banerjee, R., Thorstad, W., Blakaj, D., Stokes, W. A., Sultanem, K., Lang, P., Lominska, C., Young, M. R., Harris, J., Le, Q. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301704

• Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234. Advances in radiation oncology Michikawa, C., Torres-Saavedra, P. A., Silver, N. L., Harari, P. M., Kies, M. S., Rosenthal, D. I., Le, Q. T., Jordan, R. C., Duose, D. Y., Mallampati, S., Trivedi, S., Luthra, R., Wistuba, I. I., Osman, A. A., Lichtarge, O., Foote, R. L., Parvathaneni, U., Hayes, D. N., Pickering, C. R., Myers, J. N. 2022; 7 (6): 100989

  Abstract

  An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy.Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other.At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival (P = .008), disease-free survival (P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant.The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM.

  View details for DOI 10.1016/j.adro.2022.100989

  View details for PubMedID 36420184

  View details for PubMedCentralID PMC9677209

• Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell phenotype. PNAS nexus Viswanathan, V., Cao, H., Saiki, J., Jiang, D., Mattingly, A., Nambiar, D., Bloomstein, J., Li, Y., Jiang, S., Chamoli, M., Sirjani, D., Kaplan, M., Holsinger, F. C., Liang, R., Von Eyben, R., Jiang, H., Guan, L., Lagory, E., Feng, Z., Nolan, G., Ye, J., Denko, N., Knox, S., Rosen, D., Le, Q. 2022; 1 (2): pgac056

  Abstract

  Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures postradiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and survival even in the absence of radiation stress. Salivary glands from Aldh3a1 -/- mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels, depletes glutathione pool, and accumulates ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.

  View details for DOI 10.1093/pnasnexus/pgac056

  View details for PubMedID 35707206

• The microdissected gene expression landscape of nasopharyngeal cancer reveals vulnerabilities in FGF and noncanonical NF-κB signaling. Science advances Tay, J. K., Zhu, C., Shin, J. H., Zhu, S. X., Varma, S., Foley, J. W., Vennam, S., Yip, Y. L., Goh, C. K., Wang, D. Y., Loh, K. S., Tsao, S. W., Le, Q. T., Sunwoo, J. B., West, R. B. 2022; 8 (14): eabh2445

  Abstract

  Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-positive epithelial malignancy with an extensive inflammatory infiltrate. Traditional RNA-sequencing techniques uncovered only microenvironment signatures, while the gene expression of the tumor epithelial compartment has remained a mystery. Here, we use Smart-3SEQ to prepare transcriptome-wide gene expression profiles from microdissected NPC tumors, dysplasia, and normal controls. We describe changes in biological pathways across the normal to tumor spectrum and show that fibroblast growth factor (FGF) ligands are overexpressed in NPC tumors, while negative regulators of FGF signaling, including SPRY1, SPRY2, and LGALS3, are down-regulated early in carcinogenesis. Within the NF-κB signaling pathway, the critical noncanonical transcription factors, RELB and NFKB2, are enriched in the majority of NPC tumors. We confirm the responsiveness of EBV-positive NPC cell lines to targeted inhibition of these pathways, reflecting the heterogeneity in NPC patient tumors. Our data comprehensively describe the gene expression landscape of NPC and unravel the mysteries of receptor tyrosine kinase and NF-κB pathways in NPC.

  View details for DOI 10.1126/sciadv.abh2445

  View details for PubMedID 35394843

• Nodal Metastasis Count and Oncologic Outcomes in Head and Neck Cancer: A Secondary Analysis of NRG/RTOG 9501, NRG/RTOG 0234, and EORTC 22931. International journal of radiation oncology, biology, physics Lu, D. J., Luu, M., Gay, C., Nguyen, A. T., Anderson, E. M., Bernier, J., Cooper, J. S., Harari, P. M., Torres-Saaverdra, P. A., Le, Q. T., Chen, M., Mallen-St Clair, J., Ho, A. S., Zumsteg, Z. S. 2022

  Abstract

  Better understanding of the relationship between spread of head and neck squamous cell carcinoma (HNSCC) to regional lymph nodes (LN) and the frequency and manner of treatment failure should help design better treatment intensification strategies. In this study, we evaluate the relationship between recurrence patterns, mortality, and number of pathologically positive (+) LN in HNSCC in three prospective randomized controlled trials.Secondary analysis of 947 HNSCC patients enrolled on XXX (N=410), XXX (N=203), and XXX (N=334) undergoing surgery and post-operative radiation +/- systemic therapy.   Multivariable models were constructed for overall survival (OS), disease-free survival (DFS), local-regional relapse (LRR), and distant metastases (DM). Restricted cubic splines were used to model the nonlinear relationship between +LN and outcomes.In multivariable analysis, OS and DFS decreased with each +LN without plateau, most pronounced up to 5 (OS: hazard ratio [HR], 1.19 per +LN; 95% confidence interval [CI], 1.10-1.29; P<0.001; DFS: HR per +LN 1.17, 95% CI 1.08-1.26; P<0.001), and more gradually beyond this (OS: HR per +LN, 1.03; 95% CI, 1.01-1.05; P<0.001; DFS: HR per +LN, 1.03; 95% CI, 1.02-1.05; P<0.001). In contrast to LRR risk, which increased sharply up to 5 +LNs (HR per +LN, 1.25; 95% CI, 1.11-1.39, P<0.001) but plateaued beyond this (HR per +LN, 1.00; 95% CI, 0.967-1.04; P=0.91), DM risk increased continuously with increasing +LN (≤5 +LN: HR per +LN, 1.14; 95% CI, 1.01-1.28; P=0.04; >5 +LN, HR per +LN, 1.05; 95% CI, 1.02-1.07; P=0.002).In high-risk resected HNSCC, increased mortality was associated with increased +LN count. LRR and DM risk both increased in parallel up to 5 +LN, but only DM continued to increase for further +LN increases. These differing recurrence patterns can help inform design of future treatments.

  View details for DOI 10.1016/j.ijrobp.2022.03.033

  View details for PubMedID 35395358

• An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy. Advances in radiation oncology Mayr, N. A., Snider, J. W., Regine, W. F., Mohiuddin, M., Hippe, D. S., Penagaricano, J., Mohiuddin, M., Kudrimoti, M. R., Zhang, H., Limoli, C. L., Le, Q., Simone, C. B. 2022; 7 (2): 100866

  Abstract

  Purpose: Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.Methods and Materials: Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.Results: Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.Conclusions: This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

  View details for DOI 10.1016/j.adro.2021.100866

  View details for PubMedID 35198833

• De-escalating elective nodal irradiation for nasopharyngeal carcinoma. The Lancet. Oncology Miller, J. A., Beadle, B. M., Gensheimer, M. F., Le, Q. 2022

  View details for DOI 10.1016/S1470-2045(22)00096-1

  View details for PubMedID 35240054

• National Effort to Re-Establish Heavy Ion Cancer Therapy in the United States. Frontiers in oncology Pompos, A., Foote, R. L., Koong, A. C., Le, Q. T., Mohan, R., Paganetti, H., Choy, H. 2022; 12: 880712

  Abstract

  In this review, we attempt to make a case for the establishment of a limited number of heavy ion cancer research and treatment facilities in the United States. Based on the basic physics and biology research, conducted largely in Japan and Germany, and early phase clinical trials involving a relatively small number of patients, we believe that heavy ions have a considerably greater potential to enhance the therapeutic ratio for many cancer types compared to conventional X-ray and proton radiotherapy. Moreover, with ongoing technological developments and with research in physical, biological, immunological, and clinical aspects, it is quite plausible that cost effectiveness of radiotherapy with heavier ions can be substantially improved.

  View details for DOI 10.3389/fonc.2022.880712

  View details for PubMedID 35774126

• Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma. European journal of cancer (Oxford, England : 1990) Lechner, M., Takahashi, Y., Turri-Zanoni, M., Liu, J., Counsell, N., Hermsen, M., Kaur, R. P., Zhao, T., Ramanathan, M. J., Schartinger, V. H., Emanuel, O., Helman, S., Varghese, J., Dudas, J., Riechelmann, H., Sprung, S., Haybaeck, J., Howard, D., Engel, N. W., Stewart, S., Brooks, L., Pickles, J. C., Jacques, T. S., Fenton, T. R., Williams, L., Vaz, F. M., O'Flynn, P., Stimpson, P., Wang, S., Hannan, S. A., Unadkat, S., Hughes, J., Dwivedi, R., Forde, C. T., Randhawa, P., Gane, S., Joseph, J., Andrews, P. J., Royle, G., Franchi, A., Maragliano, R., Battocchio, S., Bewicke-Copley, H., Pipinikas, C., Webster, A., Thirlwell, C., Ho, D., Teschendorff, A., Zhu, T., Steele, C. D., Pillay, N., Vanhaesebroeck, B., Mohyeldin, A., Fernandez-Miranda, J., Park, K. W., Le, Q., West, R. B., Saade, R., Manes, R. P., Omay, S. B., Vining, E. M., Judson, B. L., Yarbrough, W. G., Sansovini, M., Silvia, N., Grassi, I., Bongiovanni, A., Capper, D., Schuller, U., Thavaraj, S., Sandison, A., Surda, P., Hopkins, C., Ferrari, M., Mattavelli, D., Rampinelli, V., Facchetti, F., Nicolai, P., Bossi, P., Henriquez, O. A., Magliocca, K., Solares, C. A., Wise, S. K., Llorente, J. L., Patel, Z. M., Nayak, J. V., Hwang, P. H., Lacy, P. D., Woods, R., O'Neill, J. P., Jay, A., Carnell, D., Forster, M. D., Ishii, M., London, N. R., Bell, D. M., Gallia, G. L., Castelnuovo, P., Severi, S., Lund, V. J., Hanna, E. Y. 1800

  Abstract

  INTRODUCTION: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy.METHODS: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763).RESULTS: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n=278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD).CONCLUSIONS: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.

  View details for DOI 10.1016/j.ejca.2021.09.046

  View details for PubMedID 34980502

• JUPITER-02 trial: advancing survival for recurrent metastatic nasopharyngeal carcinoma and next steps. Cancer communications (London, England) Tan, L. L., Le, Q., Lee, N. Y., Chua, M. L. 1800

  View details for DOI 10.1002/cac2.12248

  View details for PubMedID 34918497

• Risk stratification after recurrence of human papillomavirus (HPV)-related and non-HPV-related oropharyngeal cancer: A secondary analysis of NRG Oncology RTOG 0129 and 0522. Head & neck Bigelow, E. O., Harris, J., Fakhry, C., Gillison, M. L., Nguyen-Tan, P. F., Rosenthal, D. I., Frank, S. J., Nair, S. G., Bahig, H., Ridge, J. A., Caudell, J., Donaldson, C., Clifford, B. T., Shenouda, G., Birrer, M. J., Chen, Y., Le, Q. 2021

  Abstract

  BACKGROUND: No risk-stratification strategies exist for patients with recurrent oropharyngeal cancer (OPC).METHODS: Retrospective analysis using data from prospective NRG Oncology clinical trials RTOG 0129 and 0522. Eligibility criteria included known p16 status and smoking history, and locoregional/distant recurrence. Overall survival (OS) was measured from date of recurrence. Recursive partitioning analysis was performed to produce mutually exclusive risk groups.RESULTS: Hundred and fifty-four patients were included with median follow-up after recurrence of 3.9years (range 0.04-9.0). The most important factors influencing survival were p16 status and type of recurrence, followed by surgical salvage and smoking history (≤20 vs. >20 pack-years). Three significantly different risk groups were identified. Patients in the low-, intermediate-, and high-risk groups had 2-year OS after recurrence of 81.1% (95%CI 68.5-93.7), 50.2% (95%CI 36.0-64.5), and 20.8% (95%CI 10.5-31.1), respectively.CONCLUSION: Patient and tumor characteristics may be used to stratify patients into risk groups at the time of OPC recurrence.

  View details for DOI 10.1002/hed.26915

  View details for PubMedID 34729846

• NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer CANCERS Bauman, J. E., Harris, J., Uppaluri, R., Yao, M., Ferris, R. L., Chen, J., Jordan, R. C., Joshi, N. P., Jujjuvaparu, S., Blakaj, D. M., Henson, C., Sheqwara, J., Mell, L. K., Sen, N., Clump, D. A., Garg, M. K., Yilmaz, E., Torres-Saavedra, P., Quynh-Thu Le 2021; 13 (12)

  Abstract

  The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin-radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III-IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

  View details for DOI 10.3390/cancers13122882

  View details for Web of Science ID 000666654800001

  View details for PubMedID 34207599

• Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination & ndash;deficient cancer models JOURNAL OF CLINICAL INVESTIGATION Mehibel, M., Xu, Y., Li, C. G., Moon, E., Thakkar, K. N., Diep, A. N., Kim, R. K., Bloomstein, J. D., Xiao, Y., Bacal, J., Saldivar, J. C., Le, Q., Cimprich, K. A., Rankin, E. B., Giaccia, A. J. 2021; 131 (11)

  View details for DOI 10.1172/JCI146256.

  View details for Web of Science ID 000656969100004

• Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models. The Journal of clinical investigation Mehibel, M., Xu, Y., Li, C. G., Moon, E. J., Thakkar, K. N., Diep, A. N., Kim, R. K., Bloomstein, J. D., Xiao, Y., Bacal, J., Saldivar, J. C., Le, Q., Cimprich, K. A., Rankin, E. B., Giaccia, A. J. 2021; 131 (11)

  Abstract

  Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells. Mechanistically, we identify reduced ROS-induced DNA damage as the cause for the observed resistance. To determine the contribution of hypoxia to PARPi resistance in tumors, we used the hypoxic cytotoxin tirapazamine to selectively kill hypoxic tumor cells. We found that the selective elimination of hypoxic tumor cells led to a substantial antitumor response when used with PARPi compared with that in tumors treated with PARPi alone, without enhancing normal tissue toxicity. Since human breast cancers with BRAC1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARPi, then eliminating hypoxic tumor cells should enhance the efficacy of PARPi therapy.

  View details for DOI 10.1172/JCI146256

  View details for PubMedID 34060485

• NRG Oncology HN006: Randomized phase II/III trial of sentinel lymph node biopsy versus elective neck dissection for early-stage oral cavity cancer. Lai, S., Torres-Saavedra, P. A., Dunlap, N. E., Beadle, B., Chang, S. S., Subramaniam, R. M., Yu, J., Lowe, V. J., Khan, S. A., Truong, M., Bell, D., Liu, C. Z., Kovalchuk, N., Rong, Y., Abazeed, M. E., Kappadath, S., Harris, J., Le, Q. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.TPS6093

  View details for Web of Science ID 000708120307003

• Evaluation of Oncology Trial Results Reporting Over a 10-Year Period. JAMA network open Liu, X., Zhang, Y., Li, W., Vokes, E., Sun, Y., Le, Q., Ma, J. 2021; 4 (5): e2110438

  Abstract

  Importance: Unreported clinical trial results represent a violation of human rights. Oncology trials account for nearly 30% of interventional biopharmaceutical clinical studies registered on ClinicalTrials.gov and are the most numerous among all disciplines.Objective: To analyze the reporting of results among all interventional oncology trials registered on ClinicalTrials.gov from 2007 through 2017.Design, Setting, and Participants: This cohort study analyzed all clinical studies registered between June 1, 2007, and May 8, 2017, on ClinicalTrials.gov, the largest public clinical trial registry in the world. Trials with a recruitment status of completed or terminated and a primary completion date of on or before September 30, 2017, were selected. Data were analyzed between February 20, 2021, and February 26, 2021.Main Outcomes and Measures: The main outcome was the percentage of trials that reported results either on ClinicalTrials.gov or in journal publications within 24 months of the primary completion date. Journal publication was ascertained by searching ClinicalTrials.gov for a link to the publication, PubMed using national clinical trial number, and Embase using national clinical trial number and filters.Results: Of the 12 240 clinical trials registered in ClinicalTrials.gov, 7425 trials (60.7%; 95% CI, 60.0%-61.5%) reported results, with a 34.0% (95% CI, 30.3%-37.7%) increase in 24-month reporting rate from 2007 to 2017. Multivariable analyses confirmed that more recent trials (adjusted hazard ratio [HR], 1.11 per year increase; 95% CI, 1.10-1.13) and trials with larger sample sizes (51-100 patients: adjusted HR, 1.17 [95% CI, 1.09-1.24]; >100 patients: adjusted HR, 1.43 [95% CI, 1.33-1.54]) were more likely to report results. Terminated trials were less likely to report results compared with completed trials (adjusted HR, 0.88; 95% CI, 0.83-0.93). Compared with trials funded by industry, those funded by the National Institutes of Health were more likely to report results (adjusted HR, 1.39; 95% CI, 1.29-1.49), whereas those funded by other academic or nonprofit organizations were less likely to report results (adjusted HR, 0.66; 95% CI, 0.62-0.70). Among all 7425 trials, the results of 2807 trials (37.8%; 95% CI, 36.7%-38.9%) were posted only on ClinicalTrials.gov. These trials tended to be terminated early and to have small sample sizes (≤50 patients) compared with trials that published results in journals.Conclusions and Relevance: This study found a gradual improvement in results reporting among oncology trials over a 10-year period. Trial registries could serve as a results reporting platform for unpublished trials and as a data source of trial outcomes for future studies.

  View details for DOI 10.1001/jamanetworkopen.2021.10438

  View details for PubMedID 34028549

• The impact of age on outcome in phase III NRG Oncology/RTOG trials of radiotherapy (XRT) +/- systemic therapy in locally advanced head and neck cancer. Journal of geriatric oncology Kish, J. A., Zhang, Q., Langer, C. J., Nguyen-Tan, P. F., Rosenthal, D. I., Weber, R. S., List, M. A., Wong, S. J., Garden, A. S., Hu, K., Trotti, A. M., Bonner, J. A., Jones, C. U., Yom, S. S., Thorstad, W., Schultz, C. J., Ridge, J. A., Shenouda, G., Harris, J., Le, Q. 2021

  Abstract

  PURPOSE: To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy.METHODS: A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated.RESULTS: A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old.CONCLUSIONS: Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.

  View details for DOI 10.1016/j.jgo.2021.03.011

  View details for PubMedID 33814339

• Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer. Cell chemical biology Tailor, D., Resendez, A., Garcia-Marques, F. J., Pandrala, M., Going, C. C., Bermudez, A., Kumar, V., Rafat, M., Nambiar, D. K., Honkala, A., Le, Q., Sledge, G. W., Graves, E., Pitteri, S. J., Malhotra, S. V. 2021

  Abstract

  Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase. Inhibitor treatment leads to enrichment of proteins associated with apoptosis and RNA degradation pathways while downregulating spliceosome pathway. Invivo, SU056 independently restrains OC progression and exerts a synergistic effect with paclitaxel to further reduce disease progression with no observable liver toxicity. Moreover, invitro mechanistic studies showed delayed disease progression via inhibition of drug efflux and multidrug resistance 1, and significantly lower neurotoxicity as compared with etoposide. These data suggest that YB-1 inhibition may be an effective strategy to reduce OC progression, antagonize TR, and decrease patient mortality.

  View details for DOI 10.1016/j.chembiol.2021.02.014

  View details for PubMedID 33713600

• Risk groups of laryngeal cancer treated with chemoradiation according to nomogram scores - A pooled analysis of RTOG 0129 and 0522. Oral oncology Awan, M. J., Gittleman, H., Barnholtz-Sloan, J., Machtay, M., Nguyen-Tan, P. F., Rosenthal, D. I., Schultz, C., Huth, B. J., Thorstad, W. L., Frank, S. J., Kim, H., Foote, R. L., Lango, M. N., Shenouda, G., Suntharalingam, M., Harris, J., Zhang, Q., Le, Q., Yao, M., NRG Oncology Group 2021; 116: 105241

  Abstract

  OBJECTIVES: To develop nomograms predicting overall survival (OS), freedom from locoregional recurrence (FFLR), and freedom from distant metastasis (FFDM) for patients receiving chemoradiation for laryngeal squamous cell carcinoma (LSCC).MATERIAL AND METHODS: Clinical and treatment data for patients with LSCC enrolled on NRG Oncology/RTOG 0129 and 0522 were extracted from the RTOG database. The dataset was partitioned into 70% training and 30% independent validation datasets. Significant predictors of OS, FFLR, and FFDM were obtained using univariate analysis on the training dataset. Nomograms were built using multivariate analysis with four a priori variables (age, gender, T-stage, and N-stage) and significant predictors from the univariate analyses. These nomograms were internally and externally validated using c-statistics (c) on the training and validation datasets, respectively.RESULTS: The OS nomogram included age, gender, T stage, N stage, and number of cisplatin cycles. The FFLR nomogram included age, gender, T-stage, N-stage, and time-equivalent biologically effective dose. The FFDM nomogram included age, gender, N-stage, and number of cisplatin cycles. Internal validation of the OS nomogram, FFLR nomogram, and FFDM nomogram yielded c=0.66, c=0.66 and c=0.73, respectively. External validation of these nomograms yielded c=0.59, c=0.70, and c=0.73, respectively. Using nomogram score cutoffs, three risk groups were separated for each outcome.CONCLUSIONS: We have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.

  View details for DOI 10.1016/j.oraloncology.2021.105241

  View details for PubMedID 33640577

• Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Chen, Y., Ismaila, N., Chua, M. L., Colevas, A. D., Haddad, R., Huang, S. H., Wee, J. T., Whitley, A. C., Yi, J., Yom, S. S., Chan, A. T., Hu, C., Lang, J., Le, Q., Lee, A. W., Lee, N., Lin, J., Ma, B., Morgan, T. J., Shah, J., Sun, Y., Ma, J. 2021: JCO2003237

  Abstract

  PURPOSE: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other healthcare providers on definitive-intent chemoradiotherapy for patients with stage II-IVA nasopharyngeal carcinoma (NPC).METHODS: The Chinese Society of Clinical Oncology (CSCO) and ASCO convened an expert panel of radiation oncology, medical oncology, surgery, and advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2020. Outcomes of interest included survival, distant and locoregional disease control, and quality of life. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations.RESULTS: The literature search identified 108 relevant studies to inform the evidence base for this guideline. Five overarching clinical questions were addressed, which included subquestions on radiotherapy (RT), chemotherapy sequence, and concurrent, induction, and adjuvant chemotherapy options.RECOMMENDATIONS: Evidence-based recommendations were developed to address aspects of care related to chemotherapy in combination with RT for the definitive-intent treatment of stage II to IVA NPC.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

  View details for DOI 10.1200/JCO.20.03237

  View details for PubMedID 33405943

• Postoperative Observation Versus Radiotherapy for Pathologic N1 Oral Cavity Squamous Cell Carcinoma. American journal of clinical oncology Xiang, M. n., Holsinger, F. C., Gensheimer, M. F., Divi, V. n., Pollom, E. L., Colevas, A. D., Le, Q. T., Beadle, B. M. 2021; Publish Ahead of Print

  Abstract

  To investigate the benefit of postoperative radiotherapy (PORT) for low-volume (pN1) nodal disease after resection of oral cavity squamous cell carcinoma.The National Cancer Database was queried for adults with nonmetastatic squamous cell carcinoma of the oral cavity treated by surgical resection with pathologic stage T1-2 N0-2 (American Joint Committee on Cancer 7th edition) and with the maximal exclusion of standard indications for PORT. Overall survival was compared within pN1 for observation versus PORT and then compared for pN1 versus pN0 and versus pN2 stratified by receipt of observation or PORT. Multivariable Cox regression was used to adjust for potential confounders between PORT and survival, including comorbidity and age.Overall 5017 pN0, 530 pN1, and 253 pN2 patients were identified, of whom 9%, 35%, and 64% received PORT, respectively. Within the pN1 cohort, PORT was associated with improved survival versus observation (adjusted hazard ratio, 0.66; 95% confidence interval, 0.46-0.97; P=0.03). Among observed patients, the prognosis of pN1 was equivalent to pN2 and inferior to pN0; in contrast, among patients treated with PORT, the prognosis of pN1 was equivalent to pN0 and superior to pN2. Without PORT, pN1 remained an adverse risk factor relative to pN0 regardless of the depth of invasion, lymph node size, lymph node location, and extent of lymph node dissection.PORT was associated with a survival benefit compared with observation. Notably, pN1 was an adverse risk factor relative to pN0 if, and only if, patients did not receive PORT, suggesting pN1 by itself may be an indication for PORT.

  View details for DOI 10.1097/COC.0000000000000792

  View details for PubMedID 33417322

• Reply to A. Cmelak et al and B. Kalra et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Yom, S. S., Torres-Saavedra, P. A., Le, Q. T. 2021: JCO2100882

  View details for DOI 10.1200/JCO.21.00882

  View details for PubMedID 34043429

• Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis. The Lancet. Oncology Petit, C. n., Lacas, B. n., Pignon, J. P., Le, Q. T., Grégoire, V. n., Grau, C. n., Hackshaw, A. n., Zackrisson, B. n., Parmar, M. K., Lee, J. W., Ghi, M. G., Sanguineti, G. n., Temam, S. n., Cheugoua-Zanetsie, M. n., O'Sullivan, B. n., Posner, M. R., Vokes, E. E., Cruz Hernandez, J. J., Szutkowski, Z. n., Lartigau, E. n., Budach, V. n., Suwiński, R. n., Poulsen, M. n., Kumar, S. n., Ghosh Laskar, S. n., Mazeron, J. J., Jeremic, B. n., Simes, J. n., Zhong, L. P., Overgaard, J. n., Fortpied, C. n., Torres-Saavedra, P. n., Bourhis, J. n., Aupérin, A. n., Blanchard, P. n. 2021

  Abstract

  Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other.We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies).115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%).The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer.French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

  View details for DOI 10.1016/S1470-2045(21)00076-0

  View details for PubMedID 33862002

• Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002). Journal of clinical oncology : official journal of the American Society of Clinical Oncology Yom, S. S., Torres-Saavedra, P. n., Caudell, J. J., Waldron, J. N., Gillison, M. L., Xia, P. n., Truong, M. T., Kong, C. n., Jordan, R. n., Subramaniam, R. M., Yao, M. n., Chung, C. H., Geiger, J. L., Chan, J. W., O'Sullivan, B. n., Blakaj, D. M., Mell, L. K., Thorstad, W. L., Jones, C. U., Banerjee, R. N., Lominska, C. n., Le, Q. T. 2021: JCO2003128

  Abstract

  Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (P = .04). For IMRT, 2-year PFS was 87.6% (P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (P = .56).The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

  View details for DOI 10.1200/JCO.20.03128

  View details for PubMedID 33507809

• Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. Nature communications Lechner, M., Schartinger, V. H., Steele, C. D., Nei, W. L., Ooft, M. L., Schreiber, L., Pipinikas, C. P., Chung, G. T., Chan, Y. Y., Wu, F., To, K., Tsang, C. M., Pearce, W., Morelli, D., Philpott, M., Masterson, L., Nibhani, R., Wells, G., Bell, C. G., Koller, J., Delecluse, S., Yip, Y. L., Liu, J., Forde, C. T., Forster, M. D., Jay, A., Dudas, J., Krapp, A., Wan, S., Uprimny, C., Sprung, S., Haybaeck, J., Fenton, T. R., Chester, K., Thirlwell, C., Royle, G., Marafioti, T., Gupta, R., Indrasari, S. R., Herdini, C., Slim, M. A., Indrawati, I., Sutton, L., Fles, R., Tan, B., Yeong, J., Jain, A., Han, S., Wang, H., Loke, K. S., He, W., Xu, R., Jin, H., Cheng, Z., Howard, D., Hwang, P. H., Le, Q., Tay, J. K., West, R. B., Tsao, S. W., Meyer, T., Riechelmann, H., Oppermann, U., Delecluse, H., Willems, S. M., Chua, M. L., Busson, P., Lo, K. W., Wollmann, G., Pillay, N., Vanhaesebroeck, B., Lund, V. J. 2021; 12 (1): 117

  Abstract

  Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-kappaB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

  View details for DOI 10.1038/s41467-020-20308-8

  View details for PubMedID 33402692

• International Recommendations on Re-irradiation by Intensity-modulated Radiotherapy for Locally Recurrent Nasopharyngeal Carcinoma. International journal of radiation oncology, biology, physics Ng, W. T., Soong, Y. L., Chan Ahn, Y. n., AlHussain, H. n., Choi, H. C., Corry, J. n., Grégoire, V. n., Harrington, K. J., Hu, C. S., Jensen, K. n., Kwong, D. L., Langendijk, J. A., Le, Q. T., Lee, N. Y., Lin, J. C., Lu, T. X., Mendenhall, W. M., O'Sullivan, B. n., Ozyar, E. n., Pan, J. J., Peters, L. J., Poh, S. S., Rosenthal, D. I., Sanguineti, G. n., Tao, Y. n., Wee, J. T., Yom, S. S., Chua, M. L., Lee, A. W. 2021

  Abstract

  Re-irradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging as prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking as available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions.A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was re-circulated to the whole panel for review and reconsideration. The current guideline was based on majority voting following repeated iteration for final agreement.The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of re-irradiation (including patient selection, targets contouring, dose prescription and constraints).This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of re-irradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's conditions, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications.

  View details for DOI 10.1016/j.ijrobp.2021.01.041

  View details for PubMedID 33571626

• Cost-Effectiveness of Nasopharyngeal Carcinoma Screening with Epstein-Barr Virus Polymerase Chain Reaction or Serology in High-Incidence Populations Worldwide. Journal of the National Cancer Institute Miller, J. A., Le, Q., Pinsky, B. A., Wang, H. 2020

  Abstract

  BACKGROUND: The incidence of endemic Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) varies considerably worldwide. In high-incidence regions, screening trials have been conducted. We estimated the mortality reduction and cost-effectiveness of EBV-based NPC screening in populations worldwide.METHODS: We identified 380 populations in 132 countries with incident NPC and developed a decision-analytic model to compare ten unique onetime screening strategies to no screening for men and women at age 50years. Screening performance and the stage distribution of undiagnosed NPC were derived from a systematic review of prospective screening trials.RESULTS: Screening was cost-effective in up to 14.5% of populations, depending on the screening strategy. These populations were limited to East Asia, Southeast Asia, North Africa, or were Asian, Pacific Islander, or Inuit populations in North America. A combination of serology and nasopharyngeal polymerase chain reaction (PCR) was most cost-effective, but other combinations of serologic and/or plasma PCR screening were also cost-effective. The estimated reduction in NPC mortality was similar across screening strategies. For a hypothetical cohort of patients in China, 10-year survival improved from 71.0% (95%CI = 68.8%-73.0%) without screening to a median of 86.3% (range = 83.5%-88.2%) with screening. This corresponded to a median 10-year reduction in NPC mortality of 52.9% (range= 43.1%-59.3%). Screening interval impacted absolute mortality reduction and cost-effectiveness.CONCLUSIONS: We observed decreased NPC mortality with EBV-based screening. Screening was cost-effective in many high-incidence populations and could be extended to men and women as early as age 40years in select regions. These findings may be useful when choosing among local public health initiatives.

  View details for DOI 10.1093/jnci/djaa198

  View details for PubMedID 33351145

• Pilot study of loss of the p53/p63 target gene PERP at the surgical margin as a potential predictor of local relapse in head and neck squamous cell carcinoma. Head & neck Holmes, B. J., von Eyben, R., Attardi, L. D., Kong, C. S., Le, Q. T., Nathan, C. O. 2020

  Abstract

  PERP (p53 apoptosis effector related to PMP22) localizes to desmosomes and suppresses squamous cell carcinoma development. Loss of PERP leads to worse local control in head and neck squamous cell carcinoma (HNSCC), likely by destabilizing desmosomes. We evaluated PERP loss at HNSCC surgical margins as a predictor of local relapse.Combining discovery (n = 17) and validation (n = 31) cohorts, we examined membranous PERP protein expression by immunohistochemistry in surgical mucosal margins with competing risk analysis of the relationship between local relapse and PERP expression.Of the 44 analyzable patients, the 2-year cumulative incidence of local relapse was 44.4% for the PERP-negative group and 16.4% for the PERP-positive group (P = .01). A trend toward worse progression-free survival (P = .09) and overall survival (P = .06) was observed with loss of PERP.PERP loss at surgical margins is associated with higher risk of local recurrence in HNSCC, warranting further evaluation in a larger prospective study.

  View details for DOI 10.1002/hed.26358

  View details for PubMedID 33034918

• Pilot study of loss of the p53/p63 target genePERPat the surgical margin as a potential predictor of local relapse in head and neck squamous cell carcinoma HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Holmes, B. J., von Eyben, R., Attardi, L. D., Kong, C. S., Le, Q., Nathan, C. O. 2020

  View details for DOI 10.1002/hed.26358

  View details for Web of Science ID 000545616600001

• Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non-small cell lung cancer. The Journal of thoracic and cardiovascular surgery Donington, J. S., Paulus, R., Edelman, M. J., Krasna, M. J., Le, Q., Suntharalingam, M., Loo, B. W., Hu, C., Bradley, J. D., NRG Oncology Lung Group 2020

  Abstract

  OBJECTIVE: Concern exists regarding surgery after thoracic radiation. We aimed to assess early results of anatomic resection following induction therapy with platinum-based chemotherapy and full-dose thoracic radiation for resectable N2+ stage IIIA non-small cell lung cancer.METHODS: Two prospective trials were recently conducted by NRG Oncology in patients with resectable N2+ stage IIIA non-small cell lung cancer with the primary end point of mediastinal node sterilization following concurrent full-dose chemoradiotherapy (Radiation Therapy Oncology Group trials 0229 and 0839). All surgeons demonstrated postinduction resection expertise. Induction consisted of weekly carboplatin (area under the curve, 2.0) and paclitaxel (50mg/m2) and concurrent thoracic radiation 60Gy (0839)/61.2Gy (0229) in 30 fractions. Patients in study 0839 were randomized 2:1 to weekly panitumumab+chemoradiotherapy or chemoradiotherapy alone during induction. Primary results were similar in all treatment arms and reported previously. Short-term surgical outcomes are reported here.RESULTS: One hundred twenty-six patients enrolled; 93 (74%) had anatomic resection, 77 underwent lobectomy, and 16 underwent extended resection. Microscopically margin-negative resections occurred in 85 (91%). Fourteen (15%) resections were attempted minimally invasively, including 2 converted without event. Grade 3 or 4 surgical adverse events were reported in 26 (28%), 30-day mortality in 4 (4%) and 90-day mortality in 5 (5%). Patients undergoing extended resection experienced similar rates of grade 3 or 4 adverse events (odds ratio, 0.95; 95% confidence interval, 0.42-3.8) but higher 30-day (1.3% vs 18.8%) (odds ratio, 17.54; 95% confidence interval, 1.75-181.8) and 90-day mortality (2.6% vs 18.8%) (odds ratio, 8.65; 95% confidence interval, 1.3-56.9).CONCLUSIONS: Lobectomy was performed safely following full-dose concurrent chemoradiotherapy in these multi-institutional prospective trials; however, increased mortality was noted with extended resections.

  View details for DOI 10.1016/j.jtcvs.2020.03.171

  View details for PubMedID 32798022

• 18 FDG PET/CT prediction of treatment outcomes in patients with p16-positive, non-smoking associated, locoregionally advanced oropharyngeal cancer (LAOPC) receiving deintensified therapy: Results from NRG-HN002. Subramaniam, R. M., Demora, L., Yao, M., Yom, S. S., Gillison, M. L., Caudell, J. J., Waldron, J., Xia, P., Chung, C. H., Truong, M., Harrison, L. B., Chan, J., Geiger, J., Mell, L., Seaward, S. A., Thorstad, W., Beitler, J., Sultanem, K., Blakaj, D., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303064

• Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: an ASTRO-ESTRO consensus statement. International journal of radiation oncology, biology, physics Thomson, D. J., Palma, D., Guckenberger, M., Balermpas, P., Beitler, J. J., Blanchard, P., Brizel, D., Budach, W., Caudell, J., Corry, J., Corvo, R., Evans, M., Garden, A. S., Giralt, J., Gregoire, V., Harari, P. M., Harrington, K., Hitchcock, Y. J., Johansen, J., Kaanders, J., Koyfman, S., Langendijk, J. A., Le, Q., Lee, N., Margalit, D., Mierzwa, M., Porceddu, S., Soong, Y. L., Sun, Y., Thariat, J., Waldron, J., Yom, S. S. 2020

  Abstract

  INTRODUCTION: Due to the unprecedented disruption of health care services by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC), in a time of heightened risk for patients and staff, and of limited resources.METHODS: A panel of international experts from ASTRO, ESTRO and select Asia-Pacific countries completed a modified rapid Delphi process. Questions and topics were presented to the group, and subsequent questions developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios: early (risk mitigation) and late (severely reduced radiotherapy resources) were evaluated. The panel developed treatment recommendations for five HNC cases.RESULTS: In total, 29/31 (94%) of those invited accepted, and after a replacement 30/30 completed all three surveys (100% response rate). There was agreement or strong agreement across a number of practice areas including: treatment prioritisation, whether to delay initiation or interrupt radiotherapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care.CONCLUSIONS: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.

  View details for DOI 10.1016/j.ijrobp.2020.04.016

  View details for PubMedID 32302681

• Head and Neck Cancer International Group (HNCIG) Consensus Guidelines for the delivery of postoperative radiation therapy in complex cutaneous squamous cell carcinoma of the head and neck (cSCCHN). International journal of radiation oncology, biology, physics Porceddu, S. V., Daniels, C., Yom, S. S., Liu, H., Waldron, J., Gregoire, V., Moore, A., Veness, M., Yao, M., Johansen, J., Mehanna, H., Rischin, D., Le, Q. 2020

  Abstract

  Radiation Therapy (RT) consensus contouring guidelines in the post-operative setting for complex cutaneous squamous cell carcinoma of the head and neck (cSCCHN) have been developed by expert clinicians in the field of head and neck and dermato-oncology and members of the Head and Neck Cancer International Group (HNCIG) to assist radiation oncologists involved in the management of this disease. These guidelines present a set of principles used to define post-operative RT (PORT) volumes and corresponding minimum doses following resection of all macroscopic tumour with or without microscopic residual disease. It is anticipated they will promote the harmonization of PORT globally and contribute to a reduction in treatment variation among clinicians, allowing for RT quality and outcomes assessment across institutions.

  View details for DOI 10.1016/j.ijrobp.2020.03.024

  View details for PubMedID 32289475

• Retraction Note: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q., Chi, J. A., Jeffrey, S. S., Giaccia, A. J. 2020; 579 (7799): 456

  Abstract

  A Retraction to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41586-020-2112-4

  View details for PubMedID 32188947

• Induced tumor heterogeneity reveals factors informing radiation and immunotherapy combinations. Clinical cancer research : an official journal of the American Association for Cancer Research Aguilera, T. A., Elghonaimy, E., Shehade, H., Rafat, M., Castellini, L., Jiang, D., Kariolis, M., Koong, A., Le, Q., Ellies, L. G., Rankin, E. B., Graves, E. E., Giaccia, A. J. 2020

  Abstract

  PURPOSE: To investigate how induced tumor heterogeneity influences immune responses to radiotherapy (RT) with different proportions of mixed immune responsive and unresponsive tumor cells in a triple negative breast cancer model. It is hypothesized that studying the immune environment of mixed tumors and responses to RT could nominate immune active therapies to enhance immune responses after RT.EXPERIMENTAL DESIGN: Evaluate efficacy and immune responses generated by RT in tumors with different proportions of immunologically responsive and unresponsive tumor cells. Then study the cellular responses and transcriptomic differences between the tumors to nominate immunotherapy combinations with RT and evaluate the combination.RESULTS: The addition of the responsive cells to unresponsive tumors led to a greater than expected therapeutic response to RT with both innate and adaptive immune components. There was a distinct change in myeloid cells, greater inflammatory macrophage activity, and enhanced antigen presentation with responsive cells after RT. Since differences in matrix components, cell adhesion biology, and innate immune signaling correlated with myeloid cell response and phenotype, we hypothesized that RT combined with CD40 agonist antibody would sensitize unresponsive tumors. The combination therapy resulted improved innate and adaptive immune response. Importantly, CD40 treatment increased tumor response to RT and protected against metastatic spread in a metastatic model.CONCLUSIONS: These data combined with transcriptomics from human patients supports RT and myeloid cell targeting for immunologically cold tumors and presents opportunities to investigate the complex overlapping biologic mechanisms that limit immunotherapy and to implement RT with different immunotherapy combinations.

  View details for DOI 10.1158/1078-0432.CCR-19-4220

  View details for PubMedID 32098769

• The role of Glial cell derived neurotrophic factor in head and neck cancer. PloS one Cao, H., He, Q., Eyben, R. v., Bloomstein, J., Nambiar, D. K., Viswanathan, V., Aggarwal, S., Kwok, S., Liang, R., Koong, A. J., Lewis, J. S., Kong, C., Xiao, N., Le, Q. 2020; 15 (2): e0229311

  Abstract

  Glial cell-derived neurotrophic factor (GDNF) is reported to promote the survival of neurons and salivary gland regeneration after radiation damage. This study investigated the effect of GDNF on cell migration, growth, and response to radiation in preclinical models of head and neck squamous cell carcinoma (HNSCC) and correlated GDNF expression to treatment outcomes in HNSCC patients. Our ultimate goal is to determine whether systemic administration of GDNF at high dose is safe for the management of hyposalivation or xerostomia in HNSCC patients. Three HPV-positive and three HPV-negative cell lines were examined for cell migration, growth, and clonogenic survival in vitro and tumor growth assay in vivo. Immunohistochemical staining of GDNF, its receptors GFRalpha1 and its co-receptor RET was performed on two independent HNSCC tissue microarrays (TMA) and correlated to treatment outcomes. Results showed that GDNF only enhanced cell migration in two HPV-positive cells at supra-physiologic doses, but not in HPV-negative cells. GDNF did not increase cell survival in the tested cell lines post-irradiation. Likewise, GDNF treatment affected neither tumor growth in vitro nor response to radiation in xenografts in two HPV-positive and two HPV-negative HNSCC models. High stromal expression of GDNF protein was associated with worse overall survival in HPV-negative HNSCC on multivariate analysis in a combined cohort of patients from Stanford University (n = 82) and Washington University (n = 189); however, the association between GDNF gene expression and worse survival was not confirmed in a separate group of HPV-negative HNSCC patients identified from the Cancer Genome Atlas (TCGA) database. Based on these data, we do not believe that GNDF is a safe systemic treatment to prevent or treat xerostomia in HNSCC and a local delivery approach such as intraglandular injection needs to be explored.

  View details for DOI 10.1371/journal.pone.0229311

  View details for PubMedID 32084217

• Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation. Communications biology Wu, P. H., Onodera, Y. n., Giaccia, A. J., Le, Q. T., Shimizu, S. n., Shirato, H. n., Nam, J. M. 2020; 3 (1): 620

  Abstract

  Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy. Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells. Notably, high expression of ARL8B and BORC-subunit genes is significantly correlated with poor prognosis in breast cancer patients. Sp1, an ATM-regulated transcription factor, is found to increase BORC-subunit genes expression after radiation. In vivo experiments show that ablation of Arl8b decreases IR-induced invasive tumor growth and distant metastasis. These findings suggest that BORC-Arl8b-mediated lysosomal trafficking is a target for improving radiotherapy by inhibiting invasive tumor growth and metastasis.

  View details for DOI 10.1038/s42003-020-01339-9

  View details for PubMedID 33110168

• Comments on the Publication by Corkum etal on "Does 5 + 5mm Equal Better Radiation Treatment Plans in Head and Neck Cancers?" Advances in radiation oncology Gregoire, V., Grau, C., Le, Q., Yom, S. S., Head and Neck Intergroup 2020; 5 (1): 140–41

  View details for DOI 10.1016/j.adro.2019.08.011

  View details for PubMedID 32051901

• Multicenter Clinical Cancer Research After COVID-19: A Perspective From NRG Oncology. International journal of radiation oncology, biology, physics Gensheimer, M. F., Yom, S. S., Soto, N., Dignam, J. J., Le, Q., Machtay, M., Curran, W. J. 2020; 108 (2): 483–85

  View details for DOI 10.1016/j.ijrobp.2020.06.056

  View details for PubMedID 32890539

• Rab27b contributes to radioresistance and exerts a paracrine effect via epiregulin in glioblastoma. Neuro-oncology advances Nishioka, S., Wu, P., Yakabe, T., Giaccia, A. J., Le, Q., Aoyama, H., Shimizu, S., Shirato, H., Onodera, Y., Nam, J. 2020; 2 (1): vdaa091

  Abstract

  Background: Radiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM.Methods: Microarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines.Results: Rab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner.Conclusions: Our results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.

  View details for DOI 10.1093/noajnl/vdaa091

  View details for PubMedID 33409495

• Reprint of: Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: An ASTRO-ESTRO consensus statement. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Thomson, D. J., Palma, D. n., Guckenberger, M. n., Balermpas, P. n., Beitler, J. J., Blanchard, P. n., Brizel, D. n., Budach, W. n., Caudell, J. n., Corry, J. n., Corvo, R. n., Evans, M. n., Garden, A. S., Giralt, J. n., Gregoire, V. n., Harari, P. M., Harrington, K. n., Hitchcock, Y. J., Johansen, J. n., Kaanders, J. n., Koyfman, S. n., Langendijk, J. A., Le, Q. T., Lee, N. n., Margalit, D. n., Mierzwa, M. n., Porceddu, S. n., Soong, Y. L., Sun, Y. n., Thariat, J. n., Waldron, J. n., Yom, S. S. 2020

  Abstract

  Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff.A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases.In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care.This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.

  View details for DOI 10.1016/j.radonc.2020.04.019

  View details for PubMedID 32730830

• De-Escalation After DE-ESCALATE and RTOG 1016: A Head and Neck Cancer InterGroup Framework for Future De-Escalation Studies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Mehanna, H. n., Rischin, D. n., Wong, S. J., Gregoire, V. n., Ferris, R. n., Waldron, J. n., Le, Q. T., Forster, M. n., Gillison, M. n., Laskar, S. n., Tahara, M. n., Psyrri, A. n., Vermorken, J. n., Porceddu, S. n. 2020: JCO2000056

  Abstract

  Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is increasing rapidly. The younger age, significantly improved prognosis, and relative morbidity of the standard-of-care cisplatin and radiotherapy in this population have led to the popularization of the concept of treatment de-escalation. The recent results of the first 3 randomized de-escalation trials, however, have shown a clear detriment in survival when cisplatin is omitted or substituted. In view of these results, the Head and Neck Cancer International Group identified the need to issue guidance regarding future de-escalation studies for patients with HPV-positive head and neck cancer to avoid the possibility of patients being harmed. We review the current state of the literature regarding HPV de-escalation trials and present a framework and guidance on future and existing clinical trials for treatment de-escalation of HPV-positive OPC. De-escalation paradigms of HPV-positive OPC should be evaluated in phase II studies, and results should be awaited before proceeding to phase III studies. Implementation into clinical practice before high-level evidence is available should not be undertaken in this context. Finally, harm-minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.

  View details for DOI 10.1200/JCO.20.00056

  View details for PubMedID 32496903

• Understanding High-Dose, Ultra-High Dose-Rate and , Spatially Fractionated Radiotherapy. International journal of radiation oncology, biology, physics Griffin, R. J., Ahmed, M. M., Amendola, B. n., Belyakov, O. n., Bentzen, S. M., Butterworth, K. T., Chang, S. n., Coleman, C. N., Djonov, V. n., Formenti, S. C., Glatstein, E. n., Guha, C. n., Kalnicki, S. n., Le, Q. T., Loo, B. W., Mahadevan, A. n., Massaccesi, M. n., Maxim, P. G., Mohiuddin, M. n., Mohiuddin, M. n., Mayr, N. A., Obcemea, C. n., Petersson, K. n., Regine, W. n., Roach, M. n., Romanelli, P. n., Simone, C. B., Snider, J. W., Spitz, D. n., Vikram, B. n., Vozenin, M. C., Abdel-Wahab, M. n., Welsh, J. n., Wu, X. n., Limoli, C. L. 2020

  Abstract

  The National Cancer Institute's Radiation Research Program in collaboration with the Radiosurgery Society hosted a workshop on Understanding High-Dose, Ultra-High Dose rate and Spatially Fractionated Radiotherapy on August 20-21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically-based clinical trials.

  View details for DOI 10.1016/j.ijrobp.2020.03.028

  View details for PubMedID 32298811

• Prolongation of definitive head and neck cancer radiotherapy: Survival impact and predisposing factors. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Xiang, M. n., Gensheimer, M. F., Pollom, E. L., Holsinger, F. C., Colevas, A. D., Le, Q. T., Beadle, B. M. 2020

  Abstract

  To quantify the survival impact of prolongation of definitive radiotherapy (RT) for head and neck cancer in a national, modern cohort, and to identify predictive factors for prolongation.The National Cancer Database was queried for adults with non-metastatic cancer of the nasopharynx, oropharynx, larynx, or hypopharynx diagnosed 2004-2015, treated with definitive RT to 66-70 Gy in 30-35 fractions at 2-2.2 Gy per fraction. Multivariable Cox regression and propensity score matching were used to model the survival impact of RT prolongation, adjusting for potential confounders such as age and comorbidity. Predictors of RT prolongation were identified using multivariable multinomial logistic regression.In total, 36,367 patients were identified. As a continuous variable, RT prolongation increased the relative hazard of death by 2% per day (P < .0001). In the matched cohorts, patients with short (4-8 days) or long prolongation (> 8 days) had lower absolute 4-year overall survival by 4% and 12% respectively (P < .0001), while prolongation of 1-3 days was not significantly adverse. Major predictors of increased risk of prolongation were administration of systemic therapy, baseline comorbidity, lack of private insurance, and tumor/nodal stage. Conversely, higher facility volume was significantly protective, with a 55% lower risk of long prolongation within the topmost quartile (> 11.5 patients/year).RT prolongation, especially > 8 days, is significantly deleterious. Systemic therapy and facility volume were major predictors. Early identification of patients at increased risk of treatment interruptions may facilitate implementation of preventive measures.

  View details for DOI 10.1016/j.radonc.2020.12.025

  View details for PubMedID 33383061

• Predictive classifier for intensive treatment of head and neck cancer. Cancer Zakeri, K. n., Rotolo, F. n., Lacas, B. n., Vitzthum, L. K., Le, Q. T., Gregoire, V. n., Overgaard, J. n., Hackshaw, A. n., Zackrisson, B. n., Parmar, M. K., Burtness, B. A., Ghi, M. G., Sanguineti, G. n., O'Sullivan, B. n., Fortpied, C. n., Bourhis, J. n., Shen, H. n., Harris, J. n., Michiels, S. n., Pignon, J. P., Mell, L. K. 2020

  Abstract

  This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer.This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS).Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011).LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.

  View details for DOI 10.1002/cncr.33212

  View details for PubMedID 33017867

• Novel Aza-podophyllotoxin derivative induces oxidative phosphorylation and cell death via AMPK activation in triple-negative breast cancer. British journal of cancer Tailor, D. n., Going, C. C., Resendez, A. n., Kumar, V. n., Nambiar, D. K., Li, Y. n., Dheeraj, A. n., LaGory, E. L., Ghoochani, A. n., Birk, A. M., Stoyanova, T. n., Ye, J. n., Giaccia, A. J., Le, Q. T., Singh, R. P., Sledge, G. W., Pitteri, S. J., Malhotra, S. V. 2020

  Abstract

  To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions.  Therefore, development of small molecules, which can activate AMPK, irrespective of the energy state, may be a better approach for triple-negative breast cancer (TNBC) treatment.Therapeutic effect of SU212 on TNBC cells was examined using in vitro and in vivo models.We developed and characterised the efficacy of novel AMPK activator (SU212) that selectively induces oxidative phosphorylation and decreases glycolysis in TNBC cells, while not affecting these pathways in normal cells.   SU212 accomplished this metabolic reprogramming by activating AMPK independent of energy stress and irrespective of the glycaemic/insulin state. This leads to mitotic phase arrest and apoptosis in TNBC cells. In vivo, SU212 inhibits tumour growth, cancer progression and metastasis.SU212 directly activates AMPK in TNBC cells, but does not hamper glucose metabolism in normal cells. Our study provides compelling preclinical data for further development of SU212 for the treatment of TNBC.

  View details for DOI 10.1038/s41416-020-01137-4

  View details for PubMedID 33139797

• Proton radiotherapy and treatment delay in head and neck squamous cell carcinoma. The Laryngoscope Jin, M. C., Harris, J. P., Sabolch, A. N., Gensheimer, M., Le, Q., Beadle, B. M., Pollom, E. L. 2019

  Abstract

  OBJECTIVE: For patients with head and neck squamous cell carcinoma (HNSCC), delays in the initiation of radiotherapy (RT) have been closely associated with worse outcomes. We sought to investigate whether RT modality (proton vs. photon) is associated with differences in the time to initiation of RT.METHODS: The National Cancer Database was queried for patients diagnosed with nonmetastatic HNSCC between 2004 and 2015 who received either proton or photon RT as part of their initial treatment. Wilcoxon rank-sum and chi-square tests were used to compare continuous and categorical variables, respectively. Multivariable logistic regression was used to determine the association between use of proton RT and delayed RT initiation.RESULTS: A total of 175,088 patients with HNSCC receiving either photon or proton RT were identified. Patients receiving proton RT were more likely to be white, reside in higher income areas, and have private insurance. Proton RT was associated with delayed RT initiation compared to photon RT (median 59days vs. 45, P <0.001). Receipt of proton therapy was independently associated with RT initiation beyond 6weeks after diagnosis (adjusted OR [aOR, definitive RT] = 1.69; 95% confidence interval [CI] 1.26-2.30) or surgery (aOR [adjuvant RT] = 4.08; 95% CI 2.64-6.62). In the context of adjuvant proton RT, increases in treatment delay were associated with worse overall survival (weeks, adjusted hazard ratio =1.099, 95% CI 1.011-1.194).CONCLUSION: Use of proton therapy is associated with delayed RT in both the definitive and adjuvant settings for patients with HNSCC and could be associated with poorer outcomes.LEVEL OF EVIDENCE: 2b Laryngoscope, 122:0000-0000, 2019 Laryngoscope, 2019.

  View details for DOI 10.1002/lary.28458

  View details for PubMedID 31837165

• Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. The Journal of clinical investigation Nambiar, D. K., Aguilera, T., Cao, H., Kwok, S., Kong, C., Bloomstein, J., Wang, Z., Rangan, V. S., Jiang, D., von Eyben, R., Liang, R., Agarwal, S., Colevas, A. D., Korman, A., Allen, C. T., Uppaluri, R., Koong, A. C., Giaccia, A., Le, Q. T. 2019

  Abstract

  Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.

  View details for DOI 10.1172/JCI129025

  View details for PubMedID 31710313

• Tumor Subregion Evolution-based Imaging Features to Assess Early Response and Predict Prognosis in Oropharyngeal Cancer. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Wu, J., Gensheimer, M., Zhang, N., Guo, M., Liang, R., Zhang, C., Fischbein, N., Pollom, E., Beadle, B., Le, Q., Li, R. 2019

  Abstract

  Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rapidly increasing. Disease stage and smoking history are often used in current clinical trials to select patients for de-intensification therapy, but these features lack sufficient accuracy for predicting disease relapse. Purpose: To develop an imaging signature to assess early response and predict outcomes of OPSCC. Methods: We retrospectively analyzed 162 OPSCC patients treated with concurrent chemoradiotherapy, equally divided into separate training and validation cohorts with similar clinical characteristics. A robust consensus clustering approach was used to spatially partition the primary tumor and involved lymph nodes into subregions (i.e., habitats) based on fluorine 18 (18F) fluorodeoxyglucose (FDG) PET and contrast CT imaging. We proposed quantitative image features to characterize the temporal volumetric change of the habitats and peritumor/nodal tissue between baseline and mid-treatment. The reproducibility of these features was evaluated. We developed an imaging signature to predict progression-free survival (PFS) by fitting an L1-regularized Cox regression model. Results: We identified three phenotypically distinct intratumoral habitats, which were (1) metabolically active and heterogeneous, (2) enhancing and heterogeneous, and (3) metabolically inactive and homogeneous. The final Cox model consisted of four habitat evolution-based features. In both cohorts, this imaging signature significantly outperformed traditional imaging metrics including mid-treatment metabolic tumor volume for predicting PFS, with C-index: 0.72 vs 0.67 (training) and 0.66 vs 0.56 (validation). The imaging signature stratified patients into high-risk vs low-risk groups with 2-year PFS rates: 59.1% vs 89.4% (HR=4.4, 95% CI: 1.4-13.4, training), and 61.4% vs 87.8% (HR=4.6, 95% CI: 1.7-12.1, validation). It remained an independent predictor of PFS in multivariable analysis adjusting for stage, human papillomavirus status, and smoking history. Conclusion: The proposed imaging signature allows more accurate prediction of disease progression and, if prospectively validated, may refine OPSCC patient selection for risk-adaptive therapy.

  View details for DOI 10.2967/jnumed.119.230037

  View details for PubMedID 31420498

• Nomogram to Predict the Benefit of Intensive Treatment for Locoregionally Advanced Head and Neck Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Mell, L. K., Shen, H., Nguyen-Tan, P. F., Rosenthal, D. I., Zakeri, K., Vitzthum, L. K., Frank, S. J., Schiff, P. B., Trotti, A., Bonner, J. A., Jones, C. U., Yom, S. S., Thorstad, W. L., Wong, S., Shenouda, G., Ridge, J. A., Zhang, Q. E., Le, Q. 2019

  Abstract

  PURPOSE: Previous studies indicate the benefit of therapy depends on patients' risk for cancer recurrence relative to non-cancer mortality (omega ratio). We sought to test the hypothesis that head and neck cancer (HNC) patients with a higher omega ratio selectively benefit from intensive therapy.EXPERIMENTAL DESIGN: We analyzed 2688 patients with stage III-IVB HNC undergoing primary radiation therapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to omega ratio, and compared the effectiveness of intensive therapy as a function of predicted omega ratio (i.e., omega score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation (AFX) and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' omega score based on tumor, demographic, and health factors. Analysis was by intention-to-treat.RESULTS: Decreasing age, improved performance status, higher body mass index, node positive status, P16 negative status, and oral cavity primary predicted a higher omega ratio. Patients with omega score ≥ 0.80 were more likely to benefit from intensive treatment (5-year OS, 70.0% vs. 56.6%; HR 0.73, 95% CI 0.57-0.94; P=0.016) than those with a omega score < 0.80 (5-year OS, 46.7% vs. 45.3%; HR 1.02, 95% CI 0.92-1.14; P=0.69;P=0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression.CONCLUSION: HNC patients with a higher omega score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

  View details for DOI 10.1158/1078-0432.CCR-19-1832

  View details for PubMedID 31420360

• Radiographic Extranodal Extension in Human Papillomavirus-Associated Oropharyngeal Carcinoma: Can it Help Tailor Treatment? International journal of radiation oncology, biology, physics Gensheimer, M. F., Le, Q. 2019; 104 (5): 1028–29

  View details for DOI 10.1016/j.ijrobp.2019.05.022

  View details for PubMedID 31327411

• Integrating Tumor and Nodal Imaging Characteristics at Baseline and Mid-Treatment Computed Tomography Scans to Predict Distant Metastasis in Oropharyngeal Cancer Treated With Concurrent Chemoradiotherapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Wu, J., Gensheimer, M. F., Zhang, N., Han, F., Liang, R., Qian, Y., Zhang, C., Fischbein, N., Pollom, E. L., Beadle, B., Quynh-Thu Le, Li, R. 2019; 104 (4): 942–52

  View details for DOI 10.1016/j.ijrobp.2019.03.036

  View details for Web of Science ID 000471624800037

• The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). Journal for immunotherapy of cancer Cohen, E. E., Bell, R. B., Bifulco, C. B., Burtness, B., Gillison, M. L., Harrington, K. J., Le, Q., Lee, N. Y., Leidner, R., Lewis, R. L., Licitra, L., Mehanna, H., Mell, L. K., Raben, A., Sikora, A. G., Uppaluri, R., Whitworth, F., Zandberg, D. P., Ferris, R. L. 2019; 7 (1): 184

  Abstract

  Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a≥50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score≥1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.

  View details for DOI 10.1186/s40425-019-0662-5

  View details for PubMedID 31307547

• International Guideline on Dose Prioritization and Acceptance Criteria in Radiotherapy Planning for Nasopharyngeal Carcinoma. International journal of radiation oncology, biology, physics Lee, A. W., Ng, W. T., Pan, J. J., Chiang, C., Poh, S. S., Choi, H. C., Chan Ahn, Y., AlHussain, H., Corry, J., Grau, C., Gregoire, V., Harrington, K. J., Hu, C. S., Kwong, D. L., Langendijk, J. A., Le, Q. T., Lee, N. Y., Lin, J. C., Lu, T. X., Mendenhall, W. M., O'Sullivan, B., Ozyar, E., Peters, L. J., Rosenthal, D. I., Sanguineti, G., Soong, Y. L., Tao, Y., Yom, S. S., Wee, J. T. 2019

  Abstract

  PURPOSE: The treatment of nasopharyngeal carcinoma (NPC) requires high radiation doses. The balance of the risks of local recurrence due to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the ALARP (As Low As Reasonably Practicable) principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference.METHODS: A literature search on dose tolerances and normal tissue complications following treatment for NPC was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications and/or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then re-circulated to the whole panel for review and re-consideration. Based on the comments of the panel, a refined second proposal was re-circulated to the same panel. The current guideline was based on majority voting following repeated iteration for final agreement.RESULTS: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed.CONCLUSIONS: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and patient's acceptance of optimal balance of risk.

  View details for DOI 10.1016/j.ijrobp.2019.06.2540

  View details for PubMedID 31276776

• Cost-effectiveness of Screening for Nasopharyngeal Carcinoma among Asian American Men in the United States OTOLARYNGOLOGY-HEAD AND NECK SURGERY Harris, J. P., Saraswathula, A., Kaplun, B., Qian, Y., Chan, K., Chan, A. C., Quynh-Thu Le, Owens, D. K., Goldhaber-Fiebert, J. D., Pollom, E. 2019; 161 (1): 82–90

  View details for DOI 10.1177/0194599819832593

  View details for Web of Science ID 000473507100011

• Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Le, Q., Colevas, A., OSullivan, B., Lee, A. M., Lee, N., Ma, B., Siu, L. L., Waldron, J., Lim, C., Riaz, N., Lynn, J., Malik, S. 2019; 111 (7): 655–63

  View details for DOI 10.1093/jnci/djz044

  View details for Web of Science ID 000484372900006

• Role of Treatment Deintensification in the Management of p16+Oropharyngeal Cancer: ASCO Provisional Clinical Opinion JOURNAL OF CLINICAL ONCOLOGY Adelstein, D. J., Ismaila, N., Ku, J. A., Burtness, B., Swiecicki, P. L., Mell, L., Gross, N., Beitler, J. J., Jones, C. U., Kaufman, M., Le, Q., Semrad, T. J., Siu, L. L., Ridge, J. A. 2019; 37 (18)

  View details for DOI 10.1200/JCO.19.00441

  View details for Web of Science ID 000474713000009

• Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials CANCER Fakhry, C., Zhang, Q., Gillison, M. L., Nguyen-Tan, P., Rosenthal, D. I., Weber, R. S., Lambert, L., Trotti, A. M., Barrett, W. L., Thorstad, W. L., Yom, S. S., Wong, S. J., Ridge, J. A., Rao, S. D., Spencer, S., Fortin, A., Raben, D., Harris, J., Quynh-Thu Le 2019; 125 (12): 2027–38

  View details for DOI 10.1002/cncr.32025

  View details for Web of Science ID 000470925600013

• Nasopharyngeal carcinoma. Lancet (London, England) Chen, Y., Chan, A. T., Le, Q., Blanchard, P., Sun, Y., Ma, J. 2019

  Abstract

  Nasopharyngeal carcinoma is characterised by distinct geographical distribution and is particularly prevalent in east and southeast Asia. Epidemiological trends in the past decade have shown that its incidence has declined gradually but progressively, and mortality has been reduced substantially. These findings probably reflect lifestyle and environmental changes, enhanced understanding of the pathogenesis and risk factors, population screening, advancements in imaging techniques, and individualised comprehensive chemoradiotherapy strategies. In particular, plasma Epstein-Barr virus (EBV) DNA has been used for population screening, prognostication, predicting treatment response for therapeutic adaptation, and disease surveillance. Moreover, the widespread application of intensity-modulated radiotherapy and optimisation of chemotherapy strategies (induction, concurrent, adjuvant) have contributed to improved survival with reduced toxicities. Among the existing developments in novel therapeutics, immune checkpoint therapies have achieved breakthroughs for treating recurrent or metastatic disease and represent a promising future direction in nasopharyngeal carcinoma.

  View details for DOI 10.1016/S0140-6736(19)30956-0

  View details for PubMedID 31178151

• Increased Galectin-1 Expression in Thymic Epithelial Tumors CLINICAL LUNG CANCER Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2019; 20 (3): E356–E361

  View details for DOI 10.1016/j.cllc.2018.12.005

  View details for Web of Science ID 000467981200020

• Integrating tumor and nodal imaging characteristics at baseline and mid-treatment CT scans to predict distant metastasis in oropharyngeal cancer treated with concurrent chemoradiotherapy. International journal of radiation oncology, biology, physics Wu, J., Gensheimer, M. F., Zhang, N., Han, F., Liang, R., Qian, Y., Zhang, C., Fischbein, N., Pollom, E. L., Beadle, B., Le, Q., Li, R. 2019

  Abstract

  PURPOSE: Prognostic biomarkers of disease relapse are needed for risk-adaptive therapy of oropharyngeal cancer (OPC). This work aims to identify an imaging signature to predict distant metastasis in OPC.MATERIALS/METHODS: This single-institution retrospective study included 140 patients treated with definitive concurrent chemoradiotherapy, for whom both pre and mid-treatment contrast-enhanced CT scans were available. Patients were divided into separate training and testing cohorts. Forty-five quantitative image features were extracted to characterize tumor and involved lymph nodes at both time points. By incorporating both imaging and clinicopathological features, a random survival forest (RSF) model was built to predict distant metastasis-free survival (DMFS). The model was optimized via repeated cross-validation in the training cohort, and then independently validated in the testing cohort.RESULTS: The most important features for predicting DMFS were the maximum distance among nodes, maximum distance between tumor and nodes at mid-treatment, and pre-treatment tumor sphericity. In the testing cohort, the RSF model achieved good discriminability for DMFS (C-index=0.73, P=0.008), and further divided patients into two risk groups with different 2-year DMFS rates: 96.7% vs. 67.6%. Similar trends were observed for patients with p16+ tumors and smoking ≤10 pack-years. The RSF model based on pre-treatment CT features alone achieved lower performance (C-index=0.68, P=0.03).CONCLUSION: Integrating tumor and nodal imaging characteristics at baseline and mid-treatment CT allows prediction of distant metastasis in OPC. The proposed imaging signature requires prospective validation, and if successful, may help identify high-risk HPV-positive patients who should not be considered for de-intensification therapy.

  View details for PubMedID 30940529

• Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy. Journal of the National Cancer Institute Thu Le, Q., Dimitrios Colevas, A., O'Sullivan, B., Lee, A. W., Lee, N., Ma, B., Siu, L. L., Waldron, J., Lim, C., Riaz, N., Lynn, J., Malik, S. 2019

  Abstract

  Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein Barr Virus infection and has a high propensity for regional and distant metastases, while at the same time it is very sensitive to radiation and chemotherapy. A common feature of Epstein Barr Virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive PD-L1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a Clinical Trial Planning Meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco-regionally advanced, non-metastatic NPC; widely metastatic NPC; and either local-recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this Clinical Trial Planning Meeting and provides a roadmap for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This roadmap, though specific for NPC, may also be applicable to other virally-driven cancers that have similar ability to evade the host's immune system.

  View details for PubMedID 30912808

• Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials. Cancer Fakhry, C., Zhang, Q., Gillison, M. L., Nguyen-Tan, P. F., Rosenthal, D. I., Weber, R. S., Lambert, L., Trotti, A. M., Barrett, W. L., Thorstad, W. L., Yom, S. S., Wong, S. J., Ridge, J. A., Rao, S. S., Spencer, S., Fortin, A., Raben, D., Harris, J., Le, Q. 2019

  Abstract

  BACKGROUND: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups.METHODS: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible.RESULTS: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9years (range, 1.7-9.9years) and 4.7years (range, 0.1-7.0years), respectively. Previous OS differences in RTOG-0129 persisted at 5years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6cm or T3 disease without contralateral or >6cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group.CONCLUSIONS: RTOG-0129 risk groups persisted at 5years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.

  View details for PubMedID 30913305

• Cost-effectiveness of Screening for Nasopharyngeal Carcinoma among Asian American Men in the United States. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Harris, J. P., Saraswathula, A., Kaplun, B., Qian, Y., Chan, K. C., Chan, A. T., Le, Q., Owens, D. K., Goldhaber-Fiebert, J. D., Pollom, E. 2019: 194599819832593

  Abstract

  OBJECTIVE: Most patients with nasopharyngeal carcinoma (NPC) in the United States are diagnosed with stage III-IV disease. Screening for NPC in endemic areas results in earlier detection and improved outcomes. We examined the cost-effectiveness of screening for NPC with plasma Epstein-Barr virus DNA among Asian American men in the United States.STUDY DESIGN: We used a Markov cohort model to estimate discounted life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios for screening as compared with usual care without screening.SETTING: The base case analysis considered onetime screening for 50-year-old Asian American men.SUBJECTS AND METHODS: Confirmatory testing was magnetic resonance imaging and nasopharyngoscopy. Cancer-specific outcomes, health utility values, and costs were determined from cancer registries and the published literature.RESULTS: For Asian American men, usual care without screening resulted in the detection of NPC at stages I, II, III-IVB, and IVC among 6%, 29%, 54%, and 11% of those with cancer, respectively, whereas screening resulted in earlier detection with a stage distribution of 43%, 24%, 32%, and 1%. This corresponded to an additional 0.00055 QALYs gained at a cost of $63 per person: an incremental cost of $113,341 per QALY gained. In probabilistic sensitivity analysis, screening Asian American men was cost-effective at $100,000 per QALY gained in 35% of samples.CONCLUSION: Although screening for NPC with plasma Epstein-Barr virus DNA for 50-year-old Asian American men may result in earlier detection, in this study it was unlikely to be cost-effective. Screening may be reasonable for certain subpopulations at higher risk for NPC, but clinical studies are necessary before implementation.

  View details for PubMedID 30832545

• Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial LANCET Gillison, M. L., Trotti, A. M., Harris, J., Eisbruch, A., Harari, P. M., Adelstein, D. J., Sturgis, E. M., Burtness, B., Ridge, J. A., Ringash, J., Galvin, J., Yao, M., Koyfman, S. A., Blakaj, D. M., Razaq, M. A., Colevas, A., Beitler, J. J., Jones, C. U., Dunlap, N. E., Seaward, S. A., Spencer, S., Galloway, T. J., Phan, J., Dignam, J. J., Quynh Thu Le 2019; 393 (10166): 40–50

  View details for DOI 10.1016/S0140-6736(18)32779-X

  View details for Web of Science ID 000454925000031

• Survival After Definitive Chemoradiotherapy With Concurrent Cisplatin or Carboplatin for Head and Neck Cancer. Journal of the National Comprehensive Cancer Network : JNCCN Xiang, M. n., Colevas, A. D., Holsinger, F. C., Le, Q. X., Beadle, B. M. 2019; 17 (9): 1065–73

  Abstract

  For definitive chemoradiotherapy (chemoRT) of head and neck squamous cell carcinoma (HNSCC), cisplatin is the preferred concurrent agent, with superiority over cetuximab for HPV-associated oropharyngeal squamous carcinoma recently shown in 2 randomized trials (RTOG 1016 and De-ESCALaTE). Patients who are not candidates for cisplatin may be treated with carboplatin instead, but its comparative efficacy is unclear. We analyzed nationwide patterns of care and cancer-specific outcomes after cisplatin- versus carboplatin-based chemoRT.Patients with locoregionally advanced (stages III-IVB according to the 6th and 7th editions of the AJCC Cancer Staging Manual) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx who received definitive radiotherapy (RT) were identified in the linked SEER-Medicare database. The concurrent chemotherapy regimen was determined through corresponding Medicare claims. Death caused by HNSCC (cancer-specific mortality [CSM]) was analyzed with competing risks. Propensity score analysis and multivariable Fine-Gray regression were used to adjust for baseline differences, including age and comorbidity.We identified 807 patients who received cisplatin-based chemoRT and 342 who received carboplatin-based chemoRT. Most carboplatin recipients (68%) had combination chemotherapy, predominantly with paclitaxel. Carboplatin- and cisplatin-based chemoRT had similar incidences of death attributable to HNSCC (3-year CSM, 29% vs 26%; P=.19), which persisted in propensity score-matched analysis. In addition, no significant difference in overall survival was seen in the matched cohorts. ChemoRT with either cisplatin or carboplatin was superior to RT alone and RT with concurrent cetuximab. In the multivariable model, the adjusted hazard ratio of CSM for carboplatin relative to cisplatin was 1.01 (95% CI, 0.79-1.28; P=.94).Definitive carboplatin-based chemoRT was equivalent to cisplatin-based therapy and superior to RT alone and RT with concurrent cetuximab. In light of recent results of the RTOG 1016 and De-ESCALaTE trials, our findings suggest that carboplatin-based regimens warrant prospective investigation as an alternative to cisplatin for patients who are not cisplatin candidates.

  View details for DOI 10.6004/jnccn.2019.7297

  View details for PubMedID 31487677

• Lambda-Carrageenan Enhances the Effects of Radiation Therapy in Cancer Treatment by Suppressing Cancer Cell Invasion and Metastasis through Racgap1 Inhibition. Cancers Wu, P. H., Onodera, Y. n., Recuenco, F. C., Giaccia, A. J., Le, Q. T., Shimizu, S. n., Shirato, H. n., Nam, J. M. 2019; 11 (8)

  Abstract

  Radiotherapy is used extensively in cancer treatment, but radioresistance and the metastatic potential of cancer cells that survive radiation remain critical issues. There is a need for novel treatments to improve radiotherapy. Here, we evaluated the therapeutic benefit of λ-carrageenan (CGN) to enhance the efficacy of radiation treatment and investigated the underlying molecular mechanism. CGN treatment decreased viability in irradiated cancer cells and enhanced reactive oxygen species accumulation, apoptosis, and polyploid formation. Additionally, CGN suppressed radiation-induced chemoinvasion and invasive growth in 3D lrECM culture. We also screened target molecules using a gene expression microarray analysis and focused on Rac GTPase-activating protein 1 (RacGAP1). Protein expression of RacGAP1 was upregulated in several cancer cell lines after radiation, which was significantly suppressed by CGN treatment. Knockdown of RacGAP1 decreased cell viability and invasiveness after radiation. Overexpression of RacGAP1 partially rescued CGN cytotoxicity. In a mouse xenograft model, local irradiation followed by CGN treatment significantly decreased tumor growth and lung metastasis compared to either treatment alone. Taken together, these results suggest that CGN may enhance the effectiveness of radiation in cancer therapy by decreasing cancer cell viability and suppressing both radiation-induced invasive activity and distal metastasis through downregulating RacGAP1 expression.

  View details for DOI 10.3390/cancers11081192

  View details for PubMedID 31426369

• Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer: ASCO Provisional Clinical Opinion. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Adelstein, D. J., Ismaila, N. n., Ku, J. A., Burtness, B. n., Swiecicki, P. L., Mell, L. n., Beitler, J. J., Gross, N. n., Jones, C. U., Kaufman, M. n., Le, Q. T., Semrad, T. J., Siu, L. L., Ridge, J. A. 2019: JCO1900441

  Abstract

  An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership after publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the role of treatment deintensification in the management of p16+ oropharyngeal cancer (OPC).For patients with p16+ OPC, current treatment approaches are well established. In the good-prognosis subset of nonsmoking p16+ patients with early-stage disease, these treatments have been highly successful, albeit with significant associated acute and late toxicity. Deintensification of surgical, radiation, and medical treatment in an effort to reduce toxicity while preserving high survival rates is an appropriate therapeutic objective currently being explored in patients who are experiencing the best treatment results. However, careful delineation of this good-risk subset is essential. While the current eighth edition of the American Joint Committee on Cancer staging system is prognostically robust, it should not be interpreted as reason to alter therapeutic decisions or justify treatment deintensification. The development of transoral surgical techniques and the adoption of intensity-modulated radiation therapy planning have been transformative in disease management and suggest potentially beneficial approaches. Recent advances in systemic treatments have been notable. The optimal integration and modification of these modalities to ameliorate toxicity has not been defined and remains an important focus of current investigation.The hypothesis that de-escalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards. Treatment deintensification for these patients should only be undertaken in a clinical trial. Additional information is available at www.asco.org/head-neck-cancer-guidelines .

  View details for PubMedID 31021656

• The changing therapeutic landscape of head and neck cancer. Nature reviews. Clinical oncology Cramer, J. D., Burtness, B. n., Le, Q. T., Ferris, R. L. 2019

  Abstract

  Head and neck cancers are a heterogeneous collection of malignancies of the upper aerodigestive tract, salivary glands and thyroid. In this Review, we primarily focus on the changing therapeutic landscape of head and neck squamous cell carcinomas (HNSCCs) that can arise in the oral cavity, oropharynx, hypopharynx and larynx. We highlight developments in surgical and non-surgical therapies (mainly involving the combination of radiotherapy and chemotherapy), outlining how these treatments are being used in the current era of widespread testing for the presence of human papillomavirus infection in patients with HNSCC. Finally, we describe the clinical trials that led to the approval of the first immunotherapeutic agents for HNSCC, and discuss the development of strategies to decrease the toxicity of different treatment modalities.

  View details for DOI 10.1038/s41571-019-0227-z

  View details for PubMedID 31189965

• Role of chemotherapy in 5000 patients with head and neck cancer treated by curative surgery: A subgroup analysis of the meta-analysis of chemotherapy in head and neck cancer. Oral oncology Dauzier, E. n., Lacas, B. n., Blanchard, P. n., Le, Q. T., Simon, C. n., Wolf, G. n., Janot, F. n., Horiuchi, M. n., Tobias, J. S., Moon, J. n., Simes, J. n., Deshmane, V. n., Mazeron, J. J., Mehta, S. n., Zaktonik, B. n., Tamura, M. n., Moyal, E. n., Licitra, L. n., Fortpied, C. n., Haffty, B. G., Ghi, M. G., Gregoire, V. n., Harris, J. n., Bourhis, J. n., Aupérin, A. n., Pignon, J. P. 2019; 95: 106–14

  Abstract

  To evaluate the effect of chemotherapy added to a surgical locoregional treatment (LRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC).We studied the sub-group of trials with surgical LRT included in the meta-analysis on chemotherapy in head and neck cancer (MACH-NC). Data from published and unpublished randomized trials comparing the addition of chemotherapy to LRT in HNSCC patients were sought using electronic database searching for the period 1965-2000, hand searching and by contacting experts in the field. Trials with less than 60 patients, or preoperative radiotherapy or where the type of LRT could not be individually determined were excluded. All individual patient data were checked for internal consistency, compared with published reports, and validated with trialists. Data were pooled using a fixed-effect model. Heterogeneity was assessed using Cochrane test and I2 statistic.Twenty-four trials were eligible (5000 patients). Chemotherapy improved overall survival (HR = 0.92 [95%CI: 0.85-0.99] p = 0.02). There was a significant interaction between treatment effect and timing of chemotherapy (p = 0.08 at pre-specified threshold of 0.10) with a greater effect for concomitant chemotherapy (HR = 0.79, 95%CI: 0.69-0.92). The benefit of chemotherapy was greater in women (HRwomen = 0.63, 95%CI: 0.50-0.80) compared to men (HRmen = 0.96, 95%CI: 0.89-1.04; p for interaction = 0.001).This analysis confirmed the benefit of concomitant chemotherapy added to surgical LRT. The role of induction therapy as yet to be determined as it did not improve OS. Women may benefit more than men from chemotherapy.

  View details for DOI 10.1016/j.oraloncology.2019.06.001

  View details for PubMedID 31345376

• Increased Galectin-1 Expression in Thymic Epithelial Tumors. Clinical lung cancer Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2018

  Abstract

  INTRODUCTION: Thymic epithelial tumors (TET) are rare malignancies with a paucity of data on biology and therapeutics. Galectin-1 is a member of the beta-galactoside binding protein family and has been shown to mediate tumor growth via modulation of immune cell function. This study examined galectin-1 expression in TET.PATIENTS AND METHODS: A tissue microarray of 68 patients with TET and 8 benign thymus controls were stained for galectin-1 expression and scored by a pathologist blinded to patient clinical and pathologic data. Galectin-1 expression+1 or greater staining intensity was considered positive. Clinical and pathologic data were abstracted from institutional databases. Expression of galectin-1 in thymic tumor was compared to benign thymus controls and correlated with pertinent clinical and pathologic data.RESULTS: Galectin-1 expression was higher in TET compared to benign thymus controls (65% vs. 0%). No significant association between galectin-1 expression and the development of recurrent disease, paraneoplastic syndromes, or overall survival was noted.CONCLUSION: Galectin-1 is overexpressed in the majority of TET. Detection of galectin-1 may differentiate benign from neoplastic thymic processes. Additional studies are needed to assess the role of galectin-1 in the development of TET.

  View details for PubMedID 30773448

• The use of texture-based radiomics CT analysis to predict outcomes in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy. The British journal of radiology Starkov, P., Aguilera, T. A., Golden, D. I., Shultz, D. B., Trakul, N., Maxim, P. G., Le, Q., Loo, B. W., Diehn, M., Depeursinge, A., Rubin, D. L. 2018: 20180228

  Abstract

  OBJECTIVE:: Stereotactic ablative radiotherapy (SABR) is being increasingly used as a non-invasive treatment for early-stage non-small cell lung cancer (NSCLC). A non-invasive method to estimate treatment outcomes in these patients would be valuable, especially since access to tissue specimens is often difficult in these cases.METHODS:: We developed a method to predict survival following SABR in NSCLC patients using analysis of quantitative image features on pre-treatment CT images. We developed a Cox Lasso model based on two-dimensional Riesz wavelet quantitative texture features on CT scans with the goal of separating patients based on survival.RESULTS:: The median log-rank p-value for 1000 cross-validations was 0.030. Our model was able to separate patients based upon predicted survival. When we added tumor size into the model, the p-value lost its significance, demonstrating that tumor size is not a key feature in the model but rather decreases significance likely due to the relatively small number of events in the dataset. Furthermore, running the model using Riesz features extracted either from the solid component of the tumor or from the ground glass opacity (GGO) component of the tumor maintained statistical significance. However, the p-value improved when combining features from the solid and the GGO components, demonstrating that there are important data that can be extracted from the entire tumor.CONCLUSIONS:: The model predicting patient survival following SABR in NSCLC may be useful in future studies by enabling prediction of survival-based outcomes using radiomics features in CT images.ADVANCES IN KNOWLEDGE:: Quantitative image features from NSCLC nodules on CT images have been found to significantly separate patient populations based on overall survival (p = 0.04). In the long term, a non-invasive method to estimate treatment outcomes in patients undergoing SABR would be valuable, especially since access to tissue specimens is often difficult in these cases.

  View details for PubMedID 30457885

• Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet (London, England) Gillison, M. L., Trotti, A. M., Harris, J., Eisbruch, A., Harari, P. M., Adelstein, D. J., Sturgis, E. M., Burtness, B., Ridge, J. A., Ringash, J., Galvin, J., Yao, M., Koyfman, S. A., Blakaj, D. M., Razaq, M. A., Colevas, A. D., Beitler, J. J., Jones, C. U., Dunlap, N. E., Seaward, S. A., Spencer, S., Galloway, T. J., Phan, J., Dignam, J. J., Le, Q. T. 2018

  Abstract

  BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.

  View details for PubMedID 30449625

• Failure of Further Validation for Survival Nomograms in Oropharyngeal Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Fakhry, C., Phuc Felix Nguyen-Tan, Lambert, L., Rosenthal, D. I., Weber, R. S., Gillison, M. L., Trotti, A. M., Barrett, W. L., Thorstad, W. L., Jones, C. U., Yom, S. S., Wong, S. J., Ridge, J. A., Rao, S. D., Bonner, J. A., Vigneault, E., Raben, D., Kudrimoti, M. R., Harris, J., Quynh-Thu Le 2018; 102 (3): 669–70

  View details for PubMedID 30238902

• Adaptive radiotherapy for head and neck cancer: Are we ready to put it into routine clinical practice? Oral oncology Gensheimer, M. F., Le, Q. 2018; 86: 19–24

  Abstract

  Patients with head and neck cancer who are treated with radiotherapy often have significant weight loss or tumor regression during treatment. Adaptive radiotherapy refers to acquiring new imaging during treatment and changing the parameters of the radiation plan based on the new imaging findings. There is accumulating evidence that adaptive radiotherapy can reduce toxicity and improve tumor control, though it is not yet known which patients benefit most. For patients with profound tumor regression, there is also uncertainty about how much to shrink the region receiving high radiation dose. Another form of adaptive radiotherapy uses advanced imaging such as positron emission tomography to visualize changes in tumor biology during treatment. Tumor regions that are thought to be more radioresistant can then be treated to a higher radiation dose, and vice-versa. Studies employing this strategy to boost radiation dose have shown a high rate of late toxicity, specifically the development of persistent mucosal ulcers. Therefore, this sort of adaptive radiotherapy is currently confined to the research setting.

  View details for PubMedID 30409300

• Focus on the Number of Radiation Oncology Trials or on Clinical Relevance-Reply. JAMA oncology Liu, X., Le, Q. T., Ma, J. 2018

  View details for PubMedID 30383125

• A pooled analysis of individual patient data from National Clinical Trials Network clinical trials of concurrent chemoradiotherapy for limited-stage small cell lung cancer in elderly patients versus younger patients. Cancer Stinchcombe, T. E., Fan, W., Schild, S. E., Vokes, E. E., Bogart, J., Le, Q., Thomas, C. R., Edelman, M. J., Horn, L., Komaki, R., Cohen, H. J., Kishor Ganti, A., Pang, H., Wang, X. 2018

  Abstract

  BACKGROUND: Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited-stage small cell lung cancer (LS-SCLC). Many patients with LS-SCLC are elderly with comorbidities.METHODS: Individual patient data were collected from 11 phase 2 or 3 trials for LS-SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression-free survival (PFS), the rate of severe adverse events, and off-treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients).RESULTS: Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18-1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03-1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently.CONCLUSIONS: Elderly patients with LS-SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies.

  View details for PubMedID 30343497

• Survival of patients with head and neck cancer treated with definitive radiotherapy and concurrent cisplatin or concurrent cetuximab: A Surveillance, Epidemiology, and End Results-Medicare analysis. Cancer Xiang, M., Holsinger, F. C., Colevas, A. D., Chen, M. M., Le, Q., Beadle, B. M. 2018

  Abstract

  BACKGROUND: Cisplatin and cetuximab are both systemic therapies commonly used in combination with radiation (RT) for the definitive treatment of head and neck cancers, but their comparative efficacy is unclear.METHODS: Patients with locoregionally advanced (American Joint Committee on Cancer stage III-IVB) squamous cell carcinomas of the oropharynx, larynx, or hypopharynx were identified in the Surveillance, Epidemiology, and End Results-Medicare database. Patients received either cisplatin or cetuximab concurrent with RT, as determined by Medicare claims. The primary study outcome was head and neck cancer-specific mortality (CSM) analyzed with competing risks. Filtering, propensity score matching, and multivariable Fine-Gray regression were used to adjust for differences between the cisplatin and cetuximab cohorts, including age, comorbidity, and cycles of systemic therapy received.RESULTS: The total cohort consisted of 1395 patients, of whom 786 (56%) received cisplatin and 609 (44%) received cetuximab; the median follow-up was 3.5 years in the patients who remained alive. In the cetuximab cohort, CSM was significantly higher than in the cisplatin cohort (39% vs 25% at 3 years; P < .0001). In the matched cohorts (n = 414), the adjusted hazard ratio of CSM for cetuximab was 1.65 (95% confidence interval, 1.30-2.09; P < .0001) relative to cisplatin, corresponding to an absolute difference of approximately 10% in both CSM and overall survival at 3 years. Cetuximab was associated with less dysphagia, more dermatitis, and a similar incidence of mucositis.CONCLUSIONS: In this sizeable, national patient population, treatment with cetuximab was associated with significantly higher CSM than cisplatin. These results suggest that cisplatin may be the preferred chemotherapeutic agent in this setting. Cancer 2018;124:000-000.

  View details for PubMedID 30332498

• Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Benej, M., Hong, X., Vibhute, S., Scott, S., Wu, J., Graves, E., Le, Q., Koong, A. C., Giaccia, A. J., Yu, B., Chen, S., Papandreou, I., Denko, N. C. 2018; 115 (42): 10756–61

  Abstract

  Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells' demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine's complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.

  View details for PubMedID 30201710

• In Regard to Beadle and Anderson. International journal of radiation oncology, biology, physics Le, Q., Yom, S. S., Wee, J. T., Lee, A. W., Grau, C., Gregoire, V., Porceddu, S., Welch, J. J., Mehanna, H. 2018; 102 (1): 229–30

  View details for PubMedID 30102198

• Feasibility of optimizing intensity-modulated radiation therapy plans based on measured mucosal dose adjacent to dental fillings and toxicity outcomes JOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS Seol, S., Aggarwal, S., von Eyben, R., Wang, Z., Chan, C., Say, C., Xing, L., Hara, W., Yang, Y., Quynh Thu Le 2018; 19 (5): 444–52

  Abstract

  We prospectively investigated the feasibility of IMRT treatment plan optimization based on dosimeter measurements of lateral tongue mucosal dose adjacent to the dental fillings and evaluated dose-toxicity relationship and factors affecting oral mucositis (OM) in head and neck cancer patients. Twenty-nine head and neck cancer patients with metallic dental fillings who were scheduled to undergo fractionated external beam radiation therapy (RT) ± chemotherapy were enrolled. The lateral tongue dose was measured and if the calculated dose for the entire treatment was ≥35 Gy, a re-plan was generated to reduce the lateral tongue mucosal dose. OM was graded weekly according to Common Terminology Criteria for Adverse Events version 4.0 and the patients completed the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer. The result showed that it was not feasible to optimize the IMRT plan based on measured tongue dose in most of the patients who needed re-plan as re-planning compromised the target coverage in 60% of these patients. The duration of grade (Gr) 2 OM was correlated with measured lateral tongue dose (P = 0.050). Concurrent cetuximab was significantly associated with faster onset of Gr2 OM than concurrent cisplatin (P = 0.006) and with longer duration of OM (P = 0.041) compared to concurrent cisplatin or IMRT-alone. The pattern of reported pain over time was significantly different for each treatment type (RT and cetuximab, RT and cisplatin and RT-alone) and depending on the dose level (P = 0.006). In conclusion, optimizing the IMRT plan based on measured lateral tongue dose was not feasible. Measured lateral tongue dose was significantly correlated with longer duration of OM ≥Gr2, and concurrent cetuximab was associated with earlier onset and longer duration of OM ≥Gr2.

  View details for PubMedID 29984915

• Characteristics of Radiotherapy Trials Compared With Other Oncological Clinical Trials in the Past 10 Years JAMA ONCOLOGY Liu, X., Zhang, Y., Tang, L., Quynh Thu Le, Chua, M. K., Wee, J. S., Lee, N. Y., O'Sullivan, B., Lee, A. M., Sun, Y., Ma, J. 2018; 4 (8): 1073–79

  Abstract

  Modern precision radiotherapy is an innovative and effective treatment of cancer, yet it is unclear how radiotherapy trials are affected by expanding targeted and immune therapies and declining National Institutes of Health funding.To analyze and compare the characteristics of radiotherapy trials with other oncological trials registered on ClinicalTrials.gov.This is a cross-sectional analysis of trials registered on ClinicalTrials.gov between June 1, 2007, and May 8, 2017. Records of all 243 758 clinical studies registered by May 8, 2017, were downloaded, but only 25 907 interventional oncological trials registered between June 1, 2007, and May 8, 2017, and whose primary purpose was "treatment" were included in the final analysis. Trials were categorized according to cancer type and other registration information.Characteristics of radiotherapy trials were compared with characteristics of other oncological trials. Chronological shifts in radiotherapy trials were also analyzed.Of the 25 907 trials selected, 1378 (5.3%) were radiotherapy trials and 24 529 (94.7%) were other oncological studies. The number of radiotherapy trials increased gradually from 94 (June 1, 2007, through May 31, 2008) to 192 (June 1, 2015, through May 31, 2016). Radiotherapy trials were less likely than other oncological studies to be registered before participant enrollment (763 of 1370 [55.7%] vs 16 105 of 24 434 [65.9%]; P < .001), to be blinded (45 of 1378 [3.3%] vs 2784 of 24 529 [11.3%]; P < .001), or to involve multiple geographic regions (2.4% vs 9.5%; P < .001), but they were more likely to be phase 2 to 3 (773 of 1124 [68.8%] vs 12 910 of 22 300 [57.9%]; P < .001) and to have a data-monitoring committee (839 of 1264 [66.4%] vs 11 728 of 21 060 [55.7%]; P < .001). Only a minority of radiotherapy trials were industry sponsored, which was significantly lower than for other oncological trials (80 of 1378 [5.8%] vs 10 651 of 24 529 [43.4%]; P < .001; adjusted odds ratio, 0.08; 95% CI, 0.06-0.10). The number of National Institutes of Health-sponsored radiotherapy trials decreased from 80 of 544 trials (14.7%) from 2007 to 2012 to 72 of 834 trials (8.6%) from 2012 to 2017 (P < .001). Radiotherapy trials with a sample size of more than 100 patients decreased from 155 of 543 trials (28.5%) from 2007 to 2012 to 157 of 833 trials (18.8%) from 2012 to 2017 (P < .001).The limited number of and the scarcity of funding for radiotherapy trials is concerning given the integral role of radiotherapy in the clinical management of patients with cancer worldwide. A multidisciplinary collaboration to promote and fund more radiotherapy research is warranted.

  View details for PubMedID 29799987

• Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proceedings of the National Academy of Sciences of the United States of America Saiki, J. P., Cao, H., Van Wassenhove, L. D., Viswanathan, V., Bloomstein, J., Nambiar, D. K., Mattingly, A. J., Jiang, D., Chen, C., Stevens, M. C., Simmons, A. L., Park, H. S., von Eyben, R., Kool, E. T., Sirjani, D., Knox, S. M., Le, Q. T., Mochly-Rosen, D. 2018

  Abstract

  Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1-/- adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.

  View details for PubMedID 29794221

• Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology LANCET ONCOLOGY Bristow, R. G., Alexander, B., Baumann, M., Bratman, S. V., Brown, J., Camphausen, K., Choyke, P., Citrin, D., Contessa, J. N., Dicker, A., Kirsch, D. G., Krause, M., Quynh-Thu Le, Milosevic, M., Morris, Z. S., Sarkaria, J. N., Sondel, P. M., Tran, P. T., Wilson, G. D., Willers, H., Wong, R. S., Harari, P. M. 2018; 19 (5): E240–E251

  Abstract

  The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents.

  View details for PubMedID 29726389

• Meeting Viewpoint CANCER RESEARCH Ahmed, M. M., Coleman, C., Mendonca, M., Bentzen, S., Vikram, B., Seltzer, S. M., Goodhead, D., Obcemea, C., Mohan, R., Prise, K. M., Capala, J., Citrin, D., Kao, G., Aryankalayil, M., Eke, I., Buchsbaum, J. C., Prasanna, P. S., Liu, F., Quynh-Thu Le, Teicher, B., Kirsch, D. G., Smart, D., Tepper, J., Formenti, S., Haas-Kogan, D., Raben, D., Mitchell, J. 2018; 78 (9): 2166–70

  View details for PubMedID 29686020

• Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update JOURNAL OF CLINICAL ONCOLOGY Forastiere, A. A., Ismaila, N., Lewin, J. S., Nathan, C., Adelstein, D. J., Eisbruch, A., Fass, G., Fisher, S. G., Laurie, S. A., Quynh-Thu Le, O'Malley, B., Mendenhall, W. M., Patel, S., Pfister, D. G., Provenzano, A. F., Weber, R., Weinstein, G. S., Wolf, G. T. 2018; 36 (11): 1143-+

  Abstract

  Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

  View details for PubMedID 29172863

• Selection of external beam radiotherapy approaches for precise and accurate cancer treatment JOURNAL OF RADIATION RESEARCH Shirato, H., Quynh-Thu Le, Kobashi, K., Prayongrat, A., Takao, S., Shimizu, S., Giaccia, A., Xing, L., Umegaki, K. 2018; 59: I2–I10

  Abstract

  Physically precise external-beam radiotherapy (EBRT) technologies may not translate to the best outcome in individual patients. On the other hand, clinical considerations alone are often insufficient to guide the selection of a specific EBRT approach in patients. We examine the ways in which to compare different EBRT approaches based on physical, biological and clinical considerations, and how they can be enhanced with the addition of biophysical models and machine-learning strategies. The process of selecting an EBRT modality is expected to improve in tandem with knowledge-based treatment planning.

  View details for PubMedID 29373709

  View details for PubMedCentralID PMC5868193

• Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines Gregoire, V., Evans, M., Quynh-Thu Le, Bourhis, J., Budach, V., Chen, A., Eisbruch, A., Feng, M., Giralt, J., Gupta, T., Hamoir, M., Helito, J. K., Hu, C., Hunter, K., Johansen, J., Kaanders, J., Laskar, S., Lee, A., Maingon, P., Makitie, A., Micciche, F., Nicolai, P., O'Sullivan, B., Poitevin, A., Porceddu, S., Skiadowski, K., Tribius, S., Waldron, J., Wee, J., Yao, M., Yom, S. S., Zimmermann, F., Grau, C. ELSEVIER IRELAND LTD. 2018: 3–24

  Abstract

  Few studies have reported large inter-observer variations in target volume selection and delineation in patients treated with radiotherapy for head and neck squamous cell carcinoma. Consensus guidelines have been published for the neck nodes (see Grégoire et al., 2003, 2014), but such recommendations are lacking for primary tumour delineation. For the latter, two main schools of thoughts are prevailing, one based on geometric expansion of the Gross Tumour Volume (GTV) as promoted by DAHANCA, and the other one based on anatomical expansion of the GTV using compartmentalization of head and neck anatomy.For each anatomic location within the larynx, hypopharynx, oropharynx and oral cavity, and for each T-stage, the DAHANCA proposal has been comprehensively reviewed and edited to include anatomic knowledge into the geometric Clinical Target Volume (CTV) delineation concept. A first proposal was put forward by the leading authors of this publication (VG and CG) and discussed with opinion leaders in head and neck radiation oncology from Europe, Asia, Australia/New Zealand, North America and South America to reach a worldwide consensus.This consensus proposes two CTVs for the primary tumour, the so called CTV-P1 and CVT-P2, corresponding to a high and lower tumour burden, and which should be associated with a high and a lower dose prescription, respectively.Implementation of these guidelines in the daily practice of radiation oncology should contribute to reduce treatment variations from clinicians to clinicians, facilitate the conduct of multi-institutional clinical trials, and contribute to improved care of patients with head and neck carcinoma.

  View details for PubMedID 29180076

• A Human Genome-wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1α-XBP1 Activation. Molecular cancer research : MCR Yang, Z. n., Zhang, J. n., Jiang, D. n., Khatri, P. n., Solow-Cordero, D. E., Toesca, D. A., Koumenis, C. n., Denko, N. C., Giaccia, A. J., Le, Q. T., Koong, A. C. 2018

  Abstract

  Activation of the unfolded protein response (UPR) signaling pathways is linked to multiple human diseases including cancer. The inositol-requiring kinase 1 (IRE1)-X-box binding protein 1 (XBP1) pathway is the most evolutionarily conserved of the three major signaling branches of the UPR. Here, we performed a genome-wide siRNA screen to obtain a systematic assessment of genes integrated in the IRE1-XBP1 axis. We monitored the expression of an XBP1-luciferase chimeric protein in which luciferase was fused in-frame with the spliced (active) form of XBP1. Using cells expressing this reporter construct, we identified 162 genes for which siRNA inhibition resulted in alteration in XBP1 splicing. These genes express diverse types of proteins modulating a wide range of cellular processes. Pathway analysis identified a set of genes implicated in the pathogenesis of breast cancer. Several genes including BCL10, GCLM, and IGF1R correlated with worse relapse-free survival (RFS) in an analysis of patients with triple negative breast cancer (TNBC). However, in this cohort of 1908 patients, only high GCLM expression correlated with worse RFS in both TNBC and non-TNBC patients. Altogether, our study revealed unidentified roles of novel pathways regulating the UPR and these findings may serve as a paradigm for exploring novel therapeutic opportunities based on modulating the UPR.Genome-wide RNAi screen identifies novel genes/pathways that modulate IRE1-XBP1 signaling in human tumor cells and leads to the development of improved therapeutic approaches targeting the UPR.

  View details for PubMedID 29440447

• International guideline for the delineation of the clinical target volumes (CTV) for nasopharyngeal carcinoma Lee, A. W., Ng, W., Pan, J., Poh, S. S., Ahn, Y., AlHussain, H., Corry, J., Grau, C., Gregoire, V., Harrington, K. J., Hu, C., Kwong, D. L., Langendijk, J. A., Quynh Thu Le, Lee, N. Y., Lin, J., Lu, T., Mendenhall, W. M., O'Sullivan, B., Ozyar, E., Peters, L. J., Rosenthal, D. I., Soong, Y., Tao, Y., Yom, S. S., Wee, J. T. ELSEVIER IRELAND LTD. 2018: 25–36

  Abstract

  Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome.A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies.Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration.Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients' factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery).

  View details for PubMedID 29153464

• Development and Validation of Nomograms Predictive of Overall and Progression-Free Survival in Patients With Oropharyngeal Cancer JOURNAL OF CLINICAL ONCOLOGY Fakhry, C., Zhang, Q., Nguyen-Tan, P., Rosenthal, D. I., Weber, R. S., Lambert, L., Trotti, A. M., Barrett, W. L., Thorstad, W. L., Jones, C. U., Yom, S. S., Wong, S. J., Ridge, J. A., Rao, S. D., Bonner, J. A., Vigneault, E., Raben, D., Kudrimoti, M. R., Harris, J., Le, Q., Gillison, M. L. 2017; 35 (36): 4057-+

  Abstract

  Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.

  View details for PubMedID 28777690

  View details for PubMedCentralID PMC5736236

• Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients Reply INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Le, Q., Yom, S. S., Ng, R. W., Bratman, S. V., Welch, J. J., Chan, K., Kim, K. Y. 2017; 99 (5): 1307

  View details for PubMedID 29165290

• Midtreatment metabolic imaging as a biomarker of treatment response Le, Q. AMER ASSOC CANCER RESEARCH. 2017

  View details for Web of Science ID 000416946500013

• Future cancer research priorities in the USA: a Lancet Oncology Commission LANCET ONCOLOGY Jaffee, E. M., Dang, C., Agus, D. B., Alexander, B. M., Anderson, K. C., Ashworth, A., Barker, A. D., Bastani, R., Bhatia, S., Bluestone, J. A., Brawley, O., Butte, A. J., Coit, D. G., Davidson, N. E., Davis, M., DePinho, R. A., Diasio, R. B., Draetta, G., Frazier, A., Futreal, A., Gambhir, S. S., Ganz, P. A., Garraway, L., Gerson, S., Gupta, S., Heath, J., Hoffman, R. I., Hudis, C., Hughes-Halbert, C., Ibrahim, R., Jadvar, H., Kavanagh, B., Kittles, R., Quynh-Thu Le, Lippman, S. M., Mankoff, D., Mardis, E. R., Mayer, D. K., McMasters, K., Meropol, N. J., Mitchell, B., Naredi, P., Ornish, D., Pawlik, T. M., Peppercorn, J., Pomper, M. G., Raghavan, D., Ritchie, C., Schwarz, S. W., Sullivan, R., Wahl, R., Wolchok, J. D., Wong, S. L., Yung, A. 2017; 18 (11): E653–E706

  View details for Web of Science ID 000414134100033

• Future cancer research priorities in the USA: a Lancet Oncology Commission. The Lancet. Oncology Jaffee, E. M., Dang, C. V., Agus, D. B., Alexander, B. M., Anderson, K. C., Ashworth, A., Barker, A. D., Bastani, R., Bhatia, S., Bluestone, J. A., Brawley, O., Butte, A. J., Coit, D. G., Davidson, N. E., Davis, M., DePinho, R. A., Diasio, R. B., Draetta, G., Frazier, A. L., Futreal, A., Gambhir, S. S., Ganz, P. A., Garraway, L., Gerson, S., Gupta, S., Heath, J., Hoffman, R. I., Hudis, C., Hughes-Halbert, C., Ibrahim, R., Jadvar, H., Kavanagh, B., Kittles, R., Le, Q. T., Lippman, S. M., Mankoff, D., Mardis, E. R., Mayer, D. K., McMasters, K., Meropol, N. J., Mitchell, B., Naredi, P., Ornish, D., Pawlik, T. M., Peppercorn, J., Pomper, M. G., Raghavan, D., Ritchie, C., Schwarz, S. W., Sullivan, R., Wahl, R., Wolchok, J. D., Wong, S. L., Yung, A. 2017; 18 (11): e653-e706

  Abstract

  We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

  View details for DOI 10.1016/S1470-2045(17)30698-8

  View details for PubMedID 29208398

  View details for PubMedCentralID PMC6178838

• Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer RADIOTHERAPY AND ONCOLOGY Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C., Zhu, H., Eclov, N. W., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q., Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. 2017; 125 (2): 338–43

  Abstract

  Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

  View details for PubMedID 28830717

• SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells CLINICAL CANCER RESEARCH Ozawa, H., Ranaweera, R. S., Izumchenko, E., Makarev, E., Zhavoronkov, A., Fertig, E. J., Howard, J. D., Markovic, A., Bedi, A., Ravi, R., Perez, J., Quynh-Thu Le, Kong, C. S., Jordan, R. C., Wang, H., Kang, H., Quon, H., Sidransky, D., Chung, C. H. 2017; 23 (17): 5162–75

  Abstract

  Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC.Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivoResults: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss.Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. Clin Cancer Res; 23(17); 5162-75. ©2017 AACR.

  View details for PubMedID 28522603

• Formation of an international intergroup to coordinate clinical trials in head and neck cancers: HNCIG. Oral oncology Le, Q. T., Welch, J. J., Vermorken, J. B., Rischin, D., Mehanna, H. 2017; 71: 180-183

  Abstract

  Clinical trials in head and neck cancer (HNC) face multiple challenges including low global incidence, excessive patient comorbidity rate, high treatment-related toxicity and more recently a changing tumor biology landscape. As clinical trials evolve to address new knowledge about HNC biology, the overall pool of eligible patients for each trial becomes smaller, leading to more accrual challenges. These challenges have led to the formation of the Head and Neck Cancer Intergroup (HNCIG) comprised of large HNC international and national cooperative groups and sites with the goal of facilitating the conduct of high quality clinical trials in a timely manner to improve outcomes in HNC. This article describes the objectives, structure, and activities of the HNCIG.

  View details for DOI 10.1016/j.oraloncology.2017.05.022

  View details for PubMedID 28648362

• Clinical Outcomes in Elderly Patients Treated for Oral Cavity Squamous Cell Carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chen, J., Shah, J. L., Harris, J. P., Bui, T. T., Schaberg, K., Kong, C. S., Kaplan, M. J., Divi, V., Schoppy, D., Quynh-Thu Le, Hara, W. Y. 2017; 98 (4): 775–83

  Abstract

  Oral cavity squamous cell carcinoma (OCSCC) commonly occurs in elderly patients. This study explores the clinical outcomes in elderly patients with OCSCC based on their functional status and clinical comorbidities.We retrospectively reviewed 180 patients aged ≥70 who were treated with definitive intent with surgery followed by adjuvant therapy if indicated for newly diagnosed OCSCC from 1998 to 2013. Pathology review was conducted, and Eastern Cooperative Oncology Group (ECOG) performance status and the Head and Neck Charlson Comorbidity Index (HN-CCI) were assessed. We performed Kaplan-Meier analyses and cumulative incidence estimates to assess overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LRR). Univariate and multivariate analyses were used to test age, adjuvant therapy, adverse pathologic features, ECOG status, and HN-CCI status as predictors.The median age was 80 years (range, 70-95 years), with a median follow-up time of 23 months. The median OS was 18 months and 46 months for patients aged 70 to 84 and ≥85, respectively (P=.0017). The LRR was 24% at 1 year and 30% at 2 years for all patients. On univariate analysis, ECOG score ≥2 (hazard ratio [HR] = 1.96; confidence interval [CI] 1.19-3.21; P=.008) and HN-CCI score ≥2 (HR=1.97; CI 1.17-3.34; P=.011) were predictors of worse OS. On multivariate analysis, HN-CCI score was a better predictor of OS, PFS, and LRR than was ECOG score. Predictors of worse OS were age ≥85 (HR=1.78; CI 1.07-2.96; P=.026), HN-CCI score of ≥2 (HR=2.21; CI 1.20-4.08; P=.011), and adverse features (HR=2.35; CI 1.34-4.13; P=.003). Adjuvant therapy did not have a significant impact on OS or LRR for patients with adverse features even though 48% of them did not receive it.Elderly patients with good health and performance status may live long enough to experience disease progression from OCSCC. ECOG and HN-CCI scores may be useful to evaluate the candidacy of elderly patients for adjuvant therapy. However, the benefit of adjuvant therapy in this population remains elusive and should be investigated prospectively.

  View details for PubMedID 28602409

• The impact of developing a speech and swallow rehab program: Improving patient satisfaction and multidisciplinary care. Laryngoscope Starmer, H. M., Ayoub, N., Byward, C., Kizner, J., Le, Q., Hara, W., Holsinger, F. C. 2017

  Abstract

  The objective of this study was to evaluate the impact of developing an integrated head and neck cancer speech and swallowing rehabilitation program on physician/team focus on functional outcomes.Prospective cross-sectional design.Surveys regarding physician behavior and patient satisfaction with speech and swallowing were administered in an academic oncology practice prior to and 1 year following establishment of a dedicated head and neck speech and swallowing rehabilitation program. Participants included new and established head and neck cancer patients recruited consecutively. The primary outcome was physician behavior regarding speech and swallowing outcomes (as measured by discussion of function, providing suggestions regarding function, and referral to speech-language pathology services).A total of 199 surveys were returned at the first time point and 271 at the second. Demographic variables were comparable between the two groups. The later cohort was more likely to report team discussion and suggestions regarding speech and swallowing function than the former (P < .001, 95% confidence interval [CI]: -0.775 to -0.265; P < .001, 95% CI: -0.928 to -0.035, respectively). Although there was no significant difference between the groups in regard to satisfaction with speech (P = .07), more favorable satisfaction with swallowing was reported by the later cohort (P = .028, 95% CI: -0.531 to -0.029).Integration of speech and swallowing rehabilitation into head and neck cancer programs is associated with increased physician focus on functional outcomes and greater patient satisfaction in regard to swallowing function. We advocate for standard integration of such services into the multidisciplinary head and neck cancer care team.4. Laryngoscope, 2017.

  View details for DOI 10.1002/lary.26695

  View details for PubMedID 28561453

• Current State of PCR-Based Epstein-Barr Virus DNA Testing for Nasopharyngeal Cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Kim, K. Y., Le, Q., Yom, S. S., Pinsky, B. A., Bratman, S. V., Ng, R. W., El Mubarak, H. S., Chan, K., Sander, M., Conley, B. A. 2017; 109 (4)

  Abstract

  Clinical studies have shown plasma Epstein-Barr virus (EBV) DNA level to be an independent prognostic biomarker for nasopharyngeal carcinoma (NPC). However, the proportion of NPC patients whose tumors are associated with EBV vary with geographic location, and there are a variety of assays for plasma EBV. To develop the level of evidence needed to demonstrate the clinical utility of plasma EBV DNA detection for NPC patients and encourage widespread adoption of this biomarker test in clinical laboratories, validated harmonized assays are needed. In 2015, the National Cancer Institute (NCI) convened a Workshop on Harmonization of EBV Testing for Nasopharyngeal Cancer, where experts in head and neck oncology and laboratory medicine addressed the limitations of currently available polymerase chain reaction-based EBV DNA quantitation assays and discussed strategies for advancing the development of harmonized EBV DNA assays and their appropriate clinical use. This article presents the key recommendations to direct future efforts in assay harmonization and validation.

  View details for PubMedID 28376165

• Immunotherapy of Head and Neck Cancer: Emerging Clinical Trials From a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting CANCER Bauman, J. E., Cohen, E., Ferris, R. L., Adelstein, D. J., Brizel, D. M., Ridge, J. A., O'Sullivan, B., Burtness, B. A., Butterfield, L. H., Carson, W. E., Disis, M. L., Fox, B. A., Gajewski, T. F., Gillison, M. L., Hodge, J. W., Quynh-Thu Le, Q. T., Raben, D., Strome, S. E., Lynn, J., Malik, S. 2017; 123 (7): 1259-1271

  Abstract

  Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2017;123:1259-1271. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30449

  View details for Web of Science ID 000397760100024

• Very high-energy electron (VHEE) beams in radiation therapy; Treatment plan comparison between VHEE, VMAT, and PPBS. Medical physics Schüler, E., Eriksson, K., Hynning, E., Hancock, S. L., Hiniker, S. M., Bazalova-Carter, M., Wong, T., Le, Q., Loo, B. W., Maxim, P. G. 2017

  Abstract

  The aim of this study was to evaluate the performance of very high-energy electron beams (VHEE) in comparison to clinically derived treatment plans generated with volumetric modulated arc therapy (VMAT) and proton pencil beam scanning (PPBS) technology. We developed a custom optimization script that could be applied automatically across modalities to eliminate operator bias during IMRT optimization.Four clinical cases were selected (prostate cancer, lung cancer, pediatric brain tumor, and head and neck cancer (HNC)). The VHEE beams were calculated in the EGSnrc/DOSXYZnrc Monte Carlo code for 100 and 200 MeV beams. Treatment plans with VHEE, VMAT, and PPBS were optimized in a research version of RayStation using an in-house developed script to minimize operator bias between the different techniques.The in-house developed script generated similar or superior plans to the clinically used plans. In the comparisons between the modalities, the integral dose was lowest for the PPBS-generated plans in all cases. For the prostate case, the 200 MeV VHEE plan showed reduced integral dose and reduced organ at risk (OAR) dose compared to the VMAT plan. For all other cases, both the 100 and the 200 MeV VHEE plans were superior to the VMAT plans, and the VHEE plans showed better conformity and lower spinal cord dose in the pediatric brain case and lower brain stem dose in the HNC case when compared to the PPBS plan.The automated optimization developed in this study generated similar or superior plans as compared to the clinically used plan and represents an unbiased approach to compare treatment plans generated for different modalities. In the present study, we also show that VHEE plans are similar or superior to VMAT plans with reduced mean OAR dose and increased target conformity for a variety of clinical cases, and VHEE plans can even achieve reductions in OAR doses compared to PPBS plans for shallow targets. With increased VHEE energy, better conformity and even higher reductions in mean OAR doses are achieved. On the whole, VHEE was intermediate between photon VMAT and PPBS for OAR sparing.

  View details for DOI 10.1002/mp.12233

  View details for PubMedID 28339108

• Robust Estimation of Electron Density From Anatomic Magnetic Resonance Imaging of the Brain Using a Unifying Multi-Atlas Approach. International journal of radiation oncology, biology, physics Ren, S., Hara, W., Wang, L., Buyyounouski, M. K., Le, Q., Xing, L., Li, R. 2017; 97 (4): 849-857

  Abstract

  To develop a reliable method to estimate electron density based on anatomic magnetic resonance imaging (MRI) of the brain.We proposed a unifying multi-atlas approach for electron density estimation based on standard T1- and T2-weighted MRI. First, a composite atlas was constructed through a voxelwise matching process using multiple atlases, with the goal of mitigating effects of inherent anatomic variations between patients. Next we computed for each voxel 2 kinds of conditional probabilities: (1) electron density given its image intensity on T1- and T2-weighted MR images; and (2) electron density given its spatial location in a reference anatomy, obtained by deformable image registration. These were combined into a unifying posterior probability density function using the Bayesian formalism, which provided the optimal estimates for electron density. We evaluated the method on 10 patients using leave-one-patient-out cross-validation. Receiver operating characteristic analyses for detecting different tissue types were performed.The proposed method significantly reduced the errors in electron density estimation, with a mean absolute Hounsfield unit error of 119, compared with 140 and 144 (P<.0001) using conventional T1-weighted intensity and geometry-based approaches, respectively. For detection of bony anatomy, the proposed method achieved an 89% area under the curve, 86% sensitivity, 88% specificity, and 90% accuracy, which improved upon intensity and geometry-based approaches (area under the curve: 79% and 80%, respectively).The proposed multi-atlas approach provides robust electron density estimation and bone detection based on anatomic MRI. If validated on a larger population, our work could enable the use of MRI as a primary modality for radiation treatment planning.

  View details for DOI 10.1016/j.ijrobp.2016.11.053

  View details for PubMedID 28244422

• The role of postoperative chemoradiation for oropharynx carcinoma: A critical appraisal revisited. Cancer Cooper, J. S., Fortpied, C., Gregoire, V., Le, Q., Pajak, T. F., Zhang, Q. E., Bernier, J. 2017; 123 (1): 12-16

  View details for DOI 10.1002/cncr.30266

  View details for PubMedID 27727449

  View details for PubMedCentralID PMC5161595

• Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients. International journal of radiation oncology, biology, physics Kim, K. Y., Le, Q. T., Yom, S. S., Ng, R. H., Chan, K. C., Bratman, S. V., Welch, J. J., Divi, R. L., Petryshyn, R. A., Conley, B. A. 2017; 98 (5): 996–1001

  Abstract

  Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion.

  View details for PubMedID 28721913

• Comprehensive Analysis of the Unfolded Protein Response in Breast Cancer Subtypes. JCO precision oncology Jiang, D., Turner, B., Song, J., Li, R., Diehn, M., Le, Q., Khatri, P., Koong, A. C. 2017; 2017

  Abstract

  Purpose: Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1alpha-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1alpha-XBP1 and hypoxia-induced factor 1 alpha (HIF1alpha) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1alpha pathways in different breast cancer subtypes in large populations of patients.Materials and Methods: We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1alpha gene signatures.Results: We identified a strong positive association between the XBP1 gene signature and estrogen receptor-positive status or the HIF1alpha gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1alpha pathway is correlated with patient survival in all the subtypes evaluated.Conclusion: These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1alpha-XBP1 branch in breast cancer treatment.

  View details for PubMedID 29888341

• Immunotherapy of head and neck cancer: Emerging clinical trials from a National Cancer Institute Head and Neck Cancer Steering Committee Planning Meeting. Cancer Bauman, J. E., Cohen, E., Ferris, R. L., Adelstein, D. J., Brizel, D. M., Ridge, J. A., O'Sullivan, B., Burtness, B. A., Butterfield, L. H., Carson, W. E., Disis, M. L., Fox, B. A., Gajewski, T. F., Gillison, M. L., Hodge, J. W., Le, Q., Raben, D., Strome, S. E., Lynn, J., Malik, S. 2016

  Abstract

  Recent advances have permitted successful therapeutic targeting of the immune system in head and neck squamous cell carcinoma (HNSCC). These new immunotherapeutic targets and agents are being rapidly adopted by the oncologic community and hold considerable promise. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issue of how to further investigate the use of immunotherapy in patients with HNSCC. The goals of the meeting were to consider phase 2 or 3 trial designs primarily in 3 different patient populations: those with previously untreated, human papillomavirus-initiated oropharyngeal cancers; those with previously untreated, human papillomavirus-negative HNSCC; and those with recurrent/metastatic HNSCC. In addition, a separate committee was formed to develop integrative biomarkers for the clinical trials. The meeting started with an overview of key immune components and principles related to HNSCC, including immunosurveillance and immune escape. Four clinical trial concepts were developed at the meeting integrating different immunotherapies with existing standards of care. These designs were presented for implementation by the head and neck committees of the National Cancer Institute-funded National Clinical Trials Network. This article summarizes the proceedings of this Clinical Trials Planning Meeting, the purpose of which was to facilitate the rigorous development and design of randomized phase 2 and 3 immunotherapeutic trials in patients with HNSCC. Although reviews usually are published immediately after the meeting is held, this report is unique because there are now tangible clinical trial designs that have been funded and put into practice and the studies are being activated to accrual. Cancer 2017;123:1259-1271. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30449

  View details for PubMedID 27906454

• Prognostic nomogram for refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer Pan, J. J., Ng, W. T., Zong, J. F., Lee, S. W., Choi, H. C., Chan, L. L., Lin, S. J., Guo, Q. J., Sze, H. C., Chen, Y. B., Xiao, Y. P., Kan, W. K., O'Sullivan, B., Xu, W., Le, Q. T., Glastonbury, C. M., Colevas, A. D., Weber, R. S., Lydiatt, W., Shah, J. P., Lee, A. W. 2016; 122 (21): 3307-3315

  Abstract

  The objective of this study was to develop a nomogram for refining prognostication for patients with nondisseminated nasopharyngeal cancer (NPC) staged with the proposed 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system.Consecutive patients who had been investigated with magnetic resonance imaging, staged with the proposed 8th edition of the AJCC/UICC staging system, and irradiated with intensity-modulated radiotherapy from June 2005 to December 2010 were analyzed. A cohort of 1197 patients treated at Fujian Provincial Cancer Hospital was used as the training set, and the results were validated with 412 patients from Pamela Youde Nethersole Eastern Hospital. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with the concordance index (c-index). A recursive partitioning algorithm was applied to the survival scores of the combined set to categorize the patients into 3 risk groups.A multivariate analysis showed that age, gross primary tumor volume, and lactate dehydrogenase were independent prognostic factors for OS in addition to the stage group. The OS nomogram based on all these factors had a statistically higher bias-corrected c-index than prognostication based on the stage group alone (0.712 vs 0.622, P <.01). These results were consistent for both the training cohort and the validation cohort. Patients with <135 points were categorized as low-risk, patients with 135 to <160 points were categorized as intermediate-risk, and patients with ≥160 points were categorized as high-risk. Their 5-year OS rates were 92%, 84%, and 58%, respectively.The proposed nomogram could improve prognostication in comparison with the TNM stage group. This could aid in risk stratification for individual NPC patients. Cancer 2016;122:3307-3315. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30198

  View details for PubMedID 27434142

• Prognostic value of midtreatment FDG-PET in oropharyngeal cancer. Head & neck Pollom, E. L., Song, J., Durkee, B. Y., Aggarwal, S., Bui, T., von Eyben, R., Li, R., Brizel, D. M., Loo, B. W., Le, Q., Hara, W. Y. 2016; 38 (10): 1472-1478

  Abstract

  Prognostic metabolic imaging indices are needed for risk stratification for patients with locally advanced oropharyngeal cancer.We retrospectively examined pretreatment and midtreatment fluorodeoxyglucose-positron emission tomography (FDG-PET) parameters in patients with locally advanced oropharyngeal cancer who were treated with definitive chemoradiation.A total of 74 patients were evaluated. Pretreatment metabolic tumor volume (MTV) using threshold of 50% standardized uptake value (SUV) maximum (MTV50% ) was associated with progression-free survival (PFS; p = .003; hazard ratio [HR] = 1.57 per 10 cc; 95% confidence interval [CI] = 1.17-2.11) and overall survival (OS; p = .01; HR = 1.36 per 10 cc; 95% CI = 1.07-1.74). Midtreatment MTV using a threshold of SUV 2.0 (MTV2.0 ) was associated with PFS (p < .001; HR = 1.24 per 10 cc; 95% CI = 1.10-1.39) and OS (p = .009; HR = 1.21 per 10 cc; 95% CI = 1.05-1.39). Nodal total lesion glycolysis (TLG) velocity >5% decrease/week was associated with improved PFS (p = .04; HR = 0.37; 95% CI = 0.15-0.95).Metabolic response during chemoradiation is associated with survival in locally advanced oropharyngeal cancer and may aid with risk-adapting treatment. © 2016 Wiley Periodicals, Inc. Head Neck, 2016.

  View details for DOI 10.1002/hed.24454

  View details for PubMedID 27043927

• Prognostic Value of p16 Status on the Development of a Complete Response in Involved Oropharynx Cancer Neck Nodes After Cisplatin-Based Chemoradiation: A Secondary Analysis of NRG Oncology RTOG 0129. International journal of radiation oncology, biology, physics Galloway, T. J., Zhang, Q. E., Nguyen-Tan, P. F., Rosenthal, D. I., Soulieres, D., Fortin, A., Silverman, C. L., Daly, M. E., Ridge, J. A., Hammond, J. A., Le, Q. 2016; 96 (2): 362-371

  Abstract

  To determine the relationship between p16 status and the regional response of patients with node-positive oropharynx cancer treated on NRG Oncology RTOG 0129.Patients with N1-N3 oropharynx cancer and known p16 status who underwent treatment on RTOG 0129 were analyzed. Pathologic complete response (pCR) rates in patients treated with a postchemoradiation neck dissection (with p16-positive or p16-negative cancer) were compared by Fisher exact test. Patients managed expectantly were compared with those treated with a neck dissection.Ninety-nine (34%) of 292 patients with node-positive oropharynx cancer and known p16 status underwent a posttreatment neck dissection (p16-positive: n=69; p16-negative: n=30). The remaining 193 patients with malignant lymphadenopathy at diagnosis were observed. Neck dissection was performed a median of 70 (range, 17-169) days after completion of chemoradiation. Neither the pretreatment nodal stage (P=.71) nor the postradiation, pre-neck dissection clinical/radiographic neck assessment (P=.42) differed by p16 status. A pCR was more common among p16-positive patients (78%) than p16-negative patients (53%, P=.02) and was associated with a reduced incidence of local-regional failure (hazard ratio 0.33, P=.003). On multivariate analysis of local-regional failure, a test for interaction between pCR and p16 status was not significant (P=.37). One-hundred ninety-three (66%) of 292 of initially node-positive patients were managed without a posttreatment neck dissection. Development of a clinical (cCR) was not significantly influenced by p16-status (P=.42). Observed patients with a clinical nodal CR had disease control outcomes similar to those in patients with a pCR neck dissection.Patients with p16-positive tumors had significantly higher pCR and locoregional control rates than those with p16-negative tumors.

  View details for DOI 10.1016/j.ijrobp.2016.05.026

  View details for PubMedID 27478170

• Flexible radioluminescence imaging for FDG-guided surgery MEDICAL PHYSICS King, M. T., Jenkins, C. H., Sun, C., Carpenter, C. M., Ma, X., Cheng, K., Quynh-Thu Le, Q. T., Sunwoo, J. B., Cheng, Z., Pratx, G., Xing, L. 2016; 43 (10)

  Abstract

  Flexible radioluminescence imaging (Flex-RLI) is an optical method for imaging (18)F-fluorodeoxyglucose (FDG)-avid tumors. The authors hypothesize that a gadolinium oxysulfide: terbium (GOS:Tb) flexible scintillator, which loosely conforms to the body contour, can enhance tumor signal-to-background ratio (SBR) compared with RLI, which utilizes a flat scintillator. The purpose of this paper is to characterize flex-RLI with respect to alternative modalities including RLI, beta-RLI (RLI with gamma rejection), and Cerenkov luminescence imaging (CLI).The photon sensitivity, spatial resolution, and signal linearity of flex-RLI were characterized with in vitro phantoms. In vivo experiments utilizing 13 nude mice inoculated with the head and neck (UMSCC1-Luc) cell line were then conducted in accordance with the institutional Administrative Panel on Laboratory Animal Care. After intravenous injection of (18)F-FDG, the tumor SBR values for flex-RLI were compared to those for RLI, beta-RLI, and CLI using the Wilcoxon signed rank test.With respect to photon sensitivity, RLI, beta-RLI, and flex-RLI produced 1216.2, 407.0, and 98.6 times more radiance per second than CLI. Respective full-width half maximum values across a 0.5 mm capillary tube were 6.9, 6.4, 2.2, and 1.5 mm, respectively. Flex-RLI demonstrated a near perfect correlation with (18)F activity (r = 0.99). Signal uniformity for flex-RLI improved after more aggressive homogenization of the GOS powder with the silicone elastomer during formulation. In vivo, the SBR value for flex-RLI (median 1.29; interquartile range 1.18-1.36) was statistically greater than that for RLI (1.08; 1.02-1.14; p < 0.01) by 26%. However, there was no statistically significant difference in SBR values between flex-RLI and beta-RLI (p = 0.92). Furthermore, there was no statistically significant difference in SBR values between flex-RLI and CLI (p = 0.11) in a more limited dataset.Flex-RLI provides high quality images with SBRs comparable to those from CLI and beta-RLI in a single 10 s acquisition.

  View details for DOI 10.1118/1.4961745

  View details for PubMedID 27782732

• Design and rationale of a prospective, multi-institutional registry for patients with sinonasal malignancy. Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W., Colevas, A. D., Le, Q., Berry, G. J., Hwang, P. H. 2016; 126 (9): 1977-1980

  Abstract

  Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

  View details for DOI 10.1002/lary.25996

  View details for PubMedID 27283472

• Acridine Derivatives as Inhibitors of the IRE1a-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. Molecular cancer therapeutics Jiang, D., Tam, A. B., Alagappan, M., Hay, M. P., Gupta, A., Kozak, M. M., Solow-Cordero, D. E., Lum, P. Y., Denko, N. C., Giaccia, A. J., Le, Q., Niwa, M., Koong, A. C. 2016; 15 (9): 2055-2065

  Abstract

  Using a luciferase reporter-based high throughput chemical library screen and topological data analysis (TDA), we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as a inhibitor of the IRE1α-XBP1 pathway of the unfolded protein response (UPR). We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships (SAR) and identified N9-(3-(dimethylamino)propyl)-N3,N3,N6,N6-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, while the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma (MM) cell survival, these analogues were cytotoxic to MM cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing and the growth of MM tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of MM.

  View details for DOI 10.1158/1535-7163.MCT-15-1023

  View details for PubMedID 27307600

• Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. Proceedings of the National Academy of Sciences of the United States of America Bhat, R., Belardi, B., Mori, H., Kuo, P., Tam, A., Hines, W. C., Le, Q., Bertozzi, C. R., Bissell, M. J. 2016; 113 (33): E4820-7

  Abstract

  Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, α2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and α2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression.

  View details for DOI 10.1073/pnas.1609135113

  View details for PubMedID 27496330

  View details for PubMedCentralID PMC4995945

• Quality of Life and Performance Status From a Substudy Conducted Within a Prospective Phase 3 Randomized Trial of Concurrent Accelerated Radiation Plus Cisplatin With or Without Cetuximab for Locally Advanced Head and Neck Carcinoma: NRG Oncology Radiation Therapy Oncology Group 0522. International journal of radiation oncology, biology, physics Truong, M. T., Zhang, Q., Rosenthal, D. I., List, M., Axelrod, R., Sherman, E., Weber, R., Nguyen-Tân, P. F., El-Naggar, A., Konski, A., Galvin, J., Schwartz, D., Trotti, A., Silverman, C., Singh, A., Godette, K., Bonner, J. A., Jones, C. U., Garden, A. S., Shenouda, G., Matthiesen, C., Le, Q., Bruner, D. 2016

  Abstract

  To analyze the quality of life (QOL) and performance status (PS) (secondary outcome) in patients with stage III to IV head and neck cancer (HNC) enrolled on a prospective randomized phase 3 trial comparing radiation-cisplatin without cetuximab (CIS) or with cetuximab (CET/CIS). The QOL hypothesis proposed a between-arm difference in Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) total score of ≥10% of the instrument range from baseline to 1 year.Patients who gave consent to the QOL/PS study completed the FACT-HN, Performance Status Scale for HNC (PSS-HN), and EuroQol (EQ-5D) at baseline through to 5 years. The pretreatment QOL/PS scores were correlated with outcome and p16 status in patients with oropharyngeal cancer (OPC).Of 818 analyzable patients, the 1-year change from baseline score for FACT-HN total was -0.41 (CIS arm) and -5.11 (CET/CIS arm) (P=.016), representing a 3.2% between-arm change of the FACT-HN total score. The mean EQ-5D index and PSS-HN scores were not significantly different between arms. The p16-positive OPC patients had significantly higher baseline and 1-year scores for PSS-HN, FACT-HN total, physical and functional subscales, and 2-years for the EQ-5D index compared with p16-negative OPC patients. Higher pretreatment PSS-HN diet, PSS-HN eating, FACT-HN, and EQ-5D index scores were associated with better overall survival (OS) and progression-free (PFS) survival on multivariate analysis. Higher baseline FACT-HN total, functional, physical subscale, and EQ-5D index scores were associated with improved OS and PFS in p16-positive OPC patients but not in p16-negative and non-OPC patients.There was no clinically meaningful difference in QOL/PS between arms. The p16-positive OPC patients had significantly higher QOL/PS than did p16-negative patients. Pretreatment QOL/PS is a significant independent predictor of outcome in locally advanced HNC.

  View details for DOI 10.1016/j.ijrobp.2016.08.003

  View details for PubMedID 27727066

• Correlation Between the Severity of Cetuximab-Induced Skin Rash and Clinical Outcome for Head and Neck Cancer Patients: The RTOG Experience. International journal of radiation oncology, biology, physics Bar-Ad, V., Zhang, Q. E., Harari, P. M., Axelrod, R., Rosenthal, D. I., Trotti, A., Jones, C. U., Garden, A. S., Song, G., Foote, R. L., Raben, D., Shenouda, G., Spencer, S. A., Harris, J., Le, Q. 2016; 95 (5): 1346-1354

  Abstract

  To evaluate the severity of cetuximab-induced skin rash and its correlation with clinical outcome and late skin toxicity in patients with head and neck squamous cell carcinoma treated with chemoradiation therapy and cetuximab.Analysis included patients who received loading dose and ≥1 cetuximab dose concurrent with definitive chemoradiation therapy (70 Gy + cisplatin) or postoperative chemoradiation therapy (60-66 Gy + docetaxel or cisplatin).Six hundred two patients were analyzed; 383 (63.6%) developed grade 2 to 4 cetuximab rash. Patients manifesting grade 2 to 4 rash had younger age (P<.001), fewer pack-years smoking history (P<.001), were more likely to be males (P=.04), and had p16-negative (P=.04) oropharyngeal tumors (P=.003). In univariate analysis, grade 2 to 4 rash was associated with better overall survival (hazard ratio [HR] 0.58, P<.001) and progression-free survival (HR 0.75, P=.02), and reduced distant metastasis rate (HR 0.61, P=.03), but not local-regional failure (HR 0.79, P=.16) relative to grade 0 to 1 rash. In multivariable analysis, HRs for overall survival, progression-free survival, distant metastasis, and local-regional failure were, respectively, 0.68 (P=.008), 0.85 (P=.21), 0.64 (P=.06), and 0.89 (P=.48). Grade ≥2 rash was associated with improved survival in p16-negative patients (HR 0.28 [95% confidence interval 0.11-0.74]) but not in p16-positive patients (HR 1.10 [0.42-2.89]) (P=.05 for interaction). Twenty-five percent of patients with grade 2 to 4 acute in-field radiation dermatitis experienced grade 2 to 4 late skin fibrosis, versus 14% of patients with grade 0 to 1 acute in-field radiation dermatitis (P=.002).Grade 2 to 4 cetuximab rash was associated with better survival, possibly due to reduction of distant metastasis. This observation was noted mainly in p16-negative patients. Grade 2 to 4 acute in-field radiation dermatitis was associated with higher rate of late grade 2 to 4 skin fibrosis.

  View details for DOI 10.1016/j.ijrobp.2016.03.011

  View details for PubMedID 27212198

• Quality of Life and Performance Status From a Substudy Conducted Within a Prospective Phase 3 Randomized Trial of Concurrent Standard Radiation Versus Accelerated Radiation Plus Cisplatin for Locally Advanced Head and Neck Carcinoma: NRG Oncology RTOG 0129. International journal of radiation oncology, biology, physics Xiao, C., Zhang, Q., Nguyen-Tân, P. F., List, M., Weber, R. S., Ang, K. K., Rosenthal, D., Filion, E. J., Kim, H., Silverman, C., Raben, A., Galloway, T., Fortin, A., Gore, E., Winquist, E., Jones, C. U., Robinson, W., Raben, D., Le, Q., Bruner, D. 2016

  Abstract

  To analyze quality of life (QOL) and performance status (PS) for head and neck cancer (HNC) patients treated on NRG Oncology RTOG 0129 by treatment (secondary outcome) and p16 status, and to examine the association between QOL/PS and survival.Eligible patients were randomized into either an accelerated-fractionation arm or a standard-fractionation arm, and completed the Performance Status Scale for the Head and Neck (PSS-HN), the Head and Neck Radiotherapy Questionnaire (HNRQ), and the Spitzer Quality of Life Index (SQLI) at 8 time points from before treatment to 5 years after treatment.The results from the analysis of area under the curve showed that QOL/PS was not significantly different between the 2 arms from baseline to year after treatment (P ranged from .39 to .98). The results from general linear mixed models further supported the nonsignificant treatment effects until 5 years after treatment (P=.95, .90, and .84 for PSS-HN Diet, Eating, and Speech, respectively). Before treatment and after 1 year after treatment, p16-positive oropharyngeal cancer (OPC) patients had better QOL than did p16-negative patients (P ranged from .0283 to <.0001 for all questionnaires). However, QOL/PS decreased more significantly from pretreatment to the last 2 weeks of treatment in the p16-positive group than in the p16-negative group (P ranged from .0002 to <.0001). Pretreatment QOL/PS was a significant independent predictor of overall survival, progression-free survival, and local-regional failure but not of distant metastasis (P ranged from .0063 to <.0001).The results indicated that patients in both arms may have experienced similar QOL/PS. p16-positive patients had better QOL/PS at baseline and after 1 year of follow-up. Patients presenting with better baseline QOL/PS scores had better survival.

  View details for DOI 10.1016/j.ijrobp.2016.07.020

  View details for PubMedID 27727063

• Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234). Cancer Divi, V., Harris, J., Harari, P. M., Cooper, J. S., McHugh, J., Bell, D., Sturgis, E. M., Cmelak, A. J., Suntharalingam, M., Raben, D., Kim, H., Spencer, S. A., Laramore, G. E., Trotti, A., Foote, R. L., Schultz, C., Thorstad, W. L., Zhang, Q. E., Le, Q. T., Holsinger, F. C. 2016

  Abstract

  Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival.The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group.Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status.The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016. © 2016 American Cancer Society.

  View details for DOI 10.1002/cncr.30204

  View details for PubMedID 27419843

• Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR). Radiotherapy and oncology Chaudhuri, A. A., Binkley, M. S., Rigdon, J., Carter, J. N., Aggarwal, S., Dudley, S. A., Qian, Y., Kumar, K. A., Hara, W. Y., Gensheimer, M., Nair, V. S., Maxim, P. G., Shultz, D. B., Bush, K., Trakul, N., Le, Q., Diehn, M., Loo, B. W., Guo, H. H. 2016; 119 (3): 454-460

  Abstract

  To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.

  View details for DOI 10.1016/j.radonc.2016.05.007

  View details for PubMedID 27267049

• Quantitative and qualitative analysis of [(18)F]FDG and [(18)F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome. European journal of nuclear medicine and molecular imaging Graves, E. E., Hicks, R. J., Binns, D., Bressel, M., Le, Q., Peters, L., Young, R. J., Rischin, D. 2016; 43 (4): 617-625

  Abstract

  While methods for imaging tumor hypoxia with positron emission tomography (PET) have been developed, optimal methods for interpreting and utilizing these datasets in the clinic remain unclear. In this study, we analyzed hypoxia PET images of head and neck cancer patients and compared imaging metrics with human papilloma virus (HPV) status and clinical outcome.Forty-one patients treated as part of a phase III trial of the hypoxic cytotoxin tirapazamine (TROG 02.02) were imaged with PET using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA). FDG and FAZA PET images were interpreted qualitatively and quantitatively, and compared with tumor T stage, HPV status, and treatment outcome using multivariate statistics.PET signals in the tumor and lymph nodes exhibited significant intra- and inter-patient variability. The FAZA hypoxic volume demonstrated a significant correlation with tumor T stage. PET-hypoxic tumors treated with cisplatin exhibited significantly worse treatment outcomes relative to PET-oxic tumors or PET-hypoxic tumors treated with tirapazamine.Quantitative analysis of FAZA PET yielded metrics that correlated with clinical T stage and were capable of stratifying patient outcome. These results encourage further development of this technology, with particular emphasis on establishment of robust quantitative methods.

  View details for DOI 10.1007/s00259-015-3247-7

  View details for PubMedID 26577940

  View details for PubMedCentralID PMC4767583

• Botulinum Toxin Confers Radioprotection in Murine Salivary Glands. International journal of radiation oncology, biology, physics Zeidan, Y. H., Xiao, N., Cao, H., Kong, C., Le, Q., Sirjani, D. 2016; 94 (5): 1190-1197

  Abstract

  Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage.We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment.Irradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation.These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.

  View details for DOI 10.1016/j.ijrobp.2015.12.371

  View details for PubMedID 26907915

• Neurotrophic Factors and Their Potential Applications in Tissue Regeneration. Archivum immunologiae et therapiae experimentalis Xiao, N., Le, Q. 2016; 64 (2): 89-99

  Abstract

  Neurotrophic factors are growth factors that can nourish neurons and promote neuron survival and regeneration. They have been studied as potential drug candidates for treating neurodegenerative diseases. Since their identification, there are more and more evidences to indicate that neurotrophic factors are also expressed in non-neuronal tissues and regulate the survival, anti-inflammation, proliferation and differentiation in these tissues. This mini review summarizes the characteristics of the neurotrophic factors and their potential clinical applications in the regeneration of neuronal and non-neuronal tissues.

  View details for DOI 10.1007/s00005-015-0376-4

  View details for PubMedID 26611762

  View details for PubMedCentralID PMC4805470

• Botulinum Toxin Confers Radioprotection in Murine Salivary Glands INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Zeidan, Y. H., Xiao, N., Cao, H., Kong, C., Le, Q., Sirjani, D. 2016; 94 (5): 1190-1197

  Abstract

  Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage.We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment.Irradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation.These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.

  View details for DOI 10.1016/j.ijrobp.2015.12.371

  View details for Web of Science ID 000372564800026

  View details for PubMedCentralID PMC4839970

• Importance of Radiation Oncologist Experience Among Patients With Head-and-Neck Cancer Treated With Intensity-Modulated Radiation Therapy. Journal of clinical oncology Boero, I. J., Paravati, A. J., Xu, B., Cohen, E. E., Mell, L. K., Le, Q., Murphy, J. D. 2016; 34 (7): 684-690

  Abstract

  Over the past decade, intensity-modulated radiation therapy (IMRT) has replaced conventional radiation techniques in the management of head-and-neck cancers (HNCs). We conducted this population-based study to evaluate the influence of radiation oncologist experience on outcomes in patients with HNC treated with IMRT compared with patients with HNC treated with conventional radiation therapy.We identified radiation providers from Medicare claims of 6,212 Medicare beneficiaries with HNC treated between 2000 and 2009. We analyzed the impact of provider volume on all-cause mortality, HNC mortality, and toxicity end points after treatment with either conventional radiation therapy or IMRT. All analyses were performed by using either multivariable Cox proportional hazards or Fine-Gray regression models controlling for potential confounding variables.Among patients treated with conventional radiation, we found no significant relationship between provider volume and patient survival or any toxicity end point. Among patients receiving IMRT, those treated by higher-volume radiation oncologists had improved survival compared with those treated by low-volume providers. The risk of all-cause mortality decreased by 21% for every additional five patients treated per provider per year (hazard ratio [HR], 0.79; 95% CI, 0.67 to 0.94). Patients treated with IMRT by higher-volume providers had decreased HNC-specific mortality (subdistribution HR, 0.68; 95% CI, 0.50 to 0.91) and decreased risk of aspiration pneumonia (subdistribution HR, 0.72; 95% CI, 0.52 to 0.99).Patients receiving IMRT for HNC had improved outcomes when treated by higher-volume providers. These findings will better inform patients and providers when making decisions about treatment, and emphasize the critical importance of high-quality radiation therapy for optimal treatment of HNC.

  View details for DOI 10.1200/JCO.2015.63.9898

  View details for PubMedID 26729432

• Proposal for the 8th edition of the AJCC/UICC staging system for nasopharyngeal cancer in the era of intensity-modulated radiotherapy. Cancer Pan, J. J., Ng, W. T., Zong, J. F., Chan, L. L., O'Sullivan, B., Lin, S. J., Sze, H. C., Chen, Y. B., Choi, H. C., Guo, Q. J., Kan, W. K., Xiao, Y. P., Wei, X., Le, Q. T., Glastonbury, C. M., Colevas, A. D., Weber, R. S., Shah, J. P., Lee, A. W. 2016; 122 (4): 546-558

  Abstract

  An accurate staging system is crucial for cancer management. Evaluations for continual suitability and improvement are needed as staging and treatment methods evolve.This was a retrospective study of 1609 patients with nasopharyngeal carcinoma investigated by magnetic resonance imaging, staged with the 7th edition of the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system, and irradiated by intensity-modulated radiotherapy at 2 centers in Hong Kong and mainland China.Among the patients without other T3/T4 involvement, there were no significant differences in overall survival (OS) between medial pterygoid muscle (MP) ± lateral pterygoid muscle (LP), prevertebral muscle, and parapharyngeal space involvement. Patients with extensive soft tissue involvement beyond the aforementioned structures had poor OS similar to that of patients with intracranial extension and/or cranial nerve palsy. Only 2% of the patients had lymph nodes > 6 cm above the supraclavicular fossa (SCF), and their outcomes resembled the outcomes of those with low extension. Replacing SCF with the lower neck (extension below the caudal border of the cricoid cartilage) did not affect the hazard distinction between different N categories. With the proposed T and N categories, there were no significant differences in outcome between T4N0-2 and T1-4N3 disease.After a review by AJCC/UICC preparatory committees, the changes recommended for the 8th edition include changing MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as T2, replacing SCF with the lower neck and merging this with a maximum nodal diameter > 6 cm as N3, and merging T4 and N3 as stage IVA criteria. These changes will lead not only to a better distinction of hazards between adjacent stages/categories but also to optimal balance in clinical practicability and global applicability. Cancer 2016;122:546-558. © 2015 American Cancer Society.

  View details for DOI 10.1002/cncr.29795

  View details for PubMedID 26588425

• Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours. Scientific reports Golias, T., Papandreou, I., Sun, R., Kumar, B., Brown, N. V., Swanson, B. J., Pai, R., Jaitin, D., Le, Q., Teknos, T. N., Denko, N. C. 2016; 6: 31146-?

  Abstract

  Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1α subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1α through reduced kinase expression or enhanced phosphatase expression. The modified cells were tested for hypoxic changes in phosphorylated E1α, mitochondrial metabolism and growth as xenografted tumours. Even though there are four PDHK genes, PDHK1 is essential for inhibitory PDH phosphorylation of E1α at serine 232, is partially responsible for modification of serines 293 and 300, and these phosphorylations are necessary for model tumour growth. In order to determine the clinical relevance, a cohort of head and neck cancer patient biopsies was examined for phosphorylated E1α and expression of PDHK1. Patients with detectable 232 phosphorylation or expression of PDHK1 tend to have worse clinical outcome. These data show that PDHK1 activity is unique and non-redundant in the family of PHDK enzymes and a PDHK1 specific inhibitor would therefore have anti-cancer activity with reduced chance of side effects from inhibition of other PDHKs.

  View details for DOI 10.1038/srep31146

  View details for PubMedID 27498883

  View details for PubMedCentralID PMC4976358

• Design and rationale of a prospective multi-institutional registry for patients with sinosodal malignancy The Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W. Y., Colevas, A. D., Le, Q. T., Berry, G. J., Hwang, P. H. 2016

  Abstract

  Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

  View details for DOI 10.1002/lary.25996

• Identification of Doxorubicin as an Inhibitor of the IRE1a-XBP1 Axis of the Unfolded Protein Response. Scientific reports Jiang, D., Lynch, C., Medeiros, B. C., Liedtke, M., Bam, R., Tam, A. B., Yang, Z., Alagappan, M., Abidi, P., Le, Q., Giaccia, A. J., Denko, N. C., Niwa, M., Koong, A. C. 2016; 6: 33353-?

  Abstract

  Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α-XBP1-dependent tumors such as MM.

  View details for DOI 10.1038/srep33353

  View details for PubMedID 27634301

  View details for PubMedCentralID PMC5025885

• A prospective study of electronic quality of life assessment using tablet devices during and after treatment of head and neck cancers. Oral oncology Pollom, E. L., Wang, E., Bui, T. T., Ognibene, G., von Eyben, R., Divi, V., Sunwoo, J., Kaplan, M., Dimitri Colevas, A., Le, Q., Hara, W. Y. 2015; 51 (12): 1132-1137

  Abstract

  Electronic data collection is increasingly used for quality of life (QOL) assessments in the field of oncology. It is important to assess the feasibility of these new data capture technologies.Patients at our institution who were 18years or older with a pathological diagnosis of head and neck cancer were prospectively enrolled. Each patient completed two questionnaires [EORTC-QLQ-C30 and EORTC-QLQ-H&N35] administered on a touch-screen tablet device (iPad™) at initial consult, during treatment, at the completion of treatment and at each subsequent follow up visit for one year after treatment.A total of 50 patients were included in this study. Although all patients completed the surveys at the initial consult, 86% of initially enrolled patients completed surveys at the end of radiation treatment, and 48% of initially enrolled patients completed surveys by the fourth follow-up visit. Average time to complete the survey for all patients over all time points was 9.8min (standard deviation 6.1). Age as a continuous variable was significantly associated with time for survey completion (p<0.001), with older age associated with longer survey completion times.QOL assessment using tablet devices in head and neck cancer patients is feasible, but may be more challenging in elderly patients. Patients ⩾70years old may benefit from more assistance with electronic forms and should be allotted more time for completing tablet-based QOL surveys.

  View details for DOI 10.1016/j.oraloncology.2015.10.003

  View details for PubMedID 26475062

• Overview of Advances in Head and Neck Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Rischin, D., Ferris, R. L., Le, Q. T. 2015; 33 (29): 3225-6

  View details for DOI 10.1200/JCO.2015.63.6761

  View details for PubMedID 26351331

• ß-Radioluminescence Imaging: A Comparative Evaluation with Cerenkov Luminescence Imaging. Journal of nuclear medicine : official publication, Society of Nuclear Medicine King, M. T., Carpenter, C. M., Sun, C., Ma, X., Le, Q., Sunwoo, J. B., Cheng, Z., Pratx, G., Xing, L. 2015; 56 (9): 1458-1464

  Abstract

  Cerenkov luminescence imaging (CLI) can provide high-resolution images of (18)F-FDG-avid tumors but requires prolonged acquisition times because of low photon sensitivity. In this study, we proposed a new modality, termed β-radioluminescence imaging (β-RLI), which incorporates a scintillator with a γ-rejection strategy for imaging β particles. We performed a comparative evaluation of β-RLI with CLI in both in vitro and in vivo systems.Using in vitro phantoms, we characterized the photon sensitivity and resolution of CLI and β-RLI. We also conducted a series of in vivo experiments with xenograft mouse models using both amelanotic (A375, UMSCC1-Luc) and melanotic (B16F10-Luc) cell lines. The B16F10 and UMSCC1 cell lines were transfected with the luciferase gene (Luc). CLI was acquired over 300 s, and β-RLI was acquired using two 10-s acquisitions. We correlated (18)F -: FDG activities, as assessed by PET, with tumor radiances for both β-RLI and CLI. We also compared tumor signal-to-background ratios (SBRs) between these modalities for amelanotic and melanotic tumors.For in vitro experiments, the photon sensitivity for β-RLI was 560-fold greater than that for CLI. However, the spatial resolution for β-RLI (4.4 mm) was inferior to that of CLI (1.0 mm). For in vivo experiments, correlations between (18)F-FDG activity and tumor radiance were 0.52 (P < 0.01) for β-RLI, 0.81 (P = 0.01) for amelanotic lesions with CLI, and -0.08 (negative contrast; P = 0.80) for melanotic lesions with CLI. Nine of 13 melanotic lesions had an SBR less than 1 for CLI, despite an SBR greater than 1 among all lesions for β-RLI.β-RLI can produce functional images of both amelanotic and melanotic tumors in a shorter time frame than CLI. Further engineering developments are needed to realize the full clinical potential of this modality.

  View details for DOI 10.2967/jnumed.115.158337

  View details for PubMedID 26205301

• Individualizing treatment for patients with nasopharyngeal cancer. Cancer Hara, W., Le, Q. T. 2015; 121 (16): 2671-3

  View details for DOI 10.1002/cncr.29418

  View details for PubMedID 25946565

• Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Trakul, N., Jacobs, L. R., von Eyben, R., Quynh-Thu Le, Q. T., Maxim, P. G., Loo, B. W., Shultz, D. B., Diehn, M. 2015; 92 (5): 1044-1052

  Abstract

  Stereotactic ablative radiation therapy (SABR) is increasingly used to treat lung oligometastases. We set out to determine the safety and efficacy of this approach and to identify factors associated with outcomes.We conducted a retrospective study of patients treated with SABR for metastatic lung tumors at our institution from 2003 to 2014. We assessed the association between various patient and treatment factors with local failure (LF), progression, subsequent treatment, systemic treatment, and overall survival (OS), using univariate and multivariate analyses.We identified 122 tumors in 77 patients meeting inclusion criteria for this study. Median follow-up was 22 months. The 12- and 24-month cumulative incidence rates of LF were 8.7% and 16.2%, respectively; the 24-month cumulative incidence rates of progression, subsequent treatment, and subsequent systemic treatment were 75.2%, 64.5%, and 35.1%, respectively. Twenty-four-month OS was 74.6%, and median OS was 36 months. Colorectal metastases had a significantly higher cumulative incidence of LF at 12 and 24 months (25.5% and 42.2%, respectively), than all other histologies (4.4% and 9.9%, respectively; P<.0004). The 24-month cumulative incidences of LF for colorectal metastases treated with a biologically effective dose at α/β = 10 (BED10) of <100 Gy versus BED10 of ≥100 Gy were 62.5% and 16.7%, respectively (P=.08). Toxicity was minimal, with only a single grade 3 or higher event observed.SABR for metastatic lung tumors appears to be safe and effective with excellent local control, treatment-free intervals, and OS. An exception is metastases from colorectal cancer, which have a high LF rate consistent with a radioresistant phenotype, suggesting a potential role for dose escalation.

  View details for DOI 10.1016/j.ijrobp.2015.04.004

  View details for Web of Science ID 000357900600024

  View details for PubMedID 26025776

• Emerging Treatment Paradigms in Radiation Oncology. Clinical cancer research Le, Q., Shirato, H., Giaccia, A. J., Koong, A. C. 2015; 21 (15): 3393-3401

  Abstract

  Rapid advancements in radiotherapy and molecularly targeted therapies have resulted in the development of potential paradigm-shifting use of radiotherapy in the treatment of cancer. In this review, we discuss some of the most promising therapeutic approaches in the field of radiation oncology. These strategies include the use of highly targeted stereotactic radiotherapy and particle therapy as well as combining radiotherapy with agents that modulate the DNA damage response, augment the immune response, or protect normal tissues. Clin Cancer Res; 21(15); 3393-401. ©2015 AACR.

  View details for DOI 10.1158/1078-0432.CCR-14-1191

  View details for PubMedID 25991820

  View details for PubMedCentralID PMC4526434

• Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy. International journal of radiation oncology, biology, physics Pollom, E. L., Deng, L., Pai, R. K., Brown, J. M., Giaccia, A., Loo, B. W., Shultz, D. B., Le, Q. T., Koong, A. C., Chang, D. T. 2015; 92 (3): 568-576

  Abstract

  Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

  View details for DOI 10.1016/j.ijrobp.2015.02.016

  View details for PubMedID 26068491

• TU-AB-BRA-10: Prognostic Value of Intra-Radiation Treatment FDG-PET and CT Imaging Features in Locally Advanced Head and Neck Cancer. Medical physics Song, J., Cui, Y., Pollom, E., Durkee, B., Aggarwal, S., Bui, T., Le, Q., Loo, B., Hara, W., Li, R. 2015; 42 (6): 3588-?

  Abstract

  To predict response to radiation treatment using computational FDG-PET and CT images in locally advanced head and neck cancer (HNC).68 patients with State III-IVB HNC treated with chemoradiation were included in this retrospective study. For each patient, we analyzed primary tumor and lymph nodes on PET and CT scans acquired both prior to and during radiation treatment, which led to 8 combinations of image datasets. From each image set, we extracted high-throughput, radiomic features of the following types: statistical, morphological, textural, histogram, and wavelet, resulting in a total of 437 features. We then performed unsupervised redundancy removal and stability test on these features. To avoid over-fitting, we trained a logistic regression model with simultaneous feature selection based on least absolute shrinkage and selection operator (LASSO). To objectively evaluate the prediction ability, we performed 5-fold cross validation (CV) with 50 random repeats of stratified bootstrapping. Feature selection and model training was solely conducted on the training set and independently validated on the holdout test set. Receiver operating characteristic (ROC) curve of the pooled Result and the area under the ROC curve (AUC) was calculated as figure of merit.For predicting local-regional recurrence, our model built on pre-treatment PET of lymph nodes achieved the best performance (AUC=0.762) on 5-fold CV, which compared favorably with node volume and SUVmax (AUC=0.704 and 0.449, p<0.001). Wavelet coefficients turned out to be the most predictive features. Prediction of distant recurrence showed a similar trend, in which pre-treatment PET features of lymph nodes had the highest AUC of 0.705.The radiomics approach identified novel imaging features that are predictive to radiation treatment response. If prospectively validated in larger cohorts, they could aid in risk-adaptive treatment of HNC.

  View details for DOI 10.1118/1.4925515

  View details for PubMedID 26128812

• Reply to B. O'Sullivan et Al. Journal of clinical oncology Fakhry, C., Zhang, Q., Nguyen-Tan, P. F., Rosenthal, D., El-Naggar, A. K., Garden, A. S., Soulieres, D., Trotti, A., Avizonis, V. N., Ridge, J. A., Harris, J., Le, Q., Gillison, M. 2015; 33 (15): 1708-1709

  View details for DOI 10.1200/JCO.2014.60.3555

  View details for PubMedID 25823732

• Survival benefit for adjuvant radiation therapy in minor salivary gland cancers. Oral oncology Zeidan, Y. H., Pekelis, L., An, Y., Holsinger, F. C., Kong, C. S., Chang, D. T., Le, Q. 2015; 51 (5): 438-445

  Abstract

  The goal of the current study is to investigate the role of adjuvant radiation therapy (adjuvant RT) in minor salivary gland tumors (mSGT) using an established national database.The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients treated with or without adjuvant RT for mSGT from 1988 to 2008. Regression analyses were performed to identify factors associated with improved overall survival (OS).Most tumors were located within the oral cavity (75%) followed by nasal cavity/paranasal sinuses (15%). Multivariate Cox analysis showed that adjuvant RT was associated with better OS compared to surgery alone. Using logistic regression analysis, we provide a novel web based tool for predicting survival impact of adjuvant RT in patients with mSGT.Adjuvant RT is associated with improved survival in patients with mSGT and adverse clinicopathologic factors such as advanced T/N category, adenoid cystic histology, high grade, and nasopharynx location.

  View details for DOI 10.1016/j.oraloncology.2015.02.096

  View details for PubMedID 25771077

• Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer. Cancer Xu, B., Boero, I. J., Hwang, L., Le, Q., Moiseenko, V., Sanghvi, P. R., Cohen, E. E., Mell, L. K., Murphy, J. D. 2015; 121 (8): 1303-1311

  Abstract

  Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in patient with head and neck cancer. The objective of the current study was to evaluate the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of patients with head and neck cancer who received concurrent chemoradiotherapy.Patients who had head and neck cancer diagnosed between 2000 and 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared with a noncancer population.Of 3513 patients with head and neck cancer, 801 developed aspiration pneumonia at a median of 5 months after initiating treatment. The 1-year and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8%, respectively, for patients with head and neck cancer and 3.6% and 8.7%, respectively, for noncancer controls. Among the patients with cancer, multivariate analysis identified independent risk factors (P < .05) for aspiration pneumonia, including hypopharyngeal and nasopharyngeal tumors, male gender, older age, increased comorbidity, no surgery before radiation, and care received at a teaching hospital. Among the patients with cancer who experienced aspiration pneumonia, 674 (84%) were hospitalized; and, of these, 301 (45%) were admitted to an intensive care unit. The 30-day mortality rate after hospitalization for aspiration pneumonia was 32.5%. Aspiration pneumonia was associated with a 42% increased risk of death (hazard ratio, 1.42; P < .001) after controlling for confounders.The current results indicated that nearly 25% of elderly patients will develop aspiration pneumonia within 5 years after receiving chemoradiotherapy for head and neck cancer. A better understanding of mitigating factors will help identify patients who are at risk for this potentially lethal complication.

  View details for DOI 10.1002/cncr.29207

  View details for PubMedID 25537836

• Long-term results of radiation therapy oncology group 9903: a randomized phase 3 trial to assess the effect of erythropoietin on local-regional control in anemic patients treated with radiation therapy for squamous cell carcinoma of the head and neck. International journal of radiation oncology, biology, physics Shenouda, G., Zhang, Q., Ang, K. K., Machtay, M., Parliament, M. B., Hershock, D., Suntharalingam, M., Lin, A., Rotman, M., Nabid, A., Hong, S., Shehata, S., Cmelak, A. J., Sultanem, K., Le, Q. 2015; 91 (5): 907-915

  Abstract

  This paper reports long-term results of RTOG 9903, to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa).The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5 g/dL (12.5 g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10 days before RT was initiated in the RT + EPO arm.A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1 g/dL. In the RT + EPO arm, the mean hemoglobin level at 4 weeks increased by 1.66 g/dL, whereas it decreased by 0.24 g/dL in the RT arm. With a median follow-up of 7.95 years (range: 1.66-10.08 years) for surviving patients and 3.33 years for all patients (range: 0.03-10.08 years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% (P=.42), local-regional progression-free survival was 31.5% versus 37.6% (P=.20), and overall survival was 36.9% versus 38.2% (P=.54) for the RT + EPO and RT arms, respectively. Late toxicity was not different between the 2 arms.This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.

  View details for DOI 10.1016/j.ijrobp.2014.12.018

  View details for PubMedID 25670542

  View details for PubMedCentralID PMC4657552

• Metabolic tumor volume as a prognostic imaging-based biomarker for head-and-neck cancer: pilot results from Radiation Therapy Oncology Group protocol 0522. International journal of radiation oncology, biology, physics Schwartz, D. L., Harris, J., Yao, M., Rosenthal, D. I., Opanowski, A., Levering, A., Ang, K. K., Trotti, A. M., Garden, A. S., Jones, C. U., Harari, P., Foote, R., Holland, J., Zhang, Q., Le, Q. 2015; 91 (4): 721-729

  Abstract

  To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial setting.Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes.Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited.High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.

  View details for DOI 10.1016/j.ijrobp.2014.12.023

  View details for PubMedID 25752384

• Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer. Head & neck Tang, C., Chan, C., Jiang, W., Murphy, J. D., von Eyben, R., Colevas, A. D., Pinto, H., Lee-Enriquez, N., Kong, C., Le, Q. 2015; 37 (3): 386-392

  Abstract

  The purpose of this study was to present our experience utilizing cetuximab and platinum-based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC).Patients (n = 177) who received definitive concurrent chemoradiotherapy for HNSCC were stratified into 3 groups: receiving cetuximab monotherapy (n = 24), cetuximab and chemotherapy combination (n = 33), or platinum-based chemotherapy without cetuximab (n = 120). Primary endpoints were freedom from relapse, event-free survival, and overall survival (OS).Patients receiving cetuximab monotherapy were older with lower Karnofsky performance status (KPS) and higher Charlson comorbidity scores compared with those treated with combination cetuximab and chemotherapy or platinum-based concurrent chemoradiotherapy. Patients treated with platinum-based concurrent chemoradiotherapy exhibited significantly better freedom from relapse, event-free survival, and OS compared with those receiving cetuximab monotherapy or cetuximab and chemotherapy combination therapies (all p < .05). Differences between patients receiving cetuximab monotherapy and platinum-based concurrent chemoradiotherapy held on multivariate Cox regression.This study suggests that platinum-based concurrent chemoradiotherapy is superior to cetuximab-based monotherapy for the definitive treatment of HNSCC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 386-392, 2015.

  View details for DOI 10.1002/hed.23609

  View details for PubMedID 24431011

• Prognostic model for distant metastasis in locally advanced nasopharyngeal carcinoma after concurrent chemoradiotherapy HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Chen, C., Chen, S., Le, Q., Chen, J., Chen, Z., Li, D., Zhou, M., Li, D. 2015; 37 (2): 209-214

  Abstract

  A prognostic model should be established for distant metastasis in locally advanced nasopharyngeal carcinoma (NPC) after concurrent chemoradiotherapy (CCRT).Patients with locally advanced NPC who received CCRT were divided into a construction set (230 patients) and a validating set (115 patients). The constructed index was derived on the former and then tested on the latter.The prognostic score was defined as the number of adverse prognostic factors: age >45, N3 category, hemoglobin <11.0 g/dL and lactate dehydrogenase ≥240 U/L. The score predicted the 5-year distant metastasis-free survival as follows: 0, 91%; 1, 74%; 2, 51%; and ≥3, 12%. In the validating set, the observed 5-year distant metastasis-free survival of these 4 groups with scores of 0, 1, 2, 3, or higher were 81%, 68%, 47%, and 15%, respectively.The established model might be useful for predicting the risk of distant metastasis in patients with locally advanced NPC who underwent CCRT and may identify the patients' need for intensified adjuvant chemotherapy.

  View details for DOI 10.1002/hed.23583

  View details for Web of Science ID 000348548700015

  View details for PubMedID 24375647

• Institutional clinical trial accrual volume and survival of patients with head and neck cancer. Journal of clinical oncology Wuthrick, E. J., Zhang, Q., Machtay, M., Rosenthal, D. I., Nguyen-Tan, P. F., Fortin, A., Silverman, C. L., Raben, A., Kim, H. E., Horwitz, E. M., Read, N. E., Harris, J., Wu, Q., Le, Q., Gillison, M. L. 2015; 33 (2): 156-164

  Abstract

  National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown.The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models.Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment.OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.

  View details for DOI 10.1200/JCO.2014.56.5218

  View details for PubMedID 25488965

  View details for PubMedCentralID PMC4279235

• p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. Journal of clinical oncology Chung, C. H., Zhang, Q., Kong, C. S., Harris, J., Fertig, E. J., Harari, P. M., Wang, D., Redmond, K. P., Shenouda, G., Trotti, A., Raben, D., Gillison, M. L., Jordan, R. C., Le, Q. 2014; 32 (35): 3930-3938

  Abstract

  Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx.p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics.p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes.Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

  View details for DOI 10.1200/JCO.2013.54.5228

  View details for PubMedID 25267748

• Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. Journal of clinical oncology Nguyen-Tan, P. F., Zhang, Q., Ang, K. K., Weber, R. S., Rosenthal, D. I., Soulieres, D., Kim, H., Silverman, C., Raben, A., Galloway, T. J., Fortin, A., Gore, E., Westra, W. H., Chung, C. H., Jordan, R. C., Gillison, M. L., List, M., Le, Q. 2014; 32 (34): 3858-3866

  Abstract

  We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC).Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m(2) once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Gray's test.In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status.When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification.

  View details for DOI 10.1200/JCO.2014.55.3925

  View details for PubMedID 25366680

• Palliative Radiation Before Hospice: The Long and the Short of It JOURNAL OF PAIN AND SYMPTOM MANAGEMENT Yeung, H. N., Mitchell, W. M., Roeland, E. J., Xu, B., Mell, L. K., Quynh-Thu Le, Q. T., Murphy, J. D. 2014; 48 (6): 1070-1079

  Abstract

  Randomized data support shorter radiotherapy courses for management of cancer-related symptoms in the palliative setting.The purpose of this study was to evaluate the length of palliative radiotherapy before hospice enrollment among the elderly U.S. population, with a further focus on factors that influence the duration of radiation and the length of survival on hospice, including whether the duration of radiation was associated with length of survival on hospice.A total of 6982 patients with breast, prostate, lung, or colorectal cancer who received a course of radiotherapy within 30 days before hospice enrollment were identified within the Surveillance, Epidemiology, and End Results-Medicare linked database. The primary end points included the duration of palliative radiotherapy and the time from hospice enrollment through death (hospice duration). Multivariate linear regression and multivariate Cox models evaluated factors associated with the length of radiotherapy course and hospice duration.The median length of palliative radiotherapy was 14 days, and the median hospice duration was 13 days. The course of palliative radiotherapy was longer than hospice duration in 48% of the patients. Breast and lung cancer were associated with longer courses of radiotherapy and shorter stays on hospice. Patients treated in freestanding radiation centers had longer courses of radiotherapy. For these groups, a longer radiotherapy course was not associated with longer hospice duration.This study found relatively long courses of radiotherapy before short lengths of survival on hospice. Future research is needed to identify barriers to shorter radiotherapy courses.

  View details for DOI 10.1016/j.jpainsymman.2014.04.004

  View details for Web of Science ID 000346742300006

  View details for PubMedID 24819083

• A unifying probabilistic Bayesian approach to derive electron density from MRI for radiation therapy treatment planning PHYSICS IN MEDICINE AND BIOLOGY Gudur, M. S., Hara, W., Le, Q., Wang, L., Xing, L., Li, R. 2014; 59 (21): 6595-6606

  Abstract

  MRI significantly improves the accuracy and reliability of target delineation in radiation therapy for certain tumors due to its superior soft tissue contrast compared to CT. A treatment planning process with MRI as the sole imaging modality will eliminate systematic CT/MRI co-registration errors, reduce cost and radiation exposure, and simplify clinical workflow. However, MRI lacks the key electron density information necessary for accurate dose calculation and generating reference images for patient setup. The purpose of this work is to develop a unifying method to derive electron density from standard T1-weighted MRI. We propose to combine both intensity and geometry information into a unifying probabilistic Bayesian framework for electron density mapping. For each voxel, we compute two conditional probability density functions (PDFs) of electron density given its: (1) T1-weighted MRI intensity, and (2) geometry in a reference anatomy, obtained by deformable image registration between the MRI of the atlas and test patient. The two conditional PDFs containing intensity and geometry information are combined into a unifying posterior PDF, whose mean value corresponds to the optimal electron density value under the mean-square error criterion. We evaluated the algorithm's accuracy of electron density mapping and its ability to detect bone in the head for eight patients, using an additional patient as the atlas or template. Mean absolute HU error between the estimated and true CT, as well as receiver operating characteristics for bone detection (HU > 200) were calculated. The performance was compared with a global intensity approach based on T1 and no density correction (set whole head to water). The proposed technique significantly reduced the errors in electron density estimation, with a mean absolute HU error of 126, compared with 139 for deformable registration (p = 2  ×  10(-4)), 283 for the intensity approach (p = 2  ×  10(-6)) and 282 without density correction (p = 5  ×  10(-6)). For 90% sensitivity in bone detection, the proposed method achieved a specificity of 86%, compared with 80, 11 and 10% using deformable registration, intensity and without density correction, respectively. Notably, the Bayesian approach was more robust against anatomical differences between patients, with a specificity of 62% in the worst case (patient), compared to 30% specificity in registration-based approach. In conclusion, the proposed unifying Bayesian method provides accurate electron density estimation and bone detection from MRI of the head with highly heterogeneous anatomy.

  View details for DOI 10.1088/0031-9155/59/21/6595

  View details for Web of Science ID 000343092900020

• A unifying probabilistic Bayesian approach to derive electron density from MRI for radiation therapy treatment planning. Physics in medicine and biology Gudur, M. S., Hara, W., Le, Q., Wang, L., Xing, L., Li, R. 2014; 59 (21): 6595-6606

  Abstract

  MRI significantly improves the accuracy and reliability of target delineation in radiation therapy for certain tumors due to its superior soft tissue contrast compared to CT. A treatment planning process with MRI as the sole imaging modality will eliminate systematic CT/MRI co-registration errors, reduce cost and radiation exposure, and simplify clinical workflow. However, MRI lacks the key electron density information necessary for accurate dose calculation and generating reference images for patient setup. The purpose of this work is to develop a unifying method to derive electron density from standard T1-weighted MRI. We propose to combine both intensity and geometry information into a unifying probabilistic Bayesian framework for electron density mapping. For each voxel, we compute two conditional probability density functions (PDFs) of electron density given its: (1) T1-weighted MRI intensity, and (2) geometry in a reference anatomy, obtained by deformable image registration between the MRI of the atlas and test patient. The two conditional PDFs containing intensity and geometry information are combined into a unifying posterior PDF, whose mean value corresponds to the optimal electron density value under the mean-square error criterion. We evaluated the algorithm's accuracy of electron density mapping and its ability to detect bone in the head for eight patients, using an additional patient as the atlas or template. Mean absolute HU error between the estimated and true CT, as well as receiver operating characteristics for bone detection (HU > 200) were calculated. The performance was compared with a global intensity approach based on T1 and no density correction (set whole head to water). The proposed technique significantly reduced the errors in electron density estimation, with a mean absolute HU error of 126, compared with 139 for deformable registration (p = 2  ×  10(-4)), 283 for the intensity approach (p = 2  ×  10(-6)) and 282 without density correction (p = 5  ×  10(-6)). For 90% sensitivity in bone detection, the proposed method achieved a specificity of 86%, compared with 80, 11 and 10% using deformable registration, intensity and without density correction, respectively. Notably, the Bayesian approach was more robust against anatomical differences between patients, with a specificity of 62% in the worst case (patient), compared to 30% specificity in registration-based approach. In conclusion, the proposed unifying Bayesian method provides accurate electron density estimation and bone detection from MRI of the head with highly heterogeneous anatomy.

  View details for DOI 10.1088/0031-9155/59/21/6595

  View details for PubMedID 25321341

• Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response. Clinical cancer research Kuo, P., Bratman, S. V., Shultz, D. B., von Eyben, R., Chan, C., Wang, Z., Say, C., Gupta, A., Loo, B. W., Giaccia, A. J., Koong, A. C., Diehn, M., Le, Q. 2014; 20 (21): 5558-5569

  Abstract

  Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non-small cell lung cancer (NSCLC)] and head and neck cancer patients.LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8(+) T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558-69. ©2014 AACR.

  View details for DOI 10.1158/1078-0432.CCR-14-1138

  View details for PubMedID 25189484

  View details for PubMedCentralID PMC4216761

• Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Journal of clinical oncology Fakhry, C., Zhang, Q., Nguyen-Tan, P. F., Rosenthal, D., El-Naggar, A., Garden, A. S., Soulieres, D., Trotti, A., Avizonis, V., Ridge, J. A., Harris, J., Le, Q., Gillison, M. 2014; 32 (30): 3365-3373

  Abstract

  Risk of cancer progression is reduced for patients with human papillomavirus (HPV) -positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced.Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol.A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment.Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

  View details for DOI 10.1200/JCO.2014.55.1937

  View details for PubMedID 24958820

  View details for PubMedCentralID PMC4195851

• Commutability of the Epstein-Barr Virus WHO International Standard across Two Quantitative PCR Methods JOURNAL OF CLINICAL MICROBIOLOGY Abeynayake, J., Johnson, R., Libiran, P., Sahoo, M. K., Cao, H., Bowen, R., Chan, K. C., Quynh-Thu Le, Q. T., Pinsky, B. A. 2014; 52 (10): 3802-3804

  Abstract

  The commutability of international reference standards is critical for ensuring quantitative agreement across different viral load assays. Here, we demonstrate the commutability of the Epstein-Barr virus (EBV) WHO international standard for the BamHI-W and artus EBV assays.

  View details for DOI 10.1128/JCM.01676-14

  View details for Web of Science ID 000342371700042

  View details for PubMedCentralID PMC4187779

• Galectin-1 links tumor hypoxia and radiotherapy GLYCOBIOLOGY Kuo, P., Quynh-Thu Le, Q. T. 2014; 24 (10): 921-925

  View details for DOI 10.1093/glycob/cwu062

  View details for Web of Science ID 000343413600008

• Commutability of the Epstein-Barr virus WHO international standard across two quantitative PCR methods. Journal of clinical microbiology Abeynayake, J., Johnson, R., Libiran, P., Sahoo, M. K., Cao, H., Bowen, R., Chan, K. C., Le, Q., Pinsky, B. A. 2014; 52 (10): 3802-3804

  Abstract

  The commutability of international reference standards is critical for ensuring quantitative agreement across different viral load assays. Here, we demonstrate the commutability of the Epstein-Barr virus (EBV) WHO international standard for the BamHI-W and artus EBV assays.

  View details for DOI 10.1128/JCM.01676-14

  View details for PubMedID 25078918

  View details for PubMedCentralID PMC4187779

• Galectin-1 links tumor hypoxia and radiotherapy. Glycobiology Kuo, P., Le, Q. 2014; 24 (10): 921-925

  Abstract

  Radiation therapy is a main stay in treating solid tumors and plays a significant role in definitive and adjuvant therapy. Unfortunately, local control remains a challenge, in which the success of radiotherapy is largely dictated by tumor hypoxia, DNA damage repair and the antitumor immune response. Extensive efforts have therefore been devoted to targeting the factors that attenuate tumor radiosensitivity, although with limited success. Mounting evidence suggests that tumor and endothelial cells may utilize galectin-1 (Gal-1) for protection against radiation through several mechanisms. Targeting Gal-1 in combination with radiotherapy provides an exciting approach to address several radiation-prohibitive mechanisms.

  View details for DOI 10.1093/glycob/cwu062

  View details for PubMedID 24973253

  View details for PubMedCentralID PMC4153759

• Age disparity in palliative radiation therapy among patients with advanced cancer. International journal of radiation oncology, biology, physics Wong, J., Xu, B., Yeung, H. N., Roeland, E. J., Martinez, M. E., Le, Q., Mell, L. K., Murphy, J. D. 2014; 90 (1): 224-230

  Abstract

  Palliative radiation therapy represents an important treatment option among patients with advanced cancer, although research shows decreased use among older patients. This study evaluated age-related patterns of palliative radiation use among an elderly Medicare population.We identified 63,221 patients with metastatic lung, breast, prostate, or colorectal cancer diagnosed between 2000 and 2007 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Receipt of palliative radiation therapy was extracted from Medicare claims. Multivariate Poisson regression analysis determined residual age-related disparity in the receipt of palliative radiation therapy after controlling for confounding covariates including age-related differences in patient and demographic covariates, length of life, and patient preferences for aggressive cancer therapy.The use of radiation decreased steadily with increasing patient age. Forty-two percent of patients aged 66 to 69 received palliative radiation therapy. Rates of palliative radiation decreased to 38%, 32%, 24%, and 14% among patients aged 70 to 74, 75 to 79, 80 to 84, and over 85, respectively. Multivariate analysis found that confounding covariates attenuated these findings, although the decreased relative rate of palliative radiation therapy among the elderly remained clinically and statistically significant. On multivariate analysis, compared to patients 66 to 69 years old, those aged 70 to 74, 75 to 79, 80 to 84, and over 85 had a 7%, 15%, 25%, and 44% decreased rate of receiving palliative radiation, respectively (all P<.0001).Age disparity with palliative radiation therapy exists among older cancer patients. Further research should strive to identify barriers to palliative radiation among the elderly, and extra effort should be made to give older patients the opportunity to receive this quality of life-enhancing treatment at the end of life.

  View details for DOI 10.1016/j.ijrobp.2014.03.050

  View details for PubMedID 25195994

  View details for PubMedCentralID PMC4187217

• Age Disparity in Palliative Radiation Therapy Among Patients With Advanced Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Wong, J., Xu, B., Yeung, H. N., Roeland, E. J., Martinez, M. E., Quynh-Thu Le, Q. T., Mell, L. K., Murphy, J. D. 2014; 90 (1): 224-230

  Abstract

  Palliative radiation therapy represents an important treatment option among patients with advanced cancer, although research shows decreased use among older patients. This study evaluated age-related patterns of palliative radiation use among an elderly Medicare population.We identified 63,221 patients with metastatic lung, breast, prostate, or colorectal cancer diagnosed between 2000 and 2007 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Receipt of palliative radiation therapy was extracted from Medicare claims. Multivariate Poisson regression analysis determined residual age-related disparity in the receipt of palliative radiation therapy after controlling for confounding covariates including age-related differences in patient and demographic covariates, length of life, and patient preferences for aggressive cancer therapy.The use of radiation decreased steadily with increasing patient age. Forty-two percent of patients aged 66 to 69 received palliative radiation therapy. Rates of palliative radiation decreased to 38%, 32%, 24%, and 14% among patients aged 70 to 74, 75 to 79, 80 to 84, and over 85, respectively. Multivariate analysis found that confounding covariates attenuated these findings, although the decreased relative rate of palliative radiation therapy among the elderly remained clinically and statistically significant. On multivariate analysis, compared to patients 66 to 69 years old, those aged 70 to 74, 75 to 79, 80 to 84, and over 85 had a 7%, 15%, 25%, and 44% decreased rate of receiving palliative radiation, respectively (all P<.0001).Age disparity with palliative radiation therapy exists among older cancer patients. Further research should strive to identify barriers to palliative radiation among the elderly, and extra effort should be made to give older patients the opportunity to receive this quality of life-enhancing treatment at the end of life.

  View details for DOI 10.1016/j.ijrobp.2014.03.050

  View details for Web of Science ID 000341456500030

  View details for PubMedCentralID PMC4187217

• CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget Murillo-Sauca, O., Chung, M. K., Shin, J. H., Karamboulas, C., Kwok, S., Jung, Y. H., Oakley, R., Tysome, J. R., Farnebo, L. O., Kaplan, M. J., Sirjani, D., Divi, V., Holsinger, F. C., Tomeh, C., Nichols, A., Le, Q. T., Colevas, A. D., Kong, C. S., Uppaluri, R., Lewis, J. S., Ailles, L. E., Sunwoo, J. B. 2014; 5 (16): 6854-6866

  Abstract

  Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.

  View details for PubMedID 25149537

• Salvage Treatment for Locally Recurrent Nasopharyngeal Carcinoma (NPC). American journal of clinical oncology Chen, C., Fee, W., Chen, J., Chan, C., Khong, B., Hara, W., Goffinet, D., Li, D., Le, Q. 2014; 37 (4): 327-331

  Abstract

  It is important to determine the outcomes of retreatment in patients with locally recurrent nasopharyngeal carcinoma.We reviewed the records of patients treated for local recurrence at Stanford and Shantou Universities. The end points were local relapse-free survival (LRFS) and overall survival after retreatment.Fifty-six patients from Stanford and 98 from Shantou qualified. For the Stanford patients, 33 had surgery alone (S group), 12 had surgery plus radiotherapy±chemotherapy (CMT group), and 22 had radiotherapy±chemotherapy (RT Stanford group). All Shantou patients received radiotherapy±chemotherapy (RT Shantou group). The 5-year LRFS rates were: 57% for S group, 25% for CMT group, 53% for RT Stanford group, and 41% for RT Shantou group (P>0.05) for rT1-2 tumors; they were 29% for S group, 25% for CMT group, 39% for RT Stanford group, and 9% for RT Shantou group for rT3-4 tumors (P>0.05). For RT patients, 5-year overall survival rates were 49% for Stanford and 25% for Shantou patients (P=0.026).Similar and durable LRFS rates were attained for both S and RT groups when stratified by rT-stage.

  View details for DOI 10.1097/COC.0b013e318277d804

  View details for PubMedID 23275273

• Neurotrophic factor GDNF promotes survival of salivary stem cells. journal of clinical investigation Xiao, N., Lin, Y., Cao, H., Sirjani, D., Giaccia, A. J., Koong, A. C., Kong, C. S., Diehn, M., Le, Q. 2014; 124 (8): 3364-3377

  Abstract

  Stem cell-based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin-CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line-derived neurotrophic factor (Gdnf) is highly expressed in Lin-CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation-induced xerostomia.

  View details for DOI 10.1172/JCI74096

  View details for PubMedID 25036711

  View details for PubMedCentralID PMC4109543

• Imaging features associated with disease progression after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer. Clinical lung cancer Shultz, D. B., Trakul, N., Abelson, J. A., Murphy, J. D., Maxim, P. G., Le, Q., Loo, B. W., Diehn, M. 2014; 15 (4): 294-301 e3

  Abstract

  The aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC.Between March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax.Ten patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases.In our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.

  View details for DOI 10.1016/j.cllc.2013.12.011

  View details for PubMedID 24594400

• Human papillomavirus 16 detected in nasopharyngeal carcinomas in white Americans but not in endemic Southern Chinese patients. Head & neck Lin, Z., Khong, B., Kwok, S., Cao, H., West, R. B., Le, Q., Kong, C. S. 2014; 36 (5): 709-714

  Abstract

  BACKGROUND: We evaluated the relationship of HPV and EBV with race in endemic and non-endemic cohorts of patients with nasopharyngeal carcinoma (NPC), and with smoking status in the non-endemic cohort. METHODS: Tissue microarrays (TMA) were constructed using samples from 86 patients treated in southern China and 108 patients from Stanford. TMAs were stained with p16, HPV ISH, and EBV ISH. PCR was used to confirm EBV(-) cases and HPV status in p16(+) cases. Survival data was available for the Stanford cohort only. RESULTS: No HPV(+) cases were detected in the Chinese cohort. In the Stanford cohort, 5/11 EBV(-) cases harbored HPV16, 10/10 occurred in Caucasians, and 8/11 were smokers. Patients with EBV(-) NPC also showed a trend towards worse survival. CONCLUSIONS: EBV(-) NPC shows an association with the presence of HPV, Caucasian race, and smoking. In contrast, EBV(-) NPC shows no association with HPV in the endemic cohort. Head Neck, 2013.

  View details for DOI 10.1002/hed.23362

  View details for PubMedID 23616441

• Acceler-dated fractionation: the end of the era of the large, "one size fits all" trial for locally advanced head and neck cancer. International journal of radiation oncology, biology, physics Le, Q. T., Machtay, M. 2014; 89 (1): 7-9

  View details for DOI 10.1016/j.ijrobp.2014.01.045

  View details for PubMedID 24725684

  View details for PubMedCentralID PMC3986724

• Risk Factors for Clinician-Reported Symptom Clusters in Patients With Advanced Head and Neck Cancer in a Phase 3 Randomized Clinical Trial: RTOG 0129 CANCER Xiao, C., Hanlon, A., Zhang, Q., Movsas, B., Ang, K., Rosenthal, D. I., Nguyen-Tan, P. F., Kim, H., Le, Q., Bruner, D. W. 2014; 120 (6): 848-854

  Abstract

  Chemoradiotherapy has become the standard of care for head and neck squamous cell carcinoma; however, those patients often experience multiple treatment-related symptoms or symptom clusters. Two symptom clusters have been identified for this population. Little is known about the risk factors of these symptom clusters.Subjects comprised 684 patients who were treated with concurrent chemoradiotherapy in a phase 3 randomized clinical trial. This trial compared standard fractionation radiotherapy to accelerated fractionation radiotherapy. Symptom clusters were evaluated at the end of the first and the second cycle of chemotherapy, and 3 months after the start of radiotherapy. Mixed-effect modeling was used to observe risk factors for symptom clusters.Race and education were independent predictors for the head and neck cluster, whereas sex and history of tobacco use were independent predictors for the gastrointestinal cluster. Primary cancer site was only significant for the head and neck cluster when other factors were not controlled: patients with oropharyngeal cancer had more severe symptoms in the head and neck clusters than did patients with laryngeal cancer. In addition, patients receiving accelerated fractionation radiotherapy experienced more symptoms of radiomucositis, pain, and nausea at 3 months after the start of radiotherapy than those receiving standard fractionation radiotherapy.Demographic characteristics were more predictive to symptom clusters, whereas clinical characteristics, such as cancer site and treatment arms, were more significant for individual symptoms. Knowing the risk factors will enhance the capability of clinicians to evaluate patients' risk of severe symptom clusters and to personalize management strategies.

  View details for DOI 10.1002/cncr.28500

  View details for Web of Science ID 000332140100013

  View details for PubMedID 24338990

  View details for PubMedCentralID PMC3947661

• A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Harris, J. P., Murphy, J. D., Hanlon, A. L., Le, Q., Loo, B. W., Diehn, M. 2014; 88 (4): 872-884

  Abstract

  Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC.We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments.The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in 2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT was associated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models.In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.

  View details for DOI 10.1016/j.ijrobp.2013.12.010

  View details for PubMedID 24495591

• Discovery of recurrent structural variants in nasopharyngeal carcinoma. Genome research Valouev, A., Weng, Z., Sweeney, R. T., Varma, S., Le, Q., Kong, C., Sidow, A., West, R. B. 2014; 24 (2): 300-309

  Abstract

  We present the discovery of genes recurrently involved in structural variation in nasopharyngeal carcinoma (NPC) and the identification of a novel type of somatic structural variant. We identified the variants with high complexity mate-pair libraries and a novel computational algorithm specifically designed for tumor-normal comparisons, SMASH. SMASH combines signals from split reads and mate-pair discordance to detect somatic structural variants. We demonstrate a >90% validation rate and a breakpoint reconstruction accuracy of 3 bp by Sanger sequencing. Our approach identified three in-frame gene fusions (YAP1-MAML2, PTPLB-RSRC1, and SP3-PTK2) that had strong levels of expression in corresponding NPC tissues. We found two cases of a novel type of structural variant, which we call "coupled inversion," one of which produced the YAP1-MAML2 fusion. To investigate whether the identified fusion genes are recurrent, we performed fluorescent in situ hybridization (FISH) to screen 196 independent NPC cases. We observed recurrent rearrangements of MAML2 (three cases), PTK2 (six cases), and SP3 (two cases), corresponding to a combined rate of structural variation recurrence of 6% among tested NPC tissues.

  View details for DOI 10.1101/gr.156224.113

  View details for PubMedID 24214394

• Delineation of the neck node levels for head and neck tumors: A 2013 update. DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines RADIOTHERAPY AND ONCOLOGY Gregoire, V., Ang, K., Budach, W., Grau, C., Hamoir, M., Langendijk, J. A., Lee, A., Quynh-Thu Le, Maingon, P., Nutting, C., O'Sullivan, B., Porceddu, S. V., Lengele, B. 2014; 110 (1): 172–81

  Abstract

  In 2003, a panel of experts published a set of consensus guidelines for the delineation of the neck node levels in node negative patients (Radiother Oncol, 69: 227-36, 2003). In 2006, these guidelines were extended to include the characteristics of the node positive and the post-operative neck (Radiother Oncol, 79: 15-20, 2006). These guidelines did not fully address all nodal regions and some of the anatomic descriptions were ambiguous, thereby limiting consistent use of the recommendations. In this framework, a task force comprising opinion leaders in the field of head and neck radiation oncology from European, Asian, Australia/New Zealand and North American clinical research organizations was formed to review and update the previously published guidelines on nodal level delineation. Based on the nomenclature proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery, and in alignment with the TNM atlas for lymph nodes in the neck, 10 node groups (some being divided into several levels) were defined with a concise description of their main anatomic boundaries, the normal structures juxtaposed to these nodes, and the main tumor sites at risk for harboring metastases in those levels. Emphasis was placed on those levels not adequately considered previously (or not addressed at all); these included the lower neck (e.g. supraclavicular nodes), the scalp (e.g. retroauricular and occipital nodes), and the face (e.g. buccal and parotid nodes). Lastly, peculiarities pertaining to the node-positive and the post-operative clinical scenarios were also discussed. In conclusion, implementation of these guidelines in the daily practice of radiation oncology should contribute to the reduction of treatment variations from clinician to clinician and facilitate the conduct of multi-institutional clinical trials.

  View details for PubMedID 24183870

• Racial Disparity in Consultation, Treatment, and the Impact on Survival in Metastatic Colorectal Cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Simpson, D. R., Martinez, M. E., Gupta, S., Hattangadi-Gluth, J., Mell, L. K., Heestand, G., Fanta, P., Ramamoorthy, S., Le, Q., Murphy, J. D. 2013; 105 (23): 1814-1820

  Abstract

  Black patients with metastatic colorectal cancer have inferior survival compared to white patients. The purpose of this study was to examine disparity in specialist consultation and multimodality treatment and the impact that treatment inequality has on survival.We identified 9935 non-Hispanic white and 1281 black patients with stage IV colorectal cancer aged 66 years and older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Logistic regression models identified race-based differences in consultation rates and subsequent treatment with surgery, chemotherapy, or radiation. Multivariable Cox regression models identified potential factors that explain race-based survival differences. All statistical tests were two-sided.Black patients had lower rates of consultation with surgery, medical oncology, and radiation oncology. Among patients seen in consultation, black patients received less surgery directed at the primary tumor, liver- or lung-directed surgery, chemotherapy, and radiotherapy. Unadjusted survival analysis found a 15% higher chance of dying for black patients compared with white patients (hazard ratio [HR] = 1.15; 95% confidence interval (CI) = 1.08 to 1.22; P < .001). Adjustment for patient, tumor, and demographic variables marginally reduced the risk of death (HR = 1.08; 95% CI = 1.01 to 1.15; P = .03). After adjustment for differences in treatment, the increased risk of death for black patients disappeared.Our study shows racial disparity in specialist consultation as well as subsequent treatment with multimodality therapy for metastatic colorectal cancer, and it suggests that inferior survival for black patients may stem from this treatment disparity. Further research into the underlying causes of this inequality will improve access to treatment and survival in metastatic colorectal cancer.

  View details for DOI 10.1093/jnci/djt318

  View details for Web of Science ID 000328370000011

  View details for PubMedID 24231453

• Long-Term Outcomes of Surgery Followed by Radiation Therapy for Minor Salivary Gland Carcinomas LARYNGOSCOPE Zeidan, Y. H., Shultz, D. B., Murphy, J. D., Chan, C., Kaplan, M. J., Colevas, A. D., Kong, C., Chang, D. T., Le, Q. 2013; 123 (11): 2675-2680

  Abstract

  Postoperative radiation therapy is often used in patients with high-risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy.Retrospective cohort study.We performed a retrospective analysis of 90 patients treated with curative intent. Median follow-up was 71 months. Fifty-eight patients (64%) had adenoid cystic carcinomas, 22 (24%) had adenocarcinomas, and 10 (11%) had mucoepidermoid cancers. Primary disease site included 39 (43%) sinonasal, 35 (39%) oral cavity, 10 (11%) oropharynx, and six (7%) others. Twenty-seven patients (30%) were treated with intensity-modulated radiation therapy.Eight local, four neck, and 24 distant relapses were detected. Local control rates at 5 and 10 years were 90% and 88%, respectively. Advanced T stage was associated with worse local control. Distant metastasis rates were 24% and 28% at 5 and 10 years, respectively. Tumor stage, histology, perineural invasion, and lymphovascular space invasion were significant predictors of distant metastasis on univariate analysis. However, on multivariate analysis only the American Joint Committee on Cancer stage was significant. Overall survival rates were 76% and 63% at 5 and 10 years, respectively. More advanced T stage and N stage correlated with worse overall survival.Tumor stage remains the best predictor for locoregional and distant disease control of minor salivary gland cancers. Postoperative radiation therapy for high-risk patients results in excellent long-term locoregional disease control. Further work is needed to improve systemic control.

  View details for DOI 10.1002/lary.24081

  View details for PubMedID 23553253

• Radio logic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status RADIOTHERAPY AND ONCOLOGY Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Quynh-Thu Le, Q. T. 2013; 109 (2): 293-296

  Abstract

  Radiation of retropharyngeal nodes (RPN) results in increased toxicities. This study assessed characteristics associated with RPN involvement in 165 oropharynx cancer patients. Factors associated with involvement were stage N2c-3 disease and stage N2b disease with either advanced T-stage, ⩾3 involved cervical LN, and ⩾1 involved contralateral LN, or lateral/posterior subsites.

  View details for DOI 10.1016/j.radonc.2013.09.001

  View details for Web of Science ID 000329019900020

• Radiologic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status. Radiotherapy and oncology Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Le, Q. 2013; 109 (2): 293-296

  Abstract

  Radiation of retropharyngeal nodes (RPN) results in increased toxicities. This study assessed characteristics associated with RPN involvement in 165 oropharynx cancer patients. Factors associated with involvement were stage N2c-3 disease and stage N2b disease with either advanced T-stage, ⩾3 involved cervical LN, and ⩾1 involved contralateral LN, or lateral/posterior subsites.

  View details for DOI 10.1016/j.radonc.2013.09.001

  View details for PubMedID 24103114

• Clinical impact of dose overestimation by effective path length calculation in stereotactic ablative radiation therapy of lung tumors. Practical radiation oncology Liu, M. B., Eclov, N. C., Trakul, N., Murphy, J., Diehn, M., Le, Q., Dieterich, S., Maxim, P. G., Loo, B. W. 2013; 3 (4): 294-300

  Abstract

  To determine the clinical impact of calculated dose differences between effective path length (EPL) and Monte Carlo (MC) algorithms in stereotactic ablative radiation therapy (SABR) of lung tumors.We retrospectively analyzed the treatment plans and clinical outcomes of 77 consecutive patients treated with SABR for 82 lung tumors between 2003 and 2009 at our institution. Sixty treatments were originally planned using EPL, and 22 using MC. All plans were recalculated for the same beam specifications using MC and EPL, respectively. The doses covering 95%, 50%, and 5% (D95, D50, D5, respectively) of the target volumes were compared between EPL and MC (assumed to be the actual delivered dose), both as physical dose and biologically effective dose. Time to local recurrence was correlated with dose by Cox regression analysis. The relationship between tumor control probability (TCP) and biologically effective dose was determined via logistic regression and used to estimate the TCP decrements due to prescribing by EPL calculations.EPL overestimated dose compared with MC in all tumor dose-volume histogram parameters in all plans. The difference was >10% of the MC D95 to the planning target volume and gross tumor volume in 60 of 82 (73%) and 52 of 82 plans (63%), respectively. Local recurrence occurred in 13 of 82 tumors. Controlling for gross tumor volume, higher physical and biologically effective planning target volume D95 correlated significantly with local control (P = .007 and P = .045, respectively). Compared with MC, prescribing based on EPL translated to a median TCP decrement of 4.3% (range, 1.2%-37%) and a >5% decrement in 46% of tumors.Clinical follow-up for local lung tumor control in a sizable cohort of patients treated with SABR demonstrates that EPL overestimates dose by amounts that substantially decrease TCP in a large proportion. EPL algorithms should be avoided for lung tumor SABR.

  View details for DOI 10.1016/j.prro.2012.09.003

  View details for PubMedID 24674401

• Radiotherapy for nonadenoid cystic carcinomas of major salivary glands. American journal of otolaryngology Chung, M. P., Tang, C., Chan, C., Hara, W. Y., Loo, B. W., Kaplan, M. J., Fischbein, N., Le, Q., Chang, D. T. 2013; 34 (5): 425-430

  Abstract

  To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands.From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years).Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients ≥65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed ≥grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities.Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

  View details for DOI 10.1016/j.amjoto.2013.03.007

  View details for PubMedID 23583094

• Patterns of care in palliative radiotherapy: a population-based study. Journal of oncology practice / American Society of Clinical Oncology Murphy, J. D., Nelson, L. M., Chang, D. T., Mell, L. K., Le, Q. 2013; 9 (5): e220-7

  Abstract

  Approximately one half of the radiotherapy (RT) prescribed in the United States is delivered with palliative intent. The purpose of this study was to investigate the patterns of delivery of palliative RT across the United States.Using the Surveillance, Epidemiology, and End Results-Medicare linked database, 51,610 patients were identified with incident stage IV breast, prostate, lung, or colorectal cancer diagnosed between 2000 and 2007 and observed through 2009. Multivariate logistic regression determined predictors of palliative RT.Forty-one percent of the study population received palliative RT, including 53% of patients with lung cancer, followed by those with breast (42%), prostate (40%), and colorectal cancers (12%). Multivariate analysis revealed that older patients (P<.001) and those with higher Charlson comorbidity scores (P<.001) were less likely to receive palliative RT. Black patients with prostate cancer were 20% less likely (P<.001), and black patients with colorectal cancer were 28% less likely (P<.001), than white patients to receive palliative RT. Among those treated with RT, 23% of patients with lung cancer died within 2 weeks of completing treatment, followed by those with colorectal (12%), breast (11%), and prostate cancers (8%). In addition to tumor site, significant predictors (P<.05) of death within 2 weeks of receiving RT included increased age, increased comorbidity, and male sex.Inequality in the receipt of palliative RT exists among the elderly and patients with comorbid conditions and varies with race. In addition, a significant number of patients die shortly after receiving RT. Understanding these patterns of care, along with further research into the underlying causes, will improve access and quality of palliative RT.

  View details for DOI 10.1200/JOP.2012.000835

  View details for PubMedID 23943892

• A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth. Clinical cancer research Xiao, N., Cao, H., Chen, C., Kong, C. S., Ali, R., Chan, C., Sirjani, D., Graves, E., Koong, A., Giaccia, A., Mochly-Rosen, D., Le, Q. 2013; 19 (16): 4455-4464

  Abstract

  To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo.Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS).Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group.Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia.

  View details for DOI 10.1158/1078-0432.CCR-13-0127

  View details for PubMedID 23812668

• Low-dose radiation therapy (2 Gy × 2) in the treatment of orbital lymphoma. International journal of radiation oncology, biology, physics Fasola, C. E., Jones, J. C., Huang, D. D., Le, Q., Hoppe, R. T., Donaldson, S. S. 2013; 86 (5): 930-935

  Abstract

  Low-dose radiation has become increasingly used in the management of indolent non-Hodgkin lymphoma (NHL), but has not been studied specifically for cases of ocular adnexal involvement. The objective of this study is to investigate the effectiveness of low-dose radiation in the treatment of NHL of the ocular adnexa.We reviewed the records of 20 NHL patients with 27 sites of ocular adnexal involvement treated with low-dose radiation consisting of 2 successive fractions of 2 Gy at our institution between 2005 and 2011. The primary endpoint of this study is freedom from local relapse (FFLR).At a median follow-up time of 26 months (range 7-92), the overall response rate for the 27 treated sites was 96%, with a complete response (CR) rate of 85% (n=23) and a partial response rate of 11% (n=3). Among all treated sites with CR, the 2-year FFLR was 100%, with no in-treatment field relapses. The 2-year freedom from regional relapse rate was 96% with 1 case of relapse within the ipsilateral orbit (outside of the treatment field). This patient underwent additional treatment with low-dose radiation of 4 Gy to the area of relapse achieving a CR and no evidence of disease at an additional 42 months of follow-up. Orbital radiation was well tolerated with only mild acute side effects (dry eye, conjunctivitis, transient periorbital edema) in 30% of treated sites without any reports of long-term toxicity.Low-dose radiation with 2 Gy × 2 is effective and well tolerated in the treatment of indolent NHL of the ocular adnexa with high response rates and durable local control with the option of reirradiation in the case of locoregional relapse.

  View details for DOI 10.1016/j.ijrobp.2013.04.035

  View details for PubMedID 23726002

• Cost-effectiveness landscape analysis of treatments addressing xerostomia in patients receiving head and neck radiation therapy. Oral surgery, oral medicine, oral pathology and oral radiology Sasportas, L. S., Hosford, D. N., Sodini, M. A., Waters, D. J., Zambricki, E. A., Barral, J. K., Graves, E. E., Brinton, T. J., Yock, P. G., Le, Q., Sirjani, D. 2013; 116 (1): e37-51

  Abstract

  Head and neck (H&N) radiation therapy (RT) can induce irreversible damage to the salivary glands thereby causing long-term xerostomia or dry mouth in 68%-85% of the patients. Not only does xerostomia significantly impair patients' quality-of-life (QOL) but it also has important medical sequelae, incurring high medical and dental costs. In this article, we review various measures to assess xerostomia and evaluate current and emerging solutions to address this condition in H&N cancer patients. These solutions typically seek to accomplish 1 of the 4 objectives: (1) to protect the salivary glands during RT, (2) to stimulate the remaining gland function, (3) to treat the symptoms of xerostomia, or (4) to regenerate the salivary glands. For each treatment, we assess its mechanisms of action, efficacy, safety, clinical utilization, and cost. We conclude that intensity-modulated radiation therapy is both the most widely used prevention approach and the most cost-effective existing solution and we highlight novel and promising techniques on the cost-effectiveness landscape.

  View details for DOI 10.1016/j.oooo.2013.02.017

  View details for PubMedID 23643579

• Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck. American journal of clinical oncology Tang, C., Fischbein, N. J., Murphy, J. D., Chu, K. P., Bavan, B., Dieterich, S., Hara, W., Kaplan, M. J., Colevas, A. D., Le, Q. 2013; 36 (3): 293-298

  Abstract

  : To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI).: Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns.: At a median 22-month follow-up, the 2-year progression-free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation.: Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed.

  View details for DOI 10.1097/COC.0b013e3182468019

  View details for PubMedID 22547009

• Opportunities and challenges in the era of molecularly targeted agents and radiation therapy. Journal of the National Cancer Institute Lin, S. H., George, T. J., Ben-Josef, E., Bradley, J., Choe, K. S., Edelman, M. J., Guha, C., Krishnan, S., Lawrence, T. S., Le, Q., Lu, B., Mehta, M., Peereboom, D., Sarkaria, J., Seong, J., Wang, D., Welliver, M. X., Coleman, C. N., Vikram, B., Yoo, S., Chung, C. H. 2013; 105 (10): 686-693

  Abstract

  The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8-9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.

  View details for DOI 10.1093/jnci/djt055

  View details for PubMedID 23503600

• An international collaboration to harmonize the quantitative plasma Epstein-Barr virus DNA assay for future biomarker-guided trials in nasopharyngeal carcinoma. Clinical cancer research Le, Q., Zhang, Q., Cao, H., Cheng, A., Pinsky, B. A., Hong, R., Chang, J. T., Wang, C., Tsao, K., Lo, Y. D., Lee, N., Ang, K. K., Chan, A. T., Chan, K. C. 2013; 19 (8): 2208-2215

  Abstract

  Persistently elevated posttreatment plasma EBV DNA is a robust predictor of relapse in nasopharyngeal carcinoma (NPC). However, assay standardization is necessary for use in biomarker-driven trials. We conducted a study to harmonize the method between four centers with expertise in EBV DNA quantitation.Plasma samples of 40 patients with NPC were distributed to four centers. DNA was extracted and EBV DNA copy number was determined by real-time quantitative PCR (BamHI-W primer/probe). Centers used the same protocol but generated their own calibrators. A harmonization study was then conducted using the same calibrators and PCR master mix and validated with ten pooled samples.The initial intraclass correlations (ICC) for the first 40 samples between each center and the index center were 0.62 [95% confidence interval (CI): 0.39-0.78], 0.70 (0.50-0.83), and 0.59 (0.35-0.76). The largest variability was the use of different PCR master mixes and calibrators. Standardization improved ICC to 0.83 (0.5-0.95), 0.95 (0.83-0.99) and 0.96 (0.86-0.99), respectively, for ten archival frozen samples. For fresh plasma with spiked-in EBV DNA, correlations were more than 0.99 between the centers. At 5 EBV DNA copies per reaction or above, the coefficient of variance (CV) was less than 10% for the cycle threshold (Ct) among all centers, suggesting this concentration can be reliably used as a cutoff for defining the presence of detectable EBV DNA.Quantitative PCR assays, even when conducted in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers without harmonization. The use of common calibrators and PCR master mix can help to reduce variability.

  View details for DOI 10.1158/1078-0432.CCR-12-3702

  View details for PubMedID 23459720

  View details for PubMedCentralID PMC3630245

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence. Cancer Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Le, Q., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for PubMedID 23225544

• Results of a phase 2 study examining the effects of omitting elective neck irradiation to nodal levels IV and Vb in patients with N(0-1) nasopharyngeal carcinoma. International journal of radiation oncology, biology, physics Chen, J., Le, Q., Han, F., Lu, L., Huang, S., Lin, C., Deng, X., Cui, N., Zhao, C. 2013; 85 (4): 929-934

  Abstract

  To evaluate the patterns of nodal failure and toxicity in clinically negative necks of N0-1 nasopharyngeal carcinoma (NPC) patients who were treated with intensity modulated radiation therapy (IMRT) but did not receive elective neck irradiation (ENI) to level IV and Vb nodes.We conducted a phase 2 prospective study in N0-1 NPC patients treated with IMRT. ENI included the retropharyngeal nodes and levels II to Va but omitted levels IV and Vb in clinically negative necks. Patterns of nodal failure, regional control (RC), and late toxicity were evaluated.Between 2001 and 2008, a total of 212 patients (128 N0 and 84 N1) were enrolled in the study. Seven patients (4 in-field and 3 out-of-field) developed nodal failure. One patient (0.5%) developed nodal failure at level Vb, but no patients developed nodal failure at level IV. The 5-year RC rates of the entire group, N0 patients and N1 patients were 95.6%, 98.2%, and 91.3%, respectively. Fifteen patients (7.1%) developed distant metastases. The 5-year distant failure-free survival (DFFS) and overall survival (OS) rates were 91.4% and 89.8%, respectively. The rates of grade 2 or greater skin dystrophy, subcutaneous fibrosis and xerostomia were 6.2%, 16.6%, and 17.9%, respectively.The rate of out-of-field nodal failure when omitting ENI to levels IV and Vb in clinically negative necks of patients with N0-1 NPC was extremely low; therefore, a further phase 3 study is warranted.

  View details for DOI 10.1016/j.ijrobp.2012.07.2356

  View details for PubMedID 22975606

• Volumetric-modulated arc radiotherapy for skull-base and non-skull-base head and neck cancer: a treatment planning comparison with fixed Beam IMRT. Technology in cancer research & treatment Chen, J., Mok, E., Wang, L., Chen, C., Le, Q. 2013; 12 (1): 11-18

  Abstract

  The purpose of this study is to compare the dose distribution, monitor units (MUs) and radiation delivery time between volumetric-modulated arc (VMAT) and fix-beam intensity modulated radiotherapy (FB-IMRT) in skull-base and non-skull-base head and neck cancer (HNC). CT datasets of 8 skull-base and 7 non-skull-base HNC were identified. IMRT and VMAT plans were generated. The prescription dose ranged 45-70 Gy (1.8-2.2 Gy/fraction). The VMAT delivery time was measured when these plans were delivered to the patients. The FB-IMRT delivery time was generated on a phantom. Comparison of dose-volume histogram data, MUs, and delivery times was performed using T-test. Our results show that both plans yield similar target volume coverage, homogeneity, and conformity. In skull-base cases, compared to FB-IMRT, VMAT generated significantly smaller hot-spot inside PTV (2.0% vs. 4.5%, p = 0.031), lower maximum chiasm dose (32 ± 11 Gy vs. 41 ± 15 Gy, p = 0.026), lower ipsilateral temporal-mandibular joint dose (D33: 41.4 Gy vs. 46.1 Gy, p = 0.016), lower mean ipsilateral middle ear dose (43 ± 9 Gy vs. 38 ± 10 Gy, p = 0.020) and a trend for lower optic nerve, temporal lobe, parotid, and oral cavity dose. In non-skull-base cases, doses to normal tissues were similar between the two plans. There was a reduction of 70% in MUs (486 ± 95 vs. 1614 ± 493, p < 0.001) and 73% in delivery times (3.0 ± 0.6 vs. 11.0 ± 3.3 min, p < 0.001) favoring VMAT. We conclude that VMAT appears to spare more normal tissues from high radiation dose for the tested skull-base tumors. Dosimetrically, both approaches were equivalent for non-skull-base tumor with VMAT using fewer MUs and shorter delivery time.

  View details for PubMedID 22905805

• Migration of implanted markers for image-guided lung tumor stereotactic ablative radiotherapy. Journal of applied clinical medical physics Hong, J. C., Eclov, N. C., Yu, Y., Rao, A. K., Dieterich, S., Le, Q., Diehn, M., Sze, D. Y., Loo, B. W., Kothary, N., Maxim, P. G. 2013; 14 (2): 4046-?

  Abstract

  The purpose of this study was to quantify postimplantation migration of percutaneously implanted cylindrical gold seeds ("seeds") and platinum endovascular embolization coils ("coils") for tumor tracking in pulmonary stereotactic ablative radiotherapy (SABR). We retrospectively analyzed the migration of markers in 32 consecutive patients with computed tomography scans postimplantation and at simulation. We implanted 147 markers (59 seeds, 88 coils) in or around 34 pulmonary tumors over 32 procedures, with one lesion implanted twice. Marker coordinates were rigidly aligned by minimizing fiducial registration error (FRE), the root mean square of the differences in marker locations for each tumor between scans. To also evaluate whether single markers were responsible for most migration, we aligned with and without the outlier causing the largest FRE increase per tumor. We applied the resultant transformation to all markers. We evaluated migration of individual markers and FRE of each group. Median scan interval was 8 days. Median individual marker migration was 1.28 mm (interquartile range [IQR] 0.78-2.63 mm). Median lesion FRE was 1.56 mm (IQR 0.92-2.95 mm). Outlier identification yielded 1.03 mm median migration (IQR 0.52-2.21 mm) and 1.97 mm median FRE (IQR 1.44-4.32 mm). Outliers caused a mean and median shift in the centroid of 1.22 and 0.80 mm (95th percentile 2.52 mm). Seeds and coils had no statistically significant difference. Univariate analysis suggested no correlation of migration with the number of markers, contact with the chest wall, or time elapsed. Marker migration between implantation and simulation is limited and unlikely to cause geometric miss during tracking.

  View details for DOI 10.1120/jacmp.v14i2.4046

  View details for PubMedID 23470933

• Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse. Oral surgery, oral medicine, oral pathology and oral radiology Kong, C. S., Cao, H., Kwok, S., Nguyen, C. M., Jordan, R. C., Beaudry, V. G., Attardi, L. D., Le, Q. 2013; 115 (1): 95-103

  Abstract

  PERP is a p53/p63-regulated gene encoding a desmosomal protein that plays a critical role in cell-cell adhesion and tumor suppression.We evaluated PERP expression in different grades of oral dysplasia (34 cases) and at different stages of invasive squamous cell carcinoma (SCC), and correlated the latter with clinical outcome. A tissue microarray consisting of nondysplastic mucosa, carcinoma in situ, SCC, and nodal metastases from 33 patients with human papilloma virus-negative SCC was stained for PERP and E-cadherin.Complete loss of PERP expression was associated with worse local control in patients with SCC. The 5-year local control rate was 91% for patients with partial PERP loss versus 31% for those with complete loss (P = .01).This is the first study to show that loss of PERP expression correlates with the transition to SCC and with increased local relapse in patients with oral cavity SCC.

  View details for DOI 10.1016/j.oooo.2012.10.017

  View details for PubMedID 23217540

• Metabolic imaging metrics correlate with survival in early stage lung cancer treated with stereotactic ablative radiotherapy. Lung cancer Abelson, J. A., Murphy, J. D., Trakul, N., Bazan, J. G., Maxim, P. G., Graves, E. E., Quon, A., Le, Q., Diehn, M., Loo, B. W. 2012; 78 (3): 219-224

  Abstract

  To test whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging metrics correlate with outcomes in patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).Fifty-four patients with stage I NSCLC underwent pre-SABR PET at simulation and/or post-SABR PET within 6 months. We analyzed maximum standardized uptake value (SUV(max)) and metabolic tumor volume defined using several thresholds (MTV50%, or MTV2, 4, 7, and 10). Endpoints included primary tumor control (PTC), progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). We performed Kaplan-Meier, competing risk, and Cox proportional hazards survival analyses.Patients received 25-60 Gy in 1 to 5 fractions. Median follow-up time was 13.2 months. The 1-year estimated PTC, PFS, OS and CSS were 100, 83, 87 and 94%, respectively. Pre-treatment SUV(max) (p=0.014), MTV(7) (p=0.0077), and MTV(10) (p=0.0039) correlated significantly with OS. In the low-MTV(7)vs. high-MTV(7) sub-groups, 1-year estimated OS was 100 vs. 78% (p=0.0077) and CSS was 100 vs. 88% (p=0.082).In this hypothesis-generating study we identified multiple pre-treatment PET-CT metrics as potential predictors of OS and CSS in patients with NSCLC treated with SABR. These could aid risk-stratification and treatment individualization if validated prospectively.

  View details for DOI 10.1016/j.lungcan.2012.08.016

  View details for PubMedID 23009727

• CD44+cells have cancer stem cell-like properties in nasopharyngeal carcinoma INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Janisiewicz, A. M., Shin, J. H., Murillo-Sauca, O., Kwok, S., Quynh-Thu Le, Q. T., Kong, C., Kaplan, M. J., Sunwoo, J. B. 2012; 2 (6): 465-470

  Abstract

  A subpopulation of cells within a tumor appears to have the exclusive ability to initiate tumors, self-renew, and differentiate. These "cancer stem cells" (CSCs) are CD44(+) in several epithelial malignancies. We examined the potential of CD44 to identify the CSC population in nasopharyngeal carcinoma (NPC).C666, an Epstein-Barr virus-positive (EBV(+) ) human NPC cell line, was stained for CD44 and sorted by fluorescence-activated cell sorting (FACS). CD44(+) and CD44(-) subpopulations were evaluated for (1) proliferative potential, (2) ability to differentiate, (3) expression of markers of epithelial-to-mesenchymal transition (EMT) and EBV genes, and (4) the ability to initiate tumors in vivo. Immunocompromised mice were injected with CD44(+) and CD44(-) populations to assess the tumor-initiating capacity. Immunohistochemistry for CD44 was performed on an 87-patient tissue microarray (TMA), and clinical correlations were examined.Heterogeneous expression of CD44 was seen among C666 cells. CD44(+) cells differentiated into CD44(-) cells, indicating a hierarchical relationship. Further, CD44(+) cells exhibited a more robust tumor-initiating capacity in the xenograft model. However, no differences were seen in proliferation rates in vitro, EBV gene expression, or expression of EMT markers between CD44(+) and CD44(-) subsets. Patient tumors were heterogeneous for CD44 staining, and a trend toward an association between CD44 expression and clinical outcome was observed.NPC contains a CD44(+) subpopulation with features consistent with CSCs. There was a trend toward an association between CD44 expression within NPC tumors and decreased time to local failure/relapse in patients.

  View details for DOI 10.1002/alr.21068

  View details for PubMedID 22887934

• Radiologic Assessment of Lymph Node Involvement in HPV/p16+Oropharyngeal Cancers 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Tang, C., Komakula, S., Chan, C., Murphy, J., Kong, C., Jensen, K., Le, Q. ELSEVIER SCIENCE INC. 2012: S473–S473

  View details for Web of Science ID 000310542901391

• Feasibility of Optimizing IMRT Plans Based on Measured Mucosal Dose to Adjacent Metallic Dental Fillings for Head-and-Neck Cancer Patients 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Wang, L., Mok, E., Xing, L., Khong, B., Hara, W., Le, Q. ELSEVIER SCIENCE INC. 2012: S462–S463

  View details for Web of Science ID 000310542901363

• Feasibility of Pulmonary Interstitial Lymphography-guided Targeting in Stereotactic Ablative Radiation Therapy of Lung Tumors 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Abelson, J. A., Kothary, N., Fleischmann, D., Hofmann, L., Kielar, K., Maxim, P., Le, Q., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2012: S173–S173

  View details for Web of Science ID 000310542900432

• The Application of FDG-PET as Prognostic Indicators in Head and Neck Squamous Cell Carcinoma. PET clinics Siddiqui, F., Faulhaber, P. F., Yao, M., Le, Q. 2012; 7 (4): 381-394

  Abstract

  This article discusses the role of FDG-PETederived parameters as prognostic indicators in patients with squamous cell carcinoma of the head and neck. The basic underlying biology of FDG-PET scans and the quantitative information that can be derived are discussed. A review of the literature is performed. Potential applications in the management of head and neck cancer and future directions in clinical trials are discussed.

  View details for DOI 10.1016/j.cpet.2012.06.003

  View details for PubMedID 27157645

• Esophageal tolerance to high-dose stereotactic ablative radiotherapy DISEASES OF THE ESOPHAGUS Abelson, J. A., Murphy, J. D., Loo, B. W., Chang, D. T., Daly, M. E., Wiegner, E. A., Hancock, S., Chang, S. D., Le, Q., Soltys, S. G., Gibbs, I. C. 2012; 25 (7): 623-629

  Abstract

  Dose-volume parameters are needed to guide the safe administration of stereotactic ablative radiotherapy (SABR). We report on esophageal tolerance to high-dose hypofractionated radiation in patients treated with SABR. Thirty-one patients with spine or lung tumors received single- or multiple-fraction SABR to targets less than 1 cm from the esophagus. End points evaluated include D(5cc) (minimum dose in Gy to 5 cm(3) of the esophagus receiving the highest dose), D(2cc) , D(1cc) , and D(max) (maximum dose to 0.01 cm(3) ). Multiple-fraction treatments were correlated using the linear quadratic and linear quadratic-linear/universal survival models. Three esophageal toxicity events occurred, including esophagitis (grade 2), tracheoesophageal fistula (grade 4-5), and esophageal perforation (grade 4-5). Chemotherapy was a cofactor in the high-grade events. The median time to development of esophageal toxicity was 4.1 months (range 0.6-6.1 months). Two of the three events occurred below a published D(5cc) threshold, all three were below a D(2cc) threshold, and one was below a D(max) threshold. We report a dosimetric analysis of incidental dose to the esophagus from SABR. High-dose hypofractionated radiotherapy led to a number of high-grade esophageal adverse events, suggesting that conservative parameters to protect the esophagus are necessary when SABR is used, especially in the setting of chemotherapy or prior radiotherapy.

  View details for DOI 10.1111/j.1442-2050.2011.01295.x

  View details for PubMedID 22168251

• Stereotactic Ablative Radiotherapy for Reirradiation of Locally Recurrent Lung Tumors JOURNAL OF THORACIC ONCOLOGY Trakul, N., Harris, J. P., Le, Q., Hara, W. Y., Maxim, P. G., Loo, B. W., Diehn, M. 2012; 7 (9): 1462-1465

  Abstract

  Patients with thoracic tumors that recur after irradiation currently have limited therapeutic options. Retreatment using stereotactic ablative radiotherapy (SABR) is appealing for these patients because of its high conformity but has not been studied extensively. Here we report our experience with SABR for lung tumors in previously irradiated regions.We conducted a retrospective study of patients with primary lung cancer or metastatic lung tumors treated with SABR. We identified 17 such tumors in 15 patients and compared their outcomes with those of a cohort of 135 previously unirradiated lung tumors treated with SABR during the same time period.Twelve-month local control (LC) for retreated tumors was 65.5%, compared with 92.1% for tumors receiving SABR as initial treatment. Twelve-month LC was significantly worse for reirradiated tumors in which the time interval between treatments was 16 months or less (46.7%), compared with those with longer intertreatment intervals (87.5%). SABR reirradiation did not lead to significant increases in treatment-related toxicity.SABR for locally recurrent lung tumors arising in previously irradiated fields seems to be feasible and safe for appropriately selected patients. LC of retreated lesions was significantly lower, likely owing to the lower doses used for retreatment. Shorter time to retreatment was associated with increased risk of local failure, suggesting that these tumors may be particularly radioresistant. Our findings suggest that dose escalation may improve LC while maintaining acceptable levels of toxicity for these patients.

  View details for DOI 10.1097/JTO.0b013e31825f22ce

  View details for Web of Science ID 000308073300024

  View details for PubMedID 22895143

• Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237

  Abstract

  Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

  View details for DOI 10.1016/j.ijrobp.2011.10.071

  View details for PubMedID 22381907

• Intrafraction Verification of Gated RapidArc by Using Beam-Level Kilovoltage X-Ray Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Li, R., Mok, E., Chang, D. T., Daly, M., Loo, B. W., Diehn, M., Quynh-Thu Le, Q. T., Koong, A., Xing, L. 2012; 83 (5): E709-E715

  Abstract

  To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.The average 3D distance between the markers and their ITVs was 0.8 ± 0.5 mm (range, 0-1.7 mm) and was 2.1 ± 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.

  View details for DOI 10.1016/j.ijrobp.2012.03.006

  View details for PubMedID 22554582

• Evaluation of ProExC as a Prognostic Marker in Oropharyngeal Squamous Cell Carcinomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Beck, A. H., Pourmand, N., Quynh Thu Le, Q. T., Kong, C. S. 2012; 36 (8): 1158-1164

  Abstract

  ProExC expression has been shown to perform similarly to p16 as an aid in the diagnosis of cervical dysplasia but has not been well characterized in head and neck squamous cell carcinomas (SCC). The purpose of this study is to determine whether ProExC performs similarly to p16 as a prognostic marker in oropharyngeal SCC and to evaluate the threshold of ProExC and p16 staining that correlates with survival. ProExC, p16, and human papillomavirus DNA in situ hybridization were performed on tissue microarray (TMA) cores and whole sections from 62 patients with oropharyngeal SCC. Sensitivity and specificity for high-risk HPV and correlation with overall survival (OS), cancer-specific survival (CSS), and time to distant metastasis (TDM) were calculated for ProExC and p16 at different thresholds. ProExC did not prove to be a robust marker. It showed strong correlation with OS at a 66% threshold on TMA cores, but correlation with OS was lost on whole sections. It also exhibited low sensitivity (53.7%) on TMA cores and low specificity on whole sections (65%). ProExC at a 33% threshold exhibited unacceptably low specificity and did not correlate with OS, CSS, or TDM. Sensitivity and specificity of p16 varied predictably with threshold: higher sensitivity and lower specificity with lower thresholds and vice versa for higher thresholds. p16 at a 50% threshold offers a balance between sensitivity and specificity, and correlates with OS, CSS, and TDM on whole sections; correlation with TDM is lost on TMA cores. These findings indicate that ProExC does not perform well enough to be used as a prognostic marker in oropharyngeal SCC. p16 should be used and scored as positive when at least half the tumor is strongly stained.

  View details for DOI 10.1097/PAS.0b013e3182600eaa

  View details for PubMedID 22790856

• Validation that metabolic tumor volume predicts outcome in head-and-neck cancer. International journal of radiation oncology, biology, physics Tang, C., Murphy, J. D., Khong, B., La, T. H., Kong, C., Fischbein, N. J., Colevas, A. D., Iagaru, A. H., Graves, E. E., Loo, B. W., Le, Q. 2012; 83 (5): 1514-1520

  Abstract

  We have previously reported that metabolic tumor volume (MTV) obtained from pretreatment (18)F-fluorodeoxydeglucose positron emission tomography (FDG PET)/ computed tomography (CT) predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study was to validate these results on an independent dataset, determine whether the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16(INK4a) status as a surrogate marker for human papillomavirus (HPV).The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan before receiving definitive radiotherapy. MTV and maximum standardized uptake value (SUV(max)) were calculated for the primary tumor, the involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor vs. nodal MTV.Similarly to our prior findings, an increase in total MTV of 17 cm(3) (difference between the 75th and 25th percentiles) was associated with a 2.1-fold increase in the risk of disease progression (p = 0.0002) and a 2.0-fold increase in the risk of death (p = 0.0048). SUV(max) was not associated with either outcome. Primary tumor MTV predicted progression-free (hazard ratio [HR] = 1.94; p < 0.0001) and overall (HR = 1.57; p < 0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR = 4.23; p < 0.0001) and overall (HR = 3.21; p = 0.0029) survival in patients with p16(INK4a)-positive oropharyngeal cancer.This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk-stratifying biomarker in future studies of HNC.

  View details for DOI 10.1016/j.ijrobp.2011.10.023

  View details for PubMedID 22270174

• Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head-and-Neck Cancer Outcomes INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Chu, K. P., Murphy, J. D., La, T. H., Krakow, T. E., Iagaru, A., Graves, E. E., Hsu, A., Maxim, P. G., Loo, B., Chang, D. T., Quynh-Thu Le, Q. T. 2012; 83 (5): 1521-1527

  Abstract

  We previously showed that metabolic tumor volume (MTV) on positron emission tomography-computed tomography (PET-CT) predicts for disease recurrence and death in head-and-neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and would predict outcome. We sought to examine tumor growth over time in serial pretreatment PET-CT scans.From 2006 to 2009, 51 patients had two PET-CT scans before receiving HNC treatment. MTV was defined as the tumor volume ≥ 50% of maximum SUV (SUV(max)). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUV(max) over time, respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival).The median follow-up time was 17.5 months. The median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUV(max) (average, -0.1 cc/week) and MTV (average, -0.3 cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio 2.94; p = 0.01) and overall survival (hazard ratio 1.85; p = 0.03).Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival in comparison to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when PET-CT biomarkers are integrated into clinical protocols for HNC.

  View details for DOI 10.1016/j.ijrobp.2011.10.022

  View details for PubMedID 22270168

• Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group. International journal of radiation oncology, biology, physics Ausborn, N. L., Le, Q. T., Bradley, J. D., Choy, H., Dicker, A. P., Saha, D., Simko, J., Story, M. D., Torossian, A., Lu, B. 2012; 83 (4): e453-64

  Abstract

  Therapeutic decisions in non-small cell lung cancer (NSCLC) have been mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Rather than applying broad treatments to unselected patients that may result in survival increase of only weeks to months, research efforts should be, and are being, focused on identifying predictive markers for molecularly targeted therapy and determining genomic signatures that predict survival and response to specific therapies. The availability of such targeted biologics requires their use to be matched to tumors of corresponding molecular vulnerability for maximum efficacy. Molecular markers such as epidermal growth factor receptor (EGFR), K-ras, vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and anaplastic lymphoma kinase (ALK) represent potential parameters guide treatment decisions. Ultimately, identifying patients who will respond to specific therapies will allow optimal efficacy with minimal toxicity, which will result in more judicious and effective application of expensive targeted therapy as the new paradigm of personalized medicine develops.

  View details for DOI 10.1016/j.ijrobp.2012.01.056

  View details for PubMedID 22520478

• A Planned Neck Dissection Is Not Necessary in All Patients With N2-3 Head-and-Neck Cancer After Sequential Chemoradiotherapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Soltys, S. G., Choi, C. Y., Fee, W. E., Pinto, H. A., Le, Q. 2012; 83 (3): 994-999

  Abstract

  To assess the role of a planned neck dissection (PND) after sequential chemoradiotherapy for patients with head-and-neck cancer with N2-N3 nodal disease.We reviewed 90 patients with N2-N3 head-and-neck squamous cell carcinoma treated between 1991 and 2001 on two sequential chemoradiotherapy protocols. All patients received induction and concurrent chemotherapy with cisplatin and 5-fluorocuracil, with or without tirapazamine. Patients with less than a clinical complete response (cCR) in the neck proceeded to a PND after chemoradiation. The primary endpoint was nodal response. Clinical outcomes and patterns of failure were analyzed.The median follow-up durations for living and all patients were 8.3 years (range, 1.5-16.3 year) and 5.4 years (range, 0.6-16.3 years), respectively. Of the 48 patients with nodal cCR whose necks were observed, 5 patients had neck failures as a component of their recurrence [neck and primary (n = 2); neck, primary, and distant (n = 1); neck only (n = 1); neck and distant (n = 1)]. Therefore, PND may have benefited only 2 patients (4%) [neck only failure (n = 1); neck and distant failure (n = 1)]. The pathologic complete response (pCR) rate for those with a clinical partial response (cPR) undergoing PND (n = 30) was 53%. The 5-year neck control rates after cCR, cPR→pCR, and cPR→pPR were 90%, 93%, and 78%, respectively (p = 0.36). The 5-year disease-free survival rates for the cCR, cPR→pCR, and cPR→pPR groups were 53%, 75%, and 42%, respectively (p = 0.04).In our series, patients with N2-N3 neck disease achieving a cCR in the neck, PND would have benefited only 4% and, therefore, is not recommended. Patients with a cPR should be treated with PND. Residual tumor in the PND specimens was associated with poor outcomes; therefore, aggressive therapy is recommended. Studies using novel imaging modalities are needed to better assess treatment response.

  View details for DOI 10.1016/j.ijrobp.2011.07.042

  View details for Web of Science ID 000305256000055

  View details for PubMedID 22137026

• Intensity-Modulated Radiotherapy for Tumors of the Nasal Cavity and Paranasal Sinuses: Clinical Outcomes and Patterns of Failure 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Wiegner, E. A., Daly, M. E., Murphy, J. D., Abelson, J., Chapman, C. H., Chung, M., Yu, Y., Colevas, A. D., Kaplan, M. J., Fischbein, N., Quynh-Thu Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 243–51

  Abstract

  To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC).Between June 2000 and December 2009, 52 patients with tumors of the PNS/NC underwent postoperative or definitive radiation with IMRT. Twenty-eight (54%) patients had squamous cell carcinoma (SCC). Twenty-nine patients (56%) received chemotherapy. The median follow-up was 26.6 months (range, 2.9-118.4) for all patients and 30.9 months for living patients.Eighteen patients (35%) developed local-regional failure (LRF) at median time of 7.2 months. Thirteen local failures (25%) were observed, 12 in-field and 1 marginal. Six regional failures were observed, two in-field and four out-of-field. No patients treated with elective nodal radiation had nodal regional failure. Two-year local-regional control (LRC), in-field LRC, freedom from distant metastasis (FFDM), and overall survival (OS) were 64%, 74%, 71%, and 66% among all patients, respectively, and 43%, 61%, 61%, and 53% among patients with SCC, respectively. On multivariate analysis, SCC and >1 subsite involved had worse LRC (p = 0.0004 and p = 0.046, respectively) and OS (p = 0.003 and p = 0.046, respectively). Cribriform plate invasion (p = 0.005) and residual disease (p = 0.047) also had worse LRC. Acute toxicities included Grade ≥3 mucositis in 19 patients (37%), and Grade 3 dermatitis in 8 patients (15%). Six patients had Grade ≥3 late toxicity including one optic toxicity.IMRT for patients with PNS/NC tumors has good outcomes compared with historical series and is well tolerated. Patients with SCC have worse LRC and OS. LRF is the predominant pattern of failure.

  View details for DOI 10.1016/j.ijrobp.2011.05.044

  View details for PubMedID 22019239

• Prognostic and Predictive Significance of Plasma HGF and IL-8 in a Phase III Trial of Chemoradiation with or without Tirapazamine in Locoregionally Advanced Head and Neck Cancer CLINICAL CANCER RESEARCH Quynh-Thu Le, Q. T., Fisher, R., Oliner, K. S., Young, R. J., Cao, H., Kong, C., Graves, E., Hicks, R. J., McArthur, G. A., Peters, L., O'Sullivan, B., Giaccia, A., Rischin, D. 2012; 18 (6): 1798-1807

  Abstract

  Hepatocyte growth factor (HGF) is a hypoxia-induced secreted protein that binds to cMet and regulates interleukin (IL)-8 expression. We evaluated the role of circulating HGF and IL-8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.Patients with stages III to IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or CIS plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL-8 assay by ELISA and no major radiation deviations (N = 498). Analyses included adjustment for major prognostic factors. p16(INK4A) staining (human papillomavirus surrogate) was carried out on available tumors. Thirty-nine patients had hypoxia imaging with (18)F-fluoroazomycin arabinoside ((18)FAZA)-positron emission tomography.Elevated IL-8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (P = 0.053); elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16(INK4A)-negative patients. Four subgroups defined by high and low HGF/IL-8 levels were examined for TPZ effect; the test for interaction with arm was P = 0.099. TPZ/CIS seemed to be beneficial for patients with high HGF and IL-8 but adverse for low HGF and high IL-8. Only HGF correlated with (18)FAZA tumor standard uptake value.IL-8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL-8/HGF levels seemed to do better with TPZ/CIS while others did worse, highlighting the complexity of hypoxia targeting in unselected patients.

  View details for DOI 10.1158/1078-0432.CCR-11-2094

  View details for PubMedID 22383739

• Quantitation of Human Papillomavirus DNA in Plasma of Oropharyngeal Carcinoma Patients INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Cao, H., Banh, A., Kwok, S., Shi, X., Wu, S., Krakow, T., Khong, B., Bavan, B., Bala, R., Pinsky, B. A., Colevas, D., Pourmand, N., Koong, A. C., Kong, C. S., Quynh-Thu Le, Q. T. 2012; 82 (3): E351-E358

  Abstract

  To determine whether human papillomavirus (HPV) DNA can be detected in the plasma of patients with HPV-positive oropharyngeal carcinoma (OPC) and to monitor its temporal change during radiotherapy.We used polymerase chain reaction to detect HPV DNA in the culture media of HPV-positive SCC90 and VU147T cells and the plasma of SCC90 and HeLa tumor-bearing mice, non-tumor-bearing controls, and those with HPV-negative tumors. We used real-time quantitative polymerase chain reaction to quantify the plasma HPV DNA in 40 HPV-positive OPC, 24 HPV-negative head-and-neck cancer patients and 10 non-cancer volunteers. The tumor HPV status was confirmed by p16(INK4a) staining and HPV16/18 polymerase chain reaction or HPV in situ hybridization. A total of 14 patients had serial plasma samples for HPV DNA quantification during radiotherapy.HPV DNA was detectable in the plasma samples of SCC90- and HeLa-bearing mice but not in the controls. It was detected in 65% of the pretreatment plasma samples from HPV-positive OPC patients using E6/7 quantitative polymerase chain reaction. None of the HPV-negative head-and-neck cancer patients or non-cancer controls had detectable HPV DNA. The pretreatment plasma HPV DNA copy number correlated significantly with the nodal metabolic tumor volume (assessed using (18)F-deoxyglucose positron emission tomography). The serial measurements in 14 patients showed a rapid decline in HPV DNA that had become undetectable at radiotherapy completion. In 3 patients, the HPV DNA level had increased to a discernable level at metastasis.Xenograft studies indicated that plasma HPV DNA is released from HPV-positive tumors. Circulating HPV DNA was detectable in most HPV-positive OPC patients. Thus, plasma HPV DNA might be a valuable tool for identifying relapse.

  View details for DOI 10.1016/j.ijrobp.2011.05.061

  View details for PubMedID 21985946

• Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial LANCET ONCOLOGY Lee, N. Y., Zhang, Q., Pfister, D. G., Kim, J., Garden, A. S., Mechalakos, J., Hu, K., Le, Q. T., Colevas, A. D., Glisson, B. S., Chan, A. T., Ang, K. K. 2012; 13 (2): 172-180

  Abstract

  We aimed to improve the outcomes for locoregionally advanced nasopharyngeal carcinoma by testing the feasibility and safety of the addition of bevacizumab to chemoradiotherapy.We enrolled patients older than 18 years with stage IIB-IVB nasopharyngeal carcinoma from 19 centres in North America and Hong Kong. Treatment consisted of three cycles of bevacizumab (15 mg/kg) and cisplatin (100 mg/m(2)) both given on days 1, 22, and 43 of radiation (70 Gy) with intensity-modulated radiation therapy delivered over 33 days on a daily basis, Monday through Friday. Patients then received three cycles of bevacizumab (15 mg/kg) and cisplatin (80 mg/m(2)), both given on days 64, 85, and 106 after radiation, and three cycles of fluorouracil (1000 mg/m(2) per day), given on days 64-67, 85-88, and 106-109 after radiation. The primary endpoint was the occurrence of treatment-related grade 4 haemorrhage or any grade 5 adverse event in the first year. Analyses were done with all eligible patients who started protocol treatment. The trial is registered at ClinicalTrials.gov, number NCT00408694.From Dec 13, 2006, to Feb 5, 2009, we enrolled 46 patients, of whom 44 were eligible for analysis. We recorded no grade 3-4 haemorrhages or grade 5 adverse events; nine patients (20%) had a treatment-related grade 1-2 haemorrhage. Nine patients had one or more grade 4 blood or bone marrow-related complication (grade 4 leucopenia was noted in six patients, grade 4 lymphopenia in five, grade 4 neutrophils in five, and grade 4 anaemia in one). One patient had two grade 4 infections with grade 3-4 neutrophils. One patient reported grade 4 tinnitus, one patient reported grade 4 thrombosis, one reported grade 4 radiation mucositis, and two reported grade 4 pharyngolaryngeal pain. With a median follow-up of 2·5 years (IQR 2·1-2·9), the estimated 2 year locoregional progression-free interval was 83·7% (95% CI 72·6-94·9), the 2 year distant metastasis-free interval was 90·8% (82·2-99·5), the 2 year progression-free survival was 74·7% (61·8-87·6), and 2 year overall survival was 90·9% (82·3-99·4).The addition of bevacizumab to standard chemoradiation treatment for patients with nasopharyngeal carcinoma is feasible, and might delay the progression of subclinical distant disease.National Cancer Institute, USA.

  View details for DOI 10.1016/S1470-2045(11)70303-5

  View details for Web of Science ID 000300197400042

  View details for PubMedID 22178121

  View details for PubMedCentralID PMC4985181

• Identification of Pathogens in Archival Tissues Using a High-Throughput Sequencing Approach, 3SEQ 101st Annual Meeting of United-States-and-Canadian-Academy-of-Pathology (USCAP) SWEENEY, R. T., Brunner, A. L., Montgomery, K. D., Zhu, S. X., Kong, C., Le, Q., West, R. B. NATURE PUBLISHING GROUP. 2012: 467A–467A

  View details for Web of Science ID 000299986902459

• Identification of Pathogens in Archival Tissues Using a High-Throughput Sequencing Approach, 35EQ 101st Annual Meeting of United-States-and-Canadian-Academy-of-Pathology (USCAP) SWEENEY, R. T., Brunner, A. L., Montgomery, K. D., Zhu, S. X., Kong, C., Le, Q., West, R. B. NATURE PUBLISHING GROUP. 2012: 467A–467A

  View details for Web of Science ID 000299799902459

• Metabolic Tumor Volume is an Independent Prognostic Factor in Patients Treated Definitively for Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Lee, P., Bazan, J. G., Lavori, P. W., Weerasuriya, D. K., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Graves, E. E., Loo, B. W. 2012; 13 (1): 52-58

  Abstract

  Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non-small-cell lung cancer (NSCLC) treated definitively.A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively.The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables.Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively.

  View details for DOI 10.1016/j.cllc.2011.05.001

  View details for PubMedID 21703935

• Evaluation of a metal artifact reduction technique in tonsillar cancer delineation. Practical radiation oncology Abelson, J. A., Murphy, J. D., Wiegner, E. A., Abelson, D., Sandman, D. N., Boas, F. E., Hristov, D., Fleischmann, D., Daly, M. E., Chang, D. T., Loo, B. W., Hara, W., Le, Q. 2012; 2 (1): 27-34

  Abstract

  Metal artifacts can degrade computed tomographic (CT) simulation imaging and impair accurate delineation of tumors for radiation treatment planning purposes. We investigated a Digital Imaging and Communications in Medicine-based metal artifact reduction technique in tonsillar cancer delineation.Eight patients with significant artifact and tonsil cancer were evaluated. Each patient had a positron emission tomography (PET)-CT and a contrast-enhanced CT obtained at the same setting during radiotherapy simulation. The CTs were corrected for artifact using the metal deletion technique (MDT). Two radiation oncologists independently delineated primary gross tumor volumes (GTVs) for each patient on native (CTnonMDT), metal corrected (CTMDT), and reference standard (CTPET/nonMDT) imaging, 1 week apart. Mixed effects models were used to determine if differences among GTVs were statistically significant. Two diagnostic radiologists and 2 radiation oncologists independently qualitatively evaluated CTs for each patient. Ratings were on an ordinal scale from -3 to +3, denoting that CTMDT was markedly, moderately, or slightly worse or better than CTnonMDT. Scores were compared with a Wilcoxon signed-rank test.The GTVPET/nonMDT were significantly smaller than GTVnonMDT (P = .004) and trended to be smaller than GTVMDT (P = .084). The GTVnonMDT and GTVMDT were not significantly different (P = .93). There was no significant difference in the extent to which GTVnonMDT or GTVMDT encompassed GTVPET/nonMDT (P = .33). In the subjective assessment of image quality, CTMDT did not significantly outperform CTnonMDT. In the majority of cases, the observer rated the CTMDT equivalent to (53%) or slightly superior (41%) to the corresponding CTnonMDT.The MTD modified images did not produce GTVMDT that more closely reproduced GTVPET/nonMDT than did GTVnonMDT. Moreover, the MTD modified images were not judged to be significantly superior when compared to the uncorrected images in terms of subjective ability to visualize the tonsilar tumors. This study failed to demonstrate value of the adjunctive use of a CT corrected for artifacts in the tumor delineation process. Artifacts do make tumor delineation challenging, and further investigation of other body sites is warranted.

  View details for DOI 10.1016/j.prro.2011.06.004

  View details for PubMedID 24674033

• Prognostic Significance of Plasma Osteopontin in Patients with Locoregionally Advanced Head and Neck Squamous Cell Carcinoma Treated on TROG 02.02 Phase III Trial CLINICAL CANCER RESEARCH Lim, A. M., Rischin, D., Fisher, R., Cao, H., Kwok, K., Truong, D., McArthur, G. A., Young, R. J., Giaccia, A., Peters, L., Le, Q. 2012; 18 (1): 301-307

  Abstract

  High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in head and neck squamous cell carcinomas (HNSCC), correlate with tumor hypoxia, and be predictive of benefit from hypoxia-targeted therapy. We sought to confirm the prognostic and predictive significance of OPN in patients treated on a large international trial.Patients with stage III/IV HNSCC were randomized to receive definitive radiotherapy concurrently with cisplatin or cisplatin plus the hypoxic cell cytotoxin, tirapazamine (TPZ). Eligibility criteria for this prospective substudy included plasma sample availability for OPN assay by ELISA and absence of major radiation therapy deviations (N = 578). OPN concentrations were analyzed for overall survival (OS) and time to locoregional failure (TTLRF), adjusting for known prognostic factors. Additional analysis was carried out in patients with available tumor p16(INK4A) staining status.The median OPN level was 544 ng/mL (range: 7-2,640). High OPN levels were not associated with worse OS (relative HR, 1.03 for highest tertile) or TTLRF (relative HR 0.91 for highest tertile). There was no interaction between OPN and treatment arm for OS or TTLRF (P = 0.93 for OS; P = 0.87 for TTLRF). For the highest tertile the 2-year OS was 66% on control arm and 67% on TPZ arm (HR = 1.11, P = 0.67). Similarly for p16(INK4A) negative patients in the highest tertile, the 2-year OS was 61% on control arm and 63% on TPZ arm (HR = 1.05, P = 0.86).We found no evidence that high plasma OPN levels were associated with an adverse prognosis in HNSCC, or were predictive of benefit with hypoxia targeting therapy.

  View details for DOI 10.1158/1078-0432.CCR-11-2295

  View details for Web of Science ID 000298758900032

  View details for PubMedID 22096023

  View details for PubMedCentralID PMC3251655

• A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo CLINICAL CANCER RESEARCH Banh, A., Xiao, N., Cao, H., Chen, C., Kuo, P., Krakow, T., Bavan, B., Khong, B., Yao, M., Ha, C., Kaplan, M. J., Sirjani, D., Jensen, K., Kong, C. S., Mochly-Rosen, D., Koong, A. C., Quynh-Thu Le, Q. T. 2011; 17 (23): 7265-7272

  Abstract

  To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit(+)/CD90(+) SMG stem cells and BrdUrd(+) salispheres.More than 99% of CD34(+) huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit(+) mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd(+) salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non-stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit(+)/CD90(+) SMG population and BrdUrd(+) sphere formation compared with control.This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy.

  View details for DOI 10.1158/1078-0432.CCR-11-0179

  View details for PubMedID 21998334

• Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity RADIOTHERAPY AND ONCOLOGY Murphy, J. D., Chisholm, K. M., Daly, M. E., Wiegner, E. A., Truong, D., Iagaru, A., Maxim, P. G., Loo, B. W., Graves, E. E., Kaplan, M. J., Kong, C., Le, Q. 2011; 101 (3): 356-361

  Abstract

  To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer.Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques.Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R(2) range 0.29-0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R(2)=0.63).Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.

  View details for DOI 10.1016/j.radonc.2011.05.040

  View details for PubMedID 21665308

• ON-BOARD IMAGING VALIDATION OF OPTICALLY GUIDED STEREOTACTIC RADIOSURGERY POSITIONING SYSTEM FOR CONVENTIONALLY FRACTIONATED RADIOTHERAPY FOR PARANASAL SINUS AND SKULL BASE CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Maxim, P. G., Loo, B. W., Murphy, J. D., Chu, K. P., Hsu, A., Quynh-Thu Le, Q. T. 2011; 81 (4): 1153-1159

  Abstract

  To evaluate the positioning accuracy of an optical positioning system for stereotactic radiosurgery in a pilot experience of optically guided, conventionally fractionated, radiotherapy for paranasal sinus and skull base tumors.Before each daily radiotherapy session, the positioning of 28 patients was set up using an optical positioning system. After this initial setup, the patients underwent standard on-board imaging that included daily orthogonal kilovoltage images and weekly cone beam computed tomography scans. Daily translational shifts were made after comparing the on-board images with the treatment planning computed tomography scans. These daily translational shifts represented the daily positional error in the optical tracking system and were recorded during the treatment course. For 13 patients treated with smaller fields, a three-degree of freedom (3DOF) head positioner was used for more accurate setup.The mean positional error for the optically guided system in patients with and without the 3DOF head positioner was 1.4 ± 1.1 mm and 3.9 ± 1.6 mm, respectively (p <.0001). The mean positional error drifted 0.11 mm/wk upward during the treatment course for patients using the 3DOF head positioner (p = .057). No positional drift was observed in the patients without the 3DOF head positioner.Our initial clinical experience with optically guided head-and-neck fractionated radiotherapy was promising and demonstrated clinical feasibility. The optically guided setup was especially useful when used in conjunction with the 3DOF head positioner and when it was recalibrated to the shifts using the weekly portal images.

  View details for DOI 10.1016/j.ijrobp.2010.08.049

  View details for Web of Science ID 000296823600035

  View details for PubMedID 21543166

• HIGH RETENTION AND SAFETY OF PERCUTANEOUSLY IMPLANTED ENDOVASCULAR EMBOLIZATION COILS AS FIDUCIAL MARKERS FOR IMAGE-GUIDED STEREOTACTIC ABLATIVE RADIOTHERAPY OF PULMONARY TUMORS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Hong, J. C., Yu, Y., Rao, A. K., Ditererich, S., Maxim, P. G., Le, Q., Diehn, M., Sze, D. Y., Kothary, N., Loo, B. W. 2011; 81 (1): 85-90

  Abstract

  To compare the retention rates of two types of implanted fiducial markers for stereotactic ablative radiotherapy (SABR) of pulmonary tumors, smooth cylindrical gold "seed" markers ("seeds") and platinum endovascular embolization coils ("coils"), and to compare the complication rates associated with the respective implantation procedures.We retrospectively analyzed the retention of percutaneously implanted markers in 54 consecutive patients between January 2004 and June 2009. A total of 270 markers (129 seeds, 141 coils) were implanted in or around 60 pulmonary tumors over 59 procedures. Markers were implanted using a percutaneous approach under computed tomography (CT) guidance. Postimplantation and follow-up imaging studies were analyzed to score marker retention relative to the number of markers implanted. Markers remaining near the tumor were scored as retained. Markers in a distant location (e.g., pleural space) were scored as lost. CT imaging artifacts near markers were quantified on radiation therapy planning scans.Immediately after implantation, 140 of 141 coils (99.3%) were retained, compared to 110 of 129 seeds (85.3%); the difference was highly significant (p<0.0001). Of the total number of lost markers, 45% were reported lost during implantation, but 55% were lost immediately afterwards. No additional markers were lost on longer-term follow-up. Implanted lesions were peripherally located for both seeds (mean distance, 0.33 cm from pleural surface) and coils (0.34 cm) (p=0.96). Incidences of all pneumothorax (including asymptomatic) and pneumothorax requiring chest tube placement were lower in implantation of coils (23% and 3%, respectively) vs. seeds (54% and 29%, respectively; p=0.02 and 0.01). The degree of CT artifact was similar between marker types.Retention of CT-guided percutaneously implanted coils is significantly better than that of seed markers. Furthermore, implanting coils is at least as safe as implanting seeds. Using coils should permit implantation of fewer markers and require fewer repeat implantation procedures owing to lost markers.

  View details for DOI 10.1016/j.ijrobp.2010.04.037

  View details for PubMedID 20675070

• New translational possibilities for microenvironmental modulation of radiosensitivity. Radiation research Glazer, P. M., Le, Q., Bristow, R., Helleday, T., Pelroy, R., Bernhard, E. J. 2011; 176 (3): 412-414

  View details for PubMedID 21867431

• Radiation Resistance in Cancer Therapy: meeting summary and research opportunities. Report of an NCI Workshop held September 1-3, 2010. Radiation research Glazer, P. M., Grandis, J., Powell, S. N., Brown, J. M., Helleday, T., Bristow, R., Powis, G., Hill, R. P., Le, Q., Pelroy, R., Mohla, S., Bernhard, E. J. 2011; 176 (3): e0016-21

  View details for PubMedID 21867428

• Targeting Galectin-1, a Hypoxia Induced Protein, in Non-Small Cell Lung Cancers European Multidisciplinary Cancer Congress on Integrating Basic and Translational Science, Surgery, Radiotherapy, Medical oncology, Advocacy and Care Banh, A., Zhang, J., Cao, H., Bouley, D., Kwok, S., Kong, C., Giaccia, A., Koong, A., Le, Q. ELSEVIER SCI LTD. 2011: S60–S60

  View details for Web of Science ID 000295752800212

• Results from a Single Institution Phase II Trial of Concurrent Docetaxel/Carboplatin/Radiotherapy Followed by Surgical Resection and Consolidation Docetaxel/Carboplatin in Stage III Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Das, M., Donington, J. S., Murphy, J., Kozak, M., Eclov, N., Whyte, R. I., Hoang, C. D., Zhou, L., Le, Q., Loo, B. W., Wakelee, H. 2011; 12 (5): 280-285

  Abstract

  The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.

  View details for DOI 10.1016/j.cllc.2011.06.003

  View details for PubMedID 21752720

• INTENSITY-MODULATED RADIOTHERAPY FOR ORAL CAVITY SQUAMOUS CELL CARCINOMA: PATTERNS OF FAILURE AND PREDICTORS OF LOCAL CONTROL INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Quynh-Thu Le, Q. T., Kozak, M. M., Maxim, P. G., Murphy, J. D., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Chang, D. T. 2011; 80 (5): 1412-1422

  Abstract

  Few studies have evaluated the use of intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma (SCC) of the oral cavity (OC). We report clinical outcomes and failure patterns for these patients.Between October 2002 and June 2009, 37 patients with newly diagnosed SCC of the OC underwent postoperative (30) or definitive (7) IMRT. Twenty-five patients (66%) received systemic therapy. The median follow-up was 38 months (range, 10-87 months). The median interval from surgery to RT was 5.9 weeks (range, 2.1-10.7 weeks).Thirteen patients experienced local-regional failure at a median of 8.1 months (range, 2.4-31.9 months), and 2 additional patients experienced local recurrence between surgery and RT. Seven local failures occurred in-field (one with simultaneous nodal and distant disease) and two at the margin. Four regional failures occurred, two in-field and two out-of-field, one with synchronous metastases. Six patients experienced distant failure. The 3-year actuarial estimates of local control, local-regional control, freedom from distant metastasis, and overall survival were 67%, 53%, 81%, and 60% among postoperative patients, respectively, and 60%, 60%, 71%, and 57% among definitive patients. Four patients developed Grade ≥ 2 chronic toxicity. Increased surgery to RT interval predicted for decreased LRC (p = 0.04).Local-regional control for SCC of the OC treated with IMRT with or without surgery remains unsatisfactory. Definitive and postoperative IMRT have favorable toxicity profiles. A surgery-to-RT interval of < 6 weeks improves local-regional control. The predominant failure pattern was local, suggesting that both improvements in target delineation and radiosensitization and/or dose escalation are needed.

  View details for DOI 10.1016/j.ijrobp.2010.04.031

  View details for PubMedID 20675073

• Palifermin Reduces Severe Mucositis in Definitive Chemoradiotherapy of Locally Advanced Head and Neck Cancer: A Randomized, Placebo-Controlled Study JOURNAL OF CLINICAL ONCOLOGY Le, Q., Kim, H. E., Schneider, C. J., Murakozy, G., Skladowski, K., Reinisch, S., Chen, Y., Hickey, M., Mo, M., Chen, M., Berger, D., Lizambri, R., Henke, M. 2011; 29 (20): 2808-2814

  Abstract

  Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC.Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m(2) on days 1, 22, and 43) received palifermin (180 μg/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4).The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade ≥ 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug-related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms.Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated.

  View details for DOI 10.1200/JCO.2010.32.4095

  View details for Web of Science ID 000292508500022

  View details for PubMedID 21670453

• Radiation Resistance in Cancer Therapy: Meeting Summary and Research Opportunities: Report of an NCI Workshop held September 1-3, 2010. Radiation research Glazer, P. M., Grandis, J., Powell, S. N., Brown, J. M., Helleday, T., Bristow, R., Powis, G., Hill, R. P., Le, Q., Pelroy, R., Mohla, S., Bernhard, E. J. 2011: -?

  View details for PubMedID 21740251

• Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis CANCER RESEARCH Banh, A., Zhang, J., Cao, H., Bouley, D. M., Kwok, S., Kong, C., Giaccia, A. J., Koong, A. C., Le, Q. 2011; 71 (13): 4423-4431

  Abstract

  Galectin-1 (Gal-1), a carbohydrate-binding protein whose secretion is enhanced by hypoxia, promotes tumor aggressiveness by promoting angiogenesis and T-cell apoptosis. However, the importance of tumor versus host Gal-1 in tumor progression is undefined. Here we offer evidence that implicates tumor Gal-1 and its modulation of T-cell immunity in progression. Comparing Gal-1-deficient mice as hosts for Lewis lung carcinoma cells where Gal-1 levels were preserved or knocked down, we found that tumor Gal-1 was more critical than host Gal-1 in promoting tumor growth and spontaneous metastasis. Enhanced growth and metastasis associated with Gal-1 related to its immunomodulatory function, insofar as the benefits of Gal-1 expression to Lewis lung carcinoma growth were abolished in immunodeficient mice. In contrast, angiogenesis, as assessed by microvessel density count, was similar between tumors with divergent Gal-1 levels when examined at a comparable size. Our findings establish that tumor rather than host Gal-1 is responsible for mediating tumor progression through intratumoral immunomodulation, with broad implications in developing novel targeting strategies for Gal-1 in cancer.

  View details for DOI 10.1158/0008-5472.CAN-10-4157

  View details for PubMedID 21546572

• POSTRADIATION METABOLIC TUMOR VOLUME PREDICTS OUTCOME IN HEAD-AND-NECK CANCER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Murphy, J. D., La, T. H., Chu, K., Quon, A., Fischbein, N. J., Maxim, P. G., Graves, E. E., Loo, B. W., Le, Q. 2011; 80 (2): 514-521

  Abstract

  To explore the prognostic value of metabolic tumor volume measured on postradiation (18)F-fluorodeoxyglucose positron emission tomography (PET) imaging in patients with head-and-neck cancer.Forty-seven patients with head-and-neck cancer who received pretreatment and posttreatment PET/computed tomography (CT) imaging along with definitive chemoradiotherapy were included in this study. The PET/CT parameters evaluated include the maximum standardized uptake value, metabolic tumor volume (MTV(2.0)-MTV(4.0); where MTV(2.0) refers to the volume above a standardized uptake value threshold of 2.0), and integrated tumor volume. Kaplan-Meier and Cox regression models were used to test for association between PET endpoints and disease-free survival and overall survival.Multiple postradiation PET endpoints correlated significantly with outcome; however, the most robust predictor of disease progression and death was MTV(2.0). An increase in MTV(2.0) of 21 cm(3) (difference between 75th and 25th percentiles) was associated with an increased risk of disease progression (hazard ratio [HR] = 2.5, p = 0.0001) and death (HR = 2.0, p = 0.003). In patients with nonnasopharyngeal carcinoma histology (n = 34), MTV(2.0) <18 cm(3) and MTV(2.0) ≥18 cm(3) yielded 2-year disease-free survival rates of 100% and 63%, respectively (p = 0.006) and 2-year overall survival rates of 100% and 81%, respectively (p = 0.009). There was no correlation between MTV(2.0) and disease-free survival or overall survival with nasopharyngeal carcinoma histology (n = 13). On multivariate analysis, only postradiation MTV(2.0) was predictive of disease-free survival (HR = 2.47, p = 0.0001) and overall survival (HR = 1.98, p = 0.003).Postradiation metabolic tumor volume is an adverse prognostic factor in head-and-neck cancer. Biomarkers such as MTV are important for risk stratification and will be valuable in the future with risk-adapted therapies.

  View details for DOI 10.1016/j.ijrobp.2010.01.057

  View details for Web of Science ID 000290837100028

  View details for PubMedID 20646870

  View details for PubMedCentralID PMC2962876

• Tumor Volume as a Potential Imaging-Based Risk-Stratification Factor in Trimodality Therapy for Locally Advanced Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Kozak, M. M., Murphy, J. D., Schipper, M. L., Donington, J. S., Zhou, L., Whyte, R. I., Shrager, J. B., Hoang, C. D., Bazan, J., Maxim, P. G., Graves, E. E., Diehn, M., Hara, W. Y., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Loo, B. W. 2011; 6 (5): 920-926

  Abstract

  The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials.We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment.All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R² = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV ≥ median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival.Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.

  View details for DOI 10.1097/JTO.0b013e31821517db

  View details for PubMedID 21774104

• Head and Neck Cancer-Specific Survival Based on Socioeconomic Status in Asians and Pacific Islanders CANCER Chu, K. P., Shema, S., Wu, S., Gomez, S. L., Chang, E. T., Quynh-Thu Le, Q. T. 2011; 117 (9): 1935-1945

  Abstract

  Lower socioeconomic status (SES) has been linked to higher incidence of head and neck cancer (HNC) and lower survival. However, little is known about the effect of SES on HNC survival in Asians and Pacific Islanders (APIs). This study's purpose was to examine the effect of SES on disease-specific survival (DSS) and overall survival (OS) in APIs with HNC using population-based data.A total of 53,544 HNC patients (4,711 = APIs) were identified from the California Cancer Registry from 1988 to 2007. Neighborhood (block-group-level) SES, based on composite Census 1990 and 2000 data, was calculated for each patient based on address at diagnosis, categorized into statewide quintiles, and collapsed into 2 groups for comparison (low SES = quintiles 1-3; high SES = quintiles 4-5). DSS and OS were computed by the Kaplan-Meier method. Adjusted hazards ratios (HR) were estimated using Cox proportional hazards regression models.Among APIs, lower neighborhood SES was significantly associated with poorer DSS (HR range for oral cavity, oropharynx, or larynx/hypopharynx cancer, 1.07-1.34) and OS (HR, 1.13-1.37) after adjusting for patient and tumor characteristics. Lower SES was significantly associated with poorer survival in API with all HNC sites combined: DSS HR: 1.26 (95% confidence interval [CI], 1.08-1.48) and OS HR, 1.30 (95% CI, 1.16-1.45).Neighborhood SES was associated with longer DSS and OS in API with HNC. The effect of SES on HNC survival should be considered in future studies, and particular attention should be paid to clinical care of lower-SES HNC patients.

  View details for DOI 10.1002/cncr.25723

  View details for Web of Science ID 000289833100020

  View details for PubMedID 21509771

  View details for PubMedCentralID PMC3117112

• Glioma-Associated Oncogene Family Zinc Finger 1 Expression and Metastasis in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiation Therapy (RTOG 9003) JOURNAL OF CLINICAL ONCOLOGY Chung, C. H., Dignam, J. J., Hammond, M. E., Klimowicz, A. C., Petrillo, S. K., Magliocco, A., Jordan, R., Trotti, A., Spencer, S., Cooper, J. S., Le, Q., Ang, K. K. 2011; 29 (10): 1326-1333

  Abstract

  Glioma-associated oncogene family zinc finger 1 (GLI1) expression was assessed to determine a potential role of hedgehog (Hh) signaling in head and neck squamous cell carcinoma (HNSCC). Additional proteins known to be modulated by Hh signaling, including beta-catenin (CTNNB1) and epidermal growth factor receptor (EGFR), were also assessed to determine the correlation among these distinct signaling pathways.Nuclear GLI1 and CTNNB1 expression levels were determined in tumors from patients enrolled on Radiation Therapy Oncology Group (RTOG) 9003, a radiation fractionation trial. The results were also correlated with previously determined EGFR expression. The expression levels were evaluated in relation to three end points: time to metastasis (TTM), time to disease progression (TDP), and overall survival (OS).Among 1,068 eligible patients, data on GLI1, CTNNB1, and EGFR were available in 339, 164, and 300 patients, respectively. Although CTNNB1 expression did not differentiate prognosis, GLI1 was associated with poorer outcomes, adjusted for age, TNM stages, and Karnofsky performance score, and the significant influence persisted in a multivariable analysis (quartile 4 [Q4] v Q1 to Q3: TTM hazard ratio [HR], 2.7; 95% CI, 1.5 to 4.9; TDP HR, 1.6; 95% CI, 1.1 to 2.5; OS HR, 1.9; 95% CI, 1.4 to 2.7). The significance of GLI1 persisted in a multivariable analysis that included EGFR expression levels.These data suggest that Hh signaling may play an important role in metastasis and that GLI1 could serve as a marker in HNSCC, but the regulatory mechanisms and oncogenic significance need further investigation. Risk classification based on this analysis needs a validation in independent cohorts.

  View details for DOI 10.1200/JCO.2010.32.3295

  View details for Web of Science ID 000288990100030

  View details for PubMedID 21357786

• MYB Expression and Translocation in Adenoid Cystic Carcinomas and Other Salivary Gland Tumors With Clinicopathologic Correlation AMERICAN JOURNAL OF SURGICAL PATHOLOGY West, R. B., Kong, C., Clarke, N., Gilks, T., Lipsick, J. S., Cao, H., Kwok, S., Montgomery, K. D., Varma, S., Le, Q. 2011; 35 (1): 92-99

  Abstract

  Adenoid cystic carcinoma is a locally aggressive salivary gland neoplasm, which has a poor long-term prognosis. A chromosomal translocation involving the genes encoding the transcription factors, MYB and NFIB, has been recently discovered in these tumors.MYB translocation and protein expression were studied in 37 adenoid cystic carcinomas, 112 other salivary gland neoplasms, and 409 nonsalivary gland neoplasms by fluorescence in situ hybridization and immunohistochemistry. MYB translocation and expression status in adenoid cystic carcinoma was correlated with clinicopathologic features including outcome, with a median follow-up of 77.1 months (range, 23.2 to 217.5 mo) for living patients.A balanced translocation between MYB and NFIB is present in 49% of adenoid cystic carcinomas but is not identified in other salivary gland tumors or nonsalivary gland neoplasms. There is no apparent translocation of MYB in 35% of the cases. Strong Myb immunostaining is very specific for adenoid cystic carcinomas but is only present in 65% of all cases. It is interesting to note that Myb immunostaining is confined to the basal cell component although the translocation is present in all the cells. Neoplasms with MYB translocation show a trend toward higher local relapse rates, but the results are not statistically significant with the current number of cases.MYB translocation and expression are useful diagnostic markers for a subset of adenoid cystic carcinomas. The presence of the translocation may be indicative of local aggressive behavior, but a larger cohort may be required to show statistical significance.

  View details for DOI 10.1097/PAS.0b013e3182002777

  View details for PubMedID 21164292

• Stereotactic Ablative Radiotherapy for Previously Irradiated Lung Tumors Trakul, N., Harris, J. P., Le, Q., Hara, W. Y., Maxim, P. G., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2011: S605–S605

  View details for Web of Science ID 000296411701321

• Radiotherapy For Adenoid Cystic Carcinomas Of The Head and Neck: Clinical Outcomes And Patterns Of Failure Shultz, D. B., Murphy, J. D., Daly, M. E., Hara, W., Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S528–S528

  View details for Web of Science ID 000296411701162

• Changes in FDG-PET/CT Parameters on Serial Pre-radiotherapy Scans Predict Disease Progression and Survival in Patients with Non-small Cell Lung Cancer Bazan, J. G., Chung, M. P., Eastham, D. V., Wakelee, H., Hara, W. Y., Maxim, P. G., Graves, E., Le, Q. T., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S579–S580

  View details for Web of Science ID 000296411701268

• Volume Doubling Times and Outcomes in Stereotactic Ablative Radiotherapy of Early-stage Non-small Cell Lung Cancer Chung, M. P., Trakul, N., Le, Q., Hara, W. Y., Dieterich, S., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S592–S592

  View details for Web of Science ID 000296411701294

• Analysis of Migration of Implanted Markers for Image-Guided Lung Tumor Stereotactic Ablative Radiotherapy Hong, J. C., Eclov, N. C., Yu, Y., Rao, A. K., Dieterich, S., Maxim, P. G., Le, Q., Diehn, M., Kothary, N., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S580–S581

  View details for Web of Science ID 000296411701270

• Targeting Lung Tumors in Image-Guided Stereotactic Ablative Radiotherapy using Pulmonary Interstitial Lymphography Abelson, J. A., Kothary, N., Fleischmann, D., Hofmann, L., Kielar, K. N., Maxim, P. G., Le, Q., Hara, W. Y., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S601–S601

  View details for Web of Science ID 000296411701313

• INTENSITY-MODULATED RADIOTHERAPY FOR LOCALLY ADVANCED CANCERS OF THE LARYNX AND HYPOPHARYNX HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Daly, M. E., Le, Q., Jain, A. K., Maxim, P. G., Hsu, A., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Colevas, A. D., Pinto, H., Chang, D. T. 2011; 33 (1): 103-111

  Abstract

  Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty-six received systemic therapy. Median follow-up was 30 months among surviving patients.Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%.IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment.

  View details for DOI 10.1002/hed.21406

  View details for PubMedID 20848427

• Intensity-Modulated and Image-Guided Radiation Therapy for Head and Neck Cancers IMRT IGRT SBRT- ADVANCES IN THE TREATMENT PLANNING AND DELIVERY OF RADIOTHERAPY Chu, K. P., Le, Q. 2011; 43: 217-254

  Abstract

  Radiation therapy is a key component of the multidisciplinary treatment of head and neck cancers (HNC), which are ideal tumors for intensity-modulated radiation therapy (IMRT) because of their location and intimate relationship to the surrounding critical structures. Several institutional studies have suggested that IMRT is superior to conventional radiation therapy in salivary preservation and holds promises for improved locoregional control of these tumors. Small randomized studies have supported the role of IMRT in reducing xerostomia and possibly improving quality of life. Target delineation for IMRT in these tumors is complex and requires detailed knowledge of head and neck anatomy and pathways of tumor spread. The advent of image-guided radiation therapy offers a new innovation that can refine IMRT delivery even further. This article focuses on the issues surrounding IMRT target delineation for typical HNC presentations and a discussion on the role of FDG-PET imaging in HNC treatment planning.

  View details for Web of Science ID 000292117400011

  View details for PubMedID 21625156

• Thymic Malignancies JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Akerley, W., Bepler, G., Blum, M. G., Chang, A., Cheney, R. T., Chineac, L. R., Amico, T. A., Demmy, T. L., Govindan, R., Grannis, F. W., Jahan, T., Johnson, D. H., Kessinger, A., Komaki, R., Kong, F., Kris, M. G., Krug, L. M., Le, Q. T., Lennes, I. T., Martins, R., Malley, J. O., Osarogiagbon, R. U., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Swanson, S. J., Wood, D. E., Yang, S. C. 2010; 8 (11): 1302-1315

  View details for Web of Science ID 000284302300005

  View details for PubMedID 21081786

• HIGHER INCIDENCE OF HEAD AND NECK CANCERS AMONG VIETNAMESE AMERICAN MEN IN CALIFORNIA HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Filion, E. J., McClure, L. A., Huang, D., Seng, K., Kaplan, M. J., Colevas, A. D., Gomez, S. L., Chang, E. T., Le, Q. 2010; 32 (10): 1336-1344

  Abstract

  Our aim was to determine the incidence rates of head and neck cancer in Vietnamese Californians compared with other Asian and non-Asian Californians.Age-adjusted incidence rates of head and neck cancer between 1988 and 2004 were computed for Vietnamese Californians compared with other racial/ethnic groups by time period, ethnicity, neighborhood-level socioeconomic status (SES), and sex using data from the population-based California Cancer Registry (CCR). Data by smoking and alcohol status were tabulated from the California Health Interview Survey.Vietnamese men had a higher incidence rate of head and neck cancer than other Asian men. Specifically, the laryngeal cancer rate was significantly higher for Vietnamese men (6.5/100,000; 95% confidence interval [CI], 5.0-8.2) than all other Asian men (range, 2.6-3.8/100,000), except Korean men (5.1/100,000; 95% CI, 3.9-6.4). Both Vietnamese and Korean men had the highest percentage of current smokers. Neighborhood SES was inversely related to head and neck cancer rates among Vietnamese men and women.The higher incidence rate of head and neck cancer in Vietnamese men may correspond to the higher smoking prevalence in this group. Individual-level data are needed to establish the link of tobacco, alcohol, and other risk factors with head and neck cancer in these patients.

  View details for DOI 10.1002/hed.21330

  View details for Web of Science ID 000282707500008

  View details for PubMedID 20091688

  View details for PubMedCentralID PMC4349526

• Hypoxia in Models of Lung Cancer: Implications for Targeted Therapeutics CLINICAL CANCER RESEARCH Graves, E. E., Vilalta, M., Cecic, I. K., Erler, J. T., Tran, P. T., Felsher, D., Sayles, L., Sweet-Cordero, A., Le, Q., Giaccia, A. J. 2010; 16 (19): 4843-4852

  Abstract

  To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response.Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers.Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types.These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies.

  View details for DOI 10.1158/1078-0432.CCR-10-1206

  View details for Web of Science ID 000282647900017

  View details for PubMedID 20858837

  View details for PubMedCentralID PMC2948600

• Prognostic Significance of p16(INK4A) and Human Papillomavirus in Patients With Oropharyngeal Cancer Treated on TROG 02.02 Phase III Trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Rischin, D., Young, R. J., Fisher, R., Fox, S. B., Le, Q., Peters, L. J., Solomon, B., Choi, J., O'Sullivan, B., Kenny, L. M., McArthur, G. A. AMER SOC CLINICAL ONCOLOGY. 2010: 4142–48

  Abstract

  To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial.Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction.Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P = .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P = .13).HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

  View details for DOI 10.1200/JCO.2010.29.2904

  View details for Web of Science ID 000281909700009

  View details for PubMedID 20697079

  View details for PubMedCentralID PMC2953971

• Dose reconstruction for volumetric modulated arc therapy (VMAT) using cone-beam CT and dynamic log files PHYSICS IN MEDICINE AND BIOLOGY Qian, J., Lee, L., Liu, W., Chu, K., Mok, E., Luxton, G., Le, Q., Xing, L. 2010; 55 (13): 3597-3610

  Abstract

  Volumetric modulated arc therapy (VMAT) has recently emerged as a new clinical modality for conformal radiation therapy. The aim of this work is to establish a methodology and procedure for retrospectively reconstructing the actual dose delivered in VMAT based on the pre-treatment cone-beam computed tomography (CBCT) and dynamic log files. CBCT was performed before the dose delivery and the system's log files were retrieved after the delivery. Actual delivery at a control point including MLC leaf positions, gantry angles and cumulative monitor units (MUs) was recorded in the log files and the information was extracted using in-house developed software. The extracted information was then embedded into the original treatment DICOM-radiation therapy (RT) file to replace the original control point parameters. This reconstituted DICOM-RT file was imported into the Eclipse treatment planning system (TPS) and dose was computed on the corresponding CBCT. A series of phantom experiments was performed to show the feasibility of dose reconstruction, validate the procedure and demonstrate the efficacy of this methodology. The resultant dose distributions and dose-volume histograms (DVHs) were compared with those of the original treatment plan. The studies indicated that CBCT-based VMAT dose reconstruction is readily achievable and provides a valuable tool for monitoring the dose actually delivered to the tumor target as well as the sensitive structures. In the absence of setup errors, the reconstructed dose shows no significant difference from the original pCT-based plan. It is also elucidated that the proposed method is capable of revealing the dosimetric changes in the presence of setup errors. The method reported here affords an objective means for dosimetric evaluation of VMAT delivery and is useful for adaptive VMAT in future.

  View details for DOI 10.1088/0031-9155/55/13/002

  View details for Web of Science ID 000279004300002

  View details for PubMedID 20526034

• The Tumor Microenvironment in Non-Small-Cell Lung Cancer SEMINARS IN RADIATION ONCOLOGY Graves, E. E., Maity, A., Le, Q. 2010; 20 (3): 156-163

  Abstract

  The tumor microenvironment (TME) of NSCLC is heterogeneous with variable blood flow through leaky immature vessels resulting in regions of acidosis and hypoxia. Hypoxia has been documented in NSCLC directly by polarographic needle electrodes and indirectly by assessing tissue and plasma hypoxia markers. In general, elevated expression of these markers portends poorer outcomes in NSCLC. Impaired vascularity and hypoxia can lead to increased metastasis and treatment resistance. Compounds that directly target hypoxic cells such as tirapazamine have been tested in clinical trials for NSCLC with mixed results. Preclinical data, however, suggest other ways of exploiting the abnormal TME in NSCLC for therapeutic gain. The inhibition of hypoxia-inducible factor-1alpha or vascular endothelial growth factor may increase local control after radiation. Inhibitors of the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, such as erlotinib or PI-103, may "normalize" tumor vessels, allowing for increased chemotherapy delivery or improved oxygenation and radiation response. To select patients who may respond to these therapies and to evaluate the effects of these agents, a noninvasive means of imaging the TME is critical. Presently, there are several promising modalities to image hypoxia and the tumor vasculature; these include dynamic perfusion imaging and positron emission tomography scanning with radiolabled nitroimidazoles.

  View details for DOI 10.1016/j.semradonc.2010.01.003

  View details for Web of Science ID 000279360800003

  View details for PubMedID 20685578

  View details for PubMedCentralID PMC2917385

• Image-based modeling of tumor shrinkage in head and neck radiation therapy 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Chao, M., Xie, Y., Moros, E. G., Le, Q., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2010: 2351–58

  Abstract

  Understanding the kinetics of tumor growth/shrinkage represents a critical step in quantitative assessment of therapeutics and realization of adaptive radiation therapy. This article presents a novel framework for image-based modeling of tumor change and demonstrates its performance with synthetic images and clinical cases.Due to significant tumor tissue content changes, similarity-based models are not suitable for describing the process of tumor volume changes. Under the hypothesis that tissue features in a tumor volume or at the boundary region are partially preserved, the kinetic change was modeled in two steps: (1) Autodetection of homologous tissue features shared by two input images using the scale invariance feature transformation (SIFT) method; and (2) establishment of a voxel-to-voxel correspondence between the images for the remaining spatial points by interpolation. The correctness of the tissue feature correspondence was assured by a bidirectional association procedure, where SIFT features were mapped from template to target images and reversely. A series of digital phantom experiments and five head and neck clinical cases were used to assess the performance of the proposed technique.The proposed technique can faithfully identify the known changes introduced when constructing the digital phantoms. The subsequent feature-guided thin plate spline calculation reproduced the "ground truth" with accuracy better than 1.5 mm. For the clinical cases, the new algorithm worked reliably for a volume change as large as 30%.An image-based tumor kinetic algorithm was developed to model the tumor response to radiation therapy. The technique provides a practical framework for future application in adaptive radiation therapy.

  View details for DOI 10.1118/1.3399872

  View details for Web of Science ID 000277242800043

  View details for PubMedID 20527569

  View details for PubMedCentralID PMC2874043

• MiR-210-micromanager of the hypoxia pathway TRENDS IN MOLECULAR MEDICINE Huang, X., Le, Q., Giaccia, A. J. 2010; 16 (5): 230-237

  Abstract

  Hypoxia inducible factors (HIFs) regulate a variety of genes to prepare cells to adapt and survive under a hypoxic environment. Recently, microRNAs (miRNAs) have emerged as a new class of genes regulated by HIFs in response to hypoxia, of which miR-210 is the most consistently and predominantly upregulated miRNA. Functional studies have demonstrated that miR-210 is a versatile gene that regulates many aspects of hypoxia pathways, both in physiological and malignant conditions. Here, we summarize recent findings on the mechanism of hypoxia regulation of miR-210 expression and its multifaceted biological functions in normal physiological and malignant conditions, and discuss the challenges we face in elucidating the biological functions of miR-210 and exploring its potential use for therapeutics.

  View details for DOI 10.1016/j.molmed.2010.03.004

  View details for Web of Science ID 000278669500004

  View details for PubMedID 20434954

  View details for PubMedCentralID PMC3408219

• Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer TRANSLATIONAL ONCOLOGY Ho, A. S., Huang, X., Cao, H., Christman-Skieller, C., Bennewith, K., Le, Q., Koong, A. C. 2010; 3 (2): 109-113

  Abstract

  MicroRNA are small noncoding transcripts involved in many cellular mechanisms, including tumorigenesis. miR-210, in particular, is induced by hypoxia and correlates with adverse outcomes in certain cancers. Because pancreatic adenocarcinomas exhibit extremely hypoxic signatures, we hypothesized that miR-210 may serve as a diagnostic marker for screening or surveillance for pancreatic cancer. Plasma samples were obtained from newly diagnosed pancreatic cancer patients and age-matched noncancer controls. miRNA was extracted directly from plasma and reverse-transcribed to complementary DNA. A known quantity of synthetic Caenorhabditis elegans miR-54 (celmiR-54) was added for normalization. miR-210 and cel-miR-54 were then measured using quantitative reverse transcription polymerase chain reaction. An initial cohort of 11 pancreatic cancer patients and 14 age-matched controls was used as the test set and a second cohort of 11 pancreatic cancer patients and 11 controls was used as the validating set in this study. miR-210 was reliably detected and quantified, with a statistically significant four-fold increase in expression in pancreatic cancer patients compared with normal controls (P < .00004) in the test set. This difference was confirmed in the validation group (P < .018). In summary, circulating miR-210 levels are elevated in pancreatic cancer patients and may potentially serve as a useful biomarker for pancreatic cancer diagnosis.

  View details for DOI 10.1593/tlo.09256

  View details for Web of Science ID 000278912800005

  View details for PubMedID 20360935

  View details for PubMedCentralID PMC2847318

• Cetuximab-Based Immunotherapy and Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma CLINICAL CANCER RESEARCH Niu, G., Sun, X., Cao, Q., Courter, D., Koong, A., Le, Q., Gambhir, S. S., Chen, X. 2010; 16 (7): 2095-2105

  Abstract

  To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab.EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.

  View details for DOI 10.1158/1078-0432.CCR-09-2495

  View details for Web of Science ID 000278595800013

  View details for PubMedID 20215534

  View details for PubMedCentralID PMC2848903

• INTENSITY-MODULATED RADIOTHERAPY IN THE TREATMENT OF OROPHARYNGEAL CANCER: CLINICAL OUTCOMES AND PATTERNS OF FAILURE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Daly, M. E., Le, Q., Maxim, P. G., Loo, B. W., Kaplan, M. J., Fischbein, N. J., Pinto, H., Chang, D. T. 2010; 76 (5): 1339-1346

  Abstract

  To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx.Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months).Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications.IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

  View details for DOI 10.1016/j.ijrobp.2009.04.006

  View details for PubMedID 19540068

• The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways PLOS ONE Courter, D., Cao, H., Kwok, S., Kong, C., Banh, A., Kuo, P., Bouley, D. M., Vice, C., Brustugun, O. T., Denko, N. C., Koong, A. C., Giaccia, A., Le, Q. 2010; 5 (3)

  Abstract

  Human osteopontin (OPN), a known tumor associated protein, exists in different isoforms, whose function is unclear. It also possesses a RGD domain, which has been implicated in diverse function. Here, we use genetic approaches to systematically investigate the function of the RGD domain in different OPN isoforms on tumor progression and metastasis for 2 different solid tumor models.Using isoform-specific qRT-PCR, we found that OPN-A and B were the main isoforms overexpressed in evaluated human tumors, which included 4 soft tissue sarcomas, 24 lung and 30 head and neck carcinomas. Overexpression of either OPN-A or B in two different cell types promoted local tumor growth and lung metastasis in SCID mouse xenografts. However, expression of either isoform with the RGD domain either mutated or deleted decreased tumor growth and metastasis, and resulted in increased apoptosis by TUNEL staining. In vitro, whereas mutation of the RGD domain did not affect cell-cell adhesion, soft agar growth or cell migration, it increased apoptosis under hypoxia and serum starvation. This effect could be mitigated when the RGD mutant cells were treated with condition media containing WT OPN. Mechanistically, the RGD region of OPN inhibited apoptosis by inducing NF-kappaB activation and FAK phosphorylation. Inhibition of NF-kappaB (by siRNA to the p65 subunit) or FAK activation (by a inhibitor) significantly increased apoptosis under hypoxia in WT OPN cells, but not in RGD mutant cells.Unlike prior reports, our data suggest that the RGD domain of both OPN-A and B promote tumor growth and metastasis mainly by protecting cells against apoptosis under stressed conditions and not via migration or invasion. Future inhibitors directed against OPN should target multiple isoforms and should inhibit cell survival mechanisms that involve the RGD domain, FAK phosphorylation and NF-kappaB activation.

  View details for DOI 10.1371/journal.pone.0009633

  View details for PubMedID 20224789

• Imaging the Unfolded Protein Response in Primary Tumors Reveals Microenvironments with Metabolic Variations that Predict Tumor Growth CANCER RESEARCH Spiotto, M. T., Banh, A., Papandreou, I., Cao, H., Galvez, M. G., Gurtner, G. C., Denko, N. C., Le, Q. T., Koong, A. C. 2010; 70 (1): 78-88

  Abstract

  Cancer cells exist in harsh microenvironments that are governed by various factors, including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect cancer cell survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real-time activation of these downstream signaling pathways in primary tumors. In this study, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. Primary mammary tumors arising in these mice exhibited luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Visualizing distinct signaling pathways in primary tumors reveals unique tumor microenvironments with distinct metabolic signatures that can predict for tumor growth.

  View details for DOI 10.1158/0008-5472.CAN-09-2747

  View details for Web of Science ID 000278404300011

  View details for PubMedID 20028872

  View details for PubMedCentralID PMC2943832

• Prognostic Value of Metabolic Tumor Volume and Velocity in Predicting Head and Neck Cancer Outcomes 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Chu, K. P., Murphy, J., La, T. H., Loo, B. W., Krakow, T. E., Hsu, A., Maxim, P. G., Graves, E., Chang, D., Le, Q. ELSEVIER SCIENCE INC. 2010: S460–S460

  View details for Web of Science ID 000288775701074

• Clinical Management of Patients with Temporal Lobe Necrosis 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Krakow, T. E., Hara, W., Yun, S., Soltys, S., Chang, S., Fischbein, N., Loo, B., Le, Q. ELSEVIER SCIENCE INC. 2010: S455–S455

  View details for Web of Science ID 000288775701063

• Definitive Radiotherapy for New Primary Tumors in the Lung: The Benefit of the Doubt 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Jones, J. C., Trakul, N., Hara, W., Abelson, J. A., Maxim, P., Dieterich, S., Le, Q., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2010: S500–S500

  View details for Web of Science ID 000288775701162

• Volume Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Trakul, N., Harris, J., Dieterich, S., Maxim, P., Le, Q., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2010: S179–S179

  View details for Web of Science ID 000288775700383

• Can Temporal Lobe Necrosis be Prevented in Patients with Nasopharyngeal/Skull Base Tumors Undergoing a Stereotactic Radiosurgery Boost? A Dose Volume Analysis 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Hara, W., Yun, S., Hsu, A., Soltys, S., Adler, J., Le, Q., Loo, B. W. ELSEVIER SCIENCE INC. 2010: S431–S431

  View details for Web of Science ID 000288775701011

• High Retention and Safety of Percutaneously Implanted Endovascular Embolization Coils as Fiducial Markers for Image-guided Stereotactic Ablative Radiotherapy of Pulmonary Tumors 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Hong, J. C., Yu, Y., Rao, A. K., Dieterich, S., Maxim, P. G., Le, Q. T., Diehn, M., Sze, D. Y., Kothary, N., Loo, B. W. ELSEVIER SCIENCE INC. 2010: S518–S519

  View details for Web of Science ID 000288775701202

• Identification of a biomarker panel using a multiplex proximity ligation assay improves accuracy of pancreatic cancer diagnosis JOURNAL OF TRANSLATIONAL MEDICINE Chang, S. T., Zahn, J. M., Horecka, J., Kunz, P. L., Ford, J. M., Fisher, G. A., Le, Q. T., Chang, D. T., Ji, H., Koong, A. C. 2009; 7

  Abstract

  Pancreatic cancer continues to prove difficult to clinically diagnose. Multiple simultaneous measurements of plasma biomarkers can increase sensitivity and selectivity of diagnosis. Proximity ligation assay (PLA) is a highly sensitive technique for multiplex detection of biomarkers in plasma with little or no interfering background signal.We examined the plasma levels of 21 biomarkers in a clinically defined cohort of 52 locally advanced (Stage II/III) pancreatic ductal adenocarcinoma cases and 43 age-matched controls using a multiplex proximity ligation assay. The optimal biomarker panel for diagnosis was computed using a combination of the PAM algorithm and logistic regression modeling. Biomarkers that were significantly prognostic for survival in combination were determined using univariate and multivariate Cox survival models.Three markers, CA19-9, OPN and CHI3L1, measured in multiplex were found to have superior sensitivity for pancreatic cancer vs. CA19-9 alone (93% vs. 80%). In addition, we identified two markers, CEA and CA125, that when measured simultaneously have prognostic significance for survival for this clinical stage of pancreatic cancer (p < 0.003).A multiplex panel assaying CA19-9, OPN and CHI3L1 in plasma improves accuracy of pancreatic cancer diagnosis. A panel assaying CEA and CA125 in plasma can predict survival for this clinical cohort of pancreatic cancer patients.

  View details for DOI 10.1186/1479-5876-7-105

  View details for PubMedID 20003342

• COMPARISON OF TREATMENT RESULTS BETWEEN ADULT AND JUVENILE NASOPHARYNGEAL CARCINOMA INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Downing, N. L., Wolden, S., Wong, P., Petrik, D. W., Hara, W., Le, Q. 2009; 75 (4): 1064-1070

  Abstract

  Nasopharyngeal carcinoma (NPC) has a bimodal age distribution. In contrast to the adult variant, little is known about the juvenile form. This study examined the treatment results between adult (aNPC) and juvenile NPC (jNPC) patients for future treatment considerations in jNPC.The jNPC population included 53 patients treated at two institutions between 1972 and 2004. The aNPC population included 84 patients treated at one institution. The patients had received a median dose of 66 Gy of external beam radiotherapy and 72% underwent chemotherapy. The mean follow-up for surviving patients was 12.6 years for jNPC and 6.6 years for aNPC.The jNPC patients presented with more advance stages than did the aNPC patients (92% vs. 67% Stage III-IV, p = .006). However, jNPC patients had significantly better overall survival (OS) than did aNPC patients. The 5-year OS rate was 71% for jNPC and 58% for aNPC (p = .03). The jNPC group also demonstrated a trend for greater relapse-free survival than the aNPC group (5-year relapse-free survival rate, 69% vs. 49%; p = .056). The pattern of failure analysis revealed that the jNPC patients had greater locoregional control and freedom from metastasis but the differences were not statistically significant. Univariate analysis for OS revealed that age group, nodal classification, and chemotherapy use were significant prognostic factors. Age group remained significant for OS on multivariate analysis, after adjusting for N classification and treatment.Despite more advance stage at presentation, jNPC patients had better survival than did aNPC patients. Future treatment strategies should take into consideration the long-term complications in these young patients.

  View details for DOI 10.1016/j.ijrobp.2008.12.030

  View details for PubMedID 19327901

• Mucositis-Related Morbidity and Resource Utilization in Head and Neck Cancer Patients Receiving Radiation Therapy With or Without Chemotherapy JOURNAL OF PAIN AND SYMPTOM MANAGEMENT Murphy, B. A., Beaumont, J. L., Isitt, J., Garden, A. S., Gwede, C. K., Trotti, A. M., Meredith, R. F., Epstein, J. B., Le, Q., Brizel, D. M., Bellm, L. A., Wells, N., Cella, D. 2009; 38 (4): 522-532

  Abstract

  The objective of this study was to estimate health care-resource utilization in head and neck cancer (HNC) patients. This was a prospective, longitudinal, multicenter, noninterventional study of mucositis in patients receiving radiation with or without chemotherapy for HNC. Mouth and throat soreness and functional impairment were measured using the Oral Mucositis Weekly Questionnaire-HNC. Resource utilization data were obtained from patient interviews and recorded from the patient's medical chart. Seventy-five patients were enrolled from six centers. Fifty (67%) patients received concurrent chemoradiation therapy; 34 (45%) received intensity-modulated radiation therapy. Over the course of treatment, 57 (76%) patients reported severe mouth and throat soreness. Pain and functional impairment because of mouth and throat soreness increased during the course of therapy despite the use of opioid analgesics in 64 (85%) of the patients. Complications of radiation therapy resulted in increased patient visits to physicians, nurses, and nutritionists. Thirty-eight (51%) patients had a feeding tube placed. Twenty-eight patients (37%) were hospitalized, five of whom were hospitalized twice; of the 33 admissions, 10 (30%) were designated as secondary to mucositis by their treating physician. Mean length of hospitalization was 4.9 days (range: 1-16). This study demonstrates that mucositis-related pain and functional impairment is associated with increased use of costly health resources. Effective treatments to reduce the pain and functional impairment of oral mucositis are needed in this patient population.

  View details for DOI 10.1016/j.jpainsymman.2008.12.004

  View details for Web of Science ID 000271297000005

  View details for PubMedID 19608377

• Hypoxia-Inducible mir-210 Regulates Normoxic Gene Expression Involved in Tumor Initiation MOLECULAR CELL Huang, X., Ding, L., Bennewith, K. L., Tong, R. T., Welford, S. M., Ang, K. K., Story, M., Le, Q., Giaccia, A. J. 2009; 35 (6): 856-867

  Abstract

  Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth.

  View details for DOI 10.1016/j.molcel.2009.09.006

  View details for Web of Science ID 000270559100018

  View details for PubMedID 19782034

  View details for PubMedCentralID PMC2782615

• Validation of Lysyl Oxidase As a Prognostic Marker for Metastasis and Survival in Head and Neck Squamous Cell Carcinoma: Radiation Therapy Oncology Group Trial 90-03 JOURNAL OF CLINICAL ONCOLOGY Le, Q., Harris, J., Magliocco, A. M., Kong, C. S., Diaz, R., Shin, B., Cao, H., Trotti, A., Erler, J. T., Chung, C. H., Dicker, A., Pajak, T. F., Giaccia, A. J., Ang, K. K. 2009; 27 (26): 4281-4286

  Abstract

  To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial.We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS).LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile.AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC.

  View details for DOI 10.1200/JCO.2008.20.6003

  View details for PubMedID 19667273

• Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors Chang, C. N., Zhou, L. Y., MacFarlane, G., Tran, P., Rao, A., Chapman, C., Le, Q., Wakelee, H., Colevas, A. D., Whyte, R., Hristov, D., Dieterich, S., Maxim, P., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S938–S939

  View details for Web of Science ID 000269496002720

• Mid-treatment PET predicts progression in hypofractionated accelerated radiation therapy for lung tumors Chang, C. N., Fillion, E., Chapman, C., Rao, A., Wakelee, H., Ganjoo, K., Le, Q., Maxim, P., Quon, A., Graves, E. E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S939–S939

  View details for Web of Science ID 000269496002721

• Quantification of pre-treatment metabolic tumor growth rate in lung cancer Eastham, D., Chapman, C. H., Rao, A. K., Balasubramanian, N., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, D. A., Maxim, P. A., Graves, E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S733–S733

  View details for Web of Science ID 000269496002262

• METABOLIC TUMOR VOLUME PREDICTS FOR RECURRENCE AND DEATH IN HEAD-AND-NECK CANCER 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) La, T. H., Filion, E. J., Turnbull, B. B., Chu, J. N., Lee, P., Nguyen, K., Maxim, P., Quon, A., Graves, E. E., Loo, B. W., Le, Q. ELSEVIER SCIENCE INC. 2009: 1335–41

  Abstract

  To evaluate the prognostic value of metabolic tumor volume measured on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and other clinical factors in patients treated for locally advanced head-and-neck cancer (HNC) at a single institution.Between March 2003 and August 2007, 85 patients received positron emission tomography (PET)/computed tomography-guided chemoradiotherapy for HNC. Metabolically active tumor regions were delineated on pretreatment PET scans semiautomatically using custom software. We evaluated the relationship of (18)F-fluorodeoxyglucose-PET maximum standardized uptake value (SUV) and total metabolic tumor volume (MTV) with disease-free survival (DFS) and overall survival (OS).Mean follow-up for surviving patients was 20.4 months. The estimated 2-year locoregional control, DFS, and OS for the group were 88.0%, 69.5%, and 78.4%, respectively. The median time to first failure was 9.8 months among the 16 patients with relapse. An increase in MTV of 17.4 mL (difference between the 75th and 25th percentiles) was significantly associated with an increased hazard of first event (recurrence or death) (1.9-fold, p < 0.001), even after controlling for Karnofsky performance status (KPS) (1.8-fold, p = 0.001), and of death (2.1-fold, p < 0.001). We did not find a significant relationship of maximum SUV, stage, or other clinical factors with DFS or OS.Metabolic tumor volume is an adverse prognostic factor for disease recurrence and death in HNC. MTV retained significance after controlling for KPS, the only other significant adverse prognostic factor found in this cohort. MTV is a direct measure of tumor burden and is a potentially valuable tool for risk stratification and guiding treatment in future studies.

  View details for DOI 10.1016/j.ijrobp.2008.10.060

  View details for Web of Science ID 000268346100006

  View details for PubMedID 19289263

  View details for PubMedCentralID PMC2752334

• PET of EGFR Antibody Distribution in Head and Neck Squamous Cell Carcinoma Models JOURNAL OF NUCLEAR MEDICINE Niu, G., Li, Z., Xie, J., Le, Q., Chen, X. 2009; 50 (7): 1116-1123

  Abstract

  Epidermal growth factor receptor (EGFR) is a well-characterized protooncogene that has been shown to promote tumor progression in solid cancers. Clinical results for EGFR targeting with specific monoclonal antibodies (mAbs) such as cetuximab and panitumumab are promising; however, most studies indicate that only a subgroup of patients receiving the mAbs benefit from the immunotherapy, independent of EGFR expression level. To understand the in vivo kinetics of antibody delivery and localization, we performed small-animal PET studies with (64)Cu-labeled panitumumab in xenografts derived from 3 cell lines of human head and neck squamous cell carcinoma (HNSCC).Nude mice bearing HNSCC tumors with different levels of EGFR expression were imaged with small-animal PET using (64)Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-panitumumab. Antibody distribution in the tumors was confirmed by ex vivo immunostaining using panitumumab and fluorescein 5(6)-isothiocyanate (FITC) panitumumab. CD31 immunostaining and Evans blue assay were also performed to assess the tumor vascular density and permeability.Among these 3 tumor models, UM-SCC-22B tumors with the lowest EGFR protein expression showed the highest (64)Cu-DOTA-panitumumab accumulation, whereas SQB20 tumors with the highest EGFR expression showed the lowest (64)Cu-DOTA-panitumumab accumulation. Ex vivo staining demonstrated that SQB20 cells still had extremely high EGFR expression after forming tumors in nude mice, indicating that the low uptake of (64)Cu-DOTA-panitumumab in SQB20 tumors was not due to the loss of EGFR expression. The results from CD31 immunostaining and Evans blue permeability assay suggest that the low vessel density, poor vascular permeability, and binding site barrier are likely responsible for the overall low tumor uptake of the highly EGFR-expressing SQB20 tumors.The results from this study provide a possible explanation for the lack of an observed correlation between therapeutic efficacy of cetuximab and panitumumab and EGFR expression level as determined by immunohistochemistry or fluorescent in situ hybridization and may shed new light on the complications of anti-EGFR mAb therapy for HNSCC and other malignancies.

  View details for DOI 10.2967/jnumed.109.061820

  View details for Web of Science ID 000272547100023

  View details for PubMedID 19525473

• THE RELATIONSHIP BETWEEN HUMAN PAPILLOMAVIRUS STATUS AND OTHER MOLECULAR PROGNOSTIC MARKERS IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Kong, C. S., Narasimhan, B., Cao, H., Kwok, S., Erickson, J. P., Koong, A., Pourmand, N., Le, Q. 2009; 74 (2): 553-561

  Abstract

  To evaluate the relationship between human papillomavirus (HPV) status and known prognostic makers for head and neck cancers including tumor hypoxia, epidermal growth factor receptor (EGFR) expression and intratumoral T-cell levels and to determine the prognostic impact of these markers by HPV status.HPV status in 82 evaluable head and neck squamous cell carcinomas patients was determined by pyrosequencing and related to p16(INK4a) staining and treatment outcomes. It was correlated with tumor hypoxia (tumor pO(2) and carbonic anhydrase [CAIX] staining), EGFR status, and intratumoral lymphocyte expression (CD3 staining).Forty-four percent of evaluable tumors had strong HPV signal by pyrosequencing. There was a significant relationship between strong HPV signal and p16(INK4a) staining as well as oropharynx location. The strong HPV signal group fared significantly better than others, both in time to progression (TTP, p = 0.008) and overall survival (OS, p = 0.004) for all patients and for the oropharyngeal subset. Positive p16(INK4a) staining was associated with better TTP (p = 0.014) and OS (p = 0.00002). There was no relationship between HPV status and tumor pO(2) or CAIX staining. However, HPV status correlated inversely with EGFR reactivity (p = 0.0006) and directly with CD3(+) T-lymphocyte level (p = 0.03). Whereas CAIX and EGFR overexpression were negative prognostic factors regardless of HPV status, CD3(+) T-cell levels was prognostic only in HPV(-) tumors.HPV status was a prognostic factor for progression and survival. It correlated inversely with EGFR expression and directly with T-cell infiltration. The prognostic effect of CAIX and EGFR expression was not influenced by HPV status, whereas intratumoral T-cell levels was significant only for HPV(-) tumors.

  View details for DOI 10.1016/j.ijrobp.2009.02.015

  View details for PubMedID 19427557

• Detection of circulating hypoxia-regulated miR-210 in pancreatic adenocarcinoma patients 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Ho, A. S., Huang, X., Cao, H., Koong, A. C., Le, Q. T. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606603212

• Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Rischin, D., Young, R., Fisher, R., Fox, S., Le, Q., Peters, L., Choi, J., O'Sullivan, B., Giralt, J., McArthur, G. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606604210

• Towards adaptive radiation therapy: Image-based tumor shrinkage modeling in head and neck cancer 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chao, M., Xie, Y., Le, Q., Xing, L. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606604339

• XBP-1 regulates angiogenesis in human pancreatic adenocarcinomas TRANSLATIONAL ONCOLOGY Romero-Ramirez, L., Cao, H., Regalado, M. P., Kambham, N., Siemann, D., Kim, J. J., Le, Q. T., Koong, A. C. 2009; 2 (1): 31-U42

  Abstract

  Tumors encounter endoplasmic reticulum stress during tumor growth and activate an adaptive pathway known as the unfolded protein response (UPR). Because this pathway is induced by the tumor microenvironment, it is a promising target for cancer therapy. We have previously demonstrated that X-box binding protein 1 (XBP-1), a key regulator of the UPR, was required for survival under hypoxia and critical for tumor growth in tumor xenografts. In this study, we investigated the role of XBP-1 in regulating tumor angiogenesis.We used an intradermal angiogenesis model to quantify the effect of XBP-1 on angiogenesis. We also used a human tumor xenograft model to assay for tumor growth delay. We determined vascular endothelial growth factor (VEGF) expression by quantitative polymerase chain reaction and ELISA. Finally, we stained human pancreatic adenocarcinoma specimens for XBP-1 expression and correlated the expression pattern of XBP-1 with CD31 (endothelial cell marker) expression.We demonstrated that XBP-1 is essential for angiogenesis during early tumor growth. Inhibiting XBP-1 expression by short-hairpin RNA sequence specific for XBP-1 reduced blood vessel formation in tumors from mouse embryonic fibroblast cells and human fibrosarcoma tumor cells (HT1080). Expressing a dominant-negative form of IRE1alpha also reduced blood vessel formation in tumors. Moreover, expression of spliced XBP-1 (XBP-1s) restored angiogenesis in IRE1alpha dominant-negative expressing cells. We further demonstrated that XBP-1-mediated angiogenesis does not depend on VEGF.We propose that the IRE1alpha-XBP-1 branch of the UPR modulates a complex proangiogenic, VEGF-independent response that depends on signals received from the tumor microenvironment.

  View details for DOI 10.1593/tlo.08211

  View details for Web of Science ID 000272550900004

  View details for PubMedCentralID PMC2647700

• X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Translational oncology Romero-Ramirez, L., Cao, H., Regalado, M. P., Kambham, N., Siemann, D., Kim, J. J., Le, Q. T., Koong, A. C. 2009; 2 (1): 31-38

  Abstract

  Tumors encounter endoplasmic reticulum stress during tumor growth and activate an adaptive pathway known as the unfolded protein response (UPR). Because this pathway is induced by the tumor microenvironment, it is a promising target for cancer therapy. We have previously demonstrated that X-box binding protein 1 (XBP-1), a key regulator of the UPR, was required for survival under hypoxia and critical for tumor growth in tumor xenografts. In this study, we investigated the role of XBP-1 in regulating tumor angiogenesis.We used an intradermal angiogenesis model to quantify the effect of XBP-1 on angiogenesis. We also used a human tumor xenograft model to assay for tumor growth delay. We determined vascular endothelial growth factor (VEGF) expression by quantitative polymerase chain reaction and ELISA. Finally, we stained human pancreatic adenocarcinoma specimens for XBP-1 expression and correlated the expression pattern of XBP-1 with CD31 (endothelial cell marker) expression.We demonstrated that XBP-1 is essential for angiogenesis during early tumor growth. Inhibiting XBP-1 expression by short-hairpin RNA sequence specific for XBP-1 reduced blood vessel formation in tumors from mouse embryonic fibroblast cells and human fibrosarcoma tumor cells (HT1080). Expressing a dominant-negative form of IRE1alpha also reduced blood vessel formation in tumors. Moreover, expression of spliced XBP-1 (XBP-1s) restored angiogenesis in IRE1alpha dominant-negative expressing cells. We further demonstrated that XBP-1-mediated angiogenesis does not depend on VEGF.We propose that the IRE1alpha-XBP-1 branch of the UPR modulates a complex proangiogenic, VEGF-independent response that depends on signals received from the tumor microenvironment.

  View details for PubMedID 19252749

• Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche CANCER CELL Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., Le, Q., Giaccia, A. J. 2009; 15 (1): 35-44

  Abstract

  Tumor cell metastasis is facilitated by "premetastatic niches" formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.

  View details for DOI 10.1016/j.ccr.2008.11.012

  View details for Web of Science ID 000262334800007

  View details for PubMedID 19111879

  View details for PubMedCentralID PMC3050620

• Integrating Biologically Targeted Therapy in Head and Neck Squamous Cell Carcinomas SEMINARS IN RADIATION ONCOLOGY Le, Q., Rabent, D. 2009; 19 (1): 53-62

  Abstract

  The integration of targeted therapies such as cetuximab to radiation therapy has revolutionized the management of head and neck cancers in the last decade. However, the use of targeted therapies raised several clinically relevant questions that have yet to be answered. These questions include the optimal patient and tumor profile for biologically targeted therapy, the optimal radiation fractionation to use with targeted therapies, how to integrate them into standard or new chemoradiation regimens, their schedule and duration of administration, their toxicity, and which direction to consider for novel targeted treatment. In this review, we highlight several of these important issues, discuss the clinical trials that are designed to address these issues, and introduce some novel targeted therapies that may contribute to the improvement of the therapeutic ratio for head and neck cancer therapy.

  View details for DOI 10.1016/j.semradonc.2008.09.010

  View details for Web of Science ID 000261524800009

  View details for PubMedID 19028346

  View details for PubMedCentralID PMC2634835

• The Unique Microenvironments of Spontaneous Tumors Differentially Sensitize Them to Radiation 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Spiotto, M. T., Bahn, A., Cao, H., Le, Q., Koong, A. C. ELSEVIER SCIENCE INC. 2009: S171–S171

  View details for Web of Science ID 000270573600365

• Does Pre-treatment Metabolic Tumor Growth Rate (MTGR) Predict Progression in Lung Cancer? 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Eastham, D. V., Chapman, C. H., Rao, A. K., Narasimhan, B., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, A. D., Loo, B. W. ELSEVIER SCIENCE INC. 2009: S446–S446

  View details for Web of Science ID 000270573601456

• Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG study S0003 JOURNAL OF CLINICAL ONCOLOGY Mack, P. C., Redman, M. W., Chansky, K., Williamson, S. K., Farneth, N. C., Lara, P. N., Franklin, W. A., Le, Q., Crowley, J. J., Gandara, D. R. 2008; 26 (29): 4771-4776

  Abstract

  S0003 was a phase III trial of carboplatin/paclitaxel with or without the hypoxic cytotoxin tirapazamine in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). We investigated the relationship between clinical outcomes and plasma levels of the hypoxia-associated protein osteopontin (OPN) in patients on this protocol.Baseline plasma was obtained from 172 patients. In 56 patients, sequential plasma was obtained after one or two cycles. Concentrations of OPN, as well as plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF), were measured using enzyme-linked immunosorbent assay. Tumor expression of OPN was assessed by immunohistochemistry in 61 matched archival specimens.Patients with lower OPN levels (below the median) had a significantly superior overall survival compared with patients with higher levels, regardless of treatment arm (hazard ratio [HR] = 0.60, P = .002). A similar correlation was observed for progression-free survival (HR = 0.69, P = .02). When examined as a continuous variable, OPN maintained its significant association with both progression-free (HR = 1.05, P = .01) and overall survival (HR = 1.09, P < .0001). Patients with lower plasma OPN levels were significantly more likely to have tumor response (P = .03). No differences were observed between treatment arms. Tumor OPN levels did not correlate with patient outcomes or with plasma levels. No associations were observed between patient outcomes and VEGF or PAI-1 levels; however, plasma concentrations of these markers were significantly interrelated (P < .0001) and significantly decreased after treatment (P = .0002 and P = .03, respectively).Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.

  View details for DOI 10.1200/JCO.2008.17.0662

  View details for Web of Science ID 000259902800014

  View details for PubMedID 18779603

• Clinical biomarkers for hypoxia targeting CANCER AND METASTASIS REVIEWS Le, Q., Courter, D. 2008; 27 (3): 351-362

  Abstract

  Tumor hypoxia or a reduction of the tissue oxygen tension is a key microenvironmental factor for tumor progression and treatment resistance in solid tumors. Because hypoxic tumor cells have been demonstrated to be more resistant to ionizing radiation, hypoxia has been a focus of laboratory and clinical research in radiation therapy for many decades. It is believed that proper detection of hypoxic regions would guide treatment options and ultimately improve tumor response. To date, most clinical efforts in targeting tumor hypoxia have yielded equivocal results due to the lack of appropriate patient selection. However, with improved understanding of the molecular pathways regulated by hypoxia and the discovery of novel hypoxia markers, the prospect of targeting hypoxia has become more tangible. This chapter will focus on the development of clinical biomarkers for hypoxia targeting.

  View details for DOI 10.1007/s10555-008-9144-9

  View details for Web of Science ID 000258592700004

  View details for PubMedID 18483785

  View details for PubMedCentralID PMC2835406

• In vivo H-1 magnetic resonance spectroscopy of lactate in patients with Stage IV head and neck squamous cell carcinoma 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Koong, A., Lieskovsky, Y. Y., Narasimhan, B., Graves, E., Pinto, H., Brown, J. M., Spielman, D. ELSEVIER SCIENCE INC. 2008: 1151–57

  Abstract

  To investigate in vivo(1)H magnetic resonance spectroscopy imaging of lactate for assessing tumor hypoxia in head and neck cancers and to determine its utility in predicting the response and outcomes.Volume-localized lactate-edited (1)H magnetic resonance spectroscopy at 1.5 T was performed in vivo on involved neck nodes and control subcutaneous tissues in 36 patients with Stage IV head and neck cancer. The signal intensities (SIs) of lactate, choline, and creatine and the choline/creatine ratio were measured. The tumor partial pressure of oxygen (pO(2)) was obtained in the same lymph node before MRS. Patients were treated with either two cycles of induction chemotherapy (tirapazamine, cisplatin, 5-fluorouracil) followed by simultaneous chemoradiotherapy or the same regimen without tirapazamine. The lactate SI and the choline/creatine ratio correlated with the tumor pO(2), nodal response, and locoregional control.The lactate SI was greater for the involved nodes (median, 0.25) than for the subcutaneous tissue (median, 0.04; p = 0.07). No significant correlation was found between the lactate SI and tumor pO(2) (mean, 0.46 +/- 0.10 for hypoxic nodes [pO(2) < or =10 mm Hg, n = 15] vs. 0.36 +/- 0.07 for nonhypoxic nodes [pO(2) >10 mm Hg, n = 21], p = 0.44). A significant correlation was found between the choline/creatine ratios and tumor pO(2) (mean, 2.74 +/- 0.34 for hypoxic nodes vs. 1.78 +/- 0.31 for nonhypoxic nodes, p = 0.02). No correlation was found between the lactate SI and the complete nodal response (p = 0.52) or locoregional control rates.The lactate SI did not correlate with tumor pO(2), treatment response, or locoregional control. Additional research is needed to refine this technique.

  View details for DOI 10.1016/j.ijrobp.2007.11.030

  View details for Web of Science ID 000257299200025

  View details for PubMedID 18258377

  View details for PubMedCentralID PMC2601688

• Excellent local control with stereotactic radiotherapy boost after external beam radiotherapy in patients with nasopharyngeal carcinoma 87th Annual Meeting of the American-Radium-Society Hara, W., Loo, B. W., Goffinet, D. R., Chang, S. D., Adler, J. R., Pinto, H. A., Fee, W. E., Kaplan, M. J., Fischbein, N. J., Le, Q. ELSEVIER SCIENCE INC. 2008: 393–400

  Abstract

  To determine long-term outcomes in patients receiving stereotactic radiotherapy (SRT) as a boost after external beam radiotherapy (EBRT) for locally advanced nasopharyngeal carcinoma (NPC).Eight-two patients received an SRT boost after EBRT between September 1992 and July 2006. Nine patients had T1, 30 had T2, 12 had T3, and 31 had T4 tumors. Sixteen patients had Stage II, 19 had Stage III, and 47 had Stage IV disease. Patients received 66 Gy of EBRT followed by a single-fraction SRT boost of 7-15 Gy, delivered 2-6 weeks after EBRT. Seventy patients also received cisplatin-based chemotherapy delivered concurrently with and adjuvant to radiotherapy.At a median follow-up of 40.7 months (range, 6.5-144.2 months) for living patients, there was only 1 local failure in a patient with a T4 tumor. At 5 years, the freedom from local relapse rate was 98%, freedom from nodal relapse 83%, freedom from distant metastasis 68%, freedom from any relapse 67%, and overall survival 69%. Late toxicity included radiation-related retinopathy in 3, carotid aneurysm in 1, and radiographic temporal lobe necrosis in 10 patients, of whom 2 patients were symptomatic with seizures. Of 10 patients with temporal lobe necrosis, 9 had T4 tumors.Stereotactic radiotherapy boost after EBRT provides excellent local control for patients with NPC. Improved target delineation and dose homogeneity of radiation delivery for both EBRT and SRT is important to avoid long-term complications. Better systemic therapies for distant control are needed.

  View details for DOI 10.1016/j.ijrobp.2007.10.027

  View details for Web of Science ID 000255971100013

  View details for PubMedID 18164839

• New developments in radiation therapy for head and neck cancer: Intensity-modulated radiation therapy and hypoxia targeting SEMINARS IN ONCOLOGY Lee, N. Y., Le, Q. 2008; 35 (3): 236-250

  Abstract

  Intensity-modulated radiation therapy (IMRT) has revolutionized radiation treatment for head and neck cancers (HNCs). When compared to the traditional techniques, IMRT has the unique ability to minimize the dose delivered to normal tissues without compromising tumor coverage. As a result, side effects from high-dose radiation have decreased and patient quality of life has improved. In addition to toxicity reduction, excellent clinical outcomes have been reported for IMRT. The first part of this review will focus on clinical results of IMRT for HNC. Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resistance. Hypoxia develops in solid tumors due to aberrant blood vessel formation, fluctuation in blood flow, and increasing oxygen demands for tumor growth. Because hypoxic tumor cells are more resistant to ionizing radiation, hypoxia has been a focus of clinical research in radiation therapy for half a decade. Interest for targeting tumor hypoxia has waxed and waned as promising treatments emerged from the laboratory, only to fail in the clinics. However, with the development of new technologies, the prospect of targeting tumor hypoxia is more tangible. The second half of the review will focus on approaches for assessing tumor hypoxia and on the strategies for targeting this important microenvironmental factor in HNC.

  View details for DOI 10.1053/j.seminoncol.2008.03.003

  View details for Web of Science ID 000257150400007

  View details for PubMedID 18544439

  View details for PubMedCentralID PMC2494523

• Molecular Imaging of Hypoxia-Inducible Factor 1 alpha and von Hippel-Lindau Interaction in Mice MOLECULAR IMAGING Choi, C. Y., Chau, D. A., Paulmurugan, R., Sutphin, P. D., Le, Q., Koong, A. C., Zundel, W., Gambhir, S. S., Giaccia, A. J. 2008; 7 (3): 139-146

  Abstract

  Tumor hypoxia plays a crucial role in tumorigenesis. Under hypoxia, hypoxia-inducible factor 1 alpha (HIF-1 alpha) regulates activation of genes promoting malignant progression. Under normoxia, HIF-1 alpha is hydroxylated on prolines 402 and 564 and is targeted for ubiquitin-mediated degradation by interacting with the von Hippel-Lindau protein complex (pVHL). We have developed a novel method of studying the interaction between HIF-1 alpha and pVHL using the split firefly luciferase complementation-based bioluminescence system in which HIF-1 alpha and pVHL are fused to amino-terminal and carboxy-terminal fragments of the luciferase, respectively. We demonstrate that hydroxylation-dependent interaction between the HIF-1 alpha and pVHL leads to complementation of the two luciferase fragments, resulting in bioluminescence in vitro and in vivo. Complementation-based bioluminescence is diminished when mutant pVHLs with decreased affinity for binding HIF-1 alpha are used. This method represents a new approach for studying interaction of proteins involved in the regulation of protein degradation.

  View details for DOI 10.2310/7290.2008.00017

  View details for Web of Science ID 000260954700004

  View details for PubMedID 19123984

• LINAC-based on-board imaging feasibility and the dosimetric consequences of head roll in head-and-neck IMRT plans MEDICAL DOSIMETRY Kim, G., Pawlicki, T., Le, Q., Luxton, G. 2008; 33 (1): 93-99

  Abstract

  Kilovoltage imaging systems on linear accelerators are used for patient localization in many clinics. The purpose of this work is to assess on-board imaging (OBI) detection of systematic setup errors and in particular, the dosimetric consequences of undetected head roll in head-and-neck intensity modulated radiation therapy (IMRT) plans when using these systems. The system used in this study was the Trilogy linear accelerator and associated software (Varian Medical Systems, Palo Alto, CA). Accuracy of OBI localization was evaluated using an anthropomorphic head phantom. The head phantom is rigidly attached to a specially designed positioning device with 5 degrees of freedom, 3 translational and 2 rotational in the axial and coronal planes. Simulated setup errors were 3 degrees and 5 degrees rotations in the axial plane and displacements of 5 mm in the left-right, anterior-posterior, and superior-inferior directions. The coordinates set by the positioning device were compared with the coordinates obtained as measured by using the image matching tools of paired 2-dimensional (2D) orthogonal image matching, and 3D cone-beam computed tomography (CT) volume matching. In addition, 6 physician-approved IMRT plans of nasopharynx and tonsil carcinoma were recalculated to evaluate the impact of undetected 3 degrees and 5 degrees head roll. Application of cone-beam CT (CBCT) for patient localization was superior to 2D matching techniques for detecting rotational setup errors. The use of CBCT allowed the determination of translational errors to within 0.5 mm, whereas kV planar was within 1 to 2 mm. Head roll in the axial plane was not easily detected with orthogonal image sets. Compared to the IMRT plans with no head roll, dose-volume histogram analysis demonstrated an average increase in the maximal spinal cord dose of 3.1% and 6.4% for 3 degrees and 5 degrees angles of rotation, respectively. Dose to the contralateral parotid was unchanged with 3 degrees roll and increased by 2.7% with 5 degrees roll. The results of this study show that volumetric setup verification using CBCT can improve bony anatomy setup detection to millimeter accuracy, and is a reliable method to detect head roll. However, the magnitude of possible dose errors due to undetected head roll suggests that CBCT does not need to be performed on a daily basis but rather weekly or bi-weekly to ensure fidelity of the head position with the immobilization system.

  View details for DOI 10.1016/j.meddos.2007.05.004

  View details for Web of Science ID 000253610200015

  View details for PubMedID 18262130

• Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose NEW ENGLAND JOURNAL OF MEDICINE Chung, C. H., Mirakhur, B., Chan, E., Le, Q., Berlin, J., Morse, M., Murphy, B. A., Satinover, S. M., Hosen, J., Mauro, D., Slebos, R. J., Zhou, Q., Gold, D., Hatley, T., Hicklin, D. J., Platts-Mills, T. A. 2008; 358 (11): 1109-1117

  Abstract

  Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston.Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain.In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose.

  View details for Web of Science ID 000253877200004

  View details for PubMedID 18337601

  View details for PubMedCentralID PMC2361129

• Retrospective IMRT dose reconstruction based on cone-beam CT and MLC log-file INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lee, L., Le, Q., Xing, L. 2008; 70 (2): 634-644

  Abstract

  Head-and-neck (HN) cone-beam computed tomography (CBCT) can be exploited to probe the IMRT dose delivered to a patient taking into account the interfraction anatomic variation and any potential inaccuracy in the IMRT delivery. The aim of this work is to reconstruct the intensity-modulated radiation therapy dose delivered to an HN patient using the CBCT and multileaf collimator (MLC) log-files.A cylindrical CT phantom was used for calibrating the electron density and validating the procedures of the dose reconstruction. Five HN patients were chosen, and for each patient, CBCTs were performed on three separate fractions spaced every 2 weeks starting from the first fraction. The respective MLC log-files were retrieved and converted into fluence maps. The dose was then reconstructed on the corresponding CBCT with the regenerated fluence maps. The reconstructed dose distribution, dosimetric endpoints, and DVHs were compared with that of the treatment plan.Phantom study showed that HN CBCT can be directly used for dose reconstruction. For most treatment sessions, the CBCT-based dose reconstructions yielded DVHs of the targets close (within 3%) to that of the original treatment plans. However, dosimetric changes (within 10%) due to anatomic variations caused by setup inaccuracy, organ deformation, tumour shrinkage, or weight loss (or a combination of these) were observed for the critical organs.The methodology we established affords an objective dosimetric basis for the clinical decision on whether a replanning is necessary during the course of treatment and provides a valuable platform for adaptive therapy in future.

  View details for DOI 10.1016/j.ijrobp.2007.09.054

  View details for Web of Science ID 000252521700042

  View details for PubMedID 18207036

• Metabolic tumor volume predicts for recurrence and death in head and neck cancer 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) La, T. H., Filion, E. J., Turnbull, B. B., CHU, J. N., Lee, P., Nguyen, K., Maxim, P., Loo, B. W., Graves, E. E., Le, Q. ELSEVIER SCIENCE INC. 2008: S159–S160

  View details for Web of Science ID 000258805300356

• Radiographic assessment of the sinuses in patients treated for nasopharyngeal carcinoma AMERICAN JOURNAL OF RHINOLOGY Raviv, J., Downing, L., Le, Q., Hwang, P. 2008; 22 (1): 64-67

  Abstract

  Patients undergoing therapy for nasopharyngeal carcinoma (NPC) often experience dysfunction of the sinonasal mucosa as a side effect of radiotherapy and chemotherapy. Sinonasal mucosal changes may vary throughout the treatment and posttreatment periods, but little objective data exist characterizing such changes. We evaluated serial radiologic changes of the paranasal sinus mucosa in patients with NPC undergoing treatment.Medical and radiographic records were reviewed for all patients treated for NPC between 2004 and 2006 at Stanford University Medical Center. Pretreatment computed tomography (CT) images served as the baseline images for comparison, and posttreatment CT and magnetic resonance imaging (MRI) images were categorized temporally into 3-month intervals, up to 25 months after initiation of treatment. Images were scored in a blinded fashion using the Lund-Mackay (LM) staging system.Thirty-five patients received treatment for NPC during the study period, of whom 27 had adequate data for analysis and inclusion in the study. The mean pretreatment LM score was 1.41, and a statistically significant increase in LM score was observed at 3, 6, 9, 12, 15, and 18, 22, and 28 months. There was continued progression of radiologic sinus opacification over the first 30 months after treatment.The treatment of NPC with radiotherapy and chemotherapy is associated with radiologic evidence of sinus mucosal thickening. The extent of mucosal thickening can be expected to progress after treatment for up to 30 months. Patients undergoing treatment for NPC should be monitored carefully throughout the posttreatment period for clinical manifestations of dysfunctional sinonasal mucosa.

  View details for DOI 10.2500/ajr.2007.21.3091

  View details for Web of Science ID 000253232100012

  View details for PubMedID 17958946

• Relationship between human papillomavirus (HPV) status, epidermal growth factor receptor (EGFR) and Phospho-EGFR (pEGFR) expression in head and neck squamous cell carcinoma (HNSCC) 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Filion, E. J., Kong, C. S., Narasimhan, B., Cao, H., Erickson, J. P., Andersson, A., Koong, A., Pourmand, N., Fredriksson, S., Le, Q. ELSEVIER SCIENCE INC. 2008: S23–S23

  View details for Web of Science ID 000258805300052

• Tumor size is a critical determinant of local control in single fraction stereotactic radiotherapy of pulmonary tumors 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Loo, B. W., Shen, J., Quinlan-Davidson, S., Filion, E., Dieterich, S., Maxim, P. G., Wakelee, H. A., Whyte, R. I., Le, Q. ELSEVIER SCIENCE INC. 2008: S467–S468

  View details for Web of Science ID 000258805301520

• Quantification of motion of different thoracic locations using four-dimensional computed tomography: Implications for radiotherapy planning 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Maxim, P. G., Loo, B. W., Shirazi, H., Thorndyke, B., Luxton, G., Le, Q. ELSEVIER SCIENCE INC. 2007: 1395–1401

  Abstract

  To assess the respiratory motion of different thoracic nodal locations and its dependence on the presence of enlarged nodes; to assess the respiratory motion of different parenchymal tumor locations; and to determine the appropriate margins to cover the respiratory motion of targets at these locations.We reviewed the four-dimensional computed tomography scans of 20 patients with thoracic tumors treated at our institution. The motion of four central thoracic locations (aortic arch, carina, and bilateral hila), parenchymal tumor locations (upper vs. lower, and anterior vs. middle vs. posterior thorax), and bilateral diaphragmatic domes was measured.For the central thoracic locations, the largest motion was in the superoinferior (SI) dimension (>5 mm for bilateral hila and carina, but <4 mm for aortic arch). No significant difference was found in the motion of these locations in the absence or presence of enlarged nodes. For parenchymal tumors, upper tumors exhibited smaller SI motion than did lower tumors (3.7 vs. 10.4 mm, p = 0.029). Similarly, anterior tumors exhibited smaller motion than did posterior tumors in both the SI (4.0 vs. 8.0 mm, p = 0.013) and lateral (2.8 vs. 4.6 mm, p = 0.045) directions. The margins that would be needed to encompass the respiratory motion of each of the evaluated locations in 95% of patients were tabulated and range from 3.4 to 37.2 mm, depending on the location and direction.The results of our study have provided data for appropriate site-specific internal target volume expansion that could be useful in the absence of four-dimensional computed tomography-based treatment planning. However, generalizing the results from a small patient population requires discretion.

  View details for Web of Science ID 000251561100008

  View details for PubMedID 17869025

• Metabolic tumor burden predicts for disease progression and death in lung cancer 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Lee, P., Weerasuriya, D. K., Lavori, P. W., Quon, A., Hara, W., Maxim, P. G., Le, Q., Wakelee, H. A., Donington, J. S., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: 328–33

  Abstract

  In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging.We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV).The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS.In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  View details for DOI 10.1016/j.ijrobp.2007.04.036

  View details for PubMedID 17869659

• Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Le, Q., Kong, C., Lavori, P. W., O'Byrne, K., Erler, J. T., Huang, X., Chen, Y., Cao, H., Tibshiran, R., Denko, N., Giaccia, A. J., Koong, A. C. ELSEVIER SCIENCE INC. 2007: 167–75

  Abstract

  To investigate the expression pattern of hypoxia-induced proteins identified as being involved in malignant progression of head-and-neck squamous cell carcinoma (HNSCC) and to determine their relationship to tumor pO(2) and prognosis.We performed immunohistochemical staining of hypoxia-induced proteins (carbonic anhydrase IX [CA IX], BNIP3L, connective tissue growth factor, osteopontin, ephrin A1, hypoxia inducible gene-2, dihydrofolate reductase, galectin-1, IkappaB kinase beta, and lysyl oxidase) on tumor tissue arrays of 101 HNSCC patients with pretreatment pO(2) measurements. Analysis of variance and Fisher's exact tests were used to evaluate the relationship between marker expression, tumor pO(2), and CA IX staining. Cox proportional hazard model and log-rank tests were used to determine the relationship between markers and prognosis.Osteopontin expression correlated with tumor pO(2) (Eppendorf measurements) (p = 0.04). However, there was a strong correlation between lysyl oxidase, ephrin A1, and galectin-1 and CA IX staining. These markers also predicted for cancer-specific survival and overall survival on univariate analysis. A hypoxia score of 0-5 was assigned to each patient, on the basis of the presence of strong staining for these markers, whereby a higher score signifies increased marker expression. On multivariate analysis, increasing hypoxia score was an independent prognostic factor for cancer-specific survival (p = 0.015) and was borderline significant for overall survival (p = 0.057) when adjusted for other independent predictors of outcomes (hemoglobin and age).We identified a panel of hypoxia-related tissue markers that correlates with treatment outcomes in HNSCC. Validation of these markers will be needed to determine their utility in identifying patients for hypoxia-targeted therapy.

  View details for DOI 10.1016/j.ijrobp.2007.01.071

  View details for PubMedID 17707270

• Retrospective IMRT dose reconstruction based on cone-beam computed tomography (CBCT) and the MLC positional log-file recorded during treatment 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine Lee, K., Le, Q., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2007: 2600–2600

  View details for Web of Science ID 000247479601165

• Longitudinal evaluation of the oral mucositis weekly questionnaire-head and neck cancer, a patient-reported outcomes questionnaire CANCER Epstein, J. B., Beaumont, J. L., Gwede, C. K., Murphy, B., Garden, A. S., Meredith, R., Le, Q., Brizel, D., Isitt, J., Cella, D. 2007; 109 (9): 1914-1922

  Abstract

  Quality-of-life instruments that measure specific functional consequences of mucositis are needed to assess the efficacy of therapeutic interventions targeted against mucositis and to guide patient care. The authors undertook a prospective, multicenter, observational study to assess the validity, reliability, and feasibility of a new instrument, the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer (OMWQ-HN). The OMWQ-HN is a patient-reported outcome questionnaire that measures the symptoms of mucositis, including mouth and throat soreness (MTS), and their impact on patient well-being and function.The OMWQ-HN, along with the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), was administered 5 times over an approximately 6-week period to patients with head and neck cancer (HNC) who were receiving radiation therapy with or without chemotherapy. Information on supportive care measures also was collected.Seventy-five patients were enrolled and completed 93% of scheduled assessments (100% at baseline). The OMWQ-HN demonstrated good test-retest reliability (correlation coefficient, 0.80-0.89). Cross-sectional analyses to assess validity showed that OMWQ-HN scores were different across levels of pain, with those in the worst pain category reporting the highest OMWQ-HN scores. Strong correlations were observed between OMWQ-HN and FACT-HN. Patients experienced increases in MTS, which corresponded with a steady decline in function. MTS scores were highest in the patients who were taking opioid analgesics, suggesting that mucositis pain continued despite standard pain therapy.The current results indicated that the OMWQ-HN is a valid, reliable, and feasible instrument for assessing the impact of mucositis on patients who are receiving radiation therapy with or without chemotherapy for HNC.

  View details for DOI 10.1002/cncr.22620

  View details for Web of Science ID 000245937000030

  View details for PubMedID 17377917

• Evaluation of patterns of failure and subjective salivary function in patients treated with intensity modulated radiotherapy for head and neck squamous cell carcinoma 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Daly, M. E., Lieskovsky, Y., Pawlicki, T., Yau, J., Pinto, H., Kaplan, M., Fee, W. E., Koong, A., Goffinet, D. R., Xing, L., Le, Q. JOHN WILEY & SONS INC. 2007: 211–20

  Abstract

  Our aim was to correlate patterns of failure with target volume delineations in patients with head and neck squamous cell carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT) and to report subjective xerostomia outcomes after IMRT as compared with conventional radiation therapy (CRT).Between January 2000 and April 2005, 69 patients with newly diagnosed nonmetastatic HNSCC underwent curative parotid-sparing IMRT at Stanford University. Sites included were oropharynx (n = 39), oral cavity (n = 8), larynx (n = 8), hypopharynx (n = 8), and unknown primary (n = 6). Forty-six patients received definitive IMRT (66 Gy, 2.2 Gy/fraction), and 23 patients received postoperative IMRT (60.2 Gy, 2.15 Gy/fraction). Fifty-one patients also received concomitant chemotherapy. Posttreatment salivary gland function was evaluated by a validated xerostomia questionnaire in 29 IMRT and 75 matched CRT patients >6 months after completing radiation treatment.At a median follow-up of 25 months for living patients (range, 10-60), 7 locoregional failures were observed, 5 in the gross target or high-risk postoperative volume, 1 in the clinical target volume, and 1 at the junction of the IMRT and supraclavicular fields. The 2-year Kaplan-Meier estimates for locoregional control and overall survival were 92% and 74% for definitive IMRT and 87% and 87% for postoperative IMRT patients, respectively. The mean total xerostomia questionnaire score was significantly better for IMRT than for CRT patients (p = .006).The predominant pattern of failure in IMRT-treated patients is in the gross tumor volume. Parotid sparing with IMRT resulted in less subjective xerostomia and may improve quality of life in irradiated HNSCC patients.

  View details for DOI 10.1002/hed.20505

  View details for Web of Science ID 000244459100002

  View details for PubMedID 17111429

• A differentiation based immunohistochemical classifier that is prognostic for head and neck tumor patients 96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Ross, D. T., Ring, B. Z., Seitz, R. S., Beck, R. A., DeFoe, S., Robert, F., Schreeder, M. T., Chung, C. H., Kong, C. S., Le, Q. T. NATURE PUBLISHING GROUP. 2007: 228A–228A

  View details for Web of Science ID 000244922401470

• Identifying and targeting hypoxia in head and neck cancer: A brief overview of current approaches 1st Multidisciplinary Head and Neck Cancer Symposium Le, Q. ELSEVIER SCIENCE INC. 2007: S56–S58

  View details for DOI 10.1016/j.ijrobp.2007.04.081

  View details for Web of Science ID 000249999000018

  View details for PubMedID 17848296

  View details for PubMedCentralID PMC2276659

• Nasopharyngeal and oropharyngeal carcinomas: Target delineation, therapy delivery and stereotactic boost procedures with intensity-modulated/image-guided radiation therapy 38th San Francisco Radiation Oncology Conference Le, Q. KARGER. 2007: 208–231

  Abstract

  Radiation therapy is a key component of the multidisciplinary treatment of nasopharyngeal and oropharyngeal carcinomas, which are ideal tumors for intensity-modulated radiation therapy (IMRT) because of their location and intimate relationship to the surrounding critical structures. Several studies have suggested that IMRT is superior to conventional radiation therapy in salivary preservation and holds promise for improved locoregional control of these tumors. Target delineation for IMRT in these tumors is complex and requires detailed knowledge of head and neck anatomy and pathways of tumor spread. This article focuses on target delineation for IMRT for oropharyngeal and nasopharyngeal carcinomas. In addition, we also present data on the use of stereotactic radiotherapy as a boost to improve local control of nasopharyngeal carcinomas.

  View details for Web of Science ID 000248596600013

  View details for PubMedID 17641511

• Clinical role of F-18-FDG PET/CT in the management of squamous cell carcinoma of the head and neck and thyroid carcinoma JOURNAL OF NUCLEAR MEDICINE Quon, A., Fischbein, N. J., McDougall, I. R., Le, Q., Loo, B. W., Pinto, H., Kaplan, M. J. 2007; 48: 58S-67S

  Abstract

  18F-FDG PET/CT has rapidly become a widely used imaging modality for evaluating a variety of malignancies, including squamous cell carcinoma of the head and neck and thyroid cancer. Using both published data and the multidisciplinary experience at our institution, we provide a practical set of guidelines and algorithms for the use of 18F-FDG PET/CT in the evaluation and management of head and neck cancer and thyroid cancer.

  View details for Web of Science ID 000243420900008

  View details for PubMedID 17204721

• Plasma osteopontin is an independent prognostic marker for head and neck cancers 41st Annual Meeting of the American-Society-of-Clinical-Oncology Petrik, D., Lavori, P. W., Cao, H., Zhu, Y., Wong, P., Christofferson, E., Kaplan, M. J., Pinto, H. A., Sutphin, P., Koong, A. C., Giaccia, A. J., Le, Q. AMER SOC CLINICAL ONCOLOGY. 2006: 5291–97

  Abstract

  To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study.One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group.Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival.In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

  View details for DOI 10.1200/JCO.2006.06.8627

  View details for Web of Science ID 000242342800017

  View details for PubMedID 17114663

• Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q., Loo, B. W., Ho, A., Cotrutz, C., Koong, A. C., Wakelee, H., Kee, S. T., Constantinescu, D., Whyte, R. I., Donington, J. LIPPINCOTT WILLIAMS & WILKINS. 2006: 802–9

  Abstract

  The purpose of this study was to report initial results of a phase I study using single-fraction stereotactic radiotherapy (RT) in patients with inoperable lung tumors.Eligible patients included those with inoperable T1-2N0 non-small cell lung cancer (NSCLC) or solitary lung metastases. Treatments were delivered by means of the CyberKnife. All patients underwent computed tomography-guided metallic fiducial placement in the tumor for image-guided targeting. Nine to 20 patients were treated per dose cohort starting at 15 Gy/fraction followed by dose escalation of 5 to 10 Gy to a maximal dose of 30 Gy/fraction. A minimal 3-month period was required between each dose level to monitor toxicity.Thirty-two patients (21 NSCLC and 11 metastatic tumors) were enrolled. At 25 Gy, pulmonary toxicity was noted in patients with prior pulmonary RT and treatment volumes greater than 50 cc; therefore, dose escalation to 30 Gy was applied only to unirradiated patients and treatment volume less than 50 cc. Ten patients received doses less than 20 Gy, 20 received 25 Gy, and two received 30 Gy. RT-related complications were noted for doses greater than 25 Gy and included four cases of grade 2 to 3 pneumonitis, one pleural effusion, and three possible treatment-related deaths. The 1-year freedom from local progression was 91% for dose greater than 20 Gy and 54% for dose less than 20 Gy in NSCLC (p = 0.03). NSCLC patients had significantly better freedom from relapse (p = 0.003) and borderline higher survival than those with metastatic tumors (p = 0.07).Single-fraction stereotactic RT is feasible for selected patients with lung tumors. For those with prior thoracic RT, 25 Gy may be too toxic. Higher dose was associated with improved local control. Longer follow-up is necessary to determine the treatment efficacy and toxicity.

  View details for PubMedID 17409963

• Indirect MR lymphangiography of the head and neck using conventional gadolinium contrast: A pilot study in humans 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Loo, B. W., Draney, M. T., Sivanandan, R., Ruehm, S. G., Pawlicki, T., Xing, L., Herfkens, R. J., Le, Q. ELSEVIER SCIENCE INC. 2006: 462–68

  Abstract

  To evaluate indirect magnetic resonance lymphangiography (MR-LAG) using interstitial injection of conventional gadolinium contrast (gadoteridol and gadopentetate dimeglumine) for delineating the primary lymphatic drainage of head-and-neck sites.We performed head-and-neck MR-LAG in 5 healthy volunteers, with injection of dermal and mucosal sites. We evaluated the safety of the procedure, the patterns of enhancement categorized by injection site and nodal level, the time course of enhancement, the optimal concentration and volume of contrast, and the optimal imaging sequence.The worst side effects of interstitial contrast injection were brief, mild pain and swelling at the injected sites that were self-limited. MR-LAG resulted in consistent visualization of the primary lymphatic drainage pattern specific to each injected site, which was reproducible on repeated examinations. The best enhancement was obtained with injection of small volumes (0.3-0.5 mL) of either agent diluted, imaging within 5-15 min of injection, and a three-dimensional fast spoiled gradient echo sequence with magnetization transfer.We found head-and-neck MR-LAG to be a safe, convenient imaging method that provides functional information about the lymphatic drainage of injected sites. Applied to head-and-neck cancer, it has the potential to identify sites at highest risk of occult metastatic spread for radiotherapy or surgical planning, and possibly to visualize micrometastases.

  View details for DOI 10.1016/j.ijrobp.2006.05.045

  View details for Web of Science ID 000240699500024

  View details for PubMedID 16965993

• A multidisciplinary approach to management in a patient with bilateral superior sulcus non-small-cell lung carcinoma CLINICAL LUNG CANCER Roy, M. S., Le, Q., Donington, J. S., Wakelee, H. A. 2006; 8 (2): 146-148

  Abstract

  Superior sulcus tumors comprise a rare subset of non-small-cell lung carcinomas that are particularly challenging to treat because of their location and extent of nerve and vessel involvement. In this report, we present a case illustrating the uncommon situation of a patient presenting with bilateral superior sulcus tumors, and we review the latest combined therapeutic approach developed to aggressively treat the more common unilateral presentation of these tumors.

  View details for PubMedID 17026817

• Advanced-staged tonsillar squamous carcinoma: Organ preservation versus surgical management of the primary site 90th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America Shirazi, H. A., Sivanandan, R., Goode, R., Fee, W. E., Kaplan, M. J., Pinto, H. A., Goffinet, D. R., Le, Q. JOHN WILEY & SONS INC. 2006: 587–94

  Abstract

  Our aim was to review our experience in the management of advanced tonsillar squamous cell carcinoma (SCC) and to compare treatment outcomes between patients treated with and without surgery to the primary site.The records of 74 patients with advanced-stage tonsillar SCC were reviewed. The median age at diagnosis was 58 years. Thirty-eight patients received definitive surgery to the primary site, and 36 were treated with an organ-preservation approach (OP) using radiotherapy +/- chemotherapy.No significant difference in overall survival (OS) or freedom from relapse (FFR) by treatment was found. T classification and N status were significant independent predictors on multivariate analysis for OS and FFR. Major late toxicity was noted in 10 patients in the surgical group and nine in the OP group.Patients treated with OP and primary surgery had comparable OS and FFR. T classification and N status were significant independent predictors for tumor relapse and survival. On the basis of these results, we favor organ-preservation therapy for patients with advanced-stage tonsillar SCC.

  View details for DOI 10.1002/hed.20372

  View details for Web of Science ID 000238690100003

  View details for PubMedID 16475199

• Lung cancer in women: Exploring sex differences in susceptibility, biology, and therapeutic response CLINICAL LUNG CANCER Donington, J. S., Le, Q., Wakelee, H. A. 2006; 8 (1): 22-29

  Abstract

  Src tyrosine kinases regulate a large number of important mechanisms in normal and cancerous cells, are overexpressed in a broad range of tumors including lung cancer, and thus represent a potential target for cancer therapy. Preclinical experiments indicate that small-molecule inhibitors of Src block tumor growth, metastasis, and angiogenesis. Phase I data from healthy volunteers also suggest that inhibitors of Src prevent bone resorption. Several phase II trials with small-molecule inhibitors of Src are under way or have been initiated in lung cancer and in other malignancies, as discussed herein.

  View details for PubMedID 16870042

• Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis CANCER RESEARCH Dornhoefer, N., Spong, S., Bennewith, K., Salim, A., Klaus, S., Kambham, N., Wong, C., Kaper, F., Sutphin, P., Nacalumi, R., Hoeckel, M., Le, Q., Longaker, M., Yang, G., Koong, A., Giaccia, A. 2006; 66 (11): 5816-5827

  Abstract

  Pancreatic cancer is highly aggressive and refractory to most existing therapies. Past studies have shown that connective tissue growth factor (CTGF) expression is elevated in human pancreatic adenocarcinomas and some pancreatic cancer cell lines. To address whether and how CTGF influences tumor growth, we generated pancreatic tumor cell lines that overexpress different levels of human CTGF. The effect of CTGF overexpression on cell proliferation was measured in vitro in monolayer culture, suspension culture, or soft agar, and in vivo in tumor xenografts. Although there was no effect of CTGF expression on proliferation in two-dimensional cultures, anchorage-independent growth (AIG) was enhanced. The capacity of CTGF to enhance AIG in vitro was linked to enhanced pancreatic tumor growth in vivo when these cells were implanted s.c. in nude mice. Administration of a neutralizing CTGF-specific monoclonal antibody, FG-3019, had no effect on monolayer cell proliferation, but blocked AIG in soft agar. Consistent with this observation, anti-CTGF treatment of mice bearing established CTGF-expressing tumors abrogated CTGF-dependent tumor growth and inhibited lymph node metastases without any toxicity observed in normal tissue. Together, these studies implicate CTGF as a new target in pancreatic cancer and suggest that inhibition of CTGF with a human monoclonal antibody may control primary and metastatic tumor growth.

  View details for DOI 10.1158/0008-5472.CAN-06-0081

  View details for Web of Science ID 000238003100038

  View details for PubMedID 16740721

• Mature results from a randomized phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable stage IV head and neck squamous cell carcinomas CANCER Le, Q. T., Taira, A. I., Budenz, S., Dorie, M. J., Goffinet, D. R., Fee, W. E., Goode, R., Bloch, D., Koong, A., Brown, J. M., Pinto, H. A. 2006; 106 (9): 1940-1949

  Abstract

  The objective of this article was to report the results from a randomized trial that evaluated the efficacy and toxicity of adding tirapazamine (TPZ) to chemoradiotherapy in the treatment of patients with head and neck squamous cell carcinomas (HNSCC).Sixty-two patients with lymph node-positive, resectable, TNM Stage IV HNSCC were randomized to receive either 2 cycles of induction chemotherapy (TPZ, cisplatin, and 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (TPZ, cisplatin, and 5-FU) or to receive the same regimen without TPZ. Patients who did not achieve a complete response at 50 Grays underwent surgical treatment. Stratification factors for randomization included tumor site, TNM stage, and median tumor oxygen tension. The primary endpoint was complete lymph node response.The addition of TPZ resulted in increased hematologic toxicity. There was 1 treatment-related death from induction chemotherapy. The complete clinical and pathologic response rate in the lymph nodes was 90% and 74% for the standard treatment arm and the TPZ arm, respectively (P = .08) and 89% and 90% at the primary site in the respective treatment arms (P = .71). The 5-year overall survival rate was 59%, the cause-specific survival rate was 68%, the rate of freedom from recurrence was 69%, and the locoregional control rate was 77% for the entire group. There was no difference with regard to any of the outcome parameters between the 2 treatment arms. The significant long-term toxicity rate also was found to be similar between the 2 arms.The addition of TPZ increased hematologic toxicity but did not improve outcomes in patients with resectable, Stage IV HNSCC using the protocol administered this small randomized study. The combination of induction and simultaneous chemoradiotherapy resulted in excellent survival in these patients.

  View details for DOI 10.1002/cncr.21785

  View details for Web of Science ID 000237187400010

  View details for PubMedID 16532436

• Lysyl oxidase is essential for hypoxia-induced metastasis NATURE Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhofer, N., Kong, C., Le, Q. T., Chi, J. T., Jeffrey, S. S., Giaccia, A. J. 2006; 440 (7088): 1222-1226

  Abstract

  Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell-cell or cell-matrix interactions) and the extended tumour microenvironment (for example vascularization). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases.

  View details for DOI 10.1038/nature04695

  View details for PubMedID 16642001

• An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers CLINICAL CANCER RESEARCH Le, Q. T., Chen, E., Salim, A., Cao, H. B., Kong, C. S., Whyte, R., Donington, J., Cannon, W., Wakelee, H., Tibshirani, R., Mitchell, J. D., Richardson, D., O'Byrne, K. J., Koong, A. C., Giaccia, A. J. 2006; 12 (5): 1507-1514

  Abstract

  To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

  View details for DOI 10.1158/1078-0432.CCR-05-2049

  View details for PubMedID 16533775

• Comment on: Osteopontin as toxic marker RADIOTHERAPY AND ONCOLOGY Le, Q. T., Cao, H. B., Giaccia, A. 2006; 78 (2): 230-230

  View details for DOI 10.1016/j.radonc.2005.12.011

  View details for Web of Science ID 000236490300018

  View details for PubMedID 16442647

• Galectin-1: A link between tumor hypoxia and tumor immune privilege 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Shi, G. Y., Cao, H. B., Nelson, D. W., Wang, Y. Y., CHEN, E. Y., Zhao, S. C., Kong, C., Richardson, D., O'Byrne, K. J., Giaccia, A. J., Koong, A. C. AMER SOC CLINICAL ONCOLOGY. 2005: 8932–41

  Abstract

  To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression.We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CD3 (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes.SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CD3 staining (P = .01). Expression of galectin-1 and CD3 were significant predictors for overall survival on multivariate analysis.Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege.

  View details for DOI 10.1200/JCO.2005.02.0206

  View details for PubMedID 16219933

• Identification of mitogen-activated protein kinase signaling pathways that confer resistance to endoplasmic reticulum stress in Saccharomyces cerevisiae MOLECULAR CANCER RESEARCH Chen, Y. J., Feldman, D. E., Deng, C. C., BROWN, J. A., De Giacomo, A. F., Gaw, A. F., Shi, G. Y., Le, Q. T., Brown, J. M., Koong, A. C. 2005; 3 (12): 669-677

  Abstract

  Hypoxia activates all components of the unfolded protein response (UPR), a stress response initiated by the accumulation of unfolded proteins within the endoplasmic reticulum (ER). Our group and others have shown previously that the UPR, a hypoxia-inducible factor-independent signaling pathway, mediates cell survival during hypoxia and is required for tumor growth. Identifying new genes and pathways that are important for survival during ER stress may lead to the discovery of new targets in cancer therapy. Using the set of 4,728 homozygous diploid deletion mutants in budding yeast, Saccharomyces cerevisiae, we did a functional screen for genes that conferred resistance to ER stress-inducing agents. Deletion mutants in 56 genes showed increased sensitivity under ER stress conditions. Besides the classic UPR pathway and genes related to calcium homeostasis, we report that two additional pathways, including the SLT2 mitogen-activated protein kinase (MAPK) pathway and the osmosensing MAPK pathway, were also required for survival during ER stress. We further show that the SLT2 MAPK pathway was activated during ER stress, was responsible for increased resistance to ER stress, and functioned independently of the classic IRE1/HAC1 pathway. We propose that the SLT2 MAPK pathway is an important cell survival signaling pathway during ER stress. This study shows the feasibility of using the yeast deletion pool to identify relevant mammalian orthologues of the UPR.

  View details for DOI 10.1158/1541-7786.MCR-05-0181

  View details for Web of Science ID 000234499800003

  View details for PubMedID 16380504

• Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Koong, A. C., Christofferson, E., Le, Q. T., Goodman, K. A., Ho, A., Kuo, T., Ford, J. M., Fisher, G. A., Greco, R., Norton, J., Yang, G. P. 2005; 63 (2): 320-323

  Abstract

  To determine the efficacy of concurrent 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT) followed by body stereotactic radiosurgery (SRS) in patients with locally advanced pancreatic cancer.In this prospective study, all patients (19) had pathologically confirmed adenocarcinoma and were uniformly staged. Our treatment protocol consisted of 45 Gy IMRT with concurrent 5-FU followed by a 25 Gy SRS boost to the primary tumor.Sixteen patients completed the planned therapy. Two patients experienced Grade 3 toxicity (none had more than Grade 3 toxicity). Fifteen of these 16 patients were free from local progression until death. Median overall survival was 33 weeks.Concurrent IMRT and 5-FU followed by SRS in patients with locally advanced pancreatic cancer results in excellent local control, but does not improve overall survival and is associated with more toxicity than SRS, alone.

  View details for DOI 10.1016/j.ijrobp.2005.07.002

  View details for PubMedID 16168826

• Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a ras-activated enhancer ONCOGENE Zhu, Y. H., Denhardt, D. T., Cao, H. B., Sutphin, P. D., Koong, A. C., Giaccia, A. J., Le, Q. T. 2005; 24 (43): 6555-6563

  Abstract

  Osteopontin (OPN) is a secreted phosphoglycoprotein that has been linked to tumor progression and survival in several solid tumors, including head and neck cancers. Previous studies showed that OPN expression is induced by tumor hypoxia, and its plasma levels can serve as a surrogate marker for tumor hypoxia and treatment outcome in head and neck cancer patients. In this study, we investigate the transcriptional mechanism by which hypoxia enhances OPN expression. We found that OPN is induced in head and neck squamous cell carcinoma (HNSCC) cell lines and in NIH3T3 cells by hypoxia at both mRNA and protein levels in a time-dependent manner. Actinomycin D chase experiments showed that hypoxic induction of OPN was not due to increased mRNA stability. Deletion analyses of the mouse OPN promoter regions indicated that a ras-activated enhancer (RAE) located at -731 to -712 relative to the transcription start site was essential for hypoxia-enhanced OPN transcription. Using electrophoretic mobility shift assays with the RAE DNA sequence, we found that hypoxia induced sequence-specific DNA-binding complexes. Furthermore, hypoxia and ras exposure resulted in an additive induction of OPN protein and mRNA levels that appeared to be mediated by the RAE. Induction of OPN through the RAE element by hypoxia is mediated by an Akt-kinase signaled pathway as decreasing Akt levels with dominant negative constructs resulted in inhibition of OPN induction by hypoxia. Taken together, these results have identified a new hypoxia responsive transcriptional enhancer that is regulated by Akt signaling.

  View details for DOI 10.1038/sj.onc.1208800

  View details for Web of Science ID 000232204100009

  View details for PubMedID 16007184

• A comparison study of different PCR assays in measuring circulating plasma Epstein-Barr virus DNA levels in patients with nasopharyngeal carcinoma CLINICAL CANCER RESEARCH Le, Q. T., Jones, C. D., Yau, T. K., Shirazi, H. A., Wong, P. H., Thomas, E. N., Patterson, B. K., Lee, A. W., Zehnder, J. L. 2005; 11 (16): 5700-5707

  Abstract

  To compare the performance of three PCR assays in measuring circulating Epstein-Barr virus (EBV). DNA levels in nasopharyngeal carcinoma patients and to confirm its prognostic significance.Plasma from 58 newly diagnosed nasopharyngeal carcinoma patients were collected before, during, and every 3 to 6 months after radiotherapy. EBV DNA levels were determined by real-time quantitative PCR using primer/probe sets for polymerase-1 (Pol-1), latent membrane protein 2 (Lmp2), and BamHI-W. Pretreatment levels from the three assays were correlated with each other and serial measurements from the Pol-1 assay were correlated with clinical variables.Pol-1 was more accurate than BamHI-W in predicting EBV DNA concentrations in cell lines. Of the three assays, BamHI-W yielded the highest concentrations followed by Pol-1 in plasmas (n = 23). The correlation coefficient was 0.99 (P < 0.0001) for Pol-1 and Lmp2, 0.66 (P < 0.0001) for Pol-1 and BamHI-W, and 0.55 (P < 0.0001) for BamHI-W and Lmp2. Elevated pretreatment DNA levels as detected by Pol-1 were correlated with advanced nodal stage (P = 0.04) and overall stage (P = 0.028). There was no correlation between pretreatment EBV DNA levels and freedom-from-relapse or overall survival; however, there was a significant correlation between posttreatment levels and these variables. The 2-year freedom-from-relapse and overall survival rates were 92% and 94% for patients with undetectable, and 37% and 55% for those with detectable, posttreatment levels (P < 0.0001 and P < 0.002).The three PCR assays yielded similar results in detecting EBV DNA in plasmas. The Pol-1-detected posttreatment EBV DNA level was the strongest predictor for treatment outcomes.

  View details for DOI 10.1158/1078-0432.CCR-05-0648

  View details for PubMedID 16115906

• A noninvasive approach for assessing tumor hypoxia in xenografts: Developing a urinary marker for hypoxia CANCER RESEARCH Nelson, D. W., Cao, H. B., Zhu, Y. H., Sunar-Reeder, B., Choi, C. Y., Faix, J. D., Brown, J. M., Koong, A. C., Giaccia, A. J., Le, Q. T. 2005; 65 (14): 6151-6158

  Abstract

  Tumor hypoxia modifies the efficacy of conventional anticancer therapy and promotes malignant tumor progression. Human chorionic gonadotropin (hCG) is a glycoprotein secreted during pregnancy that has been used to monitor tumor burden in xenografts engineered to express this marker. We adapted this approach to use urinary beta-hCG as a secreted reporter protein for tumor hypoxia. We used a hypoxia-inducible promoter containing five tandem repeats of the hypoxia-response element (HRE) ligated upstream of the beta-hCG gene. This construct was stably integrated into two different cancer cell lines, FaDu, a human head and neck squamous cell carcinoma, and RKO, a human colorectal cancer cell line. In vitro studies showed that tumor cells stably transfected with this plasmid construct secrete beta-hCG in response to hypoxia or hypoxia-inducible factor 1alpha (HIF-1alpha) stabilizing agents. The hypoxia responsiveness of this construct can be blocked by treatment with agents that affect the HIF-1alpha pathways, including topotecan, 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1), and flavopiridol. Immunofluorescent analysis of tumor sections and quantitative assessment with flow cytometry indicate colocalization between beta-hCG and 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and beta-hCG and pimonidazole, two extrinsic markers for tumor hypoxia. Secretion of beta-hCG from xenografts that contain these stable constructs is directly responsive to changes in tumor oxygenation, including exposure of the animals to 10% O2 and tumor bed irradiation. Similarly, urinary beta-hCG levels decline after treatment with flavopiridol, an inhibitor of HIF-1 transactivation. This effect was observed only in tumor cells expressing a HRE-regulated reporter gene and not in tumor cells expressing a cytomegalovirus-regulated reporter gene. The 5HRE beta-hCG reporter system described here enables serial, noninvasive monitoring of tumor hypoxia in a mouse model by measuring a urinary reporter protein.

  View details for Web of Science ID 000230633400024

  View details for PubMedID 16024616

• Nonsurgical therapy for stages I and II non-small cell lung cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Le, Q. T., Petrik, D. W. 2005; 19 (2): 237-?

  Abstract

  For patients who have stages I and II non-small cell lung cancer (NSCLC) and who are unable or unwilling to undergo surgical resection, nonsurgical treatment modalities have been used with curative intent. Conventionally fractionated radiotherapy has been the mainstay of nonsurgical therapy; however, advances in technology and the clinical application of radiobiologic principles have allowed more accurately targeted treatment that delivers higher effective doses to the tumor, while respecting the tolerance of surrounding normal tissues. This article discusses nonsurgical approaches to the treatment of early-stage NSCLC, including several promising techniques, such as radiation dose escalation, altered radiation fractionation, stereotactic radiotherapy, and radiofrequency ablation.

  View details for DOI 10.1016/j.hoc.2005.02.003

  View details for Web of Science ID 000228810400004

  View details for PubMedID 15833405

• Positron-emission tomography for surveillance of head and neck cancer LARYNGOSCOPE Ryan, W. R., Fee, W. E., Le, Q. T., Pinto, H. A. 2005; 115 (4): 645-650

  Abstract

  To determine the diagnostic accuracy and the ideal timing of fluoro-fluorodeoxyglucose positron-emission tomography (PET) in the posttreatment surveillance of head and neck mucosal squamous cell carcinoma (HNSCC).Retrospective chart review.Our sample includes 103 adult patients with 118 posttreatment PET scans who had undergone treatment for HNSCC. We correlated PET results with surgical pathology and clinical outcome in the subsequent 6 months.For the detection of locoregional persistent or recurrent HNSCC, PET scans had a sensitivity of 82%, specificity of 92%, positive predictive value (PPV) of 64%, negative predictive value (NPV) of 97%, and overall accuracy of 90%. For the detection of distant metastases, PET scans had a sensitivity of 89%, specificity of 97%, PPV of 85%, NPV of 98%, and overall accuracy of 96%. PET scans of the head and neck region performed greater than 1 month after the completion of radiation compared with scans performed within 1 month had a significantly higher sensitivity of 95% versus 55% (P < .01) and NPV of 99% versus 90% (P < .01).PET is effective in detecting distant metastases in the posttreatment surveillance for HNSCC patients. A negative PET is highly reliable for all sites. However, a positive PET in the head and neck region is unreliable because of a high false-positivity rate. PET of the head and neck region has a statistically significant risk of a false-negative reading when performed within 1 month of radiation.

  View details for DOI 10.1097/01.mlg.0000161345.23128.d4

  View details for Web of Science ID 000228280300016

  View details for PubMedID 15805874

• Long-term results of 100 consecutive comprehensive neck dissections - Implications for selective neck dissections ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Sivanandan, R., Kaplan, M. J., Lee, K. J., Lebl, D., PINTO, H., Le, Q. T., Goffinet, D. R., Fee, W. E. 2004; 130 (12): 1369-1373

  Abstract

  The optimal surgical procedure for the neck in patients with squamous head and neck cancers is controversial. Selective neck dissections have replaced modified radical neck dissections as the procedure of choice for the clinically negative (N0) neck and are now being considered for patients with early-stage neck disease. We report the long-term local recurrence rates in 100 consecutive patients undergoing a radical or modified radical neck dissection for clinically positive (N+) and N0 neck disease and review comprehensively the literature reporting and comparing regional control rates for both neck dissection types.The clinical records of 100 consecutive patients who underwent a comprehensive neck dissection (levels I-V) for squamous head and neck cancers with a minimum of a 2-year follow-up were retrospectively reviewed for primary site of disease, clinical and pathologic neck status, histopathologic grade, neck dissection type, and the site and time of recurrence.Complete data were available for 97 patients on whom 99 neck dissections were performed. Three patients died from unknown causes. Seventy-six patients with N+ disease underwent a therapeutic neck dissection, while 24 patients with clinically N0 disease underwent an elective dissection. The overall neck recurrence rate in patients with controlled primary disease was 7%. The neck or regional failure rate for patients completing the recommended adjuvant radiotherapy was 4%. Six (25%) of 24 patients with clinically N0 disease had occult metastases. The recurrence rate for this group was 4%.Further study is needed to determine the optimal surgical management of the N0 and limited N+ neck.

  View details for PubMedID 15611394

• Sample classification from protein mass spectrometry, by 'peak probability contrasts' BIOINFORMATICS Tibshirani, R., Hastie, T., Narasimhan, B., Soltys, S., Shi, G. Y., Koong, A., Le, Q. T. 2004; 20 (17): 3034-3044

  Abstract

  Early cancer detection has always been a major research focus in solid tumor oncology. Early tumor detection can theoretically result in lower stage tumors, more treatable diseases and ultimately higher cure rates with less treatment-related morbidities. Protein mass spectrometry is a potentially powerful tool for early cancer detection. We propose a novel method for sample classification from protein mass spectrometry data. When applied to spectra from both diseased and healthy patients, the 'peak probability contrast' technique provides a list of all common peaks among the spectra, their statistical significance and their relative importance in discriminating between the two groups. We illustrate the method on matrix-assisted laser desorption and ionization mass spectrometry data from a study of ovarian cancers.Compared to other statistical approaches for class prediction, the peak probability contrast method performs as well or better than several methods that require the full spectra, rather than just labelled peaks. It is also much more interpretable biologically. The peak probability contrast method is a potentially useful tool for sample classification from protein mass spectrometry data.

  View details for DOI 10.1093/bioinformatics/bth357

  View details for Web of Science ID 000225361400017

  View details for PubMedID 15226172

• Identification of hypoxia-regulated proteins in head and neck cancer by proteomic and tissue array profiling CANCER RESEARCH Chen, Y. J., Shi, G. Y., Wei, X., Kong, C., Zhao, S. C., Gaw, A. F., CHEN, E. Y., Yang, G. P., Giaccia, A. J., Le, Q. T., Koong, A. C. 2004; 64 (20): 7302-7310

  Abstract

  Hypoxia within solid tumors decreases therapeutic efficacy, and identification of hypoxia markers may influence the choice of therapeutic modality. Here, we used a proteomic approach to identify hypoxia-regulated proteins and validated their use as endogenous indicators of tumor hypoxia. Using two-dimensional gel electrophoresis and PowerBlot (antibody-based array), we identified a group of 20 proteins that are increased >/=1.5-fold during hypoxia. The majority of these proteins such as IkappaB kinase beta (IKKbeta), MKK3b, highly expressed in cancer (HEC), density-regulated protein 1, P150(glued), nuclear transport factor 2, binder of ARL 2, Paxillin, and transcription termination factor I have not been previously reported to be hypoxia inducible. The increase in these proteins under hypoxia was mediated through posttranscriptional mechanisms. We additionally characterized the role of IKKbeta, a regulator of the nuclear factor-kappaB transcription factor, during hypoxia. We demonstrated that IKKbeta mediates cell survival during hypoxia and is induced in a variety of squamous cell carcinoma cell lines. Furthermore, we showed that IKKbeta expression from tumor specimens correlated with tumor oxygenation in patients with head and neck squamous cell carcinomas. These data suggest that IKKbeta is a novel endogenous marker of tumor hypoxia and may represent a new target for anticancer therapy.

  View details for Web of Science ID 000224522200021

  View details for PubMedID 15492250

• XBP1 is essential for survival under hypoxic conditions and is required for tumor growth CANCER RESEARCH Romero-Ramirez, L., Cao, H. B., Nelson, D., Hammond, E., Lee, A. H., Yoshida, H., Mori, K., Glimcher, L. H., Denko, N. C., Giaccia, A. J., Le, Q. T., Koong, A. C. 2004; 64 (17): 5943-5947

  Abstract

  Hypoxia within solid tumors is a major determinant of outcome after anticancer therapy. Analysis of gene expression changes during hypoxia indicated that unfolded protein response genes were one of the most robustly induced groups of genes. In this study, we investigated the hypoxic regulation of X-box binding protein (XBP1), a major transcriptional regulator of the unfolded protein response. Hypoxia induced XBP1 at the transcriptional level and activated splicing of its mRNA, resulting in increased levels of activated XBP1 protein. After exposure to hypoxia, apoptosis increased and clonogenic survival decreased in XBP1-deficient cells. Loss of XBP1 severely inhibited tumor growth due to a reduced capacity for these transplanted tumor cells to survive in a hypoxic microenvironment. Taken together, these studies directly implicate XBP1 as an essential survival factor for hypoxic stress and tumor growth.

  View details for PubMedID 15342372

• Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms 39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Su, C. K., Mehta, V., Ravikumar, L., Shah, R., PINTO, H., Halpern, J., Koong, A., Goffinet, D., Le, Q. T. ELSEVIER SCIENCE INC. 2004: 171–77

  Abstract

  In a single-institution, double-blind, prospective, randomized trial, we determined whether oral aloe vera gel can reduce radiation-induced mucositis in head-and-neck cancer patients.We randomized 58 head-and-neck cancer patients between oral aloe vera and placebo. To be included in this Phase II protocol, patients had to be treated with radiotherapy with curative intent at Stanford University between February 1999 and March 2002. We examined patients biweekly for mucositis at 15 head-and-neck subsites and administered quality-of-life questionnaires.Patients in the aloe and placebo groups were statistically identical in baseline characteristics. By the end of treatment, the two groups were also statistically identical in maximal grade of toxicity, duration of Grade 2 or worse mucositis, quality-of-life scores, percentage of weight loss, use of pain medications, hydration requirement, oral infections, and prolonged radiation breaks.In our randomized study, oral aloe vera was not a beneficial adjunct to head-and-neck radiotherapy. The mean quality-of-life scores were greater in the aloe vera group, but the differences were not statistically significant. Oral aloe vera did not improve tolerance to head-and-neck radiotherapy, decrease mucositis, reduce soreness, or otherwise improve patient well-being.

  View details for DOI 10.1016/j.ijrobp.2004.02.012

  View details for Web of Science ID 000223854500022

  View details for PubMedID 15337553

• Phase I study of tirapazamine plus cisplatin/etoposide and concurrent thoracic radiotherapy in limited-stage small cell lung cancer (S0004): A Southwest Oncology Group Study CLINICAL CANCER RESEARCH Le, Q. T., McCoy, J., Williamson, S., Ryu, J., Gaspar, L. E., EDELMAN, M. J., Dakhil, S. R., Sides, S. A., Crowley, J. J., Gandara, D. R. 2004; 10 (16): 5418-5424

  Abstract

  To determine the feasibility and a recommended phase II dose of tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC).Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m2) was given 1 h before cisplatin with planned dose escalation to 330 mg/m2 in the absence of dose-limiting toxicity, defined as > or =33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of tirapazamine (330 mg/m2), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation.Thirty patients were enrolled at the 260 mg/m2 tirapazamine dose. All had performance status of 0-1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without tirapazamine, the present trial showed a higher rate of grade 3-4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months.Protocol-defined dose-limiting toxicity was observed at the initial tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of tirapazamine in LSCLC is warranted.

  View details for Web of Science ID 000223454600016

  View details for PubMedID 15328179

• Hypoxic gene expression and metastasis CANCER AND METASTASIS REVIEWS Le, Q. T., Denko, N. C., Giaccia, A. J. 2004; 23 (3-4): 293-310

  Abstract

  Solid tumors possess malformed vasculature that results in the exposure of tumor cells to a low oxygen environment. Tumor hypoxia has been demonstrated in human and mouse tumors through the use of oxygen microelectrodes, hypoxic specific biomarkers, specific transcriptional changes induced by hypoxia, and secreted proteins. While many elegant experiments have demonstrated that hypoxia enhances metastatic potential, it is still unknown what mechanisms are involved in this enhancement. In this review, we discuss the clinical and basic science studies that support an important role for hypoxia in increasing the metastatic potential of tumor cells by promoting tissue remodeling, inducing angiogenesis and reducing apoptosis. Particular emphasis is given to recent findings that provide insight to the role of hypoxia in the metastatic process.

  View details for Web of Science ID 000222017400009

  View details for PubMedID 15197330

• The use of plasma surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomic patterns for detection of head and neck squamous cell cancers 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Soltys, S. G., Le, Q. T., Shi, G. Y., Tibshirani, R., Giaccia, A. J., Koong, A. C. AMER ASSOC CANCER RESEARCH. 2004: 4806–12

  Abstract

  Our study was undertaken to determine the utility of plasma proteomic profiling using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry for the detection of head and neck squamous cell carcinomas (HNSCCs).Pretreatment plasma samples from HNSCC patients or controls without known neoplastic disease were analyzed on the Protein Biology System IIc SELDI-TOF mass spectrometer (Ciphergen Biosystems, Fremont, CA). Proteomic spectra of mass:charge ratio (m/z) were generated by the application of plasma to immobilized metal-affinity-capture (IMAC) ProteinChip arrays activated with copper. A total of 37356 data points were generated for each sample. A training set of spectra from 56 cancer patients and 52 controls were applied to the "Lasso" technique to identify protein profiles that can distinguish cancer from noncancer, and cross-validation was used to determine test errors in this training set. The discovery pattern was then used to classify a separate masked test set of 57 cancer and 52 controls. In total, we analyzed the proteomic spectra of 113 cancer patients and 104 controls.The Lasso approach identified 65 significant data points for the discrimination of normal from cancer profiles. The discriminatory pattern correctly identified 39 of 57 HNSCC patients and 40 of 52 noncancer controls in the masked test set. These results yielded a sensitivity of 68% and specificity of 73%. Subgroup analyses in the test set of four different demographic factors (age, gender, and cigarette and alcohol use) that can potentially confound the interpretation of the results suggest that this model tended to overpredict cancer in control smokers.Plasma proteomic profiling with SELDI-TOF mass spectrometry provides moderate sensitivity and specificity in discriminating HNSCC. Further improvement and validation of this approach is needed to determine its usefulness in screening for this disease.

  View details for Web of Science ID 000222840700027

  View details for PubMedID 15269156

• Extranodal nonorbital indolent lymphomas of the head and neck: Relationship between tumor control and radiotherapy 45th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) MacDermed, D., Thurber, L., George, T. I., Hoppe, R. T., Le, Q. T. ELSEVIER SCIENCE INC. 2004: 788–95

  Abstract

  To review our experience managing extranodal nonorbital indolent lymphomas of the head and neck.A retrospective review was made of 40 patients with indolent lymphomas of the head and neck evaluated at Stanford. The tumor head-and-neck location was Waldeyer's ring, 14; salivary glands, 16; thyroid, 4; and other sites, 6. Twenty-five were Stage I-IIE. Pathology was re-reviewed in 37. The most common histologies were marginal zone lymphoma and follicular grade 2. Patients received combinations of surgery, chemotherapy, and radiotherapy. Local therapy included surgery alone in 6 patients, radiotherapy alone in 7, and surgery plus radiotherapy in 12. Median follow-up was 70.5 months.Freedom from local progression was 86%, and freedom from progression was 61% at 5 years. Patients with radiotherapy had significantly better freedom from local progression (5-year, 100% vs. 72% for patients without radiotherapy, p = 0.006) and freedom from progression (5-year, 90% vs. 34% for patients without radiotherapy, p = 0.001). Improvement in freedom from progression with radiotherapy was statistically significant for Stage I-II patients (88% vs. 50%, p = 0.02) and of borderline significance in Stage III-IV patients (100% vs. 23%, p = 0.07). Overall survival at 10 years was 70%. Multivariate analysis revealed that significant prognostic factors for survival were tumor site (favoring salivary and thyroid, p = 0.02) and age (favoring younger, p = 0.04).Survival is excellent in patients with indolent lymphomas of the head and neck. Patients with salivary and thyroid primary tumors had better survival compared with others. Early use of radiotherapy resulted in significantly higher rates of freedom from progression and freedom from local progression in early-stage patients.

  View details for DOI 10.1016/j.ijrobp.2003.11.007

  View details for PubMedID 15183482

• Lens dose in MLC-based IMRT treatments of the head and neck INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pawlicki, T., Luxton, G., Le, Q. T., Findley, D., Ma, C. M. 2004; 59 (1): 293-299

  Abstract

  The objectives of this work are: (1) to determine typical dose to the lens during step-and-shoot intensity modulated radiotherapy (IMRT) treatments of the head and neck, and (2) to report on the dose calculation accuracy of a commercial inverse planning system in predicting lens dose.The Corvus inverse treatment planning system (Nomos, Cranberry Township, PA) was used to plan IMRT treatments for patients with head-and-neck cancers in our clinic. Patients were treated on Varian C-series linacs (Varian, Palo Alto, CA) with 4-MV or 6-MV X-rays. A Rando phantom (Alderson Laboratories, Stamford, CT) was specially modified to accommodate 1 x 1 x 1 mm(3) thermoluminescent dosimeters at the position of the lens. The IMRT treatment plans were then delivered to the modified Rando phantom. The thermoluminescent dosimeter measurements were converted to dose and taken as an estimate of the lens dose. A total of 20 cases were used in this study (15 cases with 4 MV and 5 cases with 6 MV).Expressed as a percentage of the prescription dose, the mean dose to the left and right lens for all 4-MV cases was 9.1% (range, 2.0% to 61.3%). For the 6-MV cases, the mean dose to the left and right lens was 12.8% (range, 3.6% to 41.3%). For both the 4-MV and 6-MV cases, the case of maximum dose occurred when the IMRT treatment target included volumes superior to the level of the lens. The field size and number of monitor units did not correlate with the measured lens dose. The only factor of significance affecting lens dose was the inferior-to-superior distance of the target to the lens. For target-lens distance >/=6 mm, the maximum measured lens doses were 5.9% and 9.0% relative to the prescribed dose for the 4-MV and 6-MV beams, respectively. These data are similar to those observed in conventional head-and-neck treatments. For all cases, the difference between the dose measured and that predicted by Corvus was less than 2% and 4% of the dose prescribed to the gross tumor volume for the 4-MV and 6-MV cases, respectively.In IMRT, factors such as leaf leakage and number of monitor units play a secondary role and are not more significant than what is observed in conventional head-and-neck treatment when the lens is shielded by the collimator jaws. The target-lens distance is the parameter that affects the lens dose most strongly. For cases where the tumor is at or above the level of the lens, the lens dose can amount to an appreciable fraction of the prescription dose. To keep the lens dose to a minimum, noncoplanar beams that enter or exit into the lens should not be used.

  View details for DOI 10.1016/j.ijrobp.2004.01.019

  View details for Web of Science ID 000221047500036

  View details for PubMedID 15093926

• Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Koong, A. C., Le, Q. T., Ho, A., Fong, B., Fisher, G., Cho, C., Ford, J., Poen, J., Gibbs, I. C., Mehta, V. K., Kee, S., Trueblood, W., Yang, G., Bastidas, J. A. 2004; 58 (4): 1017-1021

  Abstract

  To determine the feasibility and toxicity of delivering stereotactic radiosurgery to patients with locally advanced pancreatic cancer.Patients with Eastern Cooperative Oncology Group performance status < or=2 and locally advanced pancreatic cancer were enrolled on this Phase I dose escalation study. Patients received a single fraction of radiosurgery consisting of either 15 Gy, 20 Gy, or 25 Gy to the primary tumor. Acute gastrointestinal toxicity was scored according to the Radiation Therapy Oncology Group criteria. Response to treatment was determined by serial high-resolution computed tomography scanning.Fifteen patients were treated at 3 dose levels (3 patients received 15 Gy, 5 patients received 20 Gy, and 7 patients received 25 Gy). At these doses, no Grade 3 or higher acute gastrointestinal toxicity was observed. This trial was stopped before any dose-limiting toxicity was reached, because the clinical objective of local control was achieved in all 6 evaluable patients treated at 25 Gy.It is feasible to deliver stereotactic radiosurgery to patients with locally advanced pancreatic cancer. The recommended dose to achieve local control without significant acute gastrointestinal toxicity is 25 Gy.

  View details for DOI 10.1016/j.ijrobp.2003.11.004

  View details for PubMedID 15001240

• Therapeutic exploitation of the physiological and molecular genetic alterations in head and neck cancer CLINICAL CANCER RESEARCH Le, Q. T., Giaccia, A. J. 2003; 9 (12): 4287-4295

  Abstract

  Despite improvements in the diagnosis and management of head and neck squamous cell carcinomas, there has been minimal increase in the long-term survival in these patients over the last 30 years. Treatment intensification with concurrent chemoradiotherapy has been shown to increase survival and improve organ preservation over radiotherapy alone in patients with locally advanced tumor; however, at a cost of increased long-term toxicity. Recent advances in molecular technology have ushered in a new age of targeted therapy, which holds promise for a better outcome for these patients with potentially less normal tissue toxicity. Some of the new approaches aim to specifically inhibit tumor growth and metastasis by targeting the tumor microenvironment or vasculature, whereas others focus on specific protein or signal transduction pathways. This review will summarize these new molecular and physiological based strategies that can be used for both treatment and chemoprevention of head and neck squamous cell carcinoma.

  View details for Web of Science ID 000185830700001

  View details for PubMedID 14555497

• Long-term outcomes after external beam irradiation and brachytherapy boost for base-of-tongue cancers INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Gibbs, I. C., Le, Q. T., Shah, R. D., Terris, D. J., Fee, W. E., Goffinet, D. R. 2003; 57 (2): 489-494

  Abstract

  To assess long-term efficacy and toxicity associated with external beam irradiation (EBRT) and interstitial (192)Ir implantation for the treatment of squamous carcinoma of the base of tongue.Between April 1975 and December 1993, 41 patients with base-of-tongue carcinomas were treated with (192)Ir interstitial implants after EBRT at Stanford University. One patient had Stage I, 6 had Stage II, 7 had Stage III, and 27 had Stage IV tumors. Twenty-eight patients had cervical lymph node involvement at diagnosis. All received EBRT to a median dose of 50 Gy (range 48.9-68 Gy) to the primary tumor and regional lymph nodes before brachytherapy. Interstitial implant was performed 2-4 weeks after EBRT. Intraoperatively, nylon catheters were placed via steel trocars into the base of tongue, glossotonsillar groove, and pharyngo-epiglottic fold using a catheter looping technique. Twenty-three of 28 node-positive patients also underwent simultaneous neck dissections. Postoperatively, the (192)Ir seeds were inserted and allowed to remain in place for approximately 35 h to achieve a median tumor dose of 26 Gy (range 20-34 Gy) to a median volume of 73 cc. Survival, local control, and complications were assessed.With a median follow-up of 62 months (range 9-215) for all patients and 90 months for alive patients, the 5-year Kaplan-Meier survival estimate was 66%. The 5-year local control rate was 82%, with 7 patients recurring locally, 2 of whom were salvaged with surgery. Nodal control was achieved in 93% of patients with either EBRT alone or in combination with neck dissection. The 5-year freedom from distant metastasis rate was 83%. Acute complications included transient bleeding (5%) and infection (8%). Late complication included soft-tissue necrosis/ulceration (7%), osteoradionecrosis (5%), and xerostomia.Base-of-tongue carcinoma can be effectively treated with EBRT and (192)Ir implant boost. Local control is excellent and complication rates are acceptable.

  View details for DOI 10.1016/S0360-3016(03)00597-2

  View details for Web of Science ID 000185315200023

  View details for PubMedID 12957261

• Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma 44th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Tate, D., Koong, A., Gibbs, I. C., Chang, S. D., Adler, J. R., Pinto, H. A., Terris, D. J., Fee, W. E., Goffinet, D. R. ELSEVIER SCIENCE INC. 2003: 1046–54

  Abstract

  Treatment of nasopharyngeal carcinoma using conventional external beam radiotherapy (EBRT) alone is associated with a significant risk of local recurrence. Stereotactic radiosurgery (STR) was used to boost the tumor site after EBRT to improve local control.Forty-five nasopharyngeal carcinoma patients received a STR boost after EBRT at Stanford University. Seven had T1, 16 had T2, 4 had T3, and 18 had T4 tumors (1997 American Joint Commission on Cancer staging). Ten had Stage II, 8 had Stage III, and 27 had Stage IV neoplasms. Most patients received 66 Gy of EBRT delivered at 2 Gy/fraction. Thirty-six received concurrent cisplatin-based chemotherapy. STR was delivered to the primary site 4-6 weeks after EBRT in one fraction of 7-15 Gy.At a medium follow-up of 31 months, no local failures had occurred. The 3-year local control rate was 100%, the freedom from distant metastasis rate was 69%, the progression-free survival rate was 71%, and the overall survival rate was 75%. Univariate and multivariate analyses revealed N stage (favoring N0-N1, p = 0.02, hazard ratio HR 4.2) and World Health Organization histologic type (favoring type III, p = 0.002, HR 13) as significant factors for freedom from distant metastasis. World Health Organization histologic type (p = 0.004, HR 10.5) and age (p = 0.01, HR 1.07/y) were significant factors for survival. Late toxicity included transient cranial nerve weakness in 4, radiation-related retinopathy in 1, and asymptomatic temporal lobe necrosis in 3 patients who originally had intracranial tumor extension.STR boost after EBRT provided excellent local control in nasopharyngeal carcinoma patients. The incidence of late toxicity was acceptable. More effective systemic treatment is needed to achieve improved survival.

  View details for DOI 10.1016/S0360-3016(03)00117-2

  View details for Web of Science ID 000183937500018

  View details for PubMedID 12829140

• HIF-alpha, a gender independent transcription factor CLINICAL CANCER RESEARCH Le, Q. T., Giaccia, A. J. 2003; 9 (7): 2391-2393

  View details for Web of Science ID 000184108700002

  View details for PubMedID 12855609

• Radiation therapy for intracranial germ cell tumors 43rd Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Haas-Kogan, D. A., Missett, B. T., Wara, W. M., Donaldson, S. S., Lamborn, K. R., Prados, M. D., Fisher, P. G., Huhn, S. L., Fisch, B. M., Berger, M. S., Le, Q. T. ELSEVIER SCIENCE INC. 2003: 511–18

  Abstract

  To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS).Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model.Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS.CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.

  View details for DOI 10.1016/S0360-3016(02)04611-4

  View details for Web of Science ID 000182861500026

  View details for PubMedID 12738328

• Comparison of the comet assay and the oxygen microelectrode for measuring tumor oxygenation in head-and-neck cancer patients Annual Meeting on Radiation Research Le, Q. T., Kovacs, M. S., Dorie, M. J., Koong, A., Terris, D. J., Pinto, H. A., Goffinet, D. R., Nowels, K., Bloch, D., Brown, J. M. ELSEVIER SCIENCE INC. 2003: 375–83

  Abstract

  To compare the Eppendorf PO2 histograph and the alkaline comet assay as methods of measuring tumor hypoxia in patients with head-and-neck squamous cell carcinomas.As part of a larger clinical trial, 65 patients with head-and-neck squamous cell carcinoma nodal metastasis underwent tumor oxygenation measurements with Eppendorf PO2 histographs and comet assays, performed on fine-needle aspirates at 1 and 2 min after 5 Gy. Fifty-four patients had sufficient tumor cells for comet analysis at 1 min and 26 at both 1 and 2 min. Individual cells were examined for DNA single-strand breaks by alkaline gel electrophoresis, and the distribution of values was quantified using median tail moment (MTM). Nonirradiated tumor cells from pretreatment fine-needle aspirates received 5 Gy in vitro to establish the oxygenated response.There was a significant correlation between the 1- and 2-min MTM (slope = 0.77 +/- 0.03). There was no relationship between DNA damage in tumor cells irradiated in vitro and in vivo. No correlation was found between Eppendorf PO2 measurements and comet MTM. There was a statistically significant correlation between the treatment response in the node studied and comet MTMs, whereas no correlation was observed between treatment response and Eppendorf measurements.Comet assays are reproducible, as shown by biopsies at 1 and 2 min. Intertumor variation in the MTM is not a result of intrinsic radiosensitivity but of tumor hypoxia. There was no correlation between Eppendorf PO2 measurements and comet MTM. Comet assays were better than Eppendorf in predicting treatment response as an end point for short-term outcome. Longer follow-up is needed to determine the role of the comet assay as a predictor for locoregional tumor control and survivals.

  View details for DOI 10.1016/S0360-3016(02)04503-0

  View details for Web of Science ID 000182861500010

  View details for PubMedID 12738312

• Stereotactic radiosurgery for lung tumors: Preliminary report of a phase I trial 38th Annual Meeting of the Society-of-Thoracic-Surgeons Whyte, R. I., Crownover, R., MURPHY, M. J., Martin, D. P., Rice, T. W., DeCamp, M. M., Rodebaugh, R., Weinhous, M. S., Le, Q. T. ELSEVIER SCIENCE INC. 2003: 1097–1101

  Abstract

  Stereotactic radiosurgery is well established for the treatment of intracranial neoplasms but its use for lung tumors is novel.Twenty-three patients with biopsy-proven lung tumors were recruited into a two-institution, dose-escalation, phase I clinical trial using a frameless stereotactic radiosurgery system (CyberKnife). Fifteen patients had primary lung tumors and 8 had metastatic tumors. The age range was 23 to 87 years (mean, 63 years). After undergoing computed tomography-guided percutaneous placement of two to four small metal fiducials directly into the tumor, patients received 1,500 cGY of radiation in a single fraction using a linear accelerator mounted on a computer-controlled robotic arm. Safety, feasibility, and efficacy were studied.Nine patients were treated with a breath-holding technique, and 14 with a respiratory-gating, automated, robotic technique. Tumor size ranged from 1 to 5 cm in maximal diameter. There were four complications related to fiducial placement: three pneumothoraces requiring chest tube insertion and one emphysema exacerbation. There were no grade 3 to 5 radiation-related complications. Follow-up ranged from 1 to 26 months (mean, 7.0 months). Radiographic response was scored as complete in 2 patients, partial in 15, stable in 4, and progressive in 2. Four patients died of non-treatment-related causes at 1, 5, 9, and 11 months after radiation.Single-fraction stereotactic radiosurgery is safe and feasible for the treatment of selected lung tumors. Additional studies are planned to investigate the optimal radiation dose, best motion-suppression technique, and overall treatment efficacy.

  View details for Web of Science ID 000181946800007

  View details for PubMedID 12683544

• Patterns of patient movement during frameless image-guided radiosurgery INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Murphy, M. J., Chang, S. D., Gibbs, I. C., Le, Q. T., Hai, J., Kim, D., Martin, D. P., Adler, J. R. 2003; 55 (5): 1400-1408

  Abstract

  Image-guided radiosurgery aligns the treatment beam to the target site by using a radiographic imaging system to locate anatomic landmarks associated with the treatment target. Because the procedure is performed without a rigid frame, the precision of dose alignment can be affected by patient movement. Movement is limited by noninvasive restraints and compensated by remeasuring the target position at short intervals throughout treatment and then realigning the beam. Frameless image-guided radiosurgery has been used at our institution to treat 250 cranial, 23 spinal, 9 lung, and 3 pancreas cases involving malignant and benign tumors as well as vascular malformations. We have analyzed the target position records for all of these cases to assess the frequency, magnitude, and case-by-case patterns of patient movement.The position of the treatment site during image-guided radiosurgery was measured at approximately 1-2-min intervals, on average, using orthogonal amorphous silicon X-ray cameras and an image registration process that determined all six degrees of freedom in the target's position. The change in position from one measurement to the next was indicative of patient movement.The treatment site position along each axis of translation was observed to vary by an average of 0.45 mm for the cranium, 0.53 mm for the cervical spine, 0.53 mm for the lumbar and thoracic spine, 1.06 mm for the lung, and 1.50 mm for the pancreas. Half of all cranial cases showed systematic drifting of the target away from the initial setup position.Using noninvasive restraints and supports, short-term movement of the head and spine during image-guided radiosurgery was limited to a radius of 0.8 mm, which satisfies the prevailing standard for radiosurgical dose alignment precision, but maintaining this margin of error throughout a treatment fraction requires regular monitoring of the target site's position.

  View details for DOI 10.1016/S0360-3016(02)04597-2

  View details for PubMedID 12654453

• Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas CLINICAL CANCER RESEARCH Le, Q. T., Sutphin, P. D., Raychaudhuri, S., Yu, S. C., Terris, D. J., Lin, H. S., Lum, B., Pinto, H. A., Koong, A. C., Giaccia, A. J. 2003; 9 (1): 59-67

  Abstract

  Tumor hypoxia modifies treatment efficacy and promotes tumor progression. Here, we investigated the relationship between osteopontin (OPN), tumor pO(2), and prognosis in patients with head and neck squamous cell carcinomas (HNSCC).We performed linear discriminant analysis, a machine learning algorithm, on the NCI-60 cancer cell line microarray expression database to identify a gene profile that best distinguish cell lines with high Von-Hippel Lindau (VHL) gene expression, an important regulator of hypoxia-related genes, from those with low expression. Plasma OPN levels in 15 volunteers, 31 VHL patients, and 54 HNSCC patients were quantitatively measured by ELISA. The relationships between plasma OPN levels, tumor pO(2) as measured by the Eppendorf microelectrode, freedom from relapse (FFR), and survival in HNSCC patients were evaluated.Microarray analysis indicated that OPN gene expression inversely correlated with that of VHL. These findings were confirmed by Northern blot analysis. ELISA studies and Western blot in a HNSCC cell line demonstrated that hypoxia exposure resulted in increased OPN secretion. Patients with VHL syndrome had significantly higher plasma OPN levels than healthy volunteers. Plasma OPN level inversely correlated with tumor pO(2) (P = 0.003, r = -0.42). OPN levels correlated with clinical outcomes. The 1-year FFR and survival rates were 80 and 100%, respectively, for patients with OPN levels 450 ng/ml (P = 0.002 and 0.0005). Multivariate analysis revealed that OPN was an independent predictor for FFR and survival.Plasma OPN levels appeared to correlate with tumor hypoxia in HNSCC patients and may serve as noninvasive tests to identify patients at high risk for tumor recurrence.

  View details for Web of Science ID 000180430600008

  View details for PubMedID 12538452

• Tumor hypoxia is important in radiotherapy, but how should we measure it? INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, J. M., Le, Q. T. 2002; 54 (5): 1299-1301

  View details for Web of Science ID 000179566100002

  View details for PubMedID 12459349

• Estimating DNA repair by sequential evaluation of head and neck tumor radiation sensitivity using the comet assay 5th International Conference on Head and Neck Cancer of the International-Society-of-Head-Neck-Cancer Terris, D. J., Ho, E. Y., Ibrahim, H. Z., Dorie, M. J., Kovacs, M. S., Le, Q. T., Koong, A. C., Pinto, H. A., Brown, J. M. AMER MEDICAL ASSOC. 2002: 698–702

  Abstract

  The alkaline comet assay is a microelectrophoretic technique for detecting single-strand DNA breaks, and may be used as an indirect measure of hypoxia by determining the radiation sensitivity of individual cells.To assess the ability of the comet assay to estimate the rate of DNA repair after irradiation in patients with head and neck cancer.The comet assay was used to evaluate DNA damage in fine-needle aspirates of lymph nodes containing metastatic squamous cell carcinoma in patients with head and neck cancer 1, 2, and 3 minutes after treatment with 500 rad (5 Gy) of irradiation. The amount of DNA damage (measured as the "tail moment" of the comet) is proportional to the number of DNA single-strand breaks after irradiation, which in turn depends on the oxygen concentration in each cell.The mean +/- SD of the median tail moment of the 1-minute postirradiation comets was 29.4 +/- 14.2 (n = 27). After 2 minutes, the mean median tail moment decreased to 25.4 +/- 13.6 (n = 25), representing a mean decrease of 11.9% in those patients with both 1- and 2-minute comet assays. Assuming a linear rate of repair, this decrease in DNA damage corresponds to a repair half-life of 4.2 minutes. A 3-minute assay was also performed on samples from a smaller number of patients (n = 9), with a mean value not significantly different from that of the 2-minute assay of the samples from this group.The comet assay is a promising tool for evaluating radiation sensitivity in individual cells. The rate of DNA repair early after irradiation is consistent with data in the literature.

  View details for Web of Science ID 000176264300013

  View details for PubMedID 12049567

• The effectiveness of breath-holding to stabilize lung and pancreas tumors during radiosurgery INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Murphy, M. J., Martin, D., Whyte, R., Hai, J., Ozhasoglu, C., Le, Q. T. 2002; 53 (2): 475-482

  Abstract

  To evaluate the effect of breath-holding on the short-term reproducibility and long-term variability of tumor position during image-guided radiosurgery.Thirteen patients have undergone single-fraction radiosurgery treatments during which the tumor was repeatedly imaged radiographically to observe its position. The imaging data were used to monitor the efficacy of breath-holding and to periodically readjust the alignment of the treatment beam with the tumor. These measurements have allowed the effects of breathing, heartbeat, patient movement, and instrumental uncertainties to be separately identified in the record of tumor position.During inspiration breath-holding, the lung tumor position was reproducible to within 1 mm, on average, in the direction of maximum displacement during regular breathing, and to within 1.8 mm in three dimensions overall. The pancreas tumor position in three dimensions was reproducible to within 2.5 mm on average. Some patients showed a slow, steady drift of tumor position during the extended sequence of breath-holds, which was compensated by periodic retargeting of the treatment beam.Breath-holding can allow the reduction of tumor motion dosimetry margins to 2 mm or less for lung cancer treatments, provided that the treatment system can detect and adapt to long-term variations in the mean tumor position during a lengthy treatment fraction.

  View details for Web of Science ID 000175923400025

  View details for PubMedID 12023152

• Primary radiotherapy for localized orbital malt lymphoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Le, Q. T., Eulau, S. M., George, T. I., Hildebrand, R., Warnke, R. A., Donaldson, S. S., Hoppe, R. T. 2002; 52 (3): 657-663

  Abstract

  To define the natural history, prognosis, and radiocurability of localized orbital extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT).Clinical records and pathologic material of 40 patients treated with local radiotherapy for localized orbital lymphoma were reviewed. Treatment consisted of 30-40 Gy in 1.8-2-Gy fractions (mean 34 Gy) of irradiation using 9-20-MeV electrons for conjunctival lesions, or 6-MV photons with complex treatment planning for retrobulbar lesions. The lens was routinely shielded with the use of a suspended eye bar.Upon pathologic review, 31 cases of orbital MALT lymphoma were identified. With the median follow-up of 5.9 years (range 9 months-0.3 years), the actuarial 10-year overall survival was 73%. Local control was 100%. Five distant failures resulted in a projected 10-year freedom from relapse of 71%. Most of the failures were extranodal in sites where MALT lymphoma has previously been shown to arise. No difference in outcome was observed among patients treated to less than or equal to 34 Gy vs. those treated to higher radiation doses. Two patients experienced clinically significant retinal damage after doses > or = Gy.In this study, localized orbital MALT lymphoma was well controlled with radiotherapy. Even following relapse, patients with orbital MALT lymphoma exhibited an indolent course. Relapse occurred predominantly in extranodal mucosal sites, implying a possible homing mechanism for MALT lymphoma cells. Given the excellent local control rates, our current treatment recommendation is to use a radiation dose of 30-30.6 Gy in 1.5-.8-Gy fractions to minimize risk of late toxicity.

  View details for PubMedID 11849787

• Tirapazamine: Prototype for a novel class of therapeutic agents targeting tumor hypoxia SEMINARS IN ONCOLOGY Gandara, D. R., Lara, P. N., Goldberg, Z., Le, Q. T., Mack, P. C., Lau, D. H., Gumerlock, P. H. 2002; 29 (1): 102-109

  Abstract

  Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.

  View details for DOI 10.1053/sonc.2002.31531

  View details for Web of Science ID 000174419200013

  View details for PubMedID 11894020

• Image-guided radiosurgery in the treatment of spinal metastases. Neurosurgical focus MURPHY, M. J., Chang, S., Gibbs, I., Le, Q. T., Martin, D., Kim, D. 2001; 11 (6)

  Abstract

  The authors describe a new method for treating metastatic spinal tumors in which noninvasive, image-guided, frameless stereotactic radiosurgery is performed. Stereotactic radiosurgery delivers a high dose of radiation in a single or limited number of fractions to a lesion while maintaining delivery of a low dose to adjacent normal structures.Image-guided radiosurgery was developed by coupling an orthogonal pair of real-time x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the radiation beam to treatment sites associated with radiographic landmarks. This procedure can be conducted in an outpatient setting without the use of framebased skeletal fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Four patients with spinal metastases underwent radiosurgery with total prescription doses of 1000 to 1600 cGy in one or two fractions. Alignment of the treatment dose with the target volume was accurate to within 1.5 mm. During the course of each treatment fraction, patient movement was less than 0.5 mm on average. Dosimetry was highly conformal, with a demonstrated ability to deliver 1600 cGy to the perimeter of an irregular target volume while keeping exposure to the cord itself below 800 cGy.These experiences indicate that frameless radiosurgery is a viable therapeutic option for metastatic spine disease.

  View details for PubMedID 16463998

• Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions NEUROSURGERY Ryu, S. I., Chang, S. D., Kim, D. H., MURPHY, M. J., Le, Q. T., Martin, D. P., Adler, J. R. 2001; 49 (4): 838-846

  Abstract

  This article demonstrates the technical feasibility of noninvasive treatment of unresectable spinal vascular malformations and primary and metastatic spinal tumors by use of image-guided frameless stereotactic radiosurgery.Stereotactic radiosurgery delivers a high dose of radiation to a tumor volume or vascular malformation in a limited number of fractions and minimizes the dose to adjacent normal structures. Frameless image-guided radiosurgery was developed by coupling an orthogonal pair of x-ray cameras to a dynamically manipulated robot-mounted linear accelerator that guides the therapy beam to treatment sites within the spine or spinal cord, in an outpatient setting, and without the use of frame-based fixation. The system relies on skeletal landmarks or implanted fiducial markers to locate treatment targets. Sixteen patients with spinal lesions (hemangioblastomas, vascular malformations, metastatic carcinomas, schwannomas, a meningioma, and a chordoma) were treated with total treatment doses of 1100 to 2500 cGy in one to five fractions by use of image-guided frameless radiosurgery with the CyberKnife system (Accuray, Inc., Sunnyvale, CA). Thirteen radiosurgery plans were analyzed for compliance with conventional radiation therapy.Tests demonstrated alignment of the treatment dose with the target volume within +/-1 mm by use of spine fiducials and the CyberKnife treatment planning system. Tumor patients with at least 6 months of follow-up have demonstrated no progression of disease. Radiographic follow-up is pending for the remaining patients. To date, no patients have experienced complications as a result of the procedure.This experience demonstrates the feasibility of image-guided robotic radiosurgery for previously untreatable spinal lesions.

  View details for PubMedID 11564244

• Treatment results and prognostic factors of advanced T3-4 laryngeal carcinoma: The University of California, San Francisco (UCSF) and Stanford University Hospital (SUH) experience 86th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America (RSNA) Nguyen-Tan, P. F., Le, Q. T., Quivey, J. M., Singer, M., Terris, D. J., Goffinet, D. R., Fu, K. K. ELSEVIER SCIENCE INC. 2001: 1172–80

  Abstract

  To review the UCSF-SUH experience in the treatment of advanced T3--4 laryngeal carcinoma and to evaluate the different factors affecting locoregional control and survival.We reviewed the records of 223 patients treated for T3--4 squamous cell carcinoma of the larynx between October 1, 1957, and December 1, 1999. There were 187 men and 36 women, with a median age of 60 years (range, 28--85 years). The primary site was glottic in 122 and supraglottic in 101 patients. We retrospectively staged the patients according to the 1997 AJCC staging system. One hundred and twenty-seven patients had T3 lesions, and 96 had T4 lesions; 132 had N0, 29 had N1, 45 had N2, and 17 had N3 disease. The overall stage was III in 93 and IV in 130 patients. Seventy-nine patients had cartilage involvement, and 144 did not. Surgery was the primary treatment modality in 161 patients, of which 134 had postoperative radiotherapy (RT), 11 had preoperative RT, 7 had surgery followed by RT and chemotherapy (CT), and 9 had surgery alone. Forty-one patients had RT alone, and 21 had CT with RT. Locoregional control (LRC) and overall survival (OS) were estimated using the Kaplan--Meier method. Log-rank statistics were employed to identify significant prognostic factors for OS and LRC.The median follow-up was 41 months (range, 2--367 months) for all patients and 78 months (range, 6--332 months) for alive patients. The LRC rate was 69% at 5 years and 68% at 10 years. Eighty-four patients relapsed, of which 53 were locoregional failures. Significant prognostic factors for LRC on univariate analysis were primary site, N stage, overall stage, the lowest hemoglobin (Hgb) level during RT, and treatment modality. Favorable prognostic factors for LRC on multivariate analysis were lower N stage and primary surgery. The overall survival rate was 48% at 5 years and 34% at 10 years. Significant prognostic factors for OS on univariate analysis were: primary site, age, overall stage, T stage, N stage, lowest Hgb level during RT, and treatment modality. Favorable prognostic factors for OS on multivariate analysis were lower N stage and higher Hgb level during RT.Lower N-stage was a favorable prognostic factor for LRC and OS. Hgb levels > or = 12.5 g/dL during RT was a favorable prognostic factor for OS. Surgery was a favorable prognostic factor for LRC but did not impact on OS. Correcting the Hbg level before and during treatment should be investigated in future clinical trials as a way of improving therapeutic outcome in patients with advanced laryngeal carcinomas.

  View details for Web of Science ID 000170266500009

  View details for PubMedID 11483326

• Role of beam orientation optimization in intensity-modulated radiation therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Pugachev, A., Li, J. G., Boyer, A. L., Hancock, S. L., Le, Q. T., Donaldson, S. S., Xing, L. 2001; 50 (2): 551-560

  Abstract

  To investigate the role of beam orientation optimization in intensity-modulated radiation therapy (IMRT) and to examine the potential benefits of noncoplanar intensity-modulated beams.A beam orientation optimization algorithm was implemented. For this purpose, system variables were divided into two groups: beam position (gantry and table angles) and beam profile (beamlet weights). Simulated annealing was used for beam orientation optimization and the simultaneous iterative inverse treatment planning algorithm (SIITP) for beam intensity profile optimization. Three clinical cases were studied: a localized prostate cancer, a nasopharyngeal cancer, and a paraspinal tumor. Nine fields were used for all treatments. For each case, 3 types of treatment plan optimization were performed: (1) beam intensity profiles were optimized for 9 equiangular spaced coplanar beams; (2) orientations and intensity profiles were optimized for 9 coplanar beams; (3) orientations and intensity profiles were optimized for 9 noncoplanar beams.For the localized prostate case, all 3 types of optimization described above resulted in dose distributions of a similar quality. For the nasopharynx case, optimized noncoplanar beams provided a significant gain in the gross tumor volume coverage. For the paraspinal case, orientation optimization using noncoplanar beams resulted in better kidney sparing and improved gross tumor volume coverage.The sensitivity of an IMRT treatment plan with respect to the selection of beam orientations varies from site to site. For some cases, the choice of beam orientations is important even when the number of beams is as large as 9. Noncoplanar beams provide an additional degree of freedom for IMRT treatment optimization and may allow for notable improvement in the quality of some complicated plans.

  View details for Web of Science ID 000168781000033

  View details for PubMedID 11380245

• Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma JOURNAL OF NEURO-ONCOLOGY Peterson, K., Harsh, G., Fisher, P. G., Adler, J., Le, Q. 2001; 53 (1): 27-32

  Abstract

  Surgical resection followed by local field radiotherapy is currently our most effective approach to treatment for most patients with malignant glioma. Carboplatin chemotherapy has direct cytotoxic effects on glioma cells and acts as a radiation sensitizer to enhance cell killing. Its demonstrated efficacy as a sensitizer in other solid tumors led to this clinical trial of carboplatin as a radiation sensitizer in the treatment of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Fourteen patients (nine GBM and five AA) were treated with daily low-dose carboplatin 25 mg/m2 intravenously within 2 h of their fractionated radiotherapy to a total dose of 600 mg/m2. No significant toxicities attributable to this combined therapy were observed. All patients have progressed, with median time to progression of 16 weeks. Eleven patients have died, with median survival of 38 weeks for the entire cohort. Although this regimen appeared safe, there was no benefit in survival time compared to historical patients treated with radiotherapy. The limitations and future potential for the strategy of radiation sensitization are discussed.

  View details for Web of Science ID 000170979800004

  View details for PubMedID 11678427

• Image-guided extracranial radiosurgery 7th International Meeting on Progress in Radio-Oncology (ICRO/OGRO 7) Sattah, M., Guerrero, T., Chang, S., Martin, D., Le, Q. T., Gibbs, I., Adler, J. MEDIMOND S R L. 2001: 153–162

  View details for Web of Science ID 000176997100020

• Treatment results of carcinoma in situ of the glottis - An analysis of 82 cases 41st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO 99) Le, Q. T., Takamiya, R., Shu, H. K., Smitt, M., Singer, M., Terris, D. J., Fee, W. E., Goffinet, D. R., Fu, K. K. AMER MEDICAL ASSOC. 2000: 1305–12

  Abstract

  To evaluate the results of different treatment modalities for carcinoma in situ of the glottis, and to identify important prognostic factors for outcome.Review of 82 cases treated definitively for glottic carcinoma in situ between 1958 and 1998. The median follow-up for all patients was 112 months, and 90% had more than 2 years of follow-up.Academic tertiary care referral centers.Fifteen patients were treated with vocal cord stripping (group 1), 13 with more extensive surgery (group 2) including endoscopic laser resection (11 patients) and hemilaryngectomy (2 patients), and 54 with radiotherapy (group 3). Thirty patients had anterior commissure involvement and 9 had bilateral vocal cord involvement. Radiotherapy was delivered via opposed lateral fields at 1.5 to 2.4 Gy per fraction per day (median fraction size, 2 Gy), 5 days per week. The median total dose was 64 Gy, and the median overall time was 47 days.Initial locoregional control (LRC), ultimate LRC, and larynx preservation.The 10-year initial LRC rates were 56% for group 1, 71% for group 2, and 79% for group 3. Of those who failed, the median time to relapse was 11 months for group 1, 17 months for group 2, and 41 months for group 3. Univariate analysis showed that the difference in initial LRC rates between groups 1 and 3 was statistically significant (P =.02), although it was not statistically significant on multivariate analysis (P =.07). Anterior commissure involvement was an important prognostic factor for LRC on both univariate (P =.03) and multivariate (P =.04; hazard ratio, 1.6) analysis, and its influence appeared to be mainly confined to the surgically treated patients (groups 1 and 2). The 10-year larynx preservation rates were 92% for group 1, 70% for group 2, and 85% for group 3. Anterior commissure involvement was the only important prognostic factor for larynx preservation (P =. 01) on univariate analysis. All but 2 patients in whom treatment failed underwent successful salvage surgery. Voice quality was deemed good to excellent in 73% of the patients in group 1, 40% in group 2, and 68% in group 3.Treatment of carcinoma in situ of the glottis with vocal cord stripping or more extensive surgery or radiotherapy provided excellent ultimate LRC and comparable larynx preservation rates. Anterior commissure involvement was associated with poorer initial LRC and larynx preservation, particularly in the surgically treated patients. The choice of initial treatment should be individualized, depending on patient age, reliability, and tumor extent. Pretreatment and posttreatment objective evaluation of voice quality should be helpful in determining the best therapy for these patients.

  View details for Web of Science ID 000165283600001

  View details for PubMedID 11074826

• Pancreatic tumors show high levels of hypoxia 36th Annual Meeting of the American-Society-of-Clinical-Oncology Koong, A. C., Mehta, V. K., Le, Q. T., Fisher, G. A., Terris, D. J., Brown, J. M., Bastidas, A. J., Vierra, M. ELSEVIER SCIENCE INC. 2000: 919–22

  Abstract

  Because of the dismal outcomes of conventional therapies for pancreatic carcinomas, we postulated that hypoxia may exist within these tumors.Seven sequential patients with adenocarcinomas of the pancreas consented to intraoperative measurements of tumor oxygenation using the Eppendorf (Hamburg, Germany) polargraphic electrode.All 7 tumors demonstrated significant tumor hypoxia. In contrast, adjacent normal pancreas showed normal oxygenation.Tumor hypoxia exists within pancreatic cancers.

  View details for Web of Science ID 000165238800002

  View details for PubMedID 11072146

• Head and neck cancer in cardiothoracic transplant recipients Meeting of the Western Section of the American-Laryngological-Rhinological-and-Otological-Society Pollard, J. D., Hanasono, M. M., Mikulec, A. A., Le, Q. T., Terris, D. J. JOHN WILEY & SONS INC. 2000: 1257–61

  Abstract

  There is an increased incidence of cancer in patients after organ transplantation. We reviewed a large series of cardiothoracic transplant recipients to determine the incidence and natural history of head and neck malignancy.A total of 1069 heart (n = 855), heart/lung (n = 111), and lung (n = 103) transplants were performed at Stanford University from January 1968 to February 1998. Demographic data, risk factors, and disease course were evaluated in patients who developed cancer. The mean length of follow-up was 8.9+/-5.2 years.One hundred twenty patients (11.2%) developed 547 non-lymphomatous malignancies. The mean number of malignancies per cancer patient was 4.6. The average time from transplantation to development of cancer was 63.1 months. A total of 50.5% of malignancies presented in the head and neck; 96.4% of these were cutaneous in origin and 3.6% were noncutaneous. Of cutaneous malignancies, 79.3% were squamous cell carcinoma and 15.9% were basal cell carcinoma Cutaneous malignancies most commonly presented on the scalp, cheek, lip, and neck. Noncutaneous malignancies involved the oral cavity (5), thyroid (4), and parotid (1). Thirteen percent of cutaneous head and neck cancers behaved aggressively, requiring extensive management including radical surgery, radiation, and/or chemotherapy. A total of 34.2% of cancer patients developed metastases and 54.9% of cancer patients died as a direct result of cancer. A total of 68% of cancer patients were smokers and 23.8% had significant alcohol use.Transplant recipients have an increased incidence of cancer presenting in the head and neck. Malignancies in transplant patients behave more aggressively than in the general population. Recognition of this aggressive biological behavior and heightened cancer surveillance should result in improved outcomes.

  View details for Web of Science ID 000088596400003

  View details for PubMedID 10942122

• Dosimetric effects of patient displacement and collimator and gantry angle misalignment on intensity modulated radiation therapy RADIOTHERAPY AND ONCOLOGY Xing, L., Lin, Z. X., Donaldson, S. S., Le, Q. T., Tate, D., Goffinet, D. R., Wolden, S., Ma, L. J., Boyer, A. L. 2000; 56 (1): 97-108

  Abstract

  The primary goal of this study was to examine systematically the dosimetric effect of small patient movements and linear accelerator angular setting misalignments in the delivery of intensity modulated radiation therapy. We will also provide a method for estimating dosimetric errors for an arbitrary combination of these uncertainties.Sites in two patients (lumbar-vertebra and nasopharynx) were studied. Optimized intensity modulated radiation therapy treatment plans were computed for each patient using a commercially available inverse planning system (CORVUS, NOMOS Corporation, Sewickley, PA). The plans used nine coplanar beams. For each patient the dose distributions and relevant dosimetric quantities were calculated, including the maximum, minimum, and average doses in targets and sensitive structures. The corresponding dose volumetric information was recalculated by purposely varying the collimator angle or gantry angle of an incident beam while keeping other beams unchanged. Similar calculations were carried out by varying the couch indices in either horizontal or vertical directions. The intensity maps of all the beams were kept the same as those in the optimized plan. The change of a dosimetric quantity, Q, for a combination of collimator and gantry angle misalignments and patient displacements was estimated using Delta=Sigma(DeltaQ/Deltax(i))Deltax(i). Here DeltaQ is the variation of Q due to Deltax(i), which is the change of the i-th variable (collimator angle, gantry angle, or couch indices), and DeltaQ/Deltax(i) is a quantity equivalent to the partial derivative of the dosimetric quantity Q with respect to x(i).While the change in dosimetric quantities was case dependent, it was found that the results were much more sensitive to small changes in the couch indices than to changes in the accelerator angular setting. For instance, in the first example in the paper, a 3-mm movement of the couch in the anterior-posterior direction can cause a 38% decrease in the minimum target dose or a 41% increase in the maximum cord dose, whereas a 5 degrees change in the θ(1)=20 degrees beam only gave rise to a 1.5% decrease in the target minimum or 5.1% in the cord maximum. The effect of systematic positioning uncertainties of the machine settings was more serious than random uncertainties, which tended to smear out the errors in dose distributions.The dose distribution of an intensity modulated radiation therapy (IMRT) plan changes with patient displacement and angular misalignment in a complex way. A method was proposed to estimate dosimetric errors for an arbitrary combination of uncertainties in these quantities. While it is important to eliminate the angular misalignment, it was found that the couch indices (or patient positioning) played a much more important role. Accurate patient set-up and patient immobilization is crucial in order to take advantage fully of the technological advances of IMRT. In practice, a sensitivity check should be useful to foresee potential IMRT treatment complications and a warning should be given if the sensitivity exceeds an empirical value. Quality assurance action levels for a given plan can be established out of the sensitivity calculation.

  View details for Web of Science ID 000088159100013

  View details for PubMedID 10869760

• Candidate genes for the hypoxic tumor phenotype CANCER RESEARCH Koong, A. C., Denko, N. C., Hudson, K. M., Schindler, C., Swiersz, L., Koch, C., Evans, S., Ibrahim, H., Le, Q. T., Terris, D. J., Giaccia, A. J. 2000; 60 (4): 883-887

  Abstract

  In this study, we have analyzed changes induced by hypoxia at the transcriptional level of genes that could be responsible for a more aggressive phenotype. Using a series of DNA array membranes, we identified a group of hypoxia-induced genes that included plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor-binding protein 3 (IGFBP-3), endothelin-2, low-density lipoprotein receptor-related protein (LRP), BCL2-interacting killer (BIK), migration-inhibitory factor (MIF), matrix metalloproteinase-13 (MMP-13), fibroblast growth factor-3 (FGF-3), GADD45, and vascular endothelial growth factor (VEGF). The induction of each gene was confirmed by Northern blot analysis in two different squamous cell carcinoma-derived cell lines. We also analyzed the kinetics of PAI-1 induction by hypoxia in more detail because it is a secreted protein that may serve as a useful molecular marker of hypoxia. On exposure to hypoxia, there was a gradual increase in PAI-1 mRNA between 2 and 24 h of hypoxia followed by a rapid decay after 2 h of reoxygenation. PAI-1 levels were also measured in the serum of a small group of head and neck cancer patients and were found to correlate with the degree of tumor hypoxia found in these patients.

  View details for Web of Science ID 000085503100022

  View details for PubMedID 10706099

• Lymph node metastasis in maxillary sinus carcinoma INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Le, Q. T., Fu, K. K., Kaplan, M. J., Terris, D. J., Fee, W. E., Goffinet, D. R. 2000; 46 (3): 541-549

  Abstract

  To evaluate the incidence and prognostic significance of lymph node metastasis in maxillary sinus carcinoma.We reviewed the records of 97 patients treated for maxillary sinus carcinoma with radiotherapy at Stanford University and at the University of California, San Francisco between 1959 and 1996. Fifty-eight patients had squamous cell carcinoma (SCC), 4 had adenocarcinoma (ADE), 16 had undifferentiated carcinoma (UC), and 19 had adenoid cystic carcinoma (AC). Eight patients had T2, 36 had T3, and 53 had T4 tumors according to the 1997 AJCC staging system. Eleven patients had nodal involvement at diagnosis: 9 with SCC, 1 with UC, and 1 with AC. The most common sites of nodal involvement were ipsilateral level 1 and 2 lymph nodes. Thirty-six patients were treated with definitive radiotherapy alone, and 61 received a combination of surgical and radiation treatment. Thirty-six patients had neck irradiation, 25 of whom received elective neck irradiation (ENI) for N0 necks. The median follow-up for alive patients was 78 months.The median survival for all patients was 22 months (range: 2.4-356 months). The 5- and 10-year actuarial survivals were 34% and 31%, respectively. Ten patients relapsed in the neck, with a 5-year actuarial risk of nodal relapse of 12%. The 5-year risk of neck relapse was 14% for SCC, 25% for ADE, and 7% for both UC and ACC. The overall risk of nodal involvement at either diagnosis or on follow-up was 28% for SCC, 25% for ADE, 12% for UC, and 10% for AC. All patients with nodal involvement had T3-4, and none had T2 tumors. ENI effectively prevented nodal relapse in patients with SCC and N0 neck; the 5-year actuarial risk of nodal relapse was 20% for patients without ENI and 0% for those with elective neck therapy. There was no correlation between neck relapse and primary tumor control or tumor extension into areas containing a rich lymphatic network. The most common sites of nodal relapse were in the ipsilateral level 1-2 nodal regions (11/13). Patients with nodal relapse had a significantly higher risk of distant metastasis on both univariate (p = 0.02) and multivariate analysis (hazard ratio = 4.5, p = 0.006). The 5-year actuarial risk of distant relapse was 29% for patients with neck control versus 81% for patients with neck failure. There was also a trend for decreased survival with nodal relapse. The 5-year actuarial survival was 37% for patients with neck control and 0% for patients with neck relapse.The overall incidence of lymph node involvement at diagnosis in patients with maxillary sinus carcinoma was 9%. Following treatment, the 5-year risk of nodal relapse was 12%. SCC histology was associated with a high incidence of initial nodal involvement and nodal relapse. None of the patients presenting with SCC histology and N0 necks had nodal relapse after elective neck irradiation. Patients who had nodal relapse had a higher risk of distant metastasis and poorer survival. Therefore, our present policy is to consider elective neck irradiation in patients with T3-4 SCC of the maxillary sinus.

  View details for Web of Science ID 000085412400004

  View details for PubMedID 10701732

• Image-guided radiosurgery for the spine and pancreas. Computer aided surgery MURPHY, M. J., Adler, J. R., Bodduluri, M., Dooley, J., Forster, K., Hai, J., Le, Q., Luxton, G., Martin, D., Poen, J. 2000; 5 (4): 278-288

  Abstract

  A robotic image-guided radiosurgical system has been modified to treat extra-cranial sites using implanted fiducials and skeletal landmarks to locate the treatment targets. The system has been used to treat an artero-venous malformation in the cervical spine, a recurrent schwannoma of the thoracic spine, a metastatic adenocarcinoma of the lumbar spine, and three pancreatic cancers. During each treatment, the image guidance system monitored the position of the target site and relayed the target coordinates to the beam-pointing system at discrete intervals. The pointing system then dynamically aligned the therapy beam with the lesion, automatically compensating for shifts in target position. Breathing-related motion of the pancreas lesions was managed by coordinating beam gating with breath-holding by the patient. The system maintained alignment with the spine lesions to within +/- 0.2 mm on average, and to within +/- 1 mm for the pancreatic tumors. This experience has demonstrated the feasibility of using image-guided robotic radiosurgery outside the cranium.

  View details for PubMedID 11029160

• Computer-assisted selection of importance factors in inverse planning 13th International Conference on the Use of Computers in Radiation Therapy Le, Q. T., Li, J. G., Pugachev, A., Boyer, A. L., Xing, L. SPRINGER-VERLAG BERLIN. 2000: 29–31

  View details for Web of Science ID 000088386600011

• Estimation theory and model parameter selection for therapeutic treatment plan optimization MEDICAL PHYSICS Xing, L., Li, J. G., Pugachev, A., Le, Q. T., Boyer, A. L. 1999; 26 (11): 2348-2358

  Abstract

  Treatment optimization is usually formulated as an inverse problem, which starts with a prescribed dose distribution and obtains an optimized solution under the guidance of an objective function. The solution is a compromise between the conflicting requirements of the target and sensitive structures. In this paper, the treatment plan optimization is formulated as an estimation problem of a discrete and possibly nonconvex system. The concept of preference function is introduced. Instead of prescribing a dose to a structure (or a set of voxels), the approach prioritizes the doses with different preference levels and reduces the problem into selecting a solution with a suitable estimator. The preference function provides a foundation for statistical analysis of the system and allows us to apply various techniques developed in statistical analysis to plan optimization. It is shown that an optimization based on a quadratic objective function is a special case of the formalism. A general two-step method for using a computer to determine the values of the model parameters is proposed. The approach provides an efficient way to include prior knowledge into the optimization process. The method is illustrated using a simplified two-pixel system as well as two clinical cases. The generality of the approach, coupled with promising demonstrations, indicates that the method has broad implications for radiotherapy treatment plan optimization.

  View details for Web of Science ID 000083775800019

  View details for PubMedID 10587216

• Treatment of maxillary sinus carcinoma - A comparison of the 1997 and 1977 American Joint Committee on Cancer staging systems CANCER Le, Q. T., Fu, K. K., Kaplan, M., Terris, D. J., Fee, W. E., Goffinet, D. R. 1999; 86 (9): 1700-1711

  Abstract

  This study was conducted to assess the effectiveness of the 1997 American Joint Committee on Cancer (AJCC) staging system to predict survival and local control of patients with maxillary sinus carcinoma and to identify significant factors for overall survival, local control, and distant metastases in patients with these tumors.Ninety-seven patients with maxillary sinus carcinoma were treated with radiotherapy at Stanford University and the University of California, San Francisco between 1959-1996. The histologic type of carcinoma among the 97 patients were: 58 squamous cell carcinomas, 4 adenocarcinomas, 16 undifferentiated carcinomas, and 19 adenoid cystic carcinomas. All patients were restaged clinically according to the 1977 and 1997 AJCC staging systems. The T classification of the tumors of the patients was as follows: 8 with T2, 18 with T3, and 71 with T4 according to the 1977 system and 8 with T2, 36 with T3, and 53 with T4 according to the 1997 system. Eleven patients had lymph node involvement at diagnosis. Thirty-six patients were treated with radiotherapy alone and 61 received a combination of surgical and radiation treatments. The median follow-up for surviving patients was 78 months.The 5-year and 10-year actuarial survival rates for all patients were 34% and 31%, respectively. The 5-year survival estimate by the 1977 AJCC system (P = 0.06) was 75% for Stage II, 19% for Stage III, and 34% for Stage IV and by the 1997 AJCC system (P = 0.006) was 75% for Stage II, 37% for Stage III, and 28% for Stage IV. Significant prognostic factors for survival by multivariate analysis included age (favoring younger age, P<0.001), 1997 T classification (favoring T2-3, P = 0. 001), lymph node involvement at diagnosis (favoring N0, P = 0.002), treatment modality of the primary tumor site (favoring surgery and radiotherapy, P = 0.009), and gender (favoring female patients, P = 0.04). The overall radiation time was of borderline significance (favoring shorter time, P = 0.06). The actuarial 5-year local control rate was 43%. By the 1977 AJCC system (P = 0.78) it was 62% with T2, 36% with T3, and 45% with T4 and using the 1997 AJCC system (P = 0.29) it was 62% with T2, 53% with T3, and 36% with T4. The only significant prognostic factor for local control for all patients by multivariate analysis was local therapy, favoring surgery and radiotherapy over radiotherapy alone (P< 0.001). For patients treated with surgery, pathologic margin status correlated with local control (P = 0.007) and for patients treated with radiation alone, higher tumor dose (P = 0.007) and shorter overall treatment time (P = 0.04) were associated with fewer local recurrences. The 5-year estimate of freedom from distant metastases was 66%. The 1997 T classification, N classification, and lymph node recurrence were adverse prognostic factors for distant metastases on multivariate analysis. There were 22 complications in 16 patients, representing a 30% actuarial risk of developing late complications at 10 years.The 1997 AJCC staging system was found to be superior to the 1977 AJCC staging system in predicting both survival and local control in this patient population. Combined surgical and radiation treatment to the primary tumor yielded higher survival and local control than radiotherapy alone. Other significant prognostic factors for survival were patient age, gender, and lymph node (N) classification. Prolonged overall radiation time was associated with poorer survival and local control. Late severe toxicity from the treatment of these tumors was a significant problem in long term survivors. Improved radiotherapy techniques should lead to decreased injury to the surrounding normal tissues. (c) 1999 American Cancer Society.

  View details for Web of Science ID 000083430700011

  View details for PubMedID 10547542

• DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine. Neoplasia Dorie, M. J., Kovacs, M. S., Gabalski, E. C., Adam, M., Le, Q. T., Bloch, D. A., Pinto, H. A., Terris, D. J., Brown, J. M. 1999; 1 (5): 461-467

  Abstract

  Tirapazamine (TPZ) [3-amino-1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZ-induced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers.

  View details for PubMedID 10933062

• Optimization of importance factors in inverse planning PHYSICS IN MEDICINE AND BIOLOGY Xing, L., Li, J. G., Donaldson, S., Le, Q. T., Boyer, A. L. 1999; 44 (10): 2525-2536

  Abstract

  Inverse treatment planning starts with a treatment objective and obtains the solution by optimizing an objective function. The clinical objectives are usually multifaceted and potentially incompatible with one another. A set of importance factors is often incorporated in the objective function to parametrize trade-off strategies and to prioritize the dose conformality in different anatomical structures. Whereas the general formalism remains the same, different sets of importance factors characterize plans of obviously different flavour and thus critically determine the final plan. Up to now, the determination of these parameters has been a 'guessing' game based on empirical knowledge because the final dose distribution depends on the parameters in a complex and implicit way. The influence of these parameters is not known until the plan optimization is completed. In order to compromise properly the conflicting requirements of the target and sensitive structures, the parameters are usually adjusted through a trial-and-error process. In this paper, a method to estimate these parameters computationally is proposed and an iterative computer algorithm is described to determine these parameters numerically. The treatment plan selection is done in two steps. First, a set of importance factors are chosen and the corresponding beam parameters (e.g. beam profiles) are optimized under the guidance of a quadratic objective function using an iterative algorithm reported earlier. The 'optimal' plan is then evaluated by an additional scoring function. The importance factors in the objective function are accordingly adjusted to improve the ranking of the plan. For every change in the importance factors, the beam parameters need to be re-optimized. This process continues in an iterative fashion until the scoring function is saturated. The algorithm was applied to two clinical cases and the results demonstrated that it has the potential to improve significantly the existing method of inverse planning. It was noticed that near the final solution the plan became insensitive to small variations of the importance factors.

  View details for Web of Science ID 000083120600011

  View details for PubMedID 10533926

• Postoperative irradiation of minor salivary gland malignancies of the head and neck 38th Annual Meeting of American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. T., Birdwell, S., Terris, D. J., Gabalski, E. C., Varghese, A., Fee, W. E., Goffinet, D. R. ELSEVIER IRELAND LTD. 1999: 165–71

  Abstract

  (1) To review the Stanford experience with postoperative radiotherapy for minor salivary gland carcinomas of the head and neck. (2) To identify patterns of failure and prognostic factors for these tumors.Fifty-four patients with localized tumors were treated with curative intent at Stanford University between 1966 and 1995. The 1992 AJCC staging for squamous cell carcinomas was used to retrospectively stage these patients. Thirteen percent had stage I, 22% stage II, 26% stage III, and 39% stage IV neoplasms. Thirty-two patients (59%) had adenoid cystic carcinoma, 15 (28%) had adenocarcinoma, and seven (13%) had mucoepidermoid carcinoma. Thirty (55%) had positive surgical margins and seven (13%) had cervical lymph node involvement at diagnosis. The median follow-up for alive patients was 7.8 years (range: 25 months-28.9 years).The 5- and 10-year actuarial local control rates were 91 and 88%, respectively. Advanced T-stage (T3-4), involved surgical margins, adenocarcinoma histology, and sinonasal and oropharyngeal primaries were associated with poorer local control. The 5- and 10-year actuarial freedom from distant metastasis were 86 and 81%, respectively. Advanced T-stage (T3-4), lymph node involvement at diagnosis, adenoid cystic and high-grade mucoepidermoid histology were associated with a higher risk of distant metastases. The 10-year cause-specific survival (CSS) and overall survival (OS) were 81 % and 63%, respectively. On multivariate analysis, prognostic factors affecting survival were T-stage (favoring T1-2), and N-stage (favoring NO). When T- and N-stage were combined to form the AJCC stage, the latter became the most significant factor for survival. The 10-year OS was 86% for stage I-II vs. 52% for stage III-IV tumors. Late treatment-related toxicity was low (3/54); most complications were mild and no cranial nerve damage was noted.Surgical resection and carefully planned post-operative radiation therapy for minor salivary gland tumors is well tolerated and effective with high local control rates. AJCC stage was the most significant predictor for survival and should be used for staging minor salivary gland carcinomas.

  View details for Web of Science ID 000082784400010

  View details for PubMedID 10577702

• Cell cycle proteins and the development of oral squamous cell carcinoma ORAL ONCOLOGY Schoelch, M. L., Regezi, J. A., Dekker, N. P., Ng, I. O., McMillan, A., Ziober, B. L., Le, Q. T., Silverman, S., Fu, K. K. 1999; 35 (3): 333-342

  Abstract

  Expression of cell cycle regulatory proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of the cell cycle may be altered in the development of oral squamous cell carcinoma. Archived paraffin-embedded specimens (n = 90) from 25 patients with recurrent or persistent lesions were evaluated in immunohistochemically stained sections for cell cycle regulatory proteins p53, Rb, Cyclin D1, p27, and p21. The cell cycle was also evaluated by expression of nuclear protein Ki 67. Sections were graded semiquantitatively using a 0-3 + scale to indicate the percentage of positively stained cells. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty-three of 90 specimens showed positive p53 expression, 11 of which were dysplasias. Eighty-nine of 90 specimens, from all stages of disease, showed positive Rb expression. Twenty-three of 90 specimens showed positive Cyclin D1 expression, typically in the later stages (carcinoma) of a patient's disease. Eighty-four of 90 specimens showed positive p21 expression; while 55 of 90 specimens were positive for p27. In control mucosa, p27 was highly expressed, while Rb and p21 proteins were expressed at relatively low levels; p53 and Cyclin D1 proteins were largely absent. Generally, staining of p53, Rb, p21, and Ki 67 increased with time in serial biopsies, while p27 showed decreased staining with disease progression. These data show that cell cycle regulatory proteins are altered in both premalignant and malignant disease, and that protein phenotypes are heterogeneous. P53 expression is seen early, and Cyclin D1 expression is seen late in the development of oral premalignant and malignant disease. Expression of p53, Rb, p21 and Ki67 increased, while p27 decreased, with disease progression.

  View details for Web of Science ID 000079456300016

  View details for PubMedID 10621856

• Apoptosis-associated proteins and the development of oral squamous cell carcinoma ORAL ONCOLOGY Schoelch, M. L., Le, Q. T., Silverman, S., McMillan, A., Dekker, N. P., Fu, K. K., Ziober, B. L., Regezi, J. A. 1999; 35 (1): 77-85

  Abstract

  Expression of apoptosis-associated proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of apoptosis may be altered in the development of oral squamous cell carcinoma. Ninety archived paraffin-embedded specimens from 25 patients (two or more sequential biopsies each) and eight control specimens were evaluated in immunohistochemically stained sections for tumor suppressor protein p53, p53 binding protein mdm-2, and apoptosis regulatory proteins Bcl-2, Bcl-X, Bax, and Bak. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately differentiated squamous cell carcinoma. Thirty of 90 specimens showed positive p53 expression, nine of which were dysplasias. In patients with one or more lesions displaying p53 expression, there was increased intensity of staining with disease progression. Bak was expressed in 57/90 specimens, including 27 dysplasias of various grades. There was also a significantly increased intensity of Bak staining with disease progression, which did not appear to be dependent upon p53 status. Bcl-X was expressed in 73/90 specimens, with staining displayed earlier in premalignant lesions than either p53 or Bak. Ten of 90 specimens were positive for Bcl-2 (all were dysplasias or carcinomas), and only 2/90 specimens were positive for Bax. Eleven of 90 specimens were positive for mdm-2; six of which were also positive for p53. These data show that apoptosis-associated proteins are altered in variable patterns in both premalignant and malignant oral epithelial lesions. p53 and especially Bak and Bcl-X are expressed early; Bax is largely absent; and Bcl-2 and mdm-2 show sporadic expression in the development of oral premalignant and malignant disease.

  View details for Web of Science ID 000077473200012

  View details for PubMedID 10211314

• Post-operative irradiation of minor salivary gland malignancies of the head and neck. Radiotherapy Oncology Le QT, Birdwell S, Terris DJ, Gabalski EC, Varghese A, Fee WE, Goffinet DR. 1999; 2 (52): 165-71
• A medical knowledge based system for the section of beam orientations in intensity modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys Le QT, Xing L, Pugachev A, Li J , Donaldson S, Goffinet DR, Hancock S, Boyer A. 1998; 3S (45): 246
• Soft-tissue sarcomas. In: Phillips TL, Leibel S, eds. Textbook of Radiation Oncology, 1st Edition. Philadelphia: WB Saunders Le QT, Phillips TL, Leibel S. 1998: 1047-1066.
• Spinal cord dose discrepancy in IMRT treated patients at Stanford revealed by Monte Carlo dose verification: clinical summary. Int J Radiat Oncol Biol Phys Le QT, Guerrero TM, Pawlicki T, Ma CM, Forster KM, Xing L, Luxton G, Boyer AL, Goffinet DR. 1998; 3S (45): 411
• Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma 38th Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology LE, Q. T., Fu, K. K., KROLL, S., Ryu, J. K., Quivey, J. M., MEYLER, T. S., Krieg, R. M., Phillips, T. L. ELSEVIER SCIENCE INC. 1997: 115–26

  Abstract

  To evaluate the influence of fraction size, overall time, total dose, and other prognostic factors on local control of T1 and T2 glottic carcinomas.Between 1956 and 1995, 398 consecutive patients with early glottic carcinoma (315 T1 and 83 T2) were treated with once-a-day definitive radiotherapy at the University of California, San Francisco, and associated institutions. Treatment was delivered 5 days per week. Minimum tumor dose ranged from 46.6 to 77.6 Gy (median: 63 Gy). The fraction size was < 1.8 Gy in 146; 1.8-1.99 Gy in 128; 2.0-2.24 Gy in 62, and > or = 2.25 Gy in 62 patients. Overall time ranged from 34 to 75 days (median: 50 days). The majority of patients treated with a fraction size of 2.25 Gy completed therapy within 43 days. Median follow-up of all alive patients was 116 months (range 3-436 months).Five-year local control was 85% for T1 and 70% for T2 glottic carcinomas (p = 0.0004). For T1 lesions, within the dose and time range evaluated, there was no apparent relationship between fraction size, overall time, total dose, and local control on multivariate analysis. Treatment era was the only significant prognostic factor (p = 0.02), and anterior commissure (AC) involvement was of borderline significance (p = 0.056). Five-year local control was 77% for patients treated between 1956-1970, 89% for between 1971-1980, and 91% for between 1981-1995; 80% for patients with AC involvement and 88% for those without. For T2 lesions, prognostic factors for local control on multivariate analysis were: overall time (p = 0.003), fraction size (p = 0.003), total dose (p = 0.01), impaired vocal cord mobility (p = 0.02), and subglottic extension (p = 0.04). Five-year local control was 100% for T2 lesions treated with overall time < or = 43 days vs. 84% for overall time > 43 days; 100% for fraction size > or = 2.25 Gy vs. 44% for fraction size < 1.8 Gy; 78% for total dose > 65 Gy vs. 60% for total dose < or = 65 Gy; 79% for normal cord mobility vs. 45% for impaired cord mobility, and 58% for lesions with subglottic extension vs. 77% for those without. The severe complication rate for the entire group was low: 1.8%.Total dose, fraction size, and overall time were significant factors for local control of T2 but not T1 glottic carcinomas. Anterior commissure involvement was associated with decreased local control for T1 but not T2 lesions. For T1 lesions, local control improved over the treatment era. For T2 lesions, local control decreased with impaired cord mobility and subglottic extension.

  View details for Web of Science ID A1997XU99400014

  View details for PubMedID 9300746

• Adult medulloblastoma: An analysis of survival and prognostic factors CANCER JOURNAL Le, Q. T., Weil, M. D., Wara, W. M., Lamborn, K. R., Prados, M. D., Edwards, M. S., Gutin, P. H. 1997; 3 (4): 238-245

  Abstract

  This analysis aimed to review the experience in the management of adult medulloblastoma at the University of California, San Francisco, and to identify important prognostic factors for survival and posterior fossa control.We performed a retrospective review of 34 adult patients, age > or = 15, with cerebellar medulloblastoma treated with radiotherapy at the University of California, San Francisco from 1970 to 1994. All patients underwent a surgical procedure (complete resection in 17, subtotal resection in 10, and biopsy alone in seven), followed by craniospinal irradiation. Most patients treated after 1979 also received chemotherapy. Twenty were classified as poor-risk due to either incomplete resection or evidence of disease outside of the posterior fossa at diagnosis.The 5-year posterior fossa control and overall survival rates were 61% and 58%, respectively. The majority of relapses occurred in the posterior fossa (14 of 17). Multivariate analysis revealed that age (favoring older patients), gender (favoring female patients), and extent of disease at diagnosis (favoring localized disease) were important prognostic factors for posterior fossa control. There was a trend toward improved posterior fossa control with higher radiation dose to the posterior fossa in patients with a complete resection. Gender and extent of disease at presentation were significant prognostic factors for survival. The 5-year survival rates were 92% for female patients versus 40% for male patients, and 67% for patients with localized disease versus 25% for those with disseminated disease. The prognosis following recurrence was poor; all died of the disease.Survival for adult medulloblastoma was comparable to its pediatric counterpart. In patients with localized disease at presentation, gender (favoring female patients) and age (favoring older patients) were important prognostic factors for posterior fossa control and survival. In patients with disseminated disease at presentation, the prognosis is poor, and innovative therapy is needed to improve survival.

  View details for Web of Science ID A1997XN19200009

  View details for PubMedID 9263630

• Prognostic factors in adult soft-tissue sarcomas of the head and neck 78th Annual Meeting of the American-Radium-Society LE, Q. T., Fu, K. K., KROLL, S., Fitts, L., Massullo, V., Ferrell, L., Kaplan, M. J., Phillips, T. L. ELSEVIER SCIENCE INC. 1997: 975–84

  Abstract

  The main objectives of this study were (a) to review the treatment results of primary head and neck soft-tissue sarcoma at our institution, (b) to identify important prognostic factors in local control and survival, and (c) to assess the efficacy of salvage therapy.Sixty-five patients were treated at the University of California, San Francisco, between 1961 and 1993. Seventeen patients (27%) had low-grade, 10 (15%) had intermediate-grade, and 38 (58%) had high-grade sarcomas. Tumors were > 5 cm in 35 patients. Local management consisted of surgery alone in 14 patients (22%), surgery and radiotherapy in 40 (61%), and radiotherapy alone in 11 (17%) patients. The median follow-up was 64 months.The 5-year actuarial local control rate of the entire group was 66%. Tumor size and grade were important predictors for local control on multivariate analysis. The actuarial local control rate at 5 years was 92% for T1 vs. 40% for T2 primaries (p = 0.004), and 80% for Grade 1-2 vs. 48% for Grade 3 tumors (p = 0.01). None of the patients treated with radiotherapy alone with a dose of 50-65 Gy were controlled locally. Combined radiotherapy and surgery appeared to yield superior local control compared to surgery alone (77% vs. 59%); however, the difference was not statistically significant. The 5-year actuarial overall and cause-specific survivals were 56% and 60%, respectively. Unfavorable prognostic factors for cause-specific survival on multivariate analysis were age > 55 (p = 0.009), high tumor grade (p = 0.0002), inadequate surgery (p = 0.008), and positive surgical margins (p = 0.0009). In patients who underwent salvage therapy for treatment failure, the 5-year actuarial survival after salvage treatment was 26%.Tumor size and grade were important predictors for local control. Age, grade, adequacy of surgery, and status of surgical margins were significant prognostic factors for survival. There was a trend of improved local control with combined surgery and radiotherapy compared to either modality alone for high-risk patients. Radiotherapy alone with doses < or = 65 Gy was insufficient for control of gross disease. Aggressive salvage therapy was worthwhile in patients whose disease was uncontrolled after the initial treatment.

  View details for Web of Science ID A1997XB01200002

  View details for PubMedID 9169803

• PATTERN OF RECURRENCE OF MEDULLOBLASTOMA AFTER LOW-DOSE CRANIOSPINAL RADIOTHERAPY 35th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Wara, W. M., LE, Q. T., Sneed, P. K., Larson, D. A., Prados, M. D., Levin, V. A., Edwards, M. S., Weil, M. D. PERGAMON-ELSEVIER SCIENCE LTD. 1994: 551–56

  Abstract

  We retrospectively evaluated relapse of medulloblastoma after low- or high-dose craniospinal radiotherapy, and after conventional or hyperfractionated posterior fossa irradiation.Ninety-two pediatric patients were treated postoperatively since 1970 at the University of California, San Francisco. Until 1989, we employed conventional fractionation with low (< or = 30 Gy) or high-dose craniospinal fields and low-dose (< or = 56 Gy) posterior fossa boosts. Recently, hyperfractionation delivered low- or high-dose to the craniospinal axis and high-dose to the posterior fossa. Most patients treated after 1979 received chemotherapy.Median follow-up was 70 months. Five-year disease-free survival was 36% (22% for poor-risk vs. 59% for good-risk patients). Five-year overall survival was 52% (43% for poor vs. 68% for good-risk). Neither the dose to the posterior fossa nor the craniospinal axis was statistically related to recurrence. Failure in the posterior fossa occurred despite boosts greater than 56 Gy. Females, over the age of 6 years, had significantly better relapse-free survival than males of the same age. Six of the 54 patients who relapsed were long-term survivors.Low-dose craniospinal radiotherapy, where the majority of patients received chemotherapy, was not associated with increased failure. High-dose posterior fossa hyperfractionation did not improve control. Long-term survival was noted in a number of patients after relapse. We recommend 60 Gy or greater with conventional fractions to the primary area, and continued study of low-dose craniospinal irradiation with adjuvant chemotherapy.

  View details for Web of Science ID A1994PK60400004

  View details for PubMedID 7928485