Lucas Kas Vitzthum, MD

All Publications

• A Balancing Act With Adaptive Hypofractionation. International journal of radiation oncology, biology, physics Vitzthum, L. K., Pollom, E. 2024; 120 (4): 930

  View details for DOI 10.1016/j.ijrobp.2024.08.030

  View details for PubMedID 39424592

• A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer. International journal of radiation oncology, biology, physics Gensheimer, M. F., Kotha, N. V., Vitzthum, L. K., Chin, A. L., Jackson, S., 't Erve, I. v., Pratapneni, A., Le-Budka, M. L., Wong, S., Brown, E., Barnick, K., Wakelee, H. A., Das, M., Ramchandran, K. J., Myall, N. J., Padda, S., Marquez, C. M., Million, L., Chen, T. T., Man, M. C., Cabebe, E. C., Chen, M. C., Hiniker, S., Hancock, S. L., Swift, P. S., Diehn, M., Loo, B. W., Neal, J. W. 2024

  Abstract

  For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS).In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%.Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis.The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.

  View details for DOI 10.1016/j.ijrobp.2024.09.038

  View details for PubMedID 39357790

• Redefining Candidates for Deintensification in Locoregionally Advanced P16+ Oropharyngeal Cancer Based on Relative Risk. International journal of radiation oncology, biology, physics Morse, R. T., Nelson, T. J., Liu, H. C., Sangchan, P., Chitti, B., Thompson, C. A., Henderson, G., Williamson, C. W., Todd, J. R., Prajapati, D. P., Vitzthum, L. K., Sharabi, A. B., Zou, J., Sacco, A. G., Coffey, C. S., Sanghvi, P., Rahn, D. A., Lominska, C. E., Shen, C. J., Chera, B. S., Mell, L. K. 2024

  Abstract

  Randomized trials have found that patients with locoregionally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC) do not benefit from treatment deintensification, even among favorable risk groups. While various methods have been used to identify candidates for treatment deintensification, the optimal approach is unknown.We conducted a multi-institutional cohort study of 444 patients with previously untreated p16+ OPSCC undergoing definitive radiotherapy with or without systemic therapy between 2009-2022. We compared two approaches for identifying candidates for deintensification: (1) favorable vs. unfavorable risk, using NRG-HN005 eligibility criteria, and (2) low vs. high relative risk for cancer events, using the HNCIG predictive classifier ("omega score"). We tested differences in outcomes and systemic therapy allocation by risk group using multivariable Cox models, competing event models, and logistic regression, and compared characteristics of hypothetical deintensification trials using the two approaches. PFS events were defined as cancer recurrence (locoregional or distant) or death from any cause.Median follow-up time was 52 months; 120 patients (27.0%) were favorable risk; a different 120 patients had low omega score; 28 patients (6.3%) met both criteria; 184 patients (41.4%) had discordant classification. On ordinal logistic regression, decreasing omega score was associated with a statistically significantly lower odds of receiving intensive therapy (normalized OR 0.37 per standard deviation; 95% CI: 0.24-0.57), with a greater magnitude than favorable risk group (OR 0.66; 95% CI: 0.44-0.99). Among patients receiving cisplatin and/or platinum-based induction (N=374), favorable risk was associated with significantly improved PFS (HR 0.59, 95% CI 0.36-0.99), whereas lower omega score was associated with a significantly decreased relative hazard for cancer events (RHR 0.18, 95% CI 0.070-0.46). In simulations, selecting patients with low omega scores increased the efficiency of hypothetical non-inferiority trials.Considering patients' relative risk for cancer events can help define optimal populations for treatment deintensification in p16+ OPSCC.

  View details for DOI 10.1016/j.ijrobp.2024.09.035

  View details for PubMedID 39307324

• Safety of pelvic and abdominal radiation therapy for patients with inflammatory bowel disease: a dosimetric analysis of acute bowel toxicity. International journal of radiation oncology, biology, physics Hall, J. C., Hall, A. K., Lozko, Y., Hui, C., Baniel, C. C., Jackson, S., Vitzthum, L. K., Chang, D. T., Rahimy, E., Pollom, E. L. 2024

  Abstract

  OBJECTIVES: Inflammatory bowel disease (IBD) has been considered a relative contraindication to radiation therapy (RT) due to the potential greater risk of RT-induced toxicities. This study aims to assess acute toxicity outcomes in patients with IBD treated with abdominal/pelvic RT.METHODS: After institutional review board approval, patients with IBD who received RT to the abdomen/pelvis were identified from an institutional research repository and their electronic medical records were reviewed. The IBD cohort was matched 1:1 with controls according to all of the following: radiotherapy, gender, disease site, age, and year of RT. Acute toxicity was defined as toxicity occurring within 3 months of RT. Primary outcomes were assessed via univariable logistic regression models and predicted probability of acute toxicity and acute gastrointestinal (GI) toxicity were plotted for the most significant covariates. IBD and control control cohorts were compared on demographic and toxicity variables using chi-square/Fisher's exact tests and Kruskal-Wallis tests where appropriate.RESULTS: We identified 62 patients with median age of 64 years (interquartile range [IQR] 54-70) who received RT from 2006-2022. Patients were treated with intensity-modulated RT (38; 61.3%), 3-dimensional conformal RT (12; 19.4%), and stereotactic body RT/brachytherapy (12; 19.4%). After RT, 28 (45.2%) and 23 (37.1%) patients experienced grade ≥2 acute (any) and acute GI toxicity, respectively. Higher overall RT dose and RT dose to small bowel were found to be signicantly associated with increased risk of grade ≥2 acute toxicities (OR=1.041 per unit Gy, 95% CI 1.005-1.084, p=0.034 and OR=1.046, 95% CI 1.018-1.082, p=0.003, respectively). Between IBD and control cohorts, there were no significant differences in grade ≥2 acute (any) and acute GI toxicities (p=0.710 and p=0.704, respectively).CONCLUSION: In patients with IBD treated with abdominal/pelvic RT for malignancy, RT was effective and well-tolerated. RT treatment planning should carefully consider the location(s) of IBD inflammation and dose to bowel structures, in particular, dose to small bowel.

  View details for DOI 10.1016/j.ijrobp.2024.09.005

  View details for PubMedID 39270827

• Cultural and social barriers to hope in gastrointestinal cancer patients. Journal of gastrointestinal oncology Qu, V., Hui, C., Fang, Z., Jackson, S., Vitzthum, L., Rahimy, E., Hall, J., Pollom, E. L. 2024; 15 (4): 1487-1496

  Abstract

  Hope is correlated with quality of life and overall survivorship among patients with cancer. We aimed to identify sociodemographic and clinical determinants of hope among patients with gastrointestinal (GI) cancer.Patients with GI cancer seen in radiation oncology between 10/2022 and 6/2023 were surveyed with the Adult Hope Scale (AHS) questionnaire, which assesses hope based on goal-setting and goal-striving beliefs. Linear regression and Pearson's/Spearman's correlation coefficients were used to evaluate associations between AHS scores and demographic or disease variables.One-hundred and forty-five (71.1% response rate) patients were included in the analysis. Most (75%) patients were symptomatic from disease, and Asian American and Pacific Islander (AAPI) patients accounted for 30.3% of our cohort. Identifying as AAPI or needing an interpreter for clinic visits was significantly associated with lower AHS scores, and more AAPI patients required interpreter assistance compared to non-AAPI patients (P=0.04). Being divorced, unemployed, or female was also linked to less hope. No other differences in hope were found.Sociodemographic rather than prognostic clinical factors were predictive of hope among patients with GI cancer. Interventions to contextualize psychosocial risk factors have the potential to improve quality of life and oncologic outcomes.

  View details for DOI 10.21037/jgo-23-938

  View details for PubMedID 39279929

  View details for PubMedCentralID PMC11399820

• Utility of radiomic features in predicting clinical outcomes in stage II-III pancreatic cancer. Itakura, H., Xu, Q., Toesca, D., Vitzthum, L., Jamalian, A., Schueler, E., Alkim, E., Baclay, J., Chang, D., Fisher, G. A. LIPPINCOTT WILLIAMS & WILKINS. 2024: 74

  View details for DOI 10.1200/JCO.2024.42.23_suppl.74

  View details for Web of Science ID 001346520000120

• Clinical determinants of survival in patients with stage II-III pancreatic cancer Itakura, H., Xu, Q., Toesca, D., Vitzthum, L., Jamalian, A., Schueler, E., Alkim, E., Baclay, J., Chang, D., Fisher Jr, G. A. LIPPINCOTT WILLIAMS & WILKINS. 2024: 56

  View details for DOI 10.1200/JCO.2024.42.23_suppl.56

  View details for Web of Science ID 001346520000095

• Phase II trial of organ preservation program using short-course radiation and FOLFOXIRI for rectal cancer (SHORT-FOX). Pollom, E. L., Fisher, G. A., Shelton, A., Johnson, T., Chen, C., Jackson, S., Shaheen, S., Holden, T., Bien, J., King, D., Morris, A. M., Kin, C., Dawes, A., Kirilcuk, N., Gahagan, J., Vitzthum, L., Sheth, V., Brown, E., Pratapneni, A., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557400852

• Commissioning of a novel PET-Linac for biology-guided radiotherapy (BgRT). Medical physics Surucu, M., Ashraf, M. R., Romero, I. O., Zalavari, L. T., Pham, D., Vitzthum, L. K., Gensheimer, M. F., Yang, Y., Xing, L., Kovalchuk, N., Han, B. 2024

  Abstract

  Biology-guided radiotherapy (BgRT) is a novel radiotherapy delivery technique that utilizes the tumor itself to guide dynamic delivery of treatment dose to the tumor. The RefleXion X1 system is the first radiotherapy system developed to deliver SCINTIX® BgRT. The X1 is characterized by its split arc design, employing two 90-degree positron emission tomography (PET) arcs to guide therapeutic radiation beams in real time, currently cleared by FDA to treat bone and lung tumors.This study aims to comprehensively evaluate the capabilities of the SCINTIX radiotherapy delivery system by evaluating its sensitivity to changes in PET contrast, its adaptability in the context of patient motion, and its performance across a spectrum of prescription doses.A series of experimental scenarios, both static and dynamic, were designed to assess the SCINTIX BgRT system's performance, including an end-to-end test. These experiments involved a range of factors, including changes in PET contrast, motion, and prescription doses. Measurements were performed using a custom-made ArcCHECK insert which included a 2.2 cm spherical target and a c-shape structure that can be filled with a PET tracer with varying concentrations. Sinusoidal and cosine4 motion patterns, simulating patient breathing, was used to test the SCINTIX system's ability to deliver BgRT during motion-induced challenges. Each experiment was evaluated against specific metrics, including Activity Concentration (AC), Normalized Target Signal (NTS), and Biology Tracking Zone (BTZ) bounded dose-volume histogram (bDVH) pass rates. The accuracy of the delivered BgRT doses on ArcCHECK and EBT-XD film were evaluated using gamma 3%/2 mm and 3%/3 mm analysis.In static scenarios, the X1 system consistently demonstrated precision and robustness in SCINTIX dose delivery. The end-to-end delivery to the spherical target yielded good results, with AC and NTS values surpassing the critical thresholds of 5 kBq/mL and 2, respectively. Furthermore, bDVH analysis consistently confirmed 100% pass rates. These results were reaffirmed in scenarios involving changes in PET contrast, emphasizing the system's ability to adapt to varying PET avidities. Gamma analysis with 3%/2 mm (10% dose threshold) criteria consistently achieved pass rates > 91.5% for the static tests. In dynamic SCINTIX delivery scenarios, the X1 system exhibited adaptability under conditions of motion. Sinusoidal and cosine4 motion patterns resulted in 3%/3 mm gamma pass rates > 87%. Moreover, the comparison with gated stereotactic body radiotherapy (SBRT) delivery on a conventional c-arm Linac resulted in 93.9% gamma pass rates and used as comparison to evaluate the interplay effect. The 1 cm step shift tests showed low overall gamma pass rates of 60.3% in ArcCHECK measurements, while the doses in the PTV agreed with the plan with 99.9% for 3%/3 mm measured with film.The comprehensive evaluation of the X1 radiotherapy delivery system for SCINTIX BgRT demonstrated good agreement for the static tests. The system consistently achieved critical metrics and delivered the BgRT doses per plan. The motion tests demonstrated its ability to co-localize the dose where the PET signal is and deliver acceptable BgRT dose distributions.

  View details for DOI 10.1002/mp.17114

  View details for PubMedID 38703397

• Chest wall pain after single-fraction thoracic stereotactic ablative Radiotherapy: Dosimetric analysis from the iSABR trial. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Lau, B., Wu, Y. F., Cui, S., Fu, J., Jackson, S., Pham, D., Dubrowski, P., Eswarappa, S., Skinner, L., Shirato, H., Taguchi, H., Gensheimer, M. F., Gee, H., Chin, A. L., Diehn, M., Loo, B. W., Moiseenko, V., Vitzthum, L. K. 2024: 110317

  Abstract

  Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk.This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting.There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall.For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

  View details for DOI 10.1016/j.radonc.2024.110317

  View details for PubMedID 38679202

• Lung Cancer Survival Trends in the Veterans Health Administration. Clinical lung cancer Moghanaki, D., Taylor, J., Bryant, A. K., Vitzthum, L. K., Sebastian, N., Gutman, D., Burns, A., Huang, Z., Lewis, J. A., Spalluto, L. B., Williams, C. D., Sullivan, D. R., Slatore, C. G., Behera, M., Stokes, W. A. 2024

  Abstract

  Lung cancer survival is improving in the United States. We investigated whether there was a similar trend within the Veterans Health Administration (VHA), the largest integrated healthcare system in the United States.Data from the Veterans Affairs Central Cancer Registry were analyzed for temporal survival trends using Kaplan-Meier estimates and linear regression.A total number of 54,922 Veterans were identified with lung cancer diagnosed from 2010 to 2017. Histologies were classified as non-small-cell lung cancer (NSCLC) (64.2%), small cell lung cancer (SCLC) (12.9%), and 'other' (22.9%). The proportion with stage I increased from 18.1% to 30.4%, while stage IV decreased from 38.9% to 34.6% (both P < .001). The 3-year overall survival (OS) improved for stage I (58.6% to 68.4%, P < .001), stage II (35.5% to 48.4%, P < .001), stage III (18.7% to 29.4%, P < .001), and stage IV (3.4% to 7.8%, P < .001). For NSCLC, the median OS increased from 12 to 21 months (P < .001), and the 3-year OS increased from 24.1% to 38.3% (P < .001). For SCLC, the median OS remained unchanged (8 to 9 months, P = .10), while the 3-year OS increased from 9.1% to 12.3% (P = .014). Compared to White Veterans, Black Veterans with NSCLC had similar OS (P = .81), and those with SCLC had higher OS (P = .003).Lung cancer survival is improving within the VHA. Compared to White Veterans, Black Veterans had similar or higher survival rates. The observed racial equity in outcomes within a geographically and socioeconomically diverse population warrants further investigation to better understand and replicate this achievement in other healthcare systems.

  View details for DOI 10.1016/j.cllc.2024.02.009

  View details for PubMedID 38553325

• Predicting rapid progression and overall survival in stage II-III pancreatic cancer using a CT-based radiomic signature. Xu, Q., Toesca, D., Schueler, E., Jamalian, A., Alkim, E., Chang, D., Fisher, G. A., Vitzthum, L., Gevaert, O., Itakura, H. LIPPINCOTT WILLIAMS & WILKINS. 2024: 706

  View details for DOI 10.1200/JCO.2024.42.3_suppl.706

  View details for Web of Science ID 001266680500362

• 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

• BIOGUIDE-X: A First-in-Human Study of the Performance of Positron Emission Tomography-Guided Radiotherapy. International journal of radiation oncology, biology, physics Vitzthum, L. K., Surucu, M., Gensheimer, M. F., Kovalchuk, N., Han, B., Pham, D., Chang, D., Shirvani, S. M., Aksoy, D., Maniyedath, A., Narayanan, M., Da Silva, A. J., Mazin, S., Feghali, K. A., Iyengar, P., Dan, T., Pompos, A., Timmerman, R., Öz, O., Cai, B., Garant, A. 2023

  Abstract

  SCINTIX® Biology-guided radiotherapy (BgRT) is a novel tracked dose delivery modality that uses real-time positron emission tomography (PET) to guide radiotherapy beamlets. The BIOGUIDE-X study was performed with sequential cohorts of participants to (1) identify the fluorodeoxyglucose (FDG) dose for SCINTIX therapy and (2) confirm that the emulated dose distribution was consistent with a physician-approved radiotherapy plan.This prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (≥2cm and ≤5cm) in the lung or bone. For Cohort I, a modified 3 + 3 design was used to determine the FDG dose that would result in adequate signal for SCINTIX therapy. For Cohort II, PET imaging data were collected on the X1 system before the first and last fractions among patients undergoing conventional stereotactic body radiotherapy. SCINTIX therapy dose distributions were modeled on the patient's CT anatomy using the collected PET data at each fraction as input to an "emulated delivery" and compared to the physician-approved plan.Cohort I demonstrated adequate FDG activity in 6/6 (100.0%) evaluable participants with the first injected dose level of 15 mCi FDG. In Cohort II, 4 patients with lung tumors and 5 with bone tumors were enrolled, and evaluable emulated delivery data points were collected for 17 treatment fractions. Sixteen of the 17 emulated deliveries resulted in SCINTIX dose distributions that were accurate with respect to the approved SCINTIX therapy plan. The 17th data point was just below the 95% threshold for accuracy (DVH Score = 94.6%). All emulated fluences were physically deliverable. No toxicities were attributed to multiple FDG administrations.SCINTIX therapy is a novel radiotherapy modality in which a radiolabeled tumor can act as its own fiducial for radiotherapy targeting. Emulated SCINTIX therapy dose distributions calculated from continuously acquired real-time PET data were accurate and machine-deliverable in tumors that were 2-5 cm in size with adequate FDG signal characteristics.

  View details for DOI 10.1016/j.ijrobp.2023.12.019

  View details for PubMedID 38147912

• Predicting Adverse Cardiac Events After Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer. JACC. CardioOncology No, H. J., Guo, F. B., Park, N. J., Kastelowitz, N., Rhee, J. W., Clark, D. E., Chin, A. L., Vitzthum, L. K., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. 2023; 5 (6): 775-787

  Abstract

  Radiotherapy may cause grade ≥3 cardiac events, necessitating a better understanding of risk factors. The potential predictive role of imaging biomarkers with radiotherapy doses for cardiac event occurrence has not been studied.The aim of this study was to establish the associations between cardiac substructure dose and coronary artery calcium (CAC) scores and cardiac event occurrence.A retrospective cohort analysis included patients with locally advanced non-small cell lung cancer treated with radiotherapy (2006-2018). Cardiac substructures, including the left anterior descending coronary artery, left main coronary artery, left circumflex coronary artery, right coronary artery, and TotalLeft (left anterior descending, left main, and left circumflex coronary arteries), were contoured. Doses were measured in 2-Gy equivalent units, and visual CAC scoring was compared with automated scoring. Grade ≥3 adverse cardiac events were recorded. Time-dependent receiver-operating characteristic modeling, the log-rank statistic, and competing-risk models were used to measure prediction performance, threshold modeling, and the cumulative incidence of cardiac events, respectively.Of the 233 eligible patients, 61.4% were men, with a median age of 68.1 years (range: 34.9-90.7 years). The median follow-up period was 73.7 months (range: 1.6-153.9 months). Following radiotherapy, 22.3% experienced cardiac events, within a median time of 21.5 months (range: 1.7-118.9 months). Visual CAC scoring showed significant correlation with automated scoring (r = 0.72; P < 0.001). In a competing-risk multivariable model, TotalLeft volume receiving 15 Gy (per 1 cc; HR: 1.38; 95% CI: 1.11-1.72; P = 0.004) and CAC score >5 (HR: 2.51; 95% CI: 1.08-5.86; P = 0.033) were independently associated with cardiac events. A model incorporating age, TotalLeft CAC (score >5), and volume receiving 15 Gy demonstrated a higher incidence of cardiac events for a high-risk group (28.9%) compared with a low-risk group (6.9%) (P < 0.001).Adverse cardiac events associated with radiation occur in more than 20% of patients undergoing thoracic radiotherapy within a median time of <2 years. The present findings provide further evidence to support significant associations between TotalLeft radiotherapy dose and cardiac events and define CAC as a predictive risk factor.

  View details for DOI 10.1016/j.jaccao.2023.08.007

  View details for PubMedID 38205000

  View details for PubMedCentralID PMC10774791

• Risk of developing subsequent primary lung cancer after receiving radiation for breast cancer. JTCVS open Wong, L., Kapula, N., He, H., Guenthart, B. A., Vitzthum, L. K., Horst, K., Liou, D. Z., Backhus, L. M., Lui, N. S., Berry, M. F., Shrager, J. B., Elliott, I. A. 2023; 16: 919-928

  Abstract

  Background: Radiotherapy (RT) is integral to breast cancer treatment, especially in the current era that emphasizes breast conservation. The aim of our study was to determine the incidence of subsequent primary lung cancer after RT exposure for breast cancer over a time span of 3decades to quantify this risk over time as modern oncologic treatment continues to evolve.Methods: The SEER (Surveillance, Epidemiology, and End Results) database was queried from 1988 to 2014 for patients diagnosed with nonmetastatic breast cancer. Patients who subsequently developed primary lung cancer were identified. Multivariable regression modeling was performed to identify independent factors associated with the development of lung cancer stratified by follow up intervals of 5 to 9years, 10 to 15years, and >15years after breast cancer diagnosis.Results: Of the 612,746 patients who met our inclusion criteria, 319,014 (52%) were irradiated. primary lung cancer developed in 5556 patients (1.74%) in the RT group versus 4935 patients (1.68%) in the non-RT group. In a multivariable model stratified by follow-up duration, the overall HR of developing subsequent ipsilateral lung cancer in the RT group was 1.14 (P=.036) after 5 to 9years of follow-up, 1.28 (P=.002) after 10 to 15years of follow-up, and 1.30 (P=.014) after >15years of follow-up. The HR of contralateral lung cancer was not increased at any time interval.Conclusions: The increased risk of developing a primary lung cancer secondary to RT exposure for breast cancer is much lower than previously published. Modern RT techniques may have contributed to the improved risk profile, and this updated study is important for counseling and surveillance of breast cancer patients.

  View details for DOI 10.1016/j.xjon.2023.10.031

  View details for PubMedID 38204675

• Volumetric MRI with sparse sampling for MR-guided 3D motion tracking via sparse prior-augmented implicit neural representation learning. Medical physics Liu, L., Shen, L., Johansson, A., Balter, J. M., Cao, Y., Vitzthum, L., Xing, L. 2023

  Abstract

  Volumetric reconstruction of magnetic resonance imaging (MRI) from sparse samples is desirable for 3D motion tracking and promises to improve magnetic resonance (MR)-guided radiation treatment precision. Data-driven sparse MRI reconstruction, however, requires large-scale training datasets for prior learning, which is time-consuming and challenging to acquire in clinical settings.To investigate volumetric reconstruction of MRI from sparse samples of two orthogonal slices aided by sparse priors of two static 3D MRI through implicit neural representation (NeRP) learning, in support of 3D motion tracking during MR-guided radiotherapy.A multi-layer perceptron network was trained to parameterize the NeRP model of a patient-specific MRI dataset, where the network takes 4D data coordinates of voxel locations and motion states as inputs and outputs corresponding voxel intensities. By first training the network to learn the NeRP of two static 3D MRI with different breathing motion states, prior information of patient breathing motion was embedded into network weights through optimization. The prior information was then augmented from two motion states to 31 motion states by querying the optimized network at interpolated and extrapolated motion state coordinates. Starting from the prior-augmented NeRP model as an initialization point, we further trained the network to fit sparse samples of two orthogonal MRI slices and the final volumetric reconstruction was obtained by querying the trained network at 3D spatial locations. We evaluated the proposed method using 5-min volumetric MRI time series with 340 ms temporal resolution for seven abdominal patients with hepatocellular carcinoma, acquired using golden-angle radial MRI sequence and reconstructed through retrospective sorting. Two volumetric MRI with inhale and exhale states respectively were selected from the first 30 s of the time series for prior embedding and augmentation. The remaining 4.5-min time series was used for volumetric reconstruction evaluation, where we retrospectively subsampled each MRI to two orthogonal slices and compared model-reconstructed images to ground truth images in terms of image quality and the capability of supporting 3D target motion tracking.Across the seven patients evaluated, the peak signal-to-noise-ratio between model-reconstructed and ground truth MR images was 38.02 ± 2.60 dB and the structure similarity index measure was 0.98 ± 0.01. Throughout the 4.5-min time period, gross tumor volume (GTV) motion estimated by deforming a reference state MRI to model-reconstructed and ground truth MRI showed good consistency. The 95-percentile Hausdorff distance between GTV contours was 2.41 ± 0.77 mm, which is less than the voxel dimension. The mean GTV centroid position difference between ground truth and model estimation was less than 1 mm in all three orthogonal directions.A prior-augmented NeRP model has been developed to reconstruct volumetric MRI from sparse samples of orthogonal cine slices. Only one exhale and one inhale 3D MRI were needed to train the model to learn prior information of patient breathing motion for sparse image reconstruction. The proposed model has the potential of supporting 3D motion tracking during MR-guided radiotherapy for improved treatment precision and promises a major simplification of the workflow by eliminating the need for large-scale training datasets.

  View details for DOI 10.1002/mp.16845

  View details for PubMedID 38014764

• Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer. Clinical lung cancer Hui, C., Marquez, C., Lau, B., Das, M., Myall, N. J., Roy, M., Wakelee, H. A., Neal, J. W., Kovalchuk, N., Chin, A., Diehn, M., Loo, B. W., Xiang, M., Vitzthum, L. K. 2023

  Abstract

  Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection.We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts.Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.

  View details for DOI 10.1016/j.cllc.2023.11.008

  View details for PubMedID 38065707

• Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial. Clinical lung cancer Hui, C., Brown, E., Wong, S., Das, M., Wakelee, H., Neal, J., Ramchandran, K., Myall, N. J., Pham, D., Xing, L., Yang, Y., Kovalchuk, N., Yuan, Y., Lu, Y., Xiang, M., Chin, A., Diehn, M., Loo, B. W., Vitzthum, L. K. 2023

  Abstract

  Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint.PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

  View details for DOI 10.1016/j.cllc.2023.11.004

  View details for PubMedID 38040540

• Outcomes and Imaging Analysis in Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy. Practical radiation oncology Hui, C., Baclay, R., Lau, B., von Eyben, R., Vitzthum, L., Pollom, E., Chang, D. T. 2023; 13 (2): e139-e148

  Abstract

  Although arterial phase enhancement is commonly used to evaluate treatment response for hepatocellular carcinoma, it may not accurately describe response for lesions treated with stereotactic body radiation therapy (SBRT). We aimed to describe the post-SBRT imaging findings to better inform the optimal timing of salvage therapy after SBRT.We retrospectively reviewed patients with hepatocellular carcinoma treated with SBRT from 2006 to 2021 at a single institution with available imaging showing lesions with characteristic arterial enhancement and portal venous washout. Patients were then stratified into 3 groups based on treatment: (1) concurrent SBRT and transarterial chemoembolization, (2) SBRT only, and (3) SBRT followed by early salvage therapy due to persistent enhancement. Overall survival was analyzed with the Kaplan-Meier method, and cumulative incidences were calculated with competing risk analysis.We included 82 lesions in 73 patients. The median follow-up time was 22.3 months (range, 2.2-88.1 months). The median time to overall survival was 43.7 months (95% confidence interval, 28.1-57.6 months) and median progression-free survival was 10.5 months (95% confidence interval, 7.2-14.0 months). There were 10 (12.2%) lesions that experienced local progression and there was no difference in rates of local progression between the 3 groups (P = .32). In the SBRT-only group, the median time to resolution of arterial enhancement and washout was 5.3 months (range, 1.6-23.7 months). At 3, 6, 9, and 12 months, 82%, 41%, 13%, and 8% of lesions, respectively, continued to show arterial hyperenhancement.Tumors treated with SBRT may continue to exhibit persistence of arterial hyperenhancement. Without an increase in size of enhancement, continued surveillance may be appropriate for these patients.

  View details for DOI 10.1016/j.prro.2022.08.012

  View details for PubMedID 36868725

• ASO Visual Abstract: Patterns of Recurrence after Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation. Annals of surgical oncology Hui, C., Ewongwo, A., Lau, B., Fisher, G., Delitto, D., Poultsides, G., Ho, Q. A., Rahimy, E., Pollom, E., Chang, D. T., Vitzthum, L. K. 2023

  View details for DOI 10.1245/s10434-023-14475-3

  View details for PubMedID 37875741

• ASO Author Reflections: A Role for Neoadjuvant Radiation in the Treatment of Locally Advanced Gastric Cancer? Annals of surgical oncology Hui, C., Vitzthum, L. K. 2023

  View details for DOI 10.1245/s10434-023-14403-5

  View details for PubMedID 37831276

  View details for PubMedCentralID 4517071

• Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation. Annals of surgical oncology Hui, C., Ewongwo, A., Lau, B., Fisher, G., Delitto, D., Poultsides, G., Ho, Q., Rahimy, E., Pollom, E., Chang, D. T., Vitzthum, L. K. 2023

  Abstract

  BACKGROUND: Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy.PATIENTS AND METHODS: We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence.RESULTS: A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR.CONCLUSIONS: Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.

  View details for DOI 10.1245/s10434-023-14350-1

  View details for PubMedID 37755563

• 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

• Diverging Roads in the Management of Metastatic EGFR Mutated Non Small Cell Lung Cancer: Ablate All, None, or Some? International journal of radiation oncology, biology, physics Vitzthum, L. K., Pollom, E. L. 2023; 116 (3): 479-480

  View details for DOI 10.1016/j.ijrobp.2022.12.043

  View details for PubMedID 37270242

• 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

• Unilateral diaphragmatic paralysis after stereotactic ablative radiotherapy to a lung tumor abutting the course of the phrenic nerve. Practical radiation oncology Eke, I., Guo, H. H., Loo, J. B., Sung, A. W., Diehn, M., Vitzthum, L., Chin, A. L., Gensheimer, M. F. 2023

  Abstract

  We present the case of a woman with metastatic adenoid cystic carcinoma who received stereotactic ablative radiotherapy (SABR) with a total dose of 50 Gy in 4 fractions to two lung metastases and developed symptomatic left phrenic nerve injury 2 years after radiation. The maximum dose to the approximate location of the phrenic nerve was 57.7 Gy which corresponds to a biologically effective dose for late effects (using α/β ratio = 3) of 335.14 Gy. Here, we discuss the case, planning considerations by radiation oncologists and medical physicists, and the multidisciplinary medical management of this patient.

  View details for DOI 10.1016/j.prro.2023.04.010

  View details for PubMedID 37150318

• Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Lau, B., Wu, Y. F., No, H. J., Ko, R. B., Devine, M., Das, M. S., Neal, J. W., Wakelee, H. A., Ramchandran, K., Gensheimer, M. F., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. K. 2023

  Abstract

  Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFi). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any grade and grade-three-plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR + VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.Treatment with VEGFi + SABR was associated with higher rates of G3+ pulmonary hemorrhage compared to those treated with SABR alone for the overall cohort (3-year incidence: 7.9% vs 0.6%, p<0.01) and those with central tumors (19.1% vs 3.3%, p=0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% vs 45.0%, p = 0.044), but not central non-abutting tumors (0.0% vs 1.3% p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi + SABR compared to VEGFi alone (9.6 vs 1.3%, p=0.04).The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.

  View details for DOI 10.1016/j.jtho.2023.04.007

  View details for PubMedID 37085030

• Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. The lancet. Diabetes & endocrinology Taïeb, D., Wanna, G. B., Ahmad, M., Lussey-Lepoutre, C., Perrier, N. D., Nölting, S., Amar, L., Timmers, H. J., Schwam, Z. G., Estrera, A. L., Lim, M., Pollom, E. L., Vitzthum, L., Bourdeau, I., Casey, R. T., Castinetti, F., Clifton-Bligh, R., Corssmit, E. P., de Krijger, R. R., Del Rivero, J., Eisenhofer, G., Ghayee, H. K., Gimenez-Roqueplo, A. P., Grossman, A., Imperiale, A., Jansen, J. C., Jha, A., Kerstens, M. N., Kunst, H. P., Liu, J. K., Maher, E. R., Marchioni, D., Mercado-Asis, L. B., Mete, O., Naruse, M., Nilubol, N., Pandit-Taskar, N., Sebag, F., Tanabe, A., Widimsky, J., Meuter, L., Lenders, J. W., Pacak, K. 2023

  Abstract

  Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

  View details for DOI 10.1016/S2213-8587(23)00038-4

  View details for PubMedID 37011647

• Real-world risk of brain metastases in stage III non-small cell lung cancer in the era of PET and MRI staging. Frontiers in oncology Alhusaini, S., Lanman, T. A., Ko, R. B., Therkelsen, K. E., Eyben, R. V., Diehn, M., Soltys, S. G., Pollom, E. L., Chin, A., Vitzthum, L., Wakelee, H. A., Padda, S. K., Ramchandran, K., Loo, B. W., Neal, J. W., Nagpal, S. 2023; 13: 1139940

  Abstract

  The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC.Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment.We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%).At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.

  View details for DOI 10.3389/fonc.2023.1139940

  View details for PubMedID 37035171

  View details for PubMedCentralID PMC10080021

• ASO Visual Abstract: Impact of Delaying Surgery After Chemoradiation on Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Annals of surgical oncology Wong, L. Y., Liou, D. Z., Vitzthum, L. K., Backhus, L. M., Lui, N. S., Chang, D., Shrager, J. B., Berry, M. F. 2023

  View details for DOI 10.1245/s10434-023-13156-5

  View details for PubMedID 36759429

• Mitigation of IMRT/SBRT treatment planning errors on the RefleXion X1 system using FMEA within Six Sigma framework Advances in Radiation Oncology Simiele, E., Han, B., Skinner, L., Pham, D., Lewis, J., Gensheimer, M., Vitzthum, L., Chang, D., Surucu, M., Kovalchuk, N. 2023

  View details for DOI 10.1016/j.adro.2023.101186

• Impact of Delaying Surgery After Chemoradiation on Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Annals of surgical oncology Wong, L., Liou, D. Z., Vitzthum, L. K., Backhus, L. M., Lui, N. S., Chang, D., Shrager, J. B., Berry, M. F. 2022

  Abstract

  BACKGROUND: Performing selective esophagectomy for locally advanced squamous cell carcinoma may spare patients morbidity, but delayed surgery may infer higher risks. This study evaluated the impact of length of time between chemoradiation and esophagectomy on perioperative outcomes and long-term survival.METHODS: The impact of surgical timing, stratified by surgery performed < 180 and ≥ 180 days from starting radiation, on perioperative outcomes and survival in patients treated with chemoradiation and esophagectomy for cT1N + M0 and cT2-4, any N, M0 squamous cell carcinoma of the mid-distal esophagus in the National Cancer Database (2006-2016) was evaluated with logistic regression, Kaplan-Meier curves, Cox proportional-hazards methods, and propensity-matched analysis.RESULTS: Median time between starting radiation and esophagectomy in 1641 patients was 93 (IQR 81-114) days. Most patients (96.8%, n = 1589) had surgery within 180 days of starting radiation, while 52 patients (3.2%) had delayed surgery. Black race and clinical T stage were associated with delayed surgery. Rates of pathologic upstaging, downstaging, complete response, and positive margins were not significantly different between the groups. Patients with delayed surgery had increased major morbidity as measured by a composite of length of hospital stay, readmission, and 30-day mortality [42.3% (22/52) vs 22.3% (355/1589), p = 0.001]. However, delayed surgery was not associated with a significant difference in survival in both univariate [5-year survival 32.8% (95% CI 21.1-50.7) vs 47.3% (44.7-50.1), p = 0.19] and multivariable analysis [hazard ratio (HR) 1.23 (0.85-1.78), p = 0.26].CONCLUSIONS: Delaying surgery longer than 180 days after starting chemoradiation for esophageal squamous cell carcinoma is associated with worse perioperative outcomes but not long-term survival.

  View details for DOI 10.1245/s10434-022-12980-5

  View details for PubMedID 36572807

• Quantitative prediction of aspiration risk in head and neck cancer patients treated with radiation therapy. Oral oncology Liu, H. C., Williamson, C. W., Zou, J., Todd, J. R., Nelson, T. J., Hill, L. M., Linnemeyer, K. E., Henderson, G., Madgula, P., Faung, B., Sacco, A. G., Vitzthum, L. K., Weissbrod, P. A., Blumenfeld, L. S., Mell, L. K. 2022; 136: 106247

  Abstract

  To determine characteristics most strongly associated with risk for aspiration events among head and neck cancer (HNC) patients undergoing curative intent treatment.This was a retrospective, cross-sectional study of 106 patients with previously untreated HNC who received definitive or postoperative radiation therapy (RT) +/- systemic therapy with curative intent. Patients who received post-treatment videofluoroscopic swallow study (VFSS) between 2018-2021 were included. Using ordinal multivariable logistic regression, we modeled the effects of age (>60 years vs. ≤60 years), sex, body mass index (BMI) (>20 kg/m2 vs. ≤20 kg/m2), American Joint Committee on Cancer 8th edition stage (I-II vs. III-IVB), treatment with cisplatin (vs. other or no systemic therapy), post-operative status, primary site (oral cavity vs. P16+ oropharynx vs. P16- Mucosal Site vs. other), and quantitative VFSS measures on Penetration-Aspiration Scale (PAS) score.On ordinal multivariable logistic regression, age >60 years (odds ratio (OR): 3.91, 95% confidence interval (CI): 1.29, 11.9), advanced stage (stage III-IVB) (OR: 3.13, 95% CI: 1.23, 7.79), pharyngeal constriction ratio (PCR) >0.25 (OR: 3.65, 95% CI: 1.14, 11.7), and bolus clearance ratio (BCR) > 0.10 (OR: 3.42, 95% CI: 1.20, 9.75) were found to be significant risk factors for higher PAS scores. Patients with ≥ 2 pre-treatment risk factors had statistically significant increased risk for post-treatment aspiration (OR 2.52, 95% CI: 1.31, 4.86) on ordinal logistic regression. This model could be useful to direct high-risk patients toward interventions designed to reduce risk of aspiration events.

  View details for DOI 10.1016/j.oraloncology.2022.106247

  View details for PubMedID 36410204

• Image-mode performance characterization of a positron emission tomography subsystem designed for Biology-guided radiotherapy (BgRT). The British journal of radiology Hu, Z., Bieniosek, M., Ferri, V., Iagaru, A., Kovalchuk, N., Han, B., Xing, L., Vitzthum, L., Olcott, P., Narayanan, M., Laurence, T., Ren, Y., Oderinde, O. M., Shirvani, S. M., Chang, D., Surucu, M. 2022: 20220387

  Abstract

  OBJECTIVES: In this study, we characterize the imaging-mode performance of the positron emission tomography (PET) subsystem of the RefleXion X1 machine using the NEMA NU-2 2018 standard.METHODS: The X1 machine consists of two symmetrically opposing 900 arcs of PET detectors incorporated into the architecture of a ring-gantry linear accelerator rotating up to 60RPM. PET emissions from a tumor are detected by the PET detectors and used to guide the delivery of radiation beam. Imaging performance of the PET subsystem on X1 machine was evaluated based on1 sensitivity of the PET detectors,2 spatial resolution,3 count-loss performance,4 Image quality, and daily system performance check.RESULTS: PET subsystem sensitivity was measured as 0.183 and 0.161 cps/kBq at the center and off-center positions, respectively. Spatial resolution: average FWHM values of 4.3, 5.1, and 6.7mm for the point sources at 1, 10, and 20cm off center, respectively were recorded. For count loss, max NECR: 2.63 kcps, max true coincidence rate: 5.56 kcps, and scatter fraction: 39.8%. The 10mm sphere was not visible. Image-quality contrast values were: 29.6%, 64.9%, 66.5%, 81.8%, 81.2%, and background variability: 14.8%, 12.4%, 10.3%, 8.8%, 8.3%, for the 13, 17, 22, 28, 37mm sphere sizes, respectively.CONCLUSIONS: When operating in an imaging mode, the spatial resolution and image contrast of the X1 PET subsystem were comparable to those of typical diagnostic imaging systems for large spheres, while the sensitivity and count rate were lower due to the significantly smaller PET detector area in the X1 system. Clinical efficacy when used in BgRT remains to be validated.ADVANCES IN KNOWLEDGE: This is the first performance evaluation of the PET subsystem on the novel BgRT machine. The dual arcs rotating PET subsystem on RefleXion X1 machine performance is comparable to those of the typical diagnostic PET system based on the spatial resolution and image contrast for larger spheres.

  View details for DOI 10.1259/bjr.20220387

  View details for PubMedID 36317922

• Regression of Malignant Pleural Mesothelioma in Absence of Chemotherapy or Surgery: A Case Series. Clinical lung cancer Nief, C. A., No, H. J., Louie, C. Y., Vitzthum, L., Das, M. 2022

  View details for DOI 10.1016/j.cllc.2022.10.002

  View details for PubMedID 36323592

• Early Outcomes and Toxicity with Concurrent Chemotherapy and Hypofractionated Radiation Therapy in Patients with Non-Small Cell Lung Cancer Hui, C., Marquez, C., Lau, B., Von Eyben, R., Das, M., Myall, N., Roy, M., Chin, A., Diehn, M., Loo, B., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2022: S44

  View details for Web of Science ID 000847787800093

• Dosimetric Predictors of Local Control after Stereotactic Ablative Radiotherapy (SABR) for Lung Tumors: A Secondary Analysis of a Phase II Prospective Trial of Individualized SABR (iSABR) Wu, Y., Lau, B., Fu, J., Skinner, L., Gensheimer, M., Gee, H., Diehn, M., Loo, B., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2022: S16

  View details for Web of Science ID 000847787800034

• Rectosigmoid Cancer-Rectal Cancer or Sigmoid Cancer? American journal of clinical oncology Hui, C., Baclay, R., Liu, K., Sandhu, N., Loo, P., von Eyben, R., Chen, C., Sheth, V., Vitzthum, L., Chang, D., Pollom, E. 2022

  Abstract

  OBJECTIVES: We aimed to determine the optimal treatment for patients with locally advanced rectosigmoid cancers, and to determine whether this can be guided by distance from anal verge (AV) and/or anatomic landmarks such as the sacral promontory and peritoneal reflection (PR).MATERIALS AND METHODS: We retrospectively reviewed patients with T3-T4 and/or node-positive rectosigmoid cancers who underwent surgery from 2006 to 2018 with available pelvic imaging. We included tumors at 9 to 20cm from the AV on either staging imaging, or colonoscopy. Patients were stratified into those who received neoadjuvant therapy, and those who underwent upfront surgery. Comparisons of characteristics were performed using chi2 test and Fischer exact test. Locoregional failure (LRF) and overall survival were compared using Cox regressions and Kaplan-Meier analysis.RESULTS: One hundred sixty-one patients were included. Ninety-seven patients had neoadjuvant therapy, and 64 patients had upfront surgery. Median follow-up time was 45.1 months. Patients who had neoadjuvant therapy had tumors that were higher cT stage (P<0.01) with more positive/close circumferential resection margins seen on imaging by radiologists (28.9% vs. 1.6%, P=0.015). The 2-year rate of LRF, distant metastases, or overall survival was not significantly different between the 2 groups. None of 15 patients with tumors below the PR treated with neoadjuvant therapy had LRF, but 1 (25%) of 4 patients with tumors below the PR treated with adjuvant therapy experienced LRF (P=0.05).CONCLUSIONS: Patients with tumors below the PR may benefit more from neoadjuvant therapy. The PR on imaging may be a reliable landmark in addition to the distance from the AV to determine the most appropriate treatment option.

  View details for DOI 10.1097/COC.0000000000000931

  View details for PubMedID 35848736

• Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. Practical radiation oncology Devine, M., Merriott, D. J., No, H. J., Lau, B., Say, C., Yoo, C., Yi, E., Ko, R. B., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. K. 2022

  Abstract

  Stereotactic ablative radiotherapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrences (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with Stage T1-3N0M0 NSCLC treated with definitive SABR from 2003-2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (6.6% -13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4 - 63.3%) and 26.7% (14.1 - 50.3%), respectively. The 34 patients with INR were treated with RT alone (26.7 %), concurrent chemoradiotherapy (CRT) (43.3 %), chemotherapy alone (13.3%), or observation (16.7%). CRT had the best survival outcomes with a 3-year OS and PFS of 81.5% (61.1 - 100.0%) and 63.9% (40.7 - 100.0%), respectively. Of the patients treated with salvage RT or CRT, 14.3% experienced grade 3 toxicity with no patients having grade 4+ toxicity.INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS an PFS among patients with INR were observed in those treated with salvage chemoradiotherapy.

  View details for DOI 10.1016/j.prro.2022.06.013

  View details for PubMedID 35858658

• Neoadjuvant therapy in the post-German rectal trial era: making sense in the absence of consensus. Practical radiation oncology Hui, C., Vitzthum, L. K., Chang, D. T., Pollom, E. L. 2022

  Abstract

  Trimodality therapy per the German Rectal trial has led to excellent locoregional outcomes for locally advanced rectal cancer. Recent efforts have shifted towards improving distant control and health-related quality of life in this disease. To this end, total neoadjuvant therapy has become an increasingly used approach where most, if not all, chemotherapy is delivered prior to surgery to improve compliance and to address micrometastases early. To avoid surgical morbidity, a "watch-and-wait" approach, in which total mesorectal excision is deferred, has also been studied for patients who achieve a clinical complete response after chemoradiation. These two concurrent treatment trends have raised many points of uncertainty in what used to be a relatively straightforward neoadjuvant treatment paradigm. We discuss here our approach to neoadjuvant therapy for locally advanced rectal cancer, based on the data we currently have and through shared decision-making with patients to help them select the treatment that best aligns with their preferences and values.

  View details for DOI 10.1016/j.prro.2022.06.010

  View details for PubMedID 35803535

• Evaluating High-Dimensional Machine Learning Models to Predict Hospital Mortality Among Older Patients With Cancer. JCO clinical cancer informatics Qiao, E. M., Qian, A. S., Nalawade, V., Voora, R. S., Kotha, N. V., Vitzthum, L. K., Murphy, J. D. 2022; 6: e2100186

  Abstract

  Older hospitalized cancer patients face high risks of hospital mortality. Improved risk stratification could help identify high-risk patients who may benefit from future interventions, although we lack validated tools to predict in-hospital mortality for patients with cancer. We evaluated the ability of a high-dimensional machine learning prediction model to predict inpatient mortality and compared the performance of this model to existing prediction indices.We identified patients with cancer older than 75 years from the National Emergency Department Sample between 2016 and 2018. We constructed a high-dimensional predictive model called Cancer Frailty Assessment Tool (cFAST), which used an extreme gradient boosting algorithm to predict in-hospital mortality. cFAST model inputs included patient demographic, hospital variables, and diagnosis codes. Model performance was assessed with an area under the curve (AUC) from receiver operating characteristic curves, with an AUC of 1.0 indicating perfect prediction. We compared model performance to existing indices including the Modified 5-Item Frailty Index, Charlson comorbidity index, and Hospital Frailty Risk Score.We identified 2,723,330 weighted emergency department visits among older patients with cancer, of whom 144,653 (5.3%) died in the hospital. Our cFAST model included 240 features and demonstrated an AUC of 0.92. Comparator models including the Modified 5-Item Frailty Index, Charlson comorbidity index, and Hospital Frailty Risk Score achieved AUCs of 0.58, 0.62, and 0.71, respectively. Predictive features of the cFAST model included acute conditions (respiratory failure and shock), chronic conditions (lipidemia and hypertension), patient demographics (age and sex), and cancer and treatment characteristics (metastasis and palliative care).High-dimensional machine learning models enabled accurate prediction of in-hospital mortality among older patients with cancer, outperforming existing prediction indices. These models show promise in identifying patients at risk of severe adverse outcomes, although additional validation and research studying clinical implementation of these tools is needed.

  View details for DOI 10.1200/CCI.21.00186

  View details for PubMedID 35671416

• Characterization of Metastatic Non-Small Cell Lung Cancer and Oligometastatic Incidence in an Era of Changing Treatment Paradigms. International journal of radiation oncology, biology, physics No, H. J., Raja, N., Von Eyben, R., Das, M., Roy, M., Myall, N., Neal, J., Wakelee, H., Chin, A., Diehn, M., Loo, B. W., Chang, D. T., Pollom, E. L., Vitzthum, L. K. 2022

  Abstract

  Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.

  View details for DOI 10.1016/j.ijrobp.2022.04.050

  View details for PubMedID 35654305

• Validation of NRG Oncology's prognostic nomograms for oropharyngeal cancer in the Veterans Affairs database. Cancer Nelson, T. J., Thompson, C. A., Zou, J., Kumar, A., Sangchan, P., Williamson, C. W., Vitzthum, L. K., Sharabi, A. B., Murphy, J. D., Fakhry, C. A., Mell, L. K. 2022

  Abstract

  BACKGROUND: To test whether nomograms developed by NRG Oncology for oropharyngeal squamous cell carcinoma (OPSCC) patients could be validated in an independent population-based sample.METHODS: The authors tested nomograms for estimating progression-free survival (PFS) and overall survival (OS) in patients from the Veterans Health Administration with previously untreated locoregionally advanced OPSCC, diagnosed between 2008 and 2017, managed with definitive radiotherapy with or without adjuvant systemic therapy. Covariates were age, performance status, p16 status, T/N category, smoking history, education history, weight loss, marital status, and anemia. We used multiple imputation to handle missing data and performed sensitivity analyses on complete cases. Validation was assessed via Cox proportional hazards models, log-rank tests, and c-indexes.RESULTS: A total of 4007 patients met inclusion criteria (658 patients had complete data). Median follow-up time was 3.20 years, with 967 progression events and 471 noncancer deaths. Each risk score was associated with poorer outcomes per unit increase (PFS score, hazard ratio [HR], 1.42 [1.37-1.47]; OS score, HR, 1.40 [1.34-1.45]). By risk score quartile, 2-year PFS estimates were 89.2%, 78.5%, 65.8%, and 48.3%; OS estimates were 92.6%, 83.6%, 73.9%, and 51.3%, respectively (P < .01 for all comparisons). C-indices for models of PFS and OS were 0.65 and 0.67, for all patients, respectively (0.69 and 0.73 for complete cases). The nomograms slightly overestimated PFS and OS in the overall cohort but exhibited high agreement in complete cases.CONCLUSIONS: NRG nomograms were effective for predicting PFS and OS for patients with OPSCC, supporting their broader applicability in the OPSCC population undergoing definitive radiotherapy.

  View details for DOI 10.1002/cncr.34141

  View details for PubMedID 35194791

• Jumping to conclusions: Misdiagnosing radiation induced sarcoma as recurrent breast cancer. Clinical imaging Chughtai, K., Negrete, L., Vitzthum, L. K. 2022; 84: 110-112

  Abstract

  Radiation therapy (RT) induced chondrosarcoma is a rare but important potential complication seen in cancer patients treated with radiation. Although uncommon, these patients tend to have a poor prognosis, so early detection and complete resection are the crucial steps towards survival. We present the case of an 81-year-old breast cancer patient who was treated with RT to the left chest wall. Eight years later, she presented with a growing left chest wall mass, initially thought to represent local breast cancer recurrence. Imaging demonstrated a well-defined mass arising from the left pectoralis major muscle. The mass was excised, and pathology demonstrated chondrosarcoma. We discuss the clinical and radiologic aspects of RT-induced sarcomas with attention to the very rare chondrosarcoma. The aim of this report is to provide a succinct but relevant summary of the diagnostic considerations for RT-induced sarcoma supported by information about epidemiology, clinical diagnostic criteria, and radiation biology to expedite patient workup and ultimately improve patient outcomes.

  View details for DOI 10.1016/j.clinimag.2022.01.014

  View details for PubMedID 35176572

• Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data. Clinical cancer research : an official journal of the American Association for Cancer Research Williamson, C. W., Nelson, T., Thompson, C. A., Vitzthum, L. K., Zakeri, K., Riviere, P., Bryant, A. K., Sharabi, A. B., Zou, J., Mell, L. K. 2022

  Abstract

  BACKGROUND: Cancer treatments can paradoxically appear to reduce the risk of non-cancer mortality in observational studies, due to residual confounding. Here we introduce a method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding.METHODS: BRACE is a novel method for adjusting for bias from residual confounding in proportional hazards models. Using standard simulation methods, we compared BRACE vs. Cox proportional hazards regression in the presence of an unmeasured confounder. We examined estimator distributions, bias, mean squared error (MSE), and coverage probability. We then estimated treatment effects of high vs. low intensity treatments in 36,630 prostate cancer, 4,069 lung cancer, and 7,117 head/neck cancer patients, using the Veterans Affairs database. We analyzed treatment effects on cancer-specific mortality (CSM), non-cancer mortality (NCM), and overall survival (OS), using conventional multivariable Cox and propensity score (adjusted using inverse probability weighting) models, vs. BRACE-adjusted estimates.RESULTS: In simulations with residual confounding, BRACE uniformly reduced both bias and MSE. In the absence of bias, BRACE introduced bias toward the null, albeit with lower MSE. BRACE markedly improved coverage probability, but with a tendency toward overcorrection for effective but non-toxic treatments. For each clinical cohort, more intensive treatments were associated with significantly reduced hazards for CSM, NCM, and OS. BRACE attenuated OS estimates, yielding results more consistent with findings from randomized trials and meta-analyses.CONCLUSIONS: BRACE reduces bias and MSE when residual confounding is present and represents a novel approach to improve treatment effect estimation in non-randomized studies.

  View details for DOI 10.1158/1078-0432.CCR-21-2468

  View details for PubMedID 35140122

• Phase II trial of organ preservation program using short-course radiation and folfoxiri for rectal cancer (SHORT-FOX) Pollom, E. L., Shelton, A., Fisher, G. A., Bien, J., King, D., Johnson, T., Chen, C., Shaheen, S., Chong, C., Vitzthum, L., Kirilcuk, N., Morris, A. M., Kin, C., Dawes, A., Sheth, V., Sundaram, V., Brown, E., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1200/JCO.2022.40.4_suppl.TPS218

  View details for Web of Science ID 000770995900213

• Temporal Trends and Predictors of Opioid Use Among Older Patients With Cancer. American journal of clinical oncology Salans, M., Riviere, P., Vitzthum, L. K., Nalawade, V., Murphy, J. D. 1800

  Abstract

  OBJECTIVES: While opioids represent a cornerstone of cancer pain management, the timing and patterns of opioid use in the cancer population have not been well studied. This study sought to explore longitudinal trends in opioid use among Medicare beneficiaries with nonmetastatic cancer.MATERIALS AND METHODS: Within a cohort of 16,072 Medicare beneficiaries ≥66 years old diagnosed with nonmetastatic cancer between 2007 and 2013, we determined the likelihood of receiving a short-term (0 to 6mo postdiagnosis), intermediate-term (6 to 12mo postdiagnosis), long-term (1 to 2y postdiagnosis), and high-risk (morphine equivalent dose ≥90mg/day) opioid prescription after cancer diagnosis. Multivariable logistic regression models were used to identify patient and cancer risk factors associated with these opioid use endpoints.RESULTS: During the study period, 74.6% of patients received an opioid prescription, while only 2.66% of patients received a high-risk prescription. Factors associated with use varied somewhat between short-term, intermediate-term, and long-term use, though in general, patients at higher risk of receiving an opioid prescription after their cancer diagnosis were younger, had higher stage disease, lived in regions of higher poverty, and had a history of prior opioid use. Prescriptions for high-risk opioids were associated with individuals living in regions with lower poverty.CONCLUSIONS: Temporal trends in opioid use in cancer patients depend on patient, demographic, and tumor characteristics. Overall, understanding these correlations may help physicians better identify patient-specific risks of opioid use and could help better inform future evidence-based, cancer-specific opioid prescription guidelines.

  View details for DOI 10.1097/COC.0000000000000888

  View details for PubMedID 35019879

• Impacts of an Opioid Safety Initiative on United States Veterans Undergoing Cancer Treatment. Journal of the National Cancer Institute Vitzthum, L. K., Nalawade, V., Riviere, P., Marar, M., Furnish, T., Lin, L. A., Thompson, R., Murphy, J. D. 2022

  Abstract

  There is limited research on how the opioid epidemic and consequent risk reduction policies have impacted pain management among cancer patients. The purpose of this study is to analyze how an Opioid Safety Initiative (OSI) implemented at the Veteran's Health Administration (VHA) affected opioid prescribing patterns and opioid-related toxicity.We performed an interrupted time series analysis of 42,064 opioid-naïve patients treated at the VHA for prostate, lung, breast, and colorectal cancer from 2011-2016. Segmented regression was used to evaluate the impact of the OSI on the incidence of any new opioid prescriptions, high-risk prescriptions, persistent use, and pain-related ED visits. We compared the cumulative incidence of adverse opioid events including an opioid related admission or diagnosis of misuse before and after the OSI. All statistical tests were 2-sided.The incidence of new opioid prescriptions was 26.7% (95% CI = 25.0-28.4%) in 2011 and increased to 50.6% (95% CI = 48.3-53.0%) by 2013 prior to OSI implementation (monthly rate of change: +3.3%, 95% CI = 1.3-4.2%, p < .001). After the OSI, there was a decrease in the monthly rate of change for new prescriptions (-3.4%, 95% CI = -3.9 - -2.9%, p < .001). The implementation of the OSI was associated with a decrease in the monthly rate of change of concomitant benzodiazepines and opioid prescriptions (-2.5%, 95% CI = -3.2 - -1.8%, p < .001), no statistically significant change in high-dose opioids (-1.2%, 95% CI = -3.2-0.9%, p = .26), a decrease in persistent opioid use (-5.7%, 95% CI = -6.8 - -4.7%, p < .001), and an increase in pain-related ED visits (+3.0%, 95% CI = 1.0-5.0%, p = .003). The OSI was associated with a decreased incidence of opioid-related admissions (3-year cumulative incidence: 0.9% [95% CI = 0.7-1.0%] vs. 0.5% [95% CI = 0.4-0.6%], p < .001) and no statistically significant change in the incidence of opioid misuse (3-year cumulative incidence: 1.2% [95% CI = 1.0-1.3%] vs. 1.2% [1.1-1.4%], p = .77).The OSI was associated with a relative decline in the rate of new, persistent, and certain high-risk opioid prescribing as well as a slight increase in the rate of pain-related ED visits. Further research on patient-centered outcomes is required to optimize opioid prescribing policies for patients with cancer.

  View details for DOI 10.1093/jnci/djac017

  View details for PubMedID 35078240

• IMRT and SBRT Treatment Planning Study for the First Clinical Biology-Guided Radiotherapy System. Technology in cancer research & treatment Pham, D., Simiele, E., Breitkreutz, D., Capaldi, D., Han, B., Surucu, M., Oderinde, S., Vitzthum, L., Gensheimer, M., Bagshaw, H., Chin, A., Xing, L., Chang, D. T., Kovalchuk, N. 2022; 21: 15330338221100231

  Abstract

  Purpose: The first clinical biology-guided radiation therapy (BgRT) system-RefleXionTM X1-was installed and commissioned for clinical use at our institution. This study aimed at evaluating the treatment plan quality and delivery efficiency for IMRT/SBRT cases without PET guidance. Methods: A total of 42 patient plans across 6 cancer sites (conventionally fractionated lung, head, and neck, anus, prostate, brain, and lung SBRT) planned with the EclipseTM treatment planning system (TPS) and treated with either a TrueBeam or Trilogy were selected for this retrospective study. For each Eclipse VMAT plan, 2 corresponding plans were generated on the X1 TPS with 10mm jaws (X1-10mm) and 20mm jaws (X1-20mm) using our institutional planning constraints. All clinically relevant metrics in this study, including PTV D95%, PTV D2%, Conformity Index (CI), R50, organs-at-risk (OAR) constraints, and beam-on time were analyzed and compared between 126 VMAT and RefleXion plans using paired t-tests. Results: All but 3 planning metrics were either equivalent or superior for the X1-10mm plans as compared to the Eclipse VMAT plans across all planning sites investigated. The Eclipse VMAT and X1-10mm plans generally achieved superior plan quality and sharper dose fall-off superior/inferior to targets as compared to the X1-20mm plans, however, the X1-20mm plans were still considered acceptable for treatment. On average, the required beam-on time increased by a factor of 1.6 across all sites for X1-10mm compared to X1-20mm plans. Conclusions: Clinically acceptable IMRT/SBRT treatment plans were generated with the X1 TPS for both the 10mm and 20mm jaw settings.

  View details for DOI 10.1177/15330338221100231

  View details for PubMedID 35579876

• Progression Versus Radiation Treatment Changes After Stereotactic Ablative Radiation Therapy of a Liver Metastasis PRACTICAL RADIATION ONCOLOGY No, H. J., Negrete, L. M., Pollom, E. L., Wakelee, H. A., Chang, D. T., Vitzthum, L. K. 2022; 12 (1): 1-2

  View details for DOI 10.1016/j.prro.2021.06.013

  View details for Web of Science ID 000740674400002

• Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents Lau, B., No, H. J., Wu, Y. F., Ko, R. B., Devine, M., Das, M., Neal, J. W., Ramchandran, K. J., Wakelee, H. A., Shaheen, S., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E423

  View details for Web of Science ID 000715803800868

• IMRT Treatment Planning Study for the First Clinical Biology-guided Radiotherapy System Kovalchuk, N., Pham, D., Breitkreutz, D., Simiele, E., Capaldi, D., Vitzthum, L., Chang, D. LIPPINCOTT WILLIAMS & WILKINS. 2021: S137-S138

  View details for Web of Science ID 000701779700218

• Treatment Patterns for Isolated Nodal Recurrences in Non-Small Cell Lung Cancer After Definitive Stereotactic Ablative Radiotherapy No, H., Devine, M., Lau, B., Loo, B., Diehn, M., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S109

  View details for Web of Science ID 000701779700174

• Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents Lau, B., No, H., (Fred) Wu, Y., Devine, M., Ko, R., Loo, B., Diehn, M., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S105

  View details for Web of Science ID 000701779700169

• Evaluating the clinical trends and benefits of low-dose computed tomography in lung cancer patients. Cancer medicine Qiao, E. M., Voora, R. S., Nalawade, V., Kotha, N. V., Qian, A. S., Nelson, T. J., Durkin, M., Vitzthum, L. K., Murphy, J. D., Stewart, T. F., Rose, B. S. 2021

  Abstract

  BACKGROUND: Despite guideline recommendations, utilization of low-dose computed tomography (LDCT) for lung cancer screening remains low. The driving factors behind these low rates and the real-world effect of LDCT utilization on lung cancer outcomes remain limited.METHODS: We identified patients diagnosed with non-small cell lung cancer (NSCLC) from 2015 to 2017 within the Veterans Health Administration. Multivariable logistic regression assessed the influence of LDCT screening on stage at diagnosis. Lead time correction using published LDCT lead times was performed. Cancer-specific mortality (CSM) was evaluated using Fine-Gray regression with non-cancer death as a competing risk. A lasso machine learning model identified important predictors for receiving LDCT screening.RESULTS: Among 4664 patients, mean age was 67.8 with 58-month median follow-up, 95% CI=[7-71], and 118 patients received ≥1 screening LDCT before NSCLC diagnosis. From 2015 to 2017, LDCT screening increased (0.1%-6.6%, mean=1.3%). Compared with no screening, patients with ≥1 LDCT were more than twice as likely to present with stage I disease at diagnosis (odds ratio [OR] 2.16 [95% CI 1.46-3.20]) and less than half as likely to present with stage IV (OR 0.38 [CI 0.21-0.70]). Screened patients had lower risk of CSM even after adjusting for LDCT lead time (subdistribution hazard ratio 0.60 [CI 0.42-0.85]). The machine learning model achieved an area under curve of 0.87 and identified diagnosis year and region as the most important predictors for receiving LDCT. White, non-Hispanic patients were more likely to receive LDCT screening, whereas minority, older, female, and unemployed patients were less likely.CONCLUSIONS: Utilization of LDCT screening is increasing, although remains low. Consistent with randomized data, LDCT-screened patients were diagnosed at earlier stages and had lower CSM. LDCT availability appeared to be the main predictor of utilization. Providing access to more patients, including those in diverse racial and socioeconomic groups, should be a priority.

  View details for DOI 10.1002/cam4.4229

  View details for PubMedID 34528761

• Trimodality Versus Bimodality Therapy in Patients With Locally Advanced Esophageal Carcinoma: Commentary on the American Society of Clinical Oncology Practice Guidelines. Practical radiation oncology Vitzthum, L. K., Hui, C., Pollom, E. L., Chang, D. T. 2021

  Abstract

  In the recent guideline statement from the American Society of Clinical Oncology, experts reviewed relevant literature and provided treatment recommendations for multimodality treatment approaches. The guidelines recommend either preoperative concurrent neoadjuvant chemoradiotherapy (CRT) or perioperative chemotherapy for locally advanced adenocarcinoma and either preoperative CRT followed by esophagectomy or definitive CRT for squamous cell carcinoma. Whether radiation can be omitted in patients with adenocarcinoma or whether surgery can be omitted in patients with squamous cell carcinoma is a subject of ongoing debate and clinical trials.

  View details for DOI 10.1016/j.prro.2021.05.004

  View details for PubMedID 34353757

• Pancreatic Stereotactic Body Radiation Therapy with or without Hypofractionated Elective Nodal Irradiation. International journal of radiation oncology, biology, physics Miller, J. A., Toesca, D. A., Baclay, J. R., Vitzthum, L. K., Dubrowski, P., Pollom, E. L., Chang, D. T. 2021

  Abstract

  PURPOSE/OBJECTIVES: Pancreatic stereotactic body radiation therapy (SBRT) is limited to gross tumor without elective coverage for subclinical disease. Given a better understanding of recurrence patterns, we hypothesized that the addition of elective nodal irradiation (ENI) to pancreatic SBRT would be tolerable and would decrease locoregional progression.MATERIALS/METHODS: We conducted a retrospective 1:2 propensity-matched cohort study to compare toxicity and locoregional progression among patients treated with pancreatic SBRT with or without ENI. In the SBRT+ENI cohort, an elective target volume was delineated per RTOG guidelines and treated to 25 Gy in 5 fractions alongside 40 Gy in 5 fractions to gross disease. The primary outcome was the cumulative incidence of locoregional progression, with death as a competing risk.RESULTS: Among 135 candidate controls treated with SBRT alone, 100 were propensity-matched to 50 patients treated with SBRT+ENI. All patients completed SBRT. Median potential radiographic follow-up was 28 months. The incidence of late and serious acute toxicity were similar between matched cohorts. However, SBRT+ENI was associated with a statistically significant increase in acute grade 1-2 nausea (60% vs. 20%, p<0.001). The 24-month cumulative incidences of locoregional progression with and without ENI were 22.6% (95% confidence interval [CI]: 10.0-35.1%) vs. 44.6% (95% CI: 34.8-54.4%, multivariable-adjusted hazard ratio 0.39, 95% CI 0.18-0.87, p=0.021). This was stable in sensitivity analyses of uniform prescription dose, multiagent chemotherapy, and resectability. There were fewer peripancreatic (0% vs. 7%), porta hepatis (2% vs. 7%), and peri-aortic/aortocaval (5% vs. 12%) recurrences after SBRT+ENI, but no difference in survival.CONCLUSIONS: Pancreatic SBRT+ENI was tolerable and did not increase late or serious acute toxicity relative to a matched cohort undergoing SBRT alone, but did increase acute grade 1-2 nausea. The addition of ENI to SBRT was associated with decreased locoregional progression but not improved survival. Further studies are warranted to determine if ENI offers meaningful benefit.

  View details for DOI 10.1016/j.ijrobp.2021.07.1698

  View details for PubMedID 34348171

• Impact of the VA opioid safety initiative on pain management for cancer patients. Marar, M., Nalawade, V., Panjwani, N., Riviere, P., Furnish, T., Lin, L. A., Thompson, R. F., Murphy, J., Vitzthum, L. K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.102

  View details for Web of Science ID 000708120600004

• Microstructural injury to corpus callosum and intra-hemispheric white matter tracts correlate with attention and processing speed decline after brain radiation. International journal of radiation oncology, biology, physics Huynh-Le, M. P., Tibbs, M. D., Karunamuni, R. n., Tringale, K. R., Salans, M. n., Yip, A. n., Connor, M. n., Simon, A. B., Vitzthum, L. K., Reyes, A. n., Macari, A. C., Moiseenko, V. n., McDonald, C. R., Hattangadi-Gluth, J. A. 2021

  Abstract

  The corpus callosum (CC) and intra-hemispheric white matter tracts (IHWM) subserve critical aspects of attention and processing speed. We analyzed imaging biomarkers of microstructural injury within these regions and association with attention/processing speed decline post-radiotherapy in primary brain tumor patients.On a prospective clinical trial, 44 primary brain tumor patients underwent cognitive testing and MRI/diffusion-weighted imaging pre-radiotherapy, and 3-, 6-, and 12-months post-radiotherapy. CC (subregions; total) and IHWM tracts (left/right without CC; total) were autosegmented; tumor/tumor bed/edema were censored. Biomarkers included: volume changes (cc); mean diffusivity (MD, higher values indicate WM injury); fractional anisotropy (FA, lower values indicate WM injury). Reliable-change indices measured changes in attention (WAIS-IV digits-forward; D-KEFS-Trail-Making visual-scanning) and processing speed (WAIS-IV coding; D-KEFS-Trail-Making number-sequencing, letter-sequencing), accounting for practice effects. Linear mixed-effects models evaluated associations between 1) mean radiation dose and biomarkers (volume, MD, FA); 2) imaging biomarkers and neurocognitive performance. Statistics were corrected for multiple comparisons.Processing speed declined at 6 months (number-sequencing, letter-sequencing; p<0.04). Seizures and anti-epileptic drug therapy were associated with lower visual-scanning attention reliable-change indices at 6 months (p=0.039). Higher radiation dose correlated with smaller mid-anterior CC volume (p=0.023), lower FA in posterior CC, anterior CC, and total CC (all p<0.03), and higher MD in anterior CC (p=0.012). Smaller mid-anterior CC and left IHWM volume correlated with worse processing speed (coding, letter-sequencing, number-sequencing, all p<0.03). Higher FA in right, left, and total IHWM correlated with better coding scores (all p<0.01). Lower FA in total IHWM (p=0.009) was associated with worse visual-scanning attention scores. Higher FA in mid-posterior CC (p=0.029) correlated with better digits-forward attention scores.The CC demonstrated radiation dose-dependent atrophy and WM injury. Microstructural injury within the CC and IHWM was associated with attention/processing speed decline after radiotherapy. These areas represent possible avoidance regions for preservation of attention/processing speed.

  View details for DOI 10.1016/j.ijrobp.2020.12.046

  View details for PubMedID 33412257

• End of treatment cone-beam computed tomography (CBCT) is predictive of radiation response and overall survival in oropharyngeal squamous cell carcinoma. Radiation oncology (London, England) Sumner, W., Kim, S. S., Vitzthum, L., Moore, K., Atwood, T., Murphy, J., Miyauchi, S., Califano, J. A., Mell, L. K., Mundt, A. J., Sharabi, A. B. 2021; 16 (1): 147

  Abstract

  Image guidance in radiation oncology has resulted in significant improvements in the accuracy and precision of radiation therapy (RT). Recently, the resolution and quality of cone beam computed tomography (CBCT) for image guidance has increased so that tumor masses and lymph nodes are readily detectable and measurable. During treatment of head and neck squamous cell carcinoma (HNSCC), on-board CBCT setup imaging is routinely obtained; however, this CBCT imaging data is not utilized to predict patient outcomes. Here, we analyzed whether changes in CBCT measurements obtained during a course of radiation therapy correlate with responses on routine 3-month follow-up diagnostic imaging and overall survival (OS).Patients with oropharyngeal primary tumors who received radiation therapy between 2015 and 2018 were included. Anatomical measurements were collected of largest nodal conglomerate (LNC) at CT simulation, end of radiation treatment (EOT CBCT), and routine 3-month post-RT imaging. At each timepoint anteroposterior (AP), mediolateral (ML) and craniocaudal (CC) measurements were obtained and used to create a 2-dimensional (2D) maximum.CBCT data from 64 node positive patients were analyzed. The largest nodal 2D maximum and CC measurements on EOT CBCT showed a statistically significant correlation with complete response on 3-month post-RT imaging (r = 0.313, p = 0.02 and r = 0.318, p = 0.02, respectively). Furthermore, patients who experienced a 30% or greater reduction in the CC dimension had improved OS (Binary Chi-Square HR 4.85, p = 0.028).Decreased size of pathologic lymph nodes measured using CBCT setup imaging during a radiation course correlates with long term therapeutic response and overall survival of HNSCC patients. These results indicate that CBCT setup imaging may have utility as an early predictor of treatment response in oropharyngeal HNSCC.

  View details for DOI 10.1186/s13014-021-01871-w

  View details for PubMedID 34372887

• Racial, Ethnic, and Socioeconomic Discrepancies in Opioid Prescriptions Among Older Patients With Cancer. JCO oncology practice Vitzthum, L. K., Nalawade, V. n., Riviere, P. n., Sumner, W. n., Nelson, T. n., Mell, L. K., Furnish, T. n., Rose, B. n., Martínez, M. E., Murphy, J. D. 2021: OP2000773

  Abstract

  Minority race and lower socioeconomic status are associated with lower rates of opioid prescription and undertreatment of pain in multiple noncancer healthcare settings. It is not known whether these differences in opioid prescribing exist among patients undergoing cancer treatment.This observational cohort study involved 33,872 opioid-naive patients of age > 65 years undergoing definitive cancer treatment. We compared rates of new opioid prescriptions by race or ethnicity and socioeconomic status controlling for differences in baseline patient, cancer, and treatment factors. To evaluate downstream impacts of opioid prescribing and pain management, we also compared rates of persistent opioid use and pain-related emergency department (ED) visits.Compared with non-Hispanic White patients, the covariate-adjusted odds of receiving an opioid prescription were 24.9% (95% CI, 16.0 to 33.9, P < .001) lower for non-Hispanic Blacks, 115.0% (84.7 to 150.3, P < .001) higher for Asian-Pacific Islanders, and not statistically different for Hispanics (-1.0 to 14.0, P = .06). There was no significant association between race or ethnicity and persistent opioid use or pain-related ED visits. Patients living in a high-poverty area had higher odds (53.9% [25.4 to 88.8, P < .001]) of developing persistent use and having a pain-related ED visit (39.4% [16.4 to 66.9, P < .001]).For older patients with cancer, rates of opioid prescriptions and pain-related outcomes significantly differed by race and area-level poverty. Non-Hispanic Black patients were associated with a significantly decreased likelihood of receiving an opioid prescription. Patients from high-poverty areas were more likely to develop persistent opioid use and have a pain-related ED visit.

  View details for DOI 10.1200/OP.20.00773

  View details for PubMedID 33534647

• Validation of an oncology-specific opioid risk calculator in cancer survivors. Cancer Riviere, P., Vitzthum, L. K., Nalawade, V., Deka, R., Furnish, T., Mell, L. K., Rose, B. S., Wallace, M., Murphy, J. D. 2020

  Abstract

  BACKGROUND: Clinical guidelines recommend that providers risk-stratify patients with cancer before prescribing opioids. Prior research has demonstrated that a simple cancer opioid risk score might help identify to patients with cancer at the time of diagnosis with a high likelihood of long-term posttreatment opioid use. This current project validates this cancer opioid risk score in a generalizable, population-based cohort of elderly cancer survivors.METHODS: This study identified 44,932 Medicare beneficiaries with cancer who had received local therapy. Longitudinal opioid use was ascertained from Medicare Part D data. A risk score was calculated for each patient, and patients were categorized into low-, moderate-, and high-risk groups on the basis of the predicted probability of persistent opioid use. Model discrimination was assessed with receiver operating characteristic curves.RESULTS: In the study cohort, 5.2% of the patients were chronic opioid users 1 to 2years after the initiation of cancer treatment. The majority of the patients (64%) were at low risk and had a 1.2% probability of long-term opioid use. Moderate-risk patients (33% of the cohort) had a 5.6% probability of long-term opioid use. High-risk patients (3.5% of the cohort) had a 75% probability of long-term opioid use. The opioid risk score had an area under the receiver operating characteristic curve of 0.869.CONCLUSIONS: This study found that a cancer opioid risk score could accurately identify individuals with a high likelihood of long-term opioid use in a large, generalizable cohort of cancer survivors. Future research should focus on the implementation of these scores into clinical practice and how this could affect prescriber behavior and patient outcomes.LAY SUMMARY: A novel 5-question clinical decision tool allows physicians treating patients with cancer to accurately predict which patients will persistently be using opioid medications after completing therapy.

  View details for DOI 10.1002/cncr.33410

  View details for PubMedID 33378556

• Comparison of Hematologic Toxicity and Bone Marrow Compensatory Response in Head and Neck vs. Cervical Cancer Patients Undergoing Chemoradiotherapy FRONTIERS IN ONCOLOGY Vitzthum, L. K., Heide, E. S., Park, H., Williamson, C. W., Sheridan, P., Huynh-Le, M., Sirak, I., Wei, L., Tarnawski, R., Mahantshetty, U., Nguyen, C., Mayadev, J., Yashar, C. M., Sacco, A. G., Mell, L. K. 2020; 10: 1179

  Abstract

  Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m2. We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 103 per μL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity.

  View details for DOI 10.3389/fonc.2020.01179

  View details for Web of Science ID 000558484800001

  View details for PubMedID 32793487

  View details for PubMedCentralID PMC7385402

• Managing Cancer Pain During the Opioid Epidemic-Balancing Caution and Compassion JAMA ONCOLOGY Vitzthum, L. K., Riviere, P., Murphy, J. D. 2020; 6 (7): 1103–4

  View details for DOI 10.1001/jamaoncol.2020.0779

  View details for Web of Science ID 000552068600025

  View details for PubMedID 32379274

• Predicting Persistent Opioid Use, Abuse, and Toxicity Among Cancer Survivors. Journal of the National Cancer Institute Vitzthum, L. K., Riviere, P., Sheridan, P., Nalawade, V., Deka, R., Furnish, T., Mell, L. K., Rose, B., Wallace, M., Murphy, J. D. 2020; 112 (7): 720–27

  Abstract

  BACKGROUND: Although opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse.METHODS: Within a cohort of 106732 military veteran cancer survivors diagnosed between 2000 and 2015, we determined rates of persistent posttreatment opioid use, diagnoses of opioid abuse or dependence, and admissions for opioid toxicity. A multivariable logistic regression model was used to identify patient, cancer, and treatment risk factors associated with adverse opioid-related outcomes. Predictive risk models were developed and validated using a least absolute shrinkage and selection operator regression technique.RESULTS: The rate of persistent opioid use in cancer survivors was 8.3% (95% CI=8.1% to 8.4%); the rate of opioid abuse or dependence was 2.9% (95% CI=2.8% to 3.0%); and the rate of opioid-related admissions was 2.1% (95% CI=2.0% to 2.2%). On multivariable analysis, several patient, demographic, and cancer and treatment factors were associated with risk of persistent opioid use. Predictive models showed a high level of discrimination when identifying individuals at risk of adverse opioid-related outcomes including persistent opioid use (area under the curve [AUC] = 0.85), future diagnoses of opioid abuse or dependence (AUC=0.87), and admission for opioid abuse or toxicity (AUC=0.78).CONCLUSION: This study demonstrates the potential to predict adverse opioid-related outcomes among cancer survivors. With further validation, personalized risk-stratification approaches could guide management when prescribing opioids in cancer patients.

  View details for DOI 10.1093/jnci/djz200

  View details for PubMedID 31754696

• Challenge of Directly Comparing Imaging-Based Diagnoses Made by Machine Learning Algorithms With Those Made by Human Clinicians JOURNAL OF CLINICAL ONCOLOGY Simon, A. B., Vitzthum, L. K., Mell, L. K. 2020; 38 (16): 1868-+

  View details for DOI 10.1200/JCO.19.03350

  View details for Web of Science ID 000537770500014

  View details for PubMedID 32271670

  View details for PubMedCentralID PMC7255980

• Tobacco smoking and death from prostate cancer in US veterans PROSTATE CANCER AND PROSTATIC DISEASES Riviere, P., Kumar, A., Luterstein, E., Vitzthum, L. K., Nalawade, V., Sarkar, R. R., Bryant, A. K., Einck, J. P., Mundt, A. J., Murphy, J. D., Rose, B. S. 2020; 23 (2): 252–59

  Abstract

  Cigarette smoking is a risk factor for mortality in several genitourinary cancers, likely due to accumulation of carcinogens in urine. However, in prostate cancer (PC) the link has been less studied. We evaluated differences in prostate cancer-specific mortality (PCSM) between current smokers, past smokers, and never smokers diagnosed with PC.This was a retrospective cohort study of PCSM in men diagnosed with PC between 2000 and 2015 treated in the US Veterans Affairs health care system, using competing risk regression analyses.The cohort included 73,668 men (current smokers: 22,608 (30.7%), past smokers: 23,695 (32.1%), and never smokers: 27,365 (37.1%)). Median follow-up was 5.9 years. Current smoker patients were younger at presentation (median age current: 63, never: 66; p < 0.001), and had more advanced disease stage (stage IV disease current: 5.3%, never: 4.3%; p < 0.04). The 10-year incidence of PCSM was 5.2%, 4.8%, and 4.5% for current, past, and never smokers, respectively. On competing risk regression, current smoking was associated with increased PCSM (subdistribution hazard ratio: 1.14, 95% confidence interval: (1.05-1.24), p = 0.002), whereas past smoking was not. Hierarchical regression suggests that this increased risk was partially attributable to tumor characteristics.Smoking at the time of diagnosis is associated with a higher risk of dying from PC as well as other causes of death. In contrast, past smoking was not associated with PCSM suggesting that smoking may be a modifiable risk factor. PC diagnosis may be an important opportunity to discuss smoking cessation.

  View details for DOI 10.1038/s41391-019-0178-6

  View details for Web of Science ID 000534552900005

  View details for PubMedID 31624316

• African-American men with low-risk prostate cancer treated with radical prostatectomy in an equal-access health care system: implications for active surveillance PROSTATE CANCER AND PROSTATIC DISEASES Deka, R., Parsons, J., Simpson, D. R., Riviere, P., Nalawade, V., Vitzthum, L. K., Kader, A., Kane, C. J., Rock, C. S., Murphy, J. D., Rose, B. S. 2020

  Abstract

  There is concern that African-American men (AA) with low-risk prostate cancer may present with more aggressive disease and thus may not be candidates for active surveillance (AS). However, it is uncertain if poorer outcomes are due to disparities in access to medical care rather than true biological differences.Observational cohort study of patients diagnosed with low-risk PC-Gleason score ≤6, clinical tumor stage ≤2A, and prostate specific antigen (PSA) level ≤10-at US Department of Veterans Affairs between January 1, 2001 and October 31, 2015 and treated with radical prostatectomy. Outcomes included upgrading to Gleason Grade Group 2 (GG2), GG ≥ 3, PSA recurrence, pathologic tumor stage ≥3, positive surgical margins, and all-cause mortality.A total of 2857 men (AA: 835 White: 2022) with a median follow-up of 7.1 years. Overall, there was no significant difference between AA and White men in upgrading to GG ≥ 3 (RR = 1.18, p = 0.43), tumor stage ≥3 (RR = 0.95, p = 0.74), positive surgical margins (RR = 1.14, p = 0.20), PSA recurrence (SHR = 1.26, p = 0.06), and all-cause mortality (SHR = 1.26, p = 0.16). However, there was a significant increase in upgrading for AA to GG2 (RR = 1.49, p < 0.01).There was no significant difference in most adverse pathologic outcomes between AA and White patients. However, GG2 upgrading was more common in AA men. The implication is that AA may need to undergo additional evaluation, such as a biopsy MRI, before initiating AS. Whether the increase in GG2 upgrading will lead to poorer long-term clinical outcomes such as metastasis and PCSM also requires further investigation.

  View details for DOI 10.1038/s41391-020-0230-6

  View details for Web of Science ID 000528293600001

  View details for PubMedID 32327702

• Survival of African American and non-Hispanic white men with prostate cancer in an equal-access health care system. Cancer Riviere, P., Luterstein, E., Kumar, A., Vitzthum, L. K., Deka, R., Sarkar, R. R., Bryant, A. K., Bruggeman, A., Einck, J. P., Murphy, J. D., Martínez, M. E., Rose, B. S. 2020; 126 (8): 1683-1690

  Abstract

  African American (AA) men in the general US population are more than twice as likely to die of prostate cancer (PC) compared with non-Hispanic white (NHW) men. The authors hypothesized that receiving care through the Veterans Affairs (VA) health system, an equal-access medical system, would attenuate this disparity.A longitudinal, centralized database of >20 million veterans was used to assemble a cohort of 60,035 men (18,201 AA men [30.3%] and 41,834 NHW men [69.7%]) who were diagnosed with PC between 2000 and 2015.AA men were more likely to live in regions with a lower median income ($40,871 for AA men vs $48,125 for NHW men; P < .001) and lower high school graduation rates (83% for AA men vs 88% for NHW men; P < .001). At the time of diagnosis, AA men were younger (median age, 63.0 years vs 66.0 years; P < .001) and had a higher prostate-specific antigen level (median, 6.7 ng/mL vs 6.2 ng/mL; P < .001), but were less likely to have Gleason score 8 to 10 disease (18.8% among AA men vs 19.7% among NHW men; P < .001), a clinical T classification ≥3 (2.2% vs 2.9%; P < .001), or distant metastatic disease (2.7% vs 3.1%; P = 0.01). The 10-year PC-specific mortality rate was slightly lower for AA men (4.4% vs 5.1%; P = .005), which was confirmed in multivariable competing-risk analysis (subdistribution hazard ratio, 0.85; 95% CI, 0.78-0.93; P < .001).AA men diagnosed with PC in the VA health system do not appear to present with more advanced disease or experience worse outcomes compared with NHW men, in contrast to national trends, suggesting that access to care is an important determinant of racial equity.

  View details for DOI 10.1002/cncr.32666

  View details for PubMedID 31984482

• Risk of Pelvic Fracture With Radiation Therapy in Older Patients INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Vitzthum, L. K., Park, H., Zakeri, K., Heide, E. S., Nalawade, V., Mundt, A. J., Vaida, F., Murphy, J. D., Mell, L. K. 2020; 106 (3): 485–92

  Abstract

  Older patients undergoing radiation therapy (RT) for pelvic malignancies are at increased risk for pelvic fracture, which is associated with significant morbidity and mortality. RT techniques such as brachytherapy or intensity modulated RT (IMRT) allow for more conformal dose distributions, but it is not known whether the risk for pelvic fracture varies by RT modality.This observational cohort study involved 28,354 patients ≥65 years old, treated with RT for pelvic malignancies. We evaluated the relative risk of pelvic fracture by type of RT when accounting for baseline factors. To test for nonspecific effects, we also evaluated risk of nonpelvic fractures in the same population.The 5-year incidence of pelvic fractures was 12.7% (95% confidence interval [CI], 11.6%-13.8%), 11.8% (10.8%-12.8%), and 3.7% (3.4%-4.0%) for patients with gastrointestinal, gynecologic, and prostate cancer, respectively. On multivariable analysis, being treated with IMRT (hazard ratio, 0.85; 95% CI, 0.73-0.99) or brachytherapy therapy alone (hazard ratio, 0.43; 95% CI, 0.34-0.54) was associated with a reduced hazard for pelvic fractures compared with 3D conformal radiation therapy in female patients. In contrast, there was no association with RT modality and the hazard for nonpelvic fractures among females. There was no significant association between pelvic fractures and IMRT or brachytherapy for male patients. White race, advanced age, and higher comorbidity were associated with an increased hazard for pelvic fracture.IMRT and brachytherapy were associated with a reduced risk of pelvic fractures in older women undergoing RT for pelvic malignancies. Pelvic insufficiency fracture risk should be considered when treating with pelvic RT.

  View details for DOI 10.1016/j.ijrobp.2019.10.006

  View details for Web of Science ID 000510861900009

  View details for PubMedID 31610251

• Associations among statins, preventive care, and prostate cancer mortality PROSTATE CANCER AND PROSTATIC DISEASES Kumar, A., Riviere, P., Luterstein, E., Nalawade, V., Vitzthum, L., Sarkar, R. R., Bryant, A. K., Einck, J. P., Mundt, A. J., Murphy, J. D., Rose, B. S. 2020; 23 (3): 475–85

  Abstract

  Increasing evidence indicates an association between statins and reduced prostate cancer-specific mortality (PCSM). However, significant bias may exist in these studies. One particularly challenging bias to assess is the healthy user effect, which may be quantified by screening patterns. We aimed to evaluate the association between statin use, screening, and PCSM in a dataset with detailed longitudinal information.We used the Veterans Affairs Informatics and Computing Infrastructure to assemble a cohort of patients diagnosed with prostate cancer (PC) between 2000 and 2015. We collected patient-level demographic, comorbidity, and tumor data. We also assessed markers of preventive care utilization including cholesterol and prostate specific antigen (PSA) screening rates. Patients were considered prediagnosis statin users if they had at least one prescription one or more years prior to PC diagnosis. We evaluated PCSM using hierarchical Fine-Gray regression models and all-cause mortality (ACM) using a cox regression model.The final cohort contained 68,432 men including 40,772 (59.6%) prediagnosis statin users and 27,660 (40.4%) nonusers. Prediagnosis statin users had higher screening rates than nonusers for cholesterol (90 vs. 69%, p < 0.001) and PSA (76 vs. 67%, p < 0.001). In the model which excluded screening, prediagnosis statin users had improved PCSM (SHR 0.90, 95% CI 0.84-0.97; p = 0.004) and ACM (HR 0.96, 95% CI 0.93-0.99; p = 0.02). However, after including cholesterol and PSA screening rates, prediagnosis statin users and nonusers showed no differences in PCSM (SHR 0.98, 95% CI 0.91-1.06; p = 0.59) or ACM (HR 1.02, 95% CI 0.98-1.05; p = 0.25).We found that statin users tend to have more screening than nonusers. When we considered screening utilization, we observed no relationship between statin use before a prostate cancer diagnosis and prostate cancer mortality.

  View details for DOI 10.1038/s41391-020-0207-5

  View details for Web of Science ID 000511538100001

  View details for PubMedID 32029930

• 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

• Selection of Head and Neck Cancer Patients for Intensive Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Vitzthum, L. K., Park, H., Zakeri, K., Bryant, A. K., Feng, C., Shen, H., Cohen, E. W., Murphy, J. D., Mell, L. K. 2020; 106 (1): 157–66

  Abstract

  Previous studies have found that patients with head and neck cancer (HNC) with a higher relative hazard for recurrence versus competing mortality (ω+ ratio) are more likely to benefit from intensive therapy. Nomograms to predict this ratio (ω scores) can be useful to guide clinical management; however, comorbidity and other risk factors are frequently lacking from trial samples.In this study of 7117 US veterans, we evaluated the ability of a ω score nomogram developed from clinical trial data to stratify patients with HNC treated with radiation therapy by their relative risk of cancer progression versus competing mortality. We then fit generalized competing event models to determine the effect of comorbidity and other covariates on the ω+ ratio.The ω score was effective in stratifying patients with HNC according to their risk for cancer recurrence relative to competing mortality, especially among patients aged >70 years. Patients with ω score ≥0.80 were more likely to receive intensive therapy compared with patients with a ω score <0.80 (66 vs. 54%; P < .001). On multivariable generalized competing event regression, T2-4 category (relative hazard ratio [RHR], 1.08; 95% confidence interval [CI], 1.01-1.16), N2-3 category (RHR, 1.07; 95% CI, 1.01-1.15), and being employed (RHR, 1.11; 95% CI, 1.03-1.20) were associated with increased ω+ ratio, and increasing age (RHR, 0.83; 95% CI, 0.78-0.89), Charlson comorbidity index ≥2 (RHR, 0.85; 95% CI, 0.79-0.91), being a current smoker (RHR, 0.90; 95% CI, 0.84-0.96), and lower body mass index (RHR, 0.89; 95% CI, 0.84-0.95) were associated with a decreased ω+ ratio.The ω scores are effective in stratifying patients with HNC and are correlated with the intensity of treatment given. The ω scores incorporating comorbidity and other risk factors could help identify patients with HNC most likely to benefit from intensive therapy.

  View details for DOI 10.1016/j.ijrobp.2019.09.011

  View details for Web of Science ID 000502338300030

  View details for PubMedID 31580929

• Cost-effectiveness Analysis of Stereotactic Ablative Radiotherapy in Patients with Oligometastatic Cancer. International journal of radiation oncology, biology, physics Kumar, A. n., Straka, C. n., Courtney, P. T., Vitzthum, L. n., Riviere, P. n., Murphy, J. D. 2020

  Abstract

  The SABR-COMET phase 2 randomized clinical trial found that stereotactic ablative radiotherapy (SABR) improved outcomes among cancer patients with oligometastatic disease. Yet, the cost of SABR along with the large number of patients with oligometastatic disease raises the important question of value. This study sought to evaluate the cost-effectiveness of the addition of SABR compared to standard therapy alone among cancer patients with oligometastatic disease.We constructed a Markov model to simulate treatment with stereotactic ablative radiotherapy or standard therapy among patients with oligometastatic cancers. The model derived transition probabilities from SABR-COMET clinical trial data to estimate risks of toxicity, disease progression and survival. Healthcare costs and health utilities were estimated from the literature. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. Cost-effectiveness was estimated from both the health care sector and societal perspectives with an incremental cost-effectiveness ratio (ICER) defined as dollars per quality-adjusted life year (QALY). An ICER less than $100,000/QALY was considered cost-effective. One-way and probabilistic sensitivity analyses were used to examine model uncertainty.The addition of SABR increased total costs by $54,260 (health care sector perspective) or $72,799 (societal perspective) and improved effectiveness by 1.88 QALYs compared with standard therapy, leading to an ICER of $28,906/QALY (health care sector perspective) or $38,783/QALY (societal perspective). The model was modestly sensitive to assumptions about tumor progression, though the model was not sensitive to assumptions about survival or cost of treatment. Probabilistic sensitivity analyses demonstrated that SABR was the cost-effective treatment option 99.8% (health care sector perspective) or 98.7% (societal perspective) of the time.The addition of SABR increased costs and improved quality adjusted survival, overall leading to a cost-effective treatment strategy for patients with oligometastatic cancer.

  View details for DOI 10.1016/j.ijrobp.2020.09.045

  View details for PubMedID 33002541

• Combined Androgen Blockade in Localized Prostate Cancer Treated With Definitive Radiation Therapy JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Vitzthum, L. K., Straka, C., Sarkar, R. R., Mckay, R., Randall, J., Sandhu, A., Murphy, J. D., Rose, B. S. 2019; 17 (12): 1497-+

  Abstract

  The addition of androgen deprivation therapy to radiation therapy (RT) improves survival in patients with intermediate- and high-risk prostate cancer (PCa), but it is not known whether combined androgen blockade (CAB) with a gonadotropin-releasing hormone agonist (GnRH-A) and a nonsteroidal antiandrogen improves survival over GnRH-A monotherapy.This study evaluated patients with intermediate- and high-risk PCa diagnosed in 2001 through 2015 who underwent RT with either GnRH-A alone or CAB using the Veterans Affairs Informatics and Computing Infrastructure. Associations between CAB and prostate cancer-specific mortality (PCSM) and overall survival (OS) were determined using multivariable regression with Fine-Gray and multivariable Cox proportional hazards models, respectively. For a positive control, the effect of long-term versus short-term GnRH-A therapy was tested.The cohort included 8,423 men (GnRH-A, 4,529; CAB, 3,894) with a median follow-up of 5.9 years. There were 1,861 deaths, including 349 resulting from PCa. The unadjusted cumulative incidences of PCSM at 10 years were 5.9% and 6.9% for those receiving GnRH-A and CAB, respectively (P=.16). Compared with GnRH-A alone, CAB was not associated with a significant difference in covariate-adjusted PCSM (subdistribution hazard ratio [SHR], 1.05; 95% CI, 0.85-1.30) or OS (hazard ratio, 1.02; 95% CI, 0.93-1.12). For high-risk patients, long-term versus short-term GnRH-A therapy was associated with improved PCSM (SHR, 0.74; 95% CI, 0.57-0.95) and OS (SHR, 0.82; 95% CI, 0.73-0.93).In men receiving definitive RT for intermediate- or high-risk PCa, CAB was not associated with improved PCSM or OS compared with GnRH alone.

  View details for DOI 10.6004/jnccn.2019.7335

  View details for Web of Science ID 000500944300010

  View details for PubMedID 31805534

• 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

• Reducing prolonged chemoradiation treatment times for cervical cancer. BMJ open quality Vitzthum, L., Yuan, J., Jones, D., Boldt, A., Dusenbery, K. 2019; 8 (3): e000516

  Abstract

  Prolonged total treatment times (TTTs) beyond 56 days are associated with worse outcomes for cervical cancer treated with radiation therapy. We reviewed treatment times in a cohort of 24 consecutive patients treated with definitive chemoradiation (CRT) at our institution and found that only 14 patients (58.3%) completed treatment in less than or equal to 56 days. The primary objectives of this institutional quality improvement initiative were to identify sources for delays in treatment completion and to implement effective measures in an effort to minimise prolonged TTT. Pareto plot and process mapping were used to identify and resolve root causes of prolonged treatment. The Plan-Do-Study-Act method was then implemented to reduce treatment duration. Post-intervention treatment times were prospectively evaluated in 81 subsequent patients treated with definitive CRT. Process mapping identified inefficiencies with scheduling, staggered treatments and inadequate patient and staff education. Institutional changes were implemented, heavily utilising oncology nurses' skill set in staff re-education and care coordination. Our workflow was redesigned to reduce/eliminate treatment delays. These interventions led to a significant improvement in the percentage of patients meeting the goal TTT compared with the pre-intervention cohort (85.2% vs 58.3%, p<0.01), and results were sustainable in additional 47 patients prospectively followed subsequently, potentially making a positive impact on their treatment outcomes.

  View details for DOI 10.1136/bmjoq-2018-000516

  View details for PubMedID 31637317

• Prognostic Role of p16 in Nonoropharyngeal Head and Neck Cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Bryant, A. K., Sojourner, E. J., Vitzthum, L. K., Zakeri, K., Shen, H., Nguyen, C., Murphy, J. D., Califano, J. A., Cohen, E. W., Mell, L. K. 2018; 110 (12): 1393–99

  Abstract

  Previous studies have reported conflicting information regarding the prognostic role of p16 in nonoropharyngeal head and neck squamous cell carcinoma (HNSCC).Using the US Veterans Affairs database, we analyzed 1448 patients with locoregionally advanced HNSCC and known p16 status diagnosed between 2005 and 2015 and treated with surgery, radiotherapy, or chemoradiotherapy. Tumor p16 status was determined through manual review of pathology reports of primary tumor specimens. Oropharyngeal (n = 1061) or nonoropharyngeal (n = 387; hypopharyngeal, laryngeal, or oral cavity) tumor site was determined from tumor registry data and manually reviewed for accuracy. We used multivariable Cox regression to analyze the effect of p16 status on overall survival (OS), cancer-specific survival (CSS), and competing mortality (CM) for oropharyngeal or nonoropharyngeal tumor sites. All statistical tests were two-sided.In multivariable models adjusting for treatment, stage, age, comorbidity, and body mass index, patients with p16-positive tumors had improved OS, CSS, and CM compared with patients with p16-negative tumors in both oropharyngeal (OS: hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.40 to 0.71, P < .001; CSS: HR = 0.50, 95% CI = 0.35 to 0.73, P < .001; CM: HR = 0.59, 95% CI = 0.38 to 0.93, P = .02) and nonoropharyngeal primary sites (OS: HR = 0.41, 95% CI = 0.25 to 0.69, P < .001; CSS: HR = 0.37, 95% CI = 0.18 to 0.77, P = .008; CM: HR = 0.46, 95% CI = 0.23 to 0.95, P = .04). The prognostic impact of p16 status did not statistically significantly differ by primary tumor site for OS, CSS, or CM (Pinteraction > .05).Our findings support the hypothesis that p16 has a similar prognostic role in both nonoropharyngeal and oropharyngeal cancer. Consideration should be given to increased testing for p16 in laryngeal, hypopharyngeal, and oral cavity primaries.

  View details for DOI 10.1093/jnci/djy072

  View details for Web of Science ID 000455209700014

  View details for PubMedID 29878161

  View details for PubMedCentralID PMC6292787

• Comparison of Comorbidity and Frailty Indices in Patients With Head and Neck Cancer Using an Online Tool JCO CLINICAL CANCER INFORMATICS Vitzthum, L. K., Feng, C. H., Noticewala, S., Hines, P. J., Nguyen, C., Zakeri, K., Sojourner, E. J., Shen, H., Mell, L. K. 2018; 2: 1–9

  Abstract

  Comorbidity is an independent predictor of mortality and treatment tolerance in head and neck cancer and should be considered with regard to treatment intensification. Multiple previously validated models can be used to evaluate comorbidity and propensity to benefit from intensive treatment, but they have not been directly compared.An online tool was developed and used to calculate the Charlson Comorbidity Index (CCI), Adult Comorbidity Evaluation-27 (ACE-27), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), Geriatric 8 (G8), Cancer and Aging Research Group (CARG), and Generalized Competing Event (GCE) scores. To assess interrater variability, five evaluators independently calculated scores on a retrospective cohort of 20 patients. Correlation between models as well as age and performance status were calculated from a cohort of 40 patients.The GCE and G8 models had an excellent (intraclass correlation coefficient and Fleiss' kappa ≥ 0.75) degree of interrater agreement. The CCI, ACE-27, CIRS-G, and CARG had a good (intraclass correlation coefficient and Fleiss' kappa 0.6-0.74) degree of interrater agreement. There was statistically significant correlation between models, especially with the CCI, ACE-27, and CIRS-G indices. Increased age was correlated with an increased CCI score and having moderate to severe comorbidity was correlated with the ACE-27 model. Except for the G8 model, the comorbidity indices were not associated with Eastern Cooperative Oncology Group performance status.We developed an online tool to calculate indices of comorbidity in patients with head and neck cancer with a high degree of reproducibility. Comorbidity is not strongly correlated with performance status and should be independently evaluated in patients.

  View details for DOI 10.1200/CCI.18.00082

  View details for Web of Science ID 000462336800001

  View details for PubMedID 30652602

• Optimism bias' in contemporary national clinical trial network phase III trials: are we improving? ANNALS OF ONCOLOGY Zakeri, K., Noticewala, S. S., Vitzthum, L. K., Sojourner, E., Shen, H., Mell, L. K. 2018; 29 (10): 2135–39

  Abstract

  Previous studies have found that overestimating treatment effects (i.e. 'optimism bias') leads to underpowered clinical trials. The prevalence of 'optimism bias' in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown.We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided.We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33-1.28) versus 1.32 (range: 0.86-2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol.Despite a reduction in 'optimism bias' compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.

  View details for DOI 10.1093/annonc/mdy340

  View details for Web of Science ID 000455165100018

  View details for PubMedID 30412223

  View details for PubMedCentralID PMC6454418

• The role of p16 as a biomarker in nonoropharyngeal head and neck cancer. Oncotarget Vitzthum, L. K., Mell, L. K. 2018; 9 (70): 33247–48

  View details for DOI 10.18632/oncotarget.26053

  View details for PubMedID 30279955

• Generalized Competing Event Models Can Reduce Cost and Duration of Cancer Clinical Trials JCO CLINICAL CANCER INFORMATICS Zakeri, K., Panjwani, N., Carmona, R., Shen, H., Vitzthum, L. K., Zhang, Q. E., Murphy, J. D., Mell, L. K. 2018; 2: 1–12

  Abstract

  Generalized competing event (GCE) models improve stratification of patients according to their risk of cancer events relative to competing causes of mortality. The potential impact of such methods on clinical trial power and cost, however, is uncertain. We sought to test the hypothesis that GCE models can reduce estimated clinical trial cost in elderly patients with cancer.Patients with nonmetastatic head and neck (n = 9,677), breast (n = 22,929), or prostate cancer (n = 51,713) were sampled from the SEER-Medicare database. Using multivariable Cox proportional hazards models, we compared risk scores for all-cause mortality (ACM) and cancer-specific mortality (CSM) with GCE-based risk scores for each disease. We applied a cost function to estimate the cost and duration of clinical trials with a primary end point of overall survival in each population and in high-risk subpopulations. We conducted sensitivity analyses to examine model uncertainty.For the purpose of enriching subpopulations, GCE models reduced estimated clinical trial cost compared with Cox models of ACM and CSM in all disease sites. The relative cost reductions with GCE models compared with ACM and CSM models, respectively, were -68.4% and -14.4% in prostate cancer, -38.8% and -18.3% in breast cancer, and -17.1% and -4.1% in head and neck cancer. Cost savings in breast and prostate cancers were on the order of millions of dollars. The GCE model also reduced relative clinical trial duration compared with CSM and ACM models for all disease sites. The optimal risk score cutoff for clinical trial enrollment occurred near the top tertile for all disease sites.GCE models have significant potential to improve clinical trial efficiency and reduce cost, with a potentially large impact in prostate and breast cancers.

  View details for DOI 10.1200/CCI.17.00124

  View details for Web of Science ID 000461551600001

  View details for PubMedID 30652559

• Head and Neck Soft Tissue Sarcomas Treated with Radiation Therapy. Rare tumors Vitzthum, L. K., Brown, L. C., Rooney, J. W., Foote, R. L. 2016; 8 (2): 6165

  Abstract

  Head and neck soft tissue sarcomas (HNSTSs) are rare and heterogeneous cancers in which radiation therapy (RT) has an important role in local tumor control (LC). The purpose of this study was to evaluate outcomes and patterns of treatment failure in patients with HNSTS treated with RT. A retrospective review was performed of adult patients with HNSTS treated with RT from January 1, 1998, to December 31, 2012. LC, locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and predictors thereof were assessed. Forty-eight patients with HNSTS were evaluated. Five-year Kaplan-Meier estimates of LC, LRC, DFS, and OS were 87, 73, 63, and 83%, respectively. Angiosarcomas were found to be associated with worse LC, LRC, DFS, and OS. Patients over the age of 60 had lower rates of DFS. HNSTSs comprise a diverse group of tumors that can be managed with various treatment regimens involving RT. Angiosarcomas have higher recurrence and mortality rates.

  View details for DOI 10.4081/rt.2016.6165

  View details for PubMedID 27441072

  View details for PubMedCentralID PMC4935821

• Study of Na+/H+ exchange-mediated pHi regulations in neuronal soma and neurites in compartmentalized microfluidic devices. Integrative biology : quantitative biosciences from nano to macro Vitzthum, L., Chen, X., Kintner, D. B., Huang, Y., Chiu, S. Y., Williams, J., Sun, D. 2010; 2 (1): 58-64

  Abstract

  Regulation of intracellular pH (pH(i)) in neurons is crucial to maintain their physiological function. In the current study, newly-developed polydimethylsiloxane (PDMS) microfluidic devices were used to independently investigate pH(i) regulation in neuronal soma and neurites. Embryonic cortical neurons were cultured in PDMS microfluidic devices with soma growing in one chamber (seeded) and neurites extending through a set of perpendicular microchannels into the opposite parallel chamber (non-seeded). Neurons in the microchambers were characterized by the vital dye calcein-red, polarized mitochondria, and expression of neuronal specific beta-tubulin (type-III), axonal Tau-1 protein, dendritic microtubule associated protein (MAP-2), and Na(+)/H(+) exchanger isoform 1 (NHE-1). Neurites exhibited higher resting pH(i) than soma (7.16 +/- 0.09 vs. 6.90 +/- 0.15). The neurites had a proton extrusion rate 3.7-fold faster than in soma following NH(4)Cl prepulse-mediated acidification (p < 0.05). The difference in the pH(i) regulation rates between neurites and soma can be accounted for by the larger surface area to volume ratio in the neurites. Interestingly, pharmacological inhibition of NHE-1 activity blocked the pH(i) regulation in soma and in neurites by approximately 70% (p < 0.05). Taken together, our study demonstrated that the microfluidic devices provide a useful tool to study neuronal pH(i) regulation in soma and their neurites. We conclude that NHE-1 plays an important role in regulation of pH(i) in both compartments.

  View details for DOI 10.1039/b918440f

  View details for PubMedID 20473413

  View details for PubMedCentralID PMC2875691

• Global engineering education initiative through student organization. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Sagstetter, A. M., Vitzthum, L. K., Meyer, J. R., Nimunkar, A. J., Webster, J. G. 2009; 2009: 2022-4

  Abstract

  Engineering is becoming a more globally aware discipline that is revolutionizing the way individuals interact internationally. Engineering World Health (EWH) - Madison Chapter is a student-initiated organization that has developed opportunities to facilitate both local and global engineering education. Through EWH - Madison Chapter student-initiated activities, this organization has developed an interface between Traditional, Technical, and Translational education mediums. This study attests to the development of global engineering programs in the context of biomedical applications.

  View details for DOI 10.1109/IEMBS.2009.5334420

  View details for PubMedID 19964768