Billy W Loo, Jr, MD PhD FASTRO FACR

All Publications

• Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract. International journal of radiation oncology, biology, physics Liu, K., Waldrop, T., Aguilar, E., Mims, N., Neill, D., Delahoussaye, A., Li, Z., Swanson, D., Lin, S. H., Koong, A. C., Taniguchi, C. M., Loo, B. W., Mitra, D., Schuler, E. 2024

  Abstract

  BACKGROUND: The understanding of how varying radiation beam parameter settings affect the induction and magnitude of the FLASH effect remains limited.PURPOSE: We sought to systematically evaluate how the magnitude of radiation-induced gastrointestinal (GI) toxicity (RIGIT) depends on the interplay between mean dose rate (MDR) and dose per pulse (DPP).METHODS: C57BL/6J mice received total abdominal irradiation (11-14 Gy, single fraction) through either conventional irradiation (low DPP and low MDR, CONV) or through various combinations of DPP and MDR up to ultra-high-dose-rate (UHDR) beam conditions. DPPs ranging from 1 Gy to 6 Gy were evaluated while the total dose and MDR (>100 Gy/s) were kept constant; the effects of MDR were evaluated for the range 0.3-1440 Gy/s while the total dose and DPP were kept constant. RIGIT was quantified in non-tumor-bearing mice through the regenerating crypt assay and survival assessment. Tumor response was evaluated through tumor growth delay.RESULTS: Within each tested total dose using a constant MDR (>100 Gy/s), increasing DPP led to an increase in sparing (an increase in number of regenerating crypts), with a more prominent effect seen at 12 and 14 Gy TAI. Interestingly, at DPPs of >4 Gy, similar level of crypt sparing was demonstrated irrespective of the MDR used (from 0.3 to 1440 Gy/s). At a fixed high DPP of 4.7 Gy, survival was equivalently improved relative to CONV irrespective of MDR. However, at a lower DPP of 0.93 Gy, a MDR of 104 Gy/s produced a greater survival effect compared to 0.3 Gy/s. We also confirmed that high DPP, regardless of MDR, produced the same magnitude of tumor growth delay relative to CONV using a clinically relevant melanoma mouse model.CONCLUSIONS: This study demonstrates the strong influence that the beam parameter settings have on the magnitude of the FLASH effect. Both high DPP and UHDR appeared independently sufficient to produce FLASH sparing of GI toxicity, while isoeffective tumor response was maintained across all conditions.

  View details for DOI 10.1016/j.ijrobp.2024.10.009

  View details for PubMedID 39424078

• Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment 18F-Fluorodeoxyglucose Position Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kong, F. S., Hu, C., Pryma, D. A., Duan, F., Matuszak, M., Xiao, Y., Ten Haken, R., Siegel, M. J., Hanna, L., Curran, W. J., Dunphy, M., Gelblum, D., Piert, M., Jolly, S., Robinson, C. G., Quon, A., Loo, B. W., Srinivas, S., Videtic, G. M., Faria, S. L., Ferguson, C., Dunlap, N. E., Kundapur, V., Paulus, R., Siegel, B. A., Bradley, J. D., Machtay, M. 2024: JCO2400022

  Abstract

  NRG-RTOG0617 demonstrated a detrimental effect of uniform high-dose radiation in stage III non-small cell lung cancer. NRG-RTOG1106/ECOG-ACRIN6697 (ClinicalTrials.gov identifier: NCT01507428), a randomized phase II trial, studied whether midtreatment 18F-fluorodeoxyglucose position emission tomography/computed tomography (FDG-PET/CT) can guide individualized/adaptive dose-intensified radiotherapy (RT) to improve and predict outcomes in patients with this disease.Patients fit for concurrent chemoradiation were randomly assigned (1:2) to standard (60 Gy/30 fractions) or FDG-PET-guided adaptive treatment, stratified by substage, primary tumor size, and histology. All patients had midtreatment FDG-PET/CT; adaptive arm patients had an individualized, intensified boost RT dose to residual metabolically active areas. The primary therapeutic end point was 2-year centrally reviewed freedom from local-regional progression (FFLP), defined as no progression in or near the planning target volume and/or regional nodes. FFLP was analyzed on a modified intent-to-treat population at a one-sided Z-test significance level of 0.15. The primary imaging end point was centrally reviewed change in SUVpeak from baseline to midtreatment; its association with FFLP was assessed using the two-sided Wald test on the basis of Cox regression.Of 138 patients enrolled, 127 were eligible. Adaptive-arm patients received a mean 71 Gy in 30 fractions, with mean lung dose 17.9 Gy. There was no significant difference in centrally reviewed 2-year FFLP (59.5% and 54.6% in standard and adaptive arms; P = .66). There were no significant differences in protocol-specified grade 3 toxicities, survival, or progression-free survival (P > .4). Median SUVpeak and metabolic tumor volume (MTV) in the adaptive arm decreased 49% and 54%, from pre-RT to mid-RT PET. However, ΔSUVpeak and ΔMTV were not associated with FFLP (hazard ratios, 0.997; P = .395 and .461).Midtreatment PET-adapted RT dose escalation as given in this study was safe and feasible but did not improve efficacy outcomes.

  View details for DOI 10.1200/JCO.24.00022

  View details for PubMedID 39365957

• Integrating Audiovisual Immersion Into Pediatric Radiation Therapy Across Multiple Centers: Methodology, Timeliness, and Cost of the Audiovisual-Assisted Therapeutic Ambience in Radiation Therapy Prospective Multi-Institutional Trial. Advances in radiation oncology Oh, J., Skinner, L., Gutkin, P. M., Jiang, A., Donaldson, S. S., Loo, B. W., Wang, Y. P., Ewongwo, A., Bredfeldt, J. S., Breneman, J. C., Constine, L. S., Faught, A. M., Haas-Kogan, D., Holmes, J. A., Krasin, M., Larkin, C., Marcus, K. J., Maxim, P. G., McClelland, S., Murphy, B., Palmer, J. D., Perkins, S. M., Shen, C. J., Terezakis, S., Bush, K., Hiniker, S. M. 2024; 9 (10): 101589

  Abstract

  The Audiovisual-Assisted Therapeutic Ambience in Radiotherapy (AVATAR) trial was a prospective multicenter study (NCT03991156) examining the combination of video immersion with radiation therapy and was successfully conducted through the collaboration of pediatric radiation oncology teams at 10 institutions independent of any pre-existing consortium. We sought to analyze and report the methodology of trial conception and development, process map, and cost.The study enrolled patients aged 3 to 10 years preparing to undergo radiation therapy, integrated the combination of AVATAR-based video immersion with radiation therapy at each institution, and offered AVATAR use as an alternative to anesthesia, with rates of anesthesia use and outcomes of serial standardized anxiety and quality-of-life assessments assessed among the 81 children enrolled. A process map was created based on the trial timeline with the following components: study development time (time from conception of the trial to the accrual of the first patient, including design phase, agreement and approval phase, and site preparation phase), and accrual duration time (time from the first to last accrual). Costs and institutional success rates were calculated.Time from inception of study to last accrual was 3.6 years (1313 days). The study development time was 417 days (31.7%), and accrual duration time was 896 days (68.3%), with the final 50% of accrual occurring in <6 months. Equipment cost was approximately $550 per institution and was covered by funding from the lead study institution. All 10 centers were successful with AVATAR implementation, defined as ≥50% of patients able to avoid anesthesia with the use of AVATAR, including centers with both photon and proton therapy.This report elaborates on the methodology and timeline of trial conception and development using data from a previously published supportive care study combining video immersion with radiation therapy among 10 cooperating pediatric oncology institutions. It highlights the potential for multicenter collaborations on prospective trials integrating supportive care therapies with radiation therapy.

  View details for DOI 10.1016/j.adro.2024.101589

  View details for PubMedID 39309703

  View details for PubMedCentralID PMC11415686

• Dosimetric calibration of anatomy-specific ultra-high dose rate electron irradiation platform for preclinical FLASH radiobiology experiments. Medical physics Wang, J., Melemenidis, S., Manjappa, R., Viswanathan, V., Ashraf, R. M., Levy, K., Skinner, L. B., Soto, L. A., Chow, S., Lau, B., Ko, R. B., Graves, E. E., Yu, A. S., Bush, K. K., Surucu, M., Rankin, E. B., Loo, B. W., Schüler, E., Maxim, P. G. 2024

  Abstract

  FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra-high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation.We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra-high dose rate irradiation to two anatomic sites in mice and for cell-culture FLASH radiobiology experiments.Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source-to-surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions.The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (± 1 pulse); adjustments to account for the linac latency improved this rate to < 1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole-abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within < 5% and had low radiation leakage (< 4%). Normalizing the dose at the center of the mouse (∼0.75 cm depth) produced UHDR and CONV doses to the irradiated volumes with > 95% agreement.We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications.

  View details for DOI 10.1002/mp.17432

  View details for PubMedID 39331834

• 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

• FLASH: New intersection of physics, chemistry, biology, and cancer medicine REVIEWS OF MODERN PHYSICS Vozenin, M., Loo Jr, B. W., Tantawi, S., Maxim, P. G., Spitz, D. R., Bailat, C., Limoli, C. L. 2024; 96 (3)

  View details for DOI 10.1103/RevModPhys.96.035002

  View details for Web of Science ID 001318306300001

• A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Drayson, O. G., Melemenidis, S., Katila, N., Viswanathan, V., Kramár, E. A., Zhang, R., Kim, R., Ru, N., Petit, B., Dutt, S., Manjappa, R., Ramish Ashraf, M., Lau, B., Soto, L., Skinner, L., Yu, A. S., Surucu, M., Maxim, P. G., Zebadua-Ballasteros, P., Wood, M. A., Gruel, P. M., Baulch, J. E., Vozenin, M. C., Loo, B. W., Limoli, C. L. 2024: 110534

  Abstract

  Ultra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions.We previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, tumor-free adult female mice were given 10 Gy whole brain FLASH and CONV irradiation at both institutions and evaluated for the reproducibility and temporal evolution of multiple neurobiological endpoints.FLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and of electrophysiologic long-term potentiation (LTP, 5 months post-irradiation) was reproduced between institutions. Differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) were not observed at early times (48 h to 2 weeks), but recovery of immature neurons by 3 weeks was greater with FLASH.In summary, we demonstrated reproducible FLASH sparing effects on the brain between two different beams at two different institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at later but not the earliest time points.

  View details for DOI 10.1016/j.radonc.2024.110534

  View details for PubMedID 39293721

• Consequences of ionizing radiation exposure to the cardiovascular system. Nature reviews. Cardiology Jahng, J. W., Little, M. P., No, H. J., Loo, B. W., Wu, J. C. 2024

  Abstract

  Ionizing radiation is widely used in various industrial and medical applications, resulting in increased exposure for certain populations. Lessons from radiation accidents and occupational exposure have highlighted the cardiovascular and cerebrovascular risks associated with radiation exposure. In addition, radiation therapy for cancer has been linked to numerous cardiovascular complications, depending on the distribution of the dose by volume in the heart and other relevant target tissues in the circulatory system. The manifestation of symptoms is influenced by numerous factors, and distinct cardiac complications have previously been observed in different groups of patients with cancer undergoing radiation therapy. However, in contemporary radiation therapy, advances in treatment planning with conformal radiation delivery have markedly reduced the mean heart dose and volume of exposure, and these variables are therefore no longer sole surrogates for predicting the risk of specific types of heart disease. Nevertheless, certain cardiac substructures remain vulnerable to radiation exposure, necessitating close monitoring. In this Review, we provide a comprehensive overview of the consequences of radiation exposure on the cardiovascular system, drawing insights from various cohorts exposed to uniform, whole-body radiation or to partial-body irradiation, and identify potential risk modifiers in the development of radiation-associated cardiovascular disease.

  View details for DOI 10.1038/s41569-024-01056-4

  View details for PubMedID 38987578

  View details for PubMedCentralID 9512240

• Navigating the Critical Translational Questions for Implementing FLASH in the Clinic. Seminars in radiation oncology Loo, B. W., Verginadis, I. I., Sørensen, B. S., Mascia, A. E., Perentesis, J. P., Koong, A. C., Schüler, E., Rankin, E. B., Maxim, P. G., Limoli, C. L., Vozenin, M. C. 2024; 34 (3): 351-364

  Abstract

  The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of experimentation required to move forward in safe and decisive clinical trials. Here we review the available preclinical data pertaining to these questions and how they may inform strategies for FLASH cancer therapy clinical trials.

  View details for DOI 10.1016/j.semradonc.2024.04.008

  View details for PubMedID 38880544

• Non-Small Cell Lung Cancer, Version 4.2024. Journal of the National Comprehensive Cancer Network : JNCCN Riely, G. J., Wood, D. E., Ettinger, D. S., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., DeCamp, M., Desai, A. P., Dilling, T. J., Dowell, J., Durm, G. A., Gettinger, S., Grotz, T. E., Gubens, M. A., Juloori, A., Lackner, R. P., Lanuti, M., Lin, J., Loo, B. W., Lovly, C. M., Maldonado, F., Massarelli, E., Morgensztern, D., Mullikin, T. C., Ng, T., Owen, D., Owen, D. H., Patel, S. P., Patil, T., Polanco, P. M., Riess, J., Shapiro, T. A., Singh, A. P., Stevenson, J., Tam, A., Tanvetyanon, T., Yanagawa, J., Yang, S. C., Yau, E., Gregory, K. M., Hang, L. 2024; 22 (4): 249-274

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

  View details for DOI 10.6004/jnccn.2204.0023

  View details for PubMedID 38754467

• 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

• First in human Phase I Clinical Trial of Stereotactic Irradiation to Achieve Lung Volume Reduction (SILVR) in Severe Emphysema. International journal of radiation oncology, biology, physics Kamtam, D. N., Binkley, M. S., Kapula, N., Sadeghi, C., Nesbit, S., Md, H. H., Chang, J., Maxim, P. G., Diehn, M., Loo, B. W., Shrager, J. B. 2024

  Abstract

  Only a subset of patients with severe emphysema qualify for lung volume reduction surgery or endobronchial valves. We previously demonstrated that Stereotactic Ablative Radiotherapy (SABR) of lung tumors reduces lung volume in treated lobes by creating localized lung fibrosis. We aimed to determine the safety and, secondarily, explore the efficacy of Stereotactic Irradiation for Lung Volume Reduction (SILVR) over 18 months following intervention in patients with severe emphysema.We conducted a single-arm prospective clinical trial in eligible patients with severe emphysema treated with unilateral SABR (45 Gy in three fractions) to a target within the most emphysematous region. Primary outcome was safety i.e., incidence of grade≥3 adverse events. Secondary outcomes of efficacy were also explored.Eight subjects received the intervention. Median (range) baseline characteristics were age 73 years (63-78), FEV1% 28.5% (19.0-42.0), DLCO% 40% (24.0-67.0), and BODE index 5.5 (5-9). The incidence of grade≥3 adverse events was 3/8 (37.5%). The relative Δtarget lobe volume was -23.1% (-1.6,-41.5) and -26.5% (-20.6,-40.8) at six and 18 months, respectively. Absolute ΔFEV1% was greater in subjects with BODE index ≤5 vs. ≥6 (+12.0% vs. -2.0%). The mean baseline lung density (in Hounsfield units, reflecting the amount of preserved parenchyma) within the intermediate dose volume (V60BED3) correlated with the absolute Δtarget lobe volume at 18 months.Stereotactic Irradiation for Lung Volume Reduction appears to be safe, with a signal for efficacy as a novel therapeutic alternative for patients with severe emphysema. SILVR may be most safe/effective in patients with lower BODE index and/or less parenchymal destruction.

  View details for DOI 10.1016/j.ijrobp.2024.03.049

  View details for PubMedID 38615887

• Multi-Institutional Audit of FLASH and Conventional Dosimetry with a 3D-Printed Anatomically Realistic Mouse Phantom. International journal of radiation oncology, biology, physics Ashraf, M. R., Melemenidis, S., Liu, K., Grilj, V., Jansen, J., Velasquez, B., Connell, L., Schulz, J. B., Bailat, C., Libed, A., Manjappa, R., Dutt, S., Soto, L., Lau, B., Garza, A., Larsen, W., Skinner, L., Yu, A. S., Surucu, M., Graves, E. E., Maxim, P. G., Kry, S. F., Vozenin, M. C., Schüler, E., Loo, B. W. 2024

  Abstract

  We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3D-printed mouse phantom.A CT scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom, and each institution performed two replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film.Compared to the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm3 for bone, 0.12 g/cm3 for lung, and 0.03 g/cm3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal impact on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3% to 1.2%), while differences from the prescribed dose decreased for both CONV (3.6% to 2.5%) and FLASH (6.4% to 2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, though these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance.This study marks the first dosimetric audit for FLASH using a non-homogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biological findings.

  View details for DOI 10.1016/j.ijrobp.2024.03.017

  View details for PubMedID 38493902

• Mesothelioma: Pleural, Version 1.2024. Journal of the National Comprehensive Cancer Network : JNCCN Stevenson, J., Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., DeCamp, M., Desai, A., Dilling, T. J., Dowell, J., Durm, G. A., Garassino, M. C., Gettinger, S., Grotz, T. E., Gubens, M. A., Lackner, R. P., Lanuti, M., Lin, J., Loo, B. W., Lovly, C. M., Maldonado, F., Massarelli, E., Morgensztern, D., Mullikin, T. C., Ng, T., Otterson, G. A., Owen, D., Patel, S. P., Patil, T., Polanco, P. M., Riely, G. J., Riess, J., Shapiro, T. A., Singh, A. P., Tam, A., Tanvetyanon, T., Yanagawa, J., Yang, S. C., Yau, E., Gregory, K., Hang, L. 2024; 22 (2): 72-81

  Abstract

  Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

  View details for DOI 10.6004/jnccn.2024.0014

  View details for PubMedID 38503043

• Exploring deep learning for estimating the isoeffective dose of FLASH irradiation from mouse intestinal histology images. International journal of radiation oncology, biology, physics Fu, J., Yang, Z., Melemenidis, S., Viswanathan, V., Dutt, S., Manjappa, R., Lau, B., Soto, L. A., Ashraf, R., Skinner, L., Yu, S. J., Surucu, M., Casey, K. M., Rankin, E. B., Graves, E., Lu, W., Loo, B. W., Gu, X. 2024

  Abstract

  Ultra-high dose rate (FLASH) irradiation has been reported to reduce normal tissue damage compared with conventional dose rate (CONV) irradiation without compromising tumor control. This proof-of-concept study aims to develop a deep learning (DL) approach to quantify the FLASH isoeffective dose (dose of CONV that would be required to produce the same effect as the given physical FLASH dose) with post-irradiation mouse intestinal histological images.84 healthy C57BL/6J female mice underwent 16 MeV electron CONV (0.12Gy/s; n=41) or FLASH (200Gy/s; n=43) single fraction whole abdominal irradiation. Physical dose ranged from 12 to 16Gy for FLASH and 11 to 15Gy for CONV in 1Gy increments. 4 days after irradiation, 9 jejunum cross-sections from each mouse were H&E stained and digitized for histological analysis. CONV dataset was randomly split into training (n=33) and testing (n=8) datasets. ResNet101-based DL models were retrained using the CONV training dataset to estimate the dose based on histological features. The classical manual crypt counting (CC) approach was implemented for model comparison. Cross-section-wise mean squared error (CS-MSE) was computed to evaluate the dose estimation accuracy of both approaches. The validated DL model was applied to the FLASH dataset to map the physical FLASH dose into the isoeffective dose.The DL model achieved a CS-MSE of 0.20Gy2 on the CONV testing dataset compared with 0.40Gy2 of the CC approach. Isoeffective doses estimated by the DL model for FLASH doses of 12, 13, 14, 15, and 16 Gy were 12.19±0.46, 12.54±0.37, 12.69±0.26, 12.84±0.26, and 13.03±0.28 Gy, respectively.Our proposed DL model achieved accurate CONV dose estimation. The DL model results indicate that in the physical dose range of 13 to 16 Gy, the biological dose response of small intestinal tissue to FLASH irradiation is represented by a lower isoeffective dose compared to the physical dose. Our DL approach can be a tool for studying isoeffective doses of other radiation dose modifying interventions.

  View details for DOI 10.1016/j.ijrobp.2023.12.032

  View details for PubMedID 38171387

• AVATAR 2.0: next level communication systems for radiotherapy through face-to-face video, biofeedback, translation, and audiovisual immersion. Frontiers in oncology Schulz, J. B., Zalavari, L., Gutkin, P., Jiang, A., Wang, Y., Gibson, C., Garza, A., Bush, K. K., Wang, L., Donaldson, S. S., Loo, B. W., Hiniker, S. M., Skinner, L. 2024; 14: 1405433

  Abstract

  Purpose: This paper discusses an advanced version of our audiovisual-assisted therapeutic ambience in radiotherapy (AVATAR) radiolucent display systems designed for pediatric radiotherapy, enabling anesthesia-free treatments, video communication, and biofeedback. The scope of the AVATAR system is expanded here in two major ways: (i) through alternative mounting systems to accommodate a broader range of radiotherapy machines (specifically to fit robotic-arm and toroidal geometry photon radiotherapy and proton radiotherapy systems) and (ii) through additional hardware to provide video-calling, optimized audio for clear communication, and combined video inputs for biofeedback, translation, and other advanced functionalities.Methods and materials: Because robustness requires strong parts and radio-transparency requires thin, light parts, three-dimensional printing was used to rapidly prototype hollow structures and to iteratively improve robustness. Two system designs were made: one that mounts superior and another that mounts inferior to the patient's head. Radiation dose measurements and calculations were conducted to assess dose perturbations at surface and depth due to the screen.Results: For 6-MV volumetric modulated arc therapy (VMAT) plans, with and without the screen, the mean and maximum dose differences inside the planning target volume were 0.2% and 2.6% of the 200 cGy prescription, respectively. For a single static beam through the screen, the maximum measured excess surface dose was 13.4 ± 0.5%, and the largest measured dose attenuation at 5-cm water-equivalent depth was 2.1 ± 0.2%. These percentages are relative to the dose without the screen at those locations.Conclusions: The radiolucent screen systems provided here are shown to give minimal dosimetric effects on megavoltage VMAT photon treatments. For static beams, however, surface dose effects should be considered when these beams pass through the thickest components of the screen. Design files are also provided.

  View details for DOI 10.3389/fonc.2024.1405433

  View details for PubMedID 39439954

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

  Abstract

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

  View details for DOI 10.1016/j.radonc.2023.110079

  View details for PubMedID 38163486

• 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

• 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

• Equivalent Dose Estimation in FLASH Irradiation with a Deep Learning Approach. International journal of radiation oncology, biology, physics Yang, Z., Fu, J., Melemenidis, S., Viswanathan, V., Dutt, S., Lau, B., Soto, L. A., Manjappa, R., Skinner, L., Yu, S. J., Surucu, M., Casey, K., Rankin, E., Lu, W., Jr, B. W., Gu, X. 2023; 117 (2S): e272

  Abstract

  PURPOSE/OBJECTIVE(S): Ultra-high dose rate (FLASH) irradiation has been reported to provide decreased normal tissue toxicity without compromising tumor control compared with conventional (CONV) irradiation. However, a comprehensive understanding of the FLASH biological effect requires precise quantification of radiobiology. The study is to explore whether deep learning (DL) can tackle the task. As a proof of concept, we investigate a DL model for estimating FLASH dose to its equivalent CONV dose.MATERIALS/METHODS: Healthy C57Bl/6 female mice underwent FLASH (200Gy/s; n = 43) or CONV (0.12Gy/s; n = 41) whole abdominal irradiation using 16 MeV electron beams with a dose escalation scheme of 5 groups (n = 8 or 9) at 1Gy increments: 12-16Gy FLASH, 11-15Gy CONV. 4 days post-irradiation, 9 jejunum cross-sections per mouse were H&E stained for histological analysis. Each cross-section image was processed to remove lumen background and oversampled into multiple large-scale and small-scale patches along jejunal circumference. In CONV dataset, we randomly selected the data of 32 mice (80%) for model training and the rest (20%) for model validation. A ResNet101-based DL model, pre-trained with an unsupervised contrastive learning scheme, was retrained with only CONV training set to estimate corresponding CONV dose. For comparison, a crypt counting (CC) approach was implemented by manually counting the number of regenerating crypts on each cross-section image. An exponential function of dose vs crypt number was fitted with the CONV training set and used for dose estimation on the testing set. Mean squared error (MSE) was used to assess the accuracy of DL and CC approaches in estimating dose levels in CONV irradiation. The validated DL model was applied to the FLASH set to project FLASH dose into corresponding CONV dose that results in equivalent biological response.RESULTS: The CONV dose estimated by DL and CC approaches and DL-estimated FLASH equivalent dose were summarized in Table 1. The DL model achieved an MSE of 0.21 Gy2 on CONV testing set compared with 0.32 Gy2 of the CC approach. FLASH equivalent dose estimated by DL model for 12, 13, 14, 15 and 16Gy were 12.16±0.40, 12.53±0.32, 12.72±0.24, 12.85±0.20 and 13.04±0.27 Sv, respectively.CONCLUSION: Our proposed DL model can accurately estimate the CONV dose based on histological images. The DL predictions of FLASH dataset demonstrate that FLASH may reduce normal tissue toxicity with a lower equivalent dose, especially at high irradiated dose levels. Our study indicates that deep learning can be potentially used to assess the equivalent dose of FLASH irradiation to normal tissue.

  View details for DOI 10.1016/j.ijrobp.2023.06.1241

  View details for PubMedID 37785029

• Hyperfractionated Reirradiation for Locally Recurrent Thoracic Tumors. International journal of radiation oncology, biology, physics Butler, S. S., Raclin, T., Lau, B., Raja, N., Chin, A. L., Skinner, L., Diehn, M., Loo, B. W., Vitzthum, L. 2023; 117 (2S): e9

  Abstract

  PURPOSE/OBJECTIVE(S): For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation.MATERIALS/METHODS: We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)-determined by treating physician and/or multidisciplinary tumor board-and overall survival (OS).RESULTS: Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations.CONCLUSION: Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients.

  View details for DOI 10.1016/j.ijrobp.2023.06.666

  View details for PubMedID 37786208

• An Online AI-Powered Interactive Histological Image Annotation Platform for Analyzing Intestinal Regenerating Crypts in Post-Irradiated Mice. International journal of radiation oncology, biology, physics Jiang, H., Fu, J., Melemenidis, S., Viswanathan, V., Dutt, S., Lau, B., Soto, L. A., Manjappa, R., Skinner, L., Yu, S. J., Surucu, M., Graves, E. E., Casey, K., Rankin, E., Lu, W., Loo, B. W., Gu, X. 2023; 117 (2S): e676

  Abstract

  PURPOSE/OBJECTIVE(S): The goal of this project is to build an online AI-powered interactive annotation platform to accurately and efficiently annotate intestinal regenerating crypts in histological images of mice after abdominal irradiation.MATERIALS/METHODS: The proposed platform is developed by the seamless integration of a front-end web client and a back-end server. Such client/server design allows the users to access the platform without software installation on local computers. Our front-end client is developed with SvelteJS + WebGL technology stack, allowing access from any common web browsers and enabling user interaction, such as image importing/visualization, interactive crypt annotating, and annotation saving/deleting. The back-end server is responsible for executing the tasks requested from the web client, for instance, image pre-processing, AI-based crypts automatic identification, and database management. The image preprocessing is designed to extract a single cross section image using morphological operations because multiple hematoxylin and eosin (H&E) stained jejunum cross sections from post-irradiated mice are scanned within one slide. The auto-crypt identification is powered by a trained and validated AI engine U-Net, classifying image grid tiles into two groups with and without regenerating crypts. The database is implemented with the self-contained SQLite to support recording and indexing the annotated grid tiles with regenerating crypts. The workflow for crypt analysis on this interactive platform has 5 steps: 1) manually import a whole H&E slide image; 2) auto-preprocess the slide by extracting single cross-section images; 3) auto-identify regenerating crypts with an AI engine; 4) interactively annotate (add, delete, modify) auto-identified crypt markers; 5) save and/or output the annotation to the database or the local drive.RESULTS: The performance of the developed interactive crypt analysis platform was evaluated in aspects of accuracy and efficiency. The AI-powered crypt auto-identification accuracy was assessed by computing the mean absolute error (MAE) on crypt number per cross section between manual and auto annotation using a testing dataset containing 80 cross sections. It achieved an MAE of 3.5±4.8 crypts per cross section, and 81.25% of the cross sections have no more than 5 crypts difference. The efficiency was assessed under two conditions with the server on the cloud and a local computer. It took about 2-3 minutes to finish the entire workflow on the cloud, while 1-2 minutes on the local by saving 1 minute on image uploading.CONCLUSION: The developed web client/server platform enables online automatic identification and interactive annotation of mice crypts in minutes. It is a convenient tool that allows accurate and efficient crypt analysis and can be extended for other histologic image analyses.

  View details for DOI 10.1016/j.ijrobp.2023.06.2130

  View details for PubMedID 37785993

• Comparison of Tumor Control between FLASH and CONV in an Orthotopic Breast Cancer Model. International journal of radiation oncology, biology, physics Melemenidis, S., Viswanathan, V., Dutt, S., Manjappa, R., Ashraf, M. R., Soto, L. A., Skinner, L., Yu, S. J., Surucu, M., Graves, E. E., Loo, B., Dirbas, F. M. 2023; 117 (2S): e251-e252

  Abstract

  PURPOSE/OBJECTIVE(S): Post-lumpectomy radiotherapy (RT) reduces in-breast tumor recurrence by eradicating residual, occult breast cancer (BC) that may be in the mm size scale. The ability of FLASH-RT to eradicate BC relative to conventional dose rate (CONV) RT is unknown. 20Gy RT is currently used clinically for single-fraction breast IORT. Determine the effectiveness of FLASH compared to CONV in eradicating small tumors in an orthotopic, syngeneic model of BC using single-fraction 20 or 30Gy RT.MATERIALS/METHODS: Radiation sensitive, mammary tumor cell line Py117 from the transgenic model of the mouse mammary tumor virus promoter driving the polyoma middle T antigen (MMTV- PyMT) efficiently forms non-metastatic, orthotopic tumors in C57BL/6 mice. 106 Py117 cells were injected orthotopically into the left 4th mammary fat pad of C57Bl/6J mice. Radiotherapy was performed with a custom jig that allows for fixed positioning of the target volume (2x2cm radiation field) with 5mm of margin into surrounding tissue. Tumors were irradiated at 30mm3 volume or, for comparison, at a range of greater volumes (200-800mm3) with 20 or 30Gy FLASH or CONV with 16-17 MeV electrons.RESULTS: Small 30mm3 tumors regressed until day 15 after 20Gy single fraction RT then regrew for both FLASH and CONV. 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy with no regrowth up to day 35 post-RT. Larger tumors irradiated with 30Gy regressed until day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth delay or tumor eradication between FLASH and CONV in any cohort.CONCLUSION: FLASH was as effective as CONV in controlling growth and eradicating murine BC. Based on other preclinical studies, single-fraction doses between 20 and 30Gy, as well as hypofractioned RT schedules, may identify FLASH doses that achieve comparable tumor control with less toxicity than CONV. Such findings would encourage clinical trials of FLASH in human BC.

  View details for DOI 10.1016/j.ijrobp.2023.06.1194

  View details for PubMedID 37784977

• Predicting Local Control with Dosimetric Parameters in Patients Receiving Individualized Stereotactic Ablative Radiotherapy for Lung Tumors. International journal of radiation oncology, biology, physics Wu, Y. F., Lau, B., Fu, J., Cui, S., Pham, D., Dubrowski, P., Eswarappa, S., Zgrabik, J., Candow, L., Skinner, L., Shirato, H., Taguchi, H., Gensheimer, M. F., Gee, H. E., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. 2023; 117 (2S): e76

  Abstract

  PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment option for lung tumors. The individualized lung tumor SABR (iSABR) trial was a phase II single-arm study that personalized lung tumor SABR dose and fractionation based on tumor size, location, and histology with very low rates of local recurrence (LR). A secondary analysis of this trial was conducted to assess for potential dosimetric predictors of LR, in order to help guide future clinical treatment planning.MATERIALS/METHODS: From 2011 to 2018, local, regional and distant recurrence data were prospectively collected from 204 patients (261 lung SABR treatments) enrolled in a prospective trial. Baseline characteristics and treatment details were evaluated. Dosimetric and treatment plan parameters were evaluated for their potential to predict LR, using logistic regression and chi-squared analyses.RESULTS: The majority of treated tumors were peripheral (71%, vs 29% central), primary lesions (76%, versus 24% metastatic), and of adenocarcinoma histology (67%, versus 13% squamous cell carcinoma and 19% other). The median follow-up was 24 months (range 2-95). Twenty-seven (10.3%) LRs occurred, with a median time to LR of 15 months (range 6-81 months). There were no significant associations between the overall cohort and the dosimetric parameters. However, for the multi-fraction cohort, an increased proportion of the PTV receiving 110% and 115% of the prescription dose were associated with lower LR (p = 0.01 and p = 0.01 respectively). Specifically for the 50 Gy in 4 fraction cohort, an increased D1cc, D0.03cc, as well as the proportion of the PTV receiving 110%, 115%, and 120% of the prescription dose were associated with lower LR (p < 0.001, p = 0.001, p = 0.003, p < 0.001, p = 0.004, respectively). There was no association of LR with prescription dose expressed as biologically effective dose using an alpha/beta of 10 Gy (BED10), D99%, or single- versus multi-fraction regimens.CONCLUSION: SABR for lung tumors using the individualized protocol on this trial showed excellent LR rates. We identified dosimetric parameters that were associated with LR, including V110% and V115% within the multi-fraction cohort, as well as the 50 Gy in 4 fraction cohort the D1cc, D0.03cc, and proportions of the PTV receiving 110%, 115%, and 120% of the prescription dose in the 50 Gy in 4 fraction cohort. Optimal thresholds for these parameters will be identified in further analyses. There did not appear to be an association with LR and BED10, D99%, or comparing single- vs multi-fraction regimens.

  View details for DOI 10.1016/j.ijrobp.2023.06.814

  View details for PubMedID 37786175

• Technical Infrastructure for Clinical Translation of Electron FLASH. International journal of radiation oncology, biology, physics Ashraf, M. R., Skinner, L., Melemenidis, S., Dworkin, M. L., Wu, Y. F., No, H. J., Manjappa, R., Yu, S. J., Surucu, M., Graves, E. E., Maxim, P. G., Loo, B. W. 2023; 117 (2S): e639

  Abstract

  PURPOSE/OBJECTIVE(S): For safe clinical translation of electron FLASH, hardware tools for real-time beam control and software tools for treatment planning are necessary. The purpose of this study is to prototype high-throughput hardware for real-time beam control, along with accurate beam modeling of a modern clinical Linac configured to deliver FLASH dose-rates.MATERIALS/METHODS: For real-time beam current monitoring, a beam current transformer (BCT) was initially coupled to a fast digitizer and its linearity was established by varying dose per pulse. The radiation pulse width was modified, and this change was measured using the BCT. The BCT was then used to measure the variability of dose per pulse and pulse width due to a mistuned linear accelerator system. Next, the BCT was interfaced with a field programmable gate array (FPGA) which provides the ability for high-throughput and deterministic control of the Linac based on dose accumulation. For beam modeling, the program, TOol for PArticle Simulation (TOPAS), was used to obtain beam parameters by using Bayesian optimization of the beam energy, source size, angular, and energy spread via comparison of simulated and representative dose profiles. The beam model would then be employed to calculate 3D dose distribution in a CT scan of a 3D-printed anatomically realistic mouse phantom.RESULTS: The area under the current-time curve from the BCT exhibited excellent linearity (response = 12.80 nC/Gy) up to 2.5 Gy/Pulse (R2 = 0.99). The peak beam current for the electron FLASH beam was measured to be 10 mA for an instantaneous dose-rate of 5*105 Gy/s. The measured radiation pulse width agreed with the expected value (3.7 mus). The pulse width was then shortened and the measurement by the BCT indicated pulse widths of 1.8 mus and 0.5 mus corresponding to 0.7 Gy/pulse and 0.3 Gy/pulse, respectively. The beamline exhibited a ramp-up in dose per pulse and pulse width when using the automatic frequency controller (AFC). For the first pulse, the dose delivered was 0.1-0.3 Gy and the pulse width was 0.6 mus. The output stabilized to nominal values of dose and pulse width after 3-4 pulses. This ramp-up was mitigated by manually tuning the RF resonance with the AFC disabled, after which the BCT exhibited constant output and pulse width. The beam modeling work is in progress.CONCLUSION: We demonstrated that a BCT can provide real-time measurement of per-pulse output suitable as input for FLASH beam control based on dose accumulation. The next steps are to quantify the accuracy of the dose control mechanism with the FPGA-based hardware. Potential failure modes will be identified and mitigated in parallel with the development of the hardware. A 3D-printed mouse phantom has been constructed to facilitate beam modeling work for treatment planning (in progress). On completion of this work, it is expected that we will have key infrastructure elements needed to move towards an eventual FDA investigational device exemption for clinical trials.

  View details for DOI 10.1016/j.ijrobp.2023.06.2046

  View details for PubMedID 37785904

• Deep Learning-Based Pipeline for Automatic Identification of Intestinal Regenerating Crypts in Mouse Histological Images. International journal of radiation oncology, biology, physics Fu, J., Jiang, H., Melemenidis, S., Viswanathan, V., Dutt, S., Lau, B., Soto, L. A., Manjappa, R., Skinner, L., Yu, S. J., Surucu, M., Graves, E. E., Casey, K., Rankin, E., Lu, W., Loo, B. W., Gu, X. 2023; 117 (2S): S117-S118

  Abstract

  PURPOSE/OBJECTIVE(S): A classical approach for evaluating normal tissue radiation response is to count the number of intestinal regenerating crypts in mouse histological images acquired after abdominal radiation. However, manual counting is time-consuming and subject to inter-observer variations. The goal of this study is to build a deep learning-based pipeline for automatically identifying intestinal regenerating crypts to facilitate high-throughput studies.MATERIALS/METHODS: Sixty-six healthy C57BL/6 female mice underwent 16 MeV whole abdominal electron irradiation. The small bowel was collected from each mouse 4 days post-irradiation, and 9 jejunal cross-sections from each were processed together in a single slide. The slides were stained with hematoxylin and eosin (H&E) and subsequently scanned (x20), providing one electronic histological image per mouse. Regenerating crypts, consisting of more than 10 basophilic crypt epithelial cells, were manually identified using point annotations in histological images. The pipeline was built to take the input of the image containing 9 cross sections and automatically identify the regenerating crypts on each cross section. It mainly consists of two components, cross section segmentation using intensity thresholding and morphological operations and crypt identification using a UNet. The dataset was randomly split into 46, 10, and 10 slide images for UNet training, validation, and testing. Each slide image was split into grid tiles with a voxel size of 200 * 200, and 40 * 40 square masks were placed with centers at manual point annotations on tiles with regenerating crypts. 5203/5198 tiles (w/wo crypt mask) were extracted to train UNet by minimizing dice loss. The mask probability map generated by the UNet was post-processed to identify the crypt position. Postprocessing hyperparameters were tuned using the validation dataset. The model accuracy was evaluated using the testing dataset by computing the mean absolute error (MAE) of the crypt number averaged across all cross sections.RESULTS: The number of regenerating crypts on testing cross sections ranges from 1 to 63. The testing cross-section-wise MAE achieved by the platform is 3.5±4.8 crypts. 81.25% of testing cross sections have absolute number differences less than or equal to 5 crypts.CONCLUSION: Our established deep learning-based pipeline can accurately count the number of regenerating crypts in mouse intestinal histological images. We have integrated it into an online platform that enables automatic crypt identification and allows users to interactively modify auto-identified crypt annotations. The acquired annotations from the platform will be used to finetune the deep learning model to achieve better identification performance.

  View details for DOI 10.1016/j.ijrobp.2023.06.451

  View details for PubMedID 37784305

• Investigating Dosimetry and Imaging Biomarkers for Prediction of Major Adverse Cardiac Events Following Locally Advanced Non-Small Cell Lung Cancer Radiotherapy. International journal of radiation oncology, biology, physics No, H. J., Park, N. J., Guo, F. B., Kastelowitz, N., Snyder, J. M., Rhee, J. W., Clark, D. E., Chin, A. L., Vitzthum, L., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. 2023; 117 (2S): S170

  Abstract

  PURPOSE/OBJECTIVE(S): Thoracic radiotherapy (RT) may confer major adverse cardiac events (MACE) following treatment. Mean heart dose positively associates with MACE and recent studies show cardiac substructure dosimetry improves MACE prediction. Use of imaging biomarkers with cardiac substructure dose has not been studied for prediction of MACE. We sought to develop an integrated model for cardiac substructure dose and baseline coronary artery calcium (CAC) scoring and establish its relationship to MACE.MATERIALS/METHODS: A retrospective cohort analysis was performed of consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with definitive RT from 2006-2018 at a single institution. Demographics, medical history, cardiac events, and treatments received were recorded. Cardiac substructures were contoured, including the left descending artery (LAD), left main coronary artery (LMCA), left circumflex (LCX), right coronary artery (RCA), TotalLeft (LAD+LMCA+LCX), and TotalCor (TotalLeft+RCA). Doses were measured in 2 Gy equivalent dose. CAC was scored by visual assessment and compared to established automated Agatston scoring. Primary endpoint was MACE incidence. Receiver operating characteristic (ROC) curves assessed dose and CAC metric model performance. Threshold modeling was conducted using the log rank statistic with 95% confidence intervals measured using bootstrap resampling with 1000 iterations. Competing risk models adjusted for death were used to measure cumulative incidence of MACE as well as in univariable and multivariable risk regression modeling. Pearson correlations were used to validate CAC scoring. P-values were two tailed and considered significant at P≤0.05.RESULTS: Of 233 eligible patients, 61.4% were male with a 68.1 years (range 34.9-90.7) median age. Median follow-up was 73.7 months (range 1.6-153.9). Median overall survival was 34.8 months. Following RT, 22.3% experienced at least one cardiac event at a median time of 21.5 months (range 1.7-118.9). Visual CAC scoring showed significant correlation with automated Agatston scoring (r = 0.72, P=1e-5). While left sided coronary arteries (TotalLeft), mean heart dose (MHD) and CAC scores individually predicted for MACE (AUC = 0.56-0.59), a multivariable model of TotalLeft CAC had the highest ROC analysis performance (AUC = 0.69). On univariable and multivariable competing risk regression analyses, TotalLeft V15 Gy >2.53 cc and CAC score >5 independently associated with MACE (P<0.05). A model incorporating age, TotalLeft CAC>5 and V15>2.53cc, showed incrementally higher MACE incidences for low (9.3%), intermediate (18.4%), and high-risk groups (27.7%) (P<0.01).CONCLUSION: RT-induced MACE occurs in >20% of those undergoing thoracic RT in a median time of <2 years. We validate significant associations between TotalLeft RT dose and MACE and establish CAC as a predictive risk factor. These findings may serve to inform personalized RT and future cardiac risk in locally advanced NSCLC.

  View details for DOI 10.1016/j.ijrobp.2023.06.273

  View details for PubMedID 37784425

• Anatomically Realistic 3D Printed Mouse Phantom for Multi-Institutional Benchmarking of FLASH and CONV Irradiation. International journal of radiation oncology, biology, physics Ashraf, M. R., Melemenidis, S., Liu, K., Velasquez, B. D., Manjappa, R., Soto, L. A., Dutt, S., Skinner, L., Yu, S. J., Surucu, M., Graves, E. E., Maxim, P. G., Schueler, E., Loo, B. W. 2023; 117 (2S): e697

  Abstract

  PURPOSE/OBJECTIVE(S): It is reported that about US$28B/year is spent on pre-clinical studies that are not reproducible. FLASH studies may suffer from the same reproducibility crisis due to the non-standard nature of the FLASH beamlines and the lack of dosimeters that can function at ultra-high dose-rates. There have been reports of different outcomes with regard to the FLASH effect across different institutions, even though similar beamlines, temporal structure, and nominal dose levels were used. This brings up the question of the accuracy of dosimetry under FLASH conditions for a fair comparison between FLASH and CONV. To answer this question, we develop and characterize an anatomically realistic 3D-printed mouse phantom to be used in a multi-institutional dosimetric benchmarking effort.MATERIALS/METHODS: Mesh files for bony anatomy, lungs, and soft tissue derived from a CT scan of a mouse were converted to an editable 3D model. The 3D model was cut along the coronal plane and modified to allow the inclusion of radiographic film. A multi-material approach was employed to print the phantom. A dual-nozzle 3D printer was used, where one of the nozzles used Acrylonitrile butadiene styrene (ABS) to mimic soft tissue and the other nozzle used Polyactic acid (PLA) to mimic bone density. The two materials were used together in a single print. Lungs were approximated by lightweight PLA and were printed separately and inserted into corresponding cavities in the phantom. Hounsfield Units (HU) and print-to-print stability were verified. Radiographic films were laser cut for different anatomical sites. Two institutes took part in this study with data pending from 3 more institutions. The institutes were instructed to deliver 10 Gy to the plane of the film for the whole abdomen, whole lung, and brain irradiations. 2D dose maps were compared between FLASH and CONV, and the deviation from the prescribed dose was also measured.RESULTS: The 3D-printed soft tissue, bone, and lung densities were measured to be 1.01 g/cc, 1.22 g/cc, and 0.44 g/cc, respectively. For soft tissue and bone, the Hounsfield unit (HU) difference from one print to another was < 10 HU. The greatest variation was within the lungs (54 HU), but this had a minimal effect on the dose distribution (<1%). For the two institutions that completed the survey, the maximum average difference between FLASH and CONV for all irradiations was 0.75 Gy (7.48%). The maximum average difference from the prescribed dose for all irradiations was 0.7 Gy (7.20%) across both institutions. The largest discrepancy was generally observed to be for lung irradiation, indicating that lack of treatment planning systems limits our ability to prescribe accurately in areas of inhomogeneities.CONCLUSION: A 3D printed anatomically realistic mouse phantom was developed, characterized, and used in a multi-institutional dosimetric benchmarking effort. Such a study is paramount for the clinical translation of FLASH as it facilitates reduced variability from one institution to another.

  View details for DOI 10.1016/j.ijrobp.2023.06.2178

  View details for PubMedID 37786044

• 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

• FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Barghouth, P. G., Melemenidis, S., Montay-Gruel, P., Ollivier, J., Viswanathan, V., Jorge, P. G., Soto, L. A., Lau, B. C., Sadeghi, C., Edlabadkar, A., Zhang, R., Ru, N., Baulch, J. E., Manjappa, R., Wang, J., Le Bouteiller, M., Surucu, M., Yu, A., Bush, K., Skinner, L., Maxim, P. G., Loo, B. W., Limoli, C. L., Vozenin, M. C., Frock, R. L. 2023: 109906

  Abstract

  The impact of radiotherapy (RT) at ultra high vs conventional dose rate (FLASH vs CONV) on the generation and repair of DNA double strand breaks (DSBs) is an important question that remains to be investigated. Here, we tested the hypothesis as to whether FLASH-RT generates decreased chromosomal translocations compared to CONV-RT.We used two FLASH validated electron beams and high-throughput rejoin and genome-wide translocation sequencing (HTGTS-JoinT-seq), employing S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs) in HEK239T cells, to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated after various irradiation doses, dose rates and oxygen tensions (normoxic, 21% O2; physiological, 4% O2; hypoxic, 2% and 0.5% O2). Electron irradiation was delivered using a FLASH capable Varian Trilogy and the eRT6/Oriatron at CONV (0.08-0.13Gy/s) and FLASH (1x102-5x106 Gy/s) dose rates. Related experiments using clonogenic survival and γH2AX foci in the 293T and the U87 glioblastoma lines were also performed to discern FLASH-RT vs CONV-RT DSB effects.Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Furthermore, RT dose rate modality on U87 cells did not change γH2AX foci numbers at 1- and 24-hours post-irradiation nor did this affect 293T clonogenic survival.Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

  View details for DOI 10.1016/j.radonc.2023.109906

  View details for PubMedID 37690668

• Shielding Analysis of a Preclinical Bremsstrahlung X-ray FLASH Radiotherapy System within a Clinical Radiation Therapy Vault. Health physics Rosenstrom, A., Santana-Leitner, M., Rokni, S., Shumail, M., Tantawi, S., Kwofie, J., Dewji, S., Loo, B. W. 2023

  Abstract

  A preclinical radiotherapy system producing FLASH dose rates with 12 MV bremsstrahlung x rays is being developed at Stanford University and SLAC National Accelerator Laboratory. Because of the high expected workload of 6,800 Gy w-1 at the isocenter, an efficient shielding methodology is needed to protect operators and the public while the preclinical system is operated in a radiation therapy vault designed for 6 MV x rays. In this study, an analysis is performed to assess the shielding of the local treatment head and radiation vault using the Monte Carlo code FLUKA and the empirical methodology given in the National Council on Radiation Protection and Measurements Report 151. Two different treatment head shielding designs were created to compare single-layer and multilayer shielding methodologies using high-Z and low-Z materials. The multilayered shielding methodology produced designs with a 17% reduction in neutron fluence leaking from the treatment head compared to the single layered design of the same size, resulting in a decreased effective dose to operators and the public. The conservative assumptions used in the empirical methods can lead to over-shielding when treatment heads use polyethylene or multilayered shielding. High-Z/Low-Z multilayered shielding optimized via Monte Carlo is shown to be effective in the case of treatment head shielding and provide more effective shielding design for external beam radiotherapy systems that use 12 MV bremsstrahlung photons. Modifications to empirical methods used in the assessment of MV radiotherapy systems may be warranted to capture the effects of polyethylene in treatment head shielding.

  View details for DOI 10.1097/HP.0000000000001718

  View details for PubMedID 37459481

• The sparing effect of FLASH-RT on synaptic plasticity is maintained in mice with standard fractionation. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Limoli, C. L., Kramár, E. A., Almeida, A., Petit, B., Grilj, V., Baulch, J. E., Ballesteros-Zebadua, P., Loo, B. W., Wood, M. A., Vozenin, M. C. 2023: 109767

  Abstract

  Long-term potentiation (LTP) was used to gauge the impact of conventional and FLASH dose rates on synaptic transmission. Data collected from the hippocampus and medial prefrontal cortex confirmed significant inhibition of LTP after 10 fractions of 3Gy (30Gy total) conventional radiotherapy. Remarkably, 10x3Gy FLASH radiotherapy and unirradiated controls were identical and exhibited normal LTP.

  View details for DOI 10.1016/j.radonc.2023.109767

  View details for PubMedID 37385377

• Frontiers in the Application of RF Vacuum Electronics. IEEE transactions on electron devices Armstrong, C. M., Snively, E. C., Shumail, M., Nantista, C., Li, Z., Tantawi, S., Loo, B. W., Temkin, R. J., Griffin, R. G., Feng, J., Dionisio, R., Mentgen, F., Ayllon, N., Henderson, M. A., Goodman, T. P. 2023; 70 (6): 2643-2655

  Abstract

  The application of radio frequency (RF) vacuum electronics for the betterment of the human condition began soon after the invention of the first vacuum tubes in the 1920s and has not stopped since. Today, microwave vacuum devices are powering important applications in health treatment, material and biological science, wireless communication-terrestrial and space, Earth environment remote sensing, and the promise of safe, reliable, and inexhaustible energy. This article highlights some of the exciting application frontiers of vacuum electronics.

  View details for DOI 10.1109/ted.2023.3239841

  View details for PubMedID 37250956

  View details for PubMedCentralID PMC10216895

• 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

• Framework for Quality Assurance of Ultra-High Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps. International journal of radiation oncology, biology, physics Zou, W., Zhang, R., Schueler, E., Taylor, P. A., Mascia, A. E., Diffenderfer, E. S., Zhao, T., Ayan, A. S., Sharma, M., Yu, S. J., Lu, W., Bosch, W. R., Tsien, C., Surucu, M., Pollard-Larkin, J. M., Schuemann, J., Moros, E. G., Bazalova-Carter, M., Gladstone, D. J., Li, H., Simone, C. B., Petersson, K., Kry, S. F., Maity, A., Loo, B. W., Dong, L., Maxim, P. G., Xiao, Y., Buchsbaum, J. C. 2023

  Abstract

  FLASH radiotherapy, delivered with ultra-high dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared to currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology (CIRO) FLASH working group on quality assurance of potential UHDR clinical trials, and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to answer clinical and scientific questions about FLASH most effectively.

  View details for DOI 10.1016/j.ijrobp.2023.04.018

  View details for PubMedID 37121362

• Clinical LINAC-based electron FLASH: Pathway for practical translation to FLASH clinical trials: LINAC electron FLASH. International journal of radiation oncology, biology, physics No, H. J., Wu, Y. F., Dworkin, M. L., Manjappa, R., Skinner, L., Ashraf, M. R., Lau, B., Melemenidis, S., Viswanathan, V., Yu, A. S., Surucu, M., Schüler, E., Graves, E. E., Maxim, P. G., Loo, B. W. 2023

  Abstract

  Ultra-high dose rate (UHDR) radiotherapy (RT) has produced the FLASH effect in preclinical models: reduced toxicity with comparable tumor control compared to conventional dose rate RT. Early clinical trials focused on UHDR RT feasibility using specialized devices. We explore the technical feasibility of practical electron UHDR RT on a standard clinical linear accelerator (LINAC).We tuned the program board of a decommissioned electron energy for UHDR electron delivery on a clinical LINAC, without hardware modification. Pulse delivery was controlled using the respiratory gating interface. A short SSD electron set-up with a standard scattering foil was configured and tested on an anthropomorphic phantom using circular blocks with 3-20 cm field sizes. Dosimetry was evaluated using radiochromic film and an ion chamber profiler.UHDR open field mean dose rates at 100, 80, 70, and 59 cm SSD were 36.82, 59.52, 82.01, and 112.83 Gy/s, respectively. At 80 cm SSD, mean dose rate was ∼60 Gy/s for all collimated field sizes, with an R80 depth of 6.1 cm corresponding to an energy of 17.5 MeV. Heterogeneity was <5.0% with asymmetry of 2.2 to 6.2%. The short SSD set-up was feasible under realistic treatment conditions simulating broad clinical indications on an anthropomorphic phantom.Short SSD and tuning for high electron beam current on a standard clinical LINAC can deliver flat, homogenous UHDR electrons over a broad, clinically relevant range of field sizes and depths with practical working distances, in a configuration easily reversible to standard clinical use.

  View details for DOI 10.1016/j.ijrobp.2023.04.011

  View details for PubMedID 37105403

• 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

• Human enteroids as a tool to study conventional and ultra-high dose rate radiation. Integrative biology : quantitative biosciences from nano to macro Klett, K. C., Martin-Villa, B. C., Villarreal, V. S., Melemenidis, S., Viswanathan, V., Manjappa, R., Ashraf, M. R., Soto, L., Lau, B., Dutt, S., Rankin, E. B., Loo, B. W., Heilshorn, S. C. 2023; 15

  Abstract

  Radiation therapy, one of the most effective therapies to treat cancer, is highly toxic to healthy tissue. The delivery of radiation at ultra-high dose rates, FLASH radiation therapy (FLASH), has been shown to maintain therapeutic anti-tumor efficacy while sparing normal tissues compared to conventional dose rate irradiation (CONV). Though promising, these studies have been limited mainly to murine models. Here, we leveraged enteroids, three-dimensional cell clusters that mimic the intestine, to study human-specific tissue response to radiation. We observed enteroids have a greater colony growth potential following FLASH compared with CONV. In addition, the enteroids that reformed following FLASH more frequently exhibited proper intestinal polarity. While we did not observe differences in enteroid damage across groups, we did see distinct transcriptomic changes. Specifically, the FLASH enteroids upregulated the expression of genes associated with the WNT-family, cell-cell adhesion, and hypoxia response. These studies validate human enteroids as a model to investigate FLASH and provide further evidence supporting clinical study of this therapy. Insight Box Promising work has been done to demonstrate the potential of ultra-high dose rate radiation (FLASH) to ablate cancerous tissue, while preserving healthy tissue. While encouraging, these findings have been primarily observed using pre-clinical murine and traditional two-dimensional cell culture. This study validates the use of human enteroids as a tool to investigate human-specific tissue response to FLASH. Specifically, the work described demonstrates the ability of enteroids to recapitulate previous in vivo findings, while also providing a lens through which to probe cellular and molecular-level responses to FLASH. The human enteroids described herein offer a powerful model that can be used to probe the underlying mechanisms of FLASH in future studies.

  View details for DOI 10.1093/intbio/zyad013

  View details for PubMedID 37874173

• Transformative Technology for FLASH Radiation Therapy. Applied sciences (Basel, Switzerland) Schulte, R., Johnstone, C., Boucher, S., Esarey, E., Geddes, C. G., Kravchenko, M., Kutsaev, S., Loo, B. W., Méot, F., Mustapha, B., Nakamura, K., Nanni, E. A., Obst-Huebl, L., Sampayan, S. E., Schroeder, C. B., Sheng, K., Snijders, A. M., Snively, E., Tantawi, S. G., Van Tilborg, J. 2023; 13 (8)

  Abstract

  The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.

  View details for DOI 10.3390/app13085021

  View details for PubMedID 38240007

  View details for PubMedCentralID PMC10795821

• Transformative Technology for FLASH Radiation Therapy APPLIED SCIENCES-BASEL Schulte, R., Johnstone, C., Boucher, S., Esarey, E., Geddes, C. R., Kravchenko, M., Kutsaev, S., Loo, B. W., Meot, F., Mustapha, B., Nakamura, K., Nanni, E. A., Obst-Huebl, L., Sampayan, S. E., Schroeder, C. B., Sheng, K., Snijders, A. M., Snively, E., Tantawi, S. G., Van Tilborg, J. 2023; 13 (8)

  View details for DOI 10.3390/app13085021

  View details for Web of Science ID 000979134200001

• Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system for anesthesia avoidance in pediatric patients: A multicenter trial. International journal of radiation oncology, biology, physics Gutkin, P. M., Skinner, L., Jiang, A., Donaldson, S. S., Loo, B. W., Oh, J., Wang, Y. P., von Eyben, R., Snyder, J., Bredfeldt, J. S., Breneman, J. C., Constine, L. S., Faught, A. M., Haas-Kogan, D., Holmes, J. A., Krasin, M., Ccls, C. L., Marcus, K. J., Maxim, P. G., Iii, S. M., Murphy, B., Palmer, J. D., Perkins, S. M., Shen, C. J., Terezakis, S., Bush, K., Hiniker, S. M. 2023

  Abstract

  The AVATAR system was the first published radiotherapy (RT) compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluate the feasibility of AVATAR implementation and effects on anesthesia use, quality of life (QoL), and anxiety in a multicenter pediatric trial.Pediatric patients 3-10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least one fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were non-successful (NS). PedsQL3.0 Cancer Module survey (PedsQL) assessed QoL and was administered to the patient and guardian at RT simulation, midway through RT, and final treatment. The modified Yale Preoperative Assessment Survey Short Form (mYPAS) assessed anxiety and was performed at the same three timepoints. Success was evaluated using Chi-square test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject.Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (p=0.04) and private versus public insurance (p<0.001). Both patient (p=0.008) and parent (p=0.006) PedsQL scores significantly improved over the course of RT for patients ages 5-7. Anxiety in the treatment room decreased for both S and NS patients over RT course (p<0.001), by age (p<0.001) and by S versus NS patients (p<0.001).In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children age 3-10 years, higher than among age-matched historical controls (49%, p<0.001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

  View details for DOI 10.1016/j.ijrobp.2023.03.063

  View details for PubMedID 37001762

• FLASH-RT does not affect chromosome translocations and junction structures beyond that of CONV-RT dose-rates. bioRxiv : the preprint server for biology Barghouth, P. G., Melemenidis, S., Montay-Gruel, P., Ollivier, J., Viswanathan, V., Jorge, P. G., Soto, L. A., Lau, B. C., Sadeghi, C., Edlabadkar, A., Manjappa, R., Wang, J., Bouteiller, M. L., Surucu, M., Yu, A., Bush, K., Skinner, L., Maxim, P. G., Loo, B. W., Limoli, C. L., Vozenin, M., Frock, R. L. 2023

  Abstract

  The molecular and cellular mechanisms driving the enhanced therapeutic ratio of ultra-high dose-rate radiotherapy (FLASH-RT) over slower conventional (CONV-RT) radiotherapy dose-rate remain to be elucidated. However, attenuated DNA damage and transient oxygen depletion are among several proposed models. Here, we tested whether FLASH-RT under physioxic (4% O 2 ) and hypoxic conditions (≤2% O 2 ) reduces genome-wide translocations relative to CONV-RT and whether any differences identified revert under normoxic (21% O 2 ) conditions. We employed high-throughput rejoin and genome-wide translocation sequencing ( HTGTS-JoinT-seq ), using S. aureus and S. pyogenes Cas9 "bait" DNA double strand breaks (DSBs), to measure differences in bait-proximal repair and their genome-wide translocations to "prey" DSBs generated by electron beam CONV-RT (0.08-0.13Gy/s) and FLASH-RT (1*10 2 -5*10 6 Gy/s), under varying ionizing radiation (IR) doses and oxygen tensions. Normoxic and physioxic irradiation of HEK293T cells increased translocations at the cost of decreasing bait-proximal repair but were indistinguishable between CONV-RT and FLASH-RT. Although no apparent increase in chromosome translocations was observed with hypoxia-induced apoptosis, the combined decrease in oxygen tension with IR dose-rate modulation did not reveal significant differences in the level of translocations nor in their junction structures. Thus, Irrespective of oxygen tension, FLASH-RT produces translocations and junction structures at levels and proportions that are indistinguishable from CONV-RT.

  View details for DOI 10.1101/2023.03.27.534408

  View details for PubMedID 37034651

• 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

• Frontiers in the Application of RF Vacuum Electronics IEEE TRANSACTIONS ON ELECTRON DEVICES Armstrong, C. M., Snively, E. C., Shumail, M., Nantista, C., Li, Z., Tantawi, S., Loo, B. W., Temkin, R. J., Griffin, R. G., Feng, J., Dionisio, R., Mentgen, F., Ayllon, N., Henderson, M. A., Goodman, T. P. 2023

  View details for DOI 10.1109/TED.2023.3239841

  View details for Web of Science ID 000947833100001

• Monte Carlo simulation of shielding designs for a cabinet form factor preclinical MV-energy photon FLASH radiotherapy system. Medical physics Rosenstrom, A., Leitner, M. S., Rokni, S. H., Shumail, M., Tantawi, S., Dewji, S., Jr, B. W. 2023

  Abstract

  A preclinical MV-energy photon FLASH radiotherapy system is being designed at Stanford and SLAC National Accelerator Laboratory. Because of the higher energy and dose rate compared to conventional kV-energy photon laboratory-scale irradiators, adequate shielding in a stand-alone cabinet form factor is more challenging to achieve. We present a Monte Carlo simulation of multilayered shielding for a compact self-shielding system without the need for a radiation therapy vault.A multilayered shielding approach using multiple alternating layers of high-Z and low-Z materials is applied to the self-shielded cabinet to effectively mitigate the secondary radiation produced and to allow the device to be housed in a Controlled Radiation Area outside of a radiation vault. The multilayered shielding approach takes advantage of the properties of high-Z and low-Z radiation shielding materials such as density, cross-section, atomic number of the shielding elements, and products of radiation interactions within each layer. The Monte Carlo radiation transport code, FLUKA, is used to simulate the total effective dose produced by the operation.The multilayered shielding designs proposed and simulated produced effective dose rates significantly lower than monolayer designs with the same total material thickness at the regulatory boundary; this is accomplished through the manipulation of the locations where secondary radiation is produced and reactions due to material properties such as neutron back reflection in hydrogen. Borated polyethylene at five weight percent significantly increased the shielding performance as compared to regular polyethylene, with the magnitude of the reduction depending upon the order of the shielding material.The multilayered shielding provides a path for shielding preclinical FLASH systems that deliver MV-energy bremsstrahlung photons. This approach promises to be more efficient with respect to the shielding material mass and space claim as compared to shielded vaults typically required for clinical radiation therapy with MV photons. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mp.16290

  View details for PubMedID 36780153

• STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer. JCO precision oncology Katipally, R. R., Spurr, L. F., Gutiontov, S. I., Turchan, W. T., Connell, P., Juloori, A., Malik, R., Binkley, M. S., Jiang, A. L., Rouhani, S. J., Chervin, C. S., Wanjari, P., Segal, J. P., Ng, V., Loo, B. W., Gomez, D. R., Bestvina, C. M., Vokes, E. E., Ferguson, M. K., Donington, J. S., Diehn, M., Pitroda, S. P. 2023; 7: e2200273

  Abstract

  Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC.This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62).Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local.In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

  View details for DOI 10.1200/PO.22.00273

  View details for PubMedID 36603171

• NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2023. Journal of the National Comprehensive Cancer Network : JNCCN Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., DeCamp, M., Dilling, T. J., Dowell, J., Durm, G. A., Gettinger, S., Grotz, T. E., Gubens, M. A., Hegde, A., Lackner, R. P., Lanuti, M., Lin, J., Loo, B. W., Lovly, C. M., Maldonado, F., Massarelli, E., Morgensztern, D., Ng, T., Otterson, G. A., Patel, S. P., Patil, T., Polanco, P. M., Riely, G. J., Riess, J., Schild, S. E., Shapiro, T. A., Singh, A. P., Stevenson, J., Tam, A., Tanvetyanon, T., Yanagawa, J., Yang, S. C., Yau, E., Gregory, K. M., Hughes, M. 2023; 21 (4): 340-350

  Abstract

  The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

  View details for DOI 10.6004/jnccn.2023.0020

  View details for PubMedID 37015337

• Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Ettinger, D. S., Wood, D. E., Stevenson, J., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., DeCamp, M., Dilling, T. J., Dowell, J., Durm, G. A., Gettinger, S., Grotz, T. E., Gubens, M. A., Hegde, A., Lackner, R. P., Lanuti, M., Lin, J., Loo, B. W., Lovly, C. M., Maldonado, F., Massarelli, E., Morgensztern, D., Mullikin, T. C., Ng, T., Otterson, G. A., Patel, S. P., Patil, T., Polanco, P. M., Riely, G. J., Riess, J., Shapiro, T. A., Singh, A. P., Tam, A., Tanvetyanon, T., Yanagawa, J., Yang, S. C., Yau, E., Gregory, K. M., Hughes, M. 2023; 21 (9): 961-979

  Abstract

  Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

  View details for DOI 10.6004/jnccn.2023.0045

  View details for PubMedID 37673108

• TopasOpt: An open-source library for optimization with Topas Monte Carlo. Medical physics Whelan, B., Loo, B. W., Wang, J., Keall, P. 2022

  Abstract

  To describe and test TopasOpt: a free, open-source and extensible library for performing mathematical optimization of Monte Carlo simulations in Topas.TopasOpt enables any Topas model to be transformed into an optimization problem, and any parameter within the model to be treated as an optimization variable. Three case studies are presented. The starting model consists of a 10 MeV electron beam striking a tungsten target. The resulting bremsstrahlung X-ray spectrum is collimated by a primary and secondary collimator before being scored in a water tank. In the first case study (electron phase space optimization), five parameters describing the electron beam were treated as optimization variables and assigned a random starting value. An objective function was defined based on differences of depth-dose and profiles in water between the original (ground truth) model and a given model generated by TopasOpt. The problem was solved using Bayesian Optimization and the Nelder-Mead method. One hundred iterations were run in each case. In the second case study, (collimator geometry optimization), this process was repeated, but three geometric parameters defining the secondary collimator were treated as optimization variables and assigned random starting values, and forty iterations were run. In the third case study, the optimization was repeated with different number of primary particles to study the effect of noise on convergence.For case 1 (phase space optimization), both optimization algorithms successfully minimized the objective function, with absolute mean differences in profile dose of 0.4% (Bayesian) and 0.3% (Nelder-Mead) and 0.2% in depth-dose for both algorithms. The beam energy was recovered to within 1%, however some parameters had relative errors of up to 171% - a result consistent with the known X-ray dose is insensitivity to many electron beam parameters. For case 2 (geometry optimization), absolute mean differences in profile dose were 0.6% (Bayesian) and 0.9% (Nelder-Mead), and 0.5% and 0.9% in depth-dose. The maximum percentage error in any parameter was 9% with Bayesian Optimization and 28% with Nelder-Mead. Finally, the Bayesian Optimization algorithm was demonstrated to be robust to moderate levels of noise; when the standard deviation of the objective function was 16% of the mean, the maximum error in any parameter value was 16%, and the absolute mean difference in dose was 0.9% (profile) and 0.8% (depth-dose).An open-source library for optimization with Topas Monte Carlo has been developed, tested, and released. This tool will improve accuracy and efficiency in any situation in which the optimal value of a parameter in a Monte Carlo simulation is unknown. Applications for this tool include (1) The design of new components (2) Reverse engineering of models based on limited experimental or published data, and (3) Tuning of Monte Carlo 'hyper parameters' such as variance reduction, physics settings, or scoring parameters. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mp.16126

  View details for PubMedID 36484499

• Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer. Cancer treatment and research communications Aredo, J. V., Wakelee, H. A., Hui, A. B., Padda, S. K., Joshi, N. D., Guo, H. H., Chaudhuri, A., Diehn, M., Loo, B. W., Neal, J. W. 2022; 33: 100659

  Abstract

  INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.

  View details for DOI 10.1016/j.ctarc.2022.100659

  View details for PubMedID 36427429

• A 10-Center Prospective Clinical Trial of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) System for Anesthesia Avoidance in Pediatric Patients Gutkin, P. M., Skinner, L., Jiang, A., Donaldson, S. S., Loo, B. W., Oh, J., Von Eyben, R., Bredfeldt, J. S., Breneman, J. C., Constine, L. S., Faught, A. M., Haas-Kogan, D. A., Holmes, J. A., Krasin, M., Larkin, C., Marcus, K. J., Maxim, P. G., Murphy, B., Palmer, J. D., Perkins, S. M., Terezakis, S. A., Bush, K., Hiniker, S. M. ELSEVIER SCIENCE INC. 2022: S70

  View details for Web of Science ID 000892639302166

• Characterizing Metastatic Non-Small Cell Lung Cancer Presenting to an Academic Medical Center in an Era of Changing Treatment Paradigms Raja, N., No, H. J., Von Eyben, R., Das, M., Roy, M., Myall, N., Chin, A. L., Diehn, M., Loo, B. W., Chang, D. T., Pollom, E., Vitzthum, L. ELSEVIER SCIENCE INC. 2022: E407

  View details for Web of Science ID 000892639301234

• Assessing Clinical Feasibility of a LINAC-Based Electron FLASH Radiotherapy System Using an Anthropomorphic Phantom under Realistic Clinical Conditions Wu, Y. F., No, H. J., Dworkin, M. L., Manjappa, R., Ashraf, R., Skinner, L., Lau, B., Melemenidis, S., Viswanathan, V., Yu, S. J., Surucu, M., Schueler, E., Graves, E. E., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2022: S140

  View details for Web of Science ID 000892639302305

• Investigating the Impact of Coronary Artery Dosimetry on Major Adverse Cardiac Events after Thoracic Radiation Therapy Guo, F. B., No, H. J., Rhee, J. W., Chin, A. L., Vitzthum, L., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. ELSEVIER SCIENCE INC. 2022: E418

  View details for Web of Science ID 000892639301258

• 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

• Intracranial and Metastatic Solitary Fibrous Tumors Treated with Radiotherapy and Radiosurgery Mendoza, M., Hui, C., von Eyben, R., Pollom, E., Loo, B., Soltys, S. LIPPINCOTT WILLIAMS & WILKINS. 2022: S34

  View details for Web of Science ID 000847787800071

• Chest Wall Toxicity after Individualized Stereotactic Ablative Radiotherapy for Lung Tumors Lau, B., Wu, Y. F., Fu, J., Cui, S., Pham, D., Gee, H., Skinner, L., Shirato, H., Taguchi, H., Chin, A., Gensheimer, M., Diehn, M., Loo, B., Vitzthum, L. ELSEVIER SCIENCE INC. 2022: S36-S37

  View details for Web of Science ID 000858678100059

• 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

• Design and validation of a dosimetric comparison scheme tailored for ultra-high dose-rate electron beams to support multicenter FLASH preclinical studies. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Gonçalves Jorge, P., Melemenidis, S., Grilj, V., Buchillier, T., Manjappa, R., Viswanathan, V., Gondré, M., Vozenin, M. C., Germond, J. F., Bochud, F., Moeckli, R., Limoli, C., Skinner, L., Joshua No, H., Fred Wu, Y., Surucu, M., Yu, A. S., Lau, B., Wang, J., Schüler, E., Bush, K., Graves, E. E., Maxim, P. G., Loo, B. W., Bailat, C. 2022

  Abstract

  We describe a multicenter cross validation of ultra-high dose rate (UHDR) (>= 40 Gy/s) irradiation in order to bring a dosimetric consensus in absorbed dose to water. UHDR refers to dose rates over 100-1000 times those of conventional clinical beams. UHDR irradiations have been a topic of intense investigation as they have been reported to induce the FLASH effect in which normal tissues exhibit reduced toxicity relative to conventional dose rates. The need to establish optimal beam parameters capable of achieving the in vivo FLASH effect has become paramount. It is therefore necessary to validate and replicate dosimetry across multiple sites conducting UHDR studies with distinct beam configurations and experimental set-ups.Using a custom cuboid phantom with a cylindrical cavity (5 mm diameter by 10.4 mm length) designed to contain three type of dosimeters (thermoluminescent dosimeters (TLDs), alanine pellets, and Gafchromic films), irradiations were conducted at expected doses of 7.5 to 16 Gy delivered at UHDR or conventional dose rates using various electron beams at the Radiation Oncology Departments of the CHUV in Lausanne, Switzerland and Stanford University, CA.Data obtained between replicate experiments for all dosimeters were in excellent agreement (+/- 3 %). In general, films and TLDs were in closer agreement with each other, while alanine provided the closest match between the expected and measured dose, with certain caveats related to absolute reference dose.In conclusion, successful cross-validation of different electron beams operating under different energies and configurations lays the foundation for establishing dosimetric consensus for UHDR irradiation studies, and, if widely implemented, decrease uncertainty between different sites investigating the mechanistic basis of the FLASH effect.

  View details for DOI 10.1016/j.radonc.2022.08.023

  View details for PubMedID 36030934

• Real-time optical oximetry during FLASH radiotherapy using a phosphorescent nanoprobe. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Ha, B., Liang, K., Liu, C., Melemenidis, S., Manjappa, R., Viswanathan, V., Das, N., Ashraf, R., Lau, B., Soto, L., Graves, E. E., Rao, J., Loo, B. W., Pratx, G. 2022

  Abstract

  The rapid depletion of oxygen during irradiation at ultra-high dose rate calls for tissue oximeters capable of high temporal resolution. This study demonstrates a water-soluble phosphorescent nanoprobe and fiber-coupled instrument, which together are used to measure the kinetics of oxygen depletion at 200 Hz during irradiation of in vitro solutions.

  View details for DOI 10.1016/j.radonc.2022.08.011

  View details for PubMedID 35964762

• Bayesian optimisation to design a novel X-ray shaping device. Medical physics Whelan, B., Trovati, S., Wang, J., Fahrig, R., Maxim, P. G., Hanuka, A., Shumail, M., Tantawi, S., Merrick, J., Perl, J., Keall, P., Jr, B. W. 2022

  Abstract

  PURPOSE: In radiation therapy, X-ray dose must be precisely sculpted to the tumor, whilst simultaneously avoiding surrounding organs at risk. This requires modulation of X-ray intensity in space and/or time. Typically, this is achieved using a Multi Leaf Collimator (MLC) - a complex mechatronic device comprising over one hundred individually powered tungsten 'leaves' that move in or out of the radiation field as required. Here, an all-electronic X-ray collimation concept with no moving parts is presented, termed "SPHINX": Scanning Pencil-beam High-speed Intensity-modulated X-ray source. SPHINX utilizes a spatially distributed bremsstrahlung target and collimator array in conjunction with magnetic scanning of a high energy electron beam to generate a plurality of small X-ray "beamlets".METHODS: A simulation framework was developed in Topas Monte Carlo incorporating a phase space electron source, transport through user defined magnetic fields, bremsstrahlung X-ray production, transport through a SPHINX collimator, and dose in water. This framework was completely parametric, meaning a simulation could be built and run for any supplied geometric parameters. This functionality was coupled with Bayesian optimization to find the best parameter set based on an objective function which included terms to maximize dose rate for a user defined beamlet width while constraining inter-channel cross talk and electron contamination. Designs for beamlet widths of 5, 7, and 10 mm2 were generated. Each optimization was run for 300 iterations and took approximately 40 hours on a 24 core computer. For the optimized seven-mm model, a simulation of all beamlets in water was carried out including a linear scanning magnet calibration simulation. Finally, a back-of-envelope dose rate formalism was developed and used to estimate dose rate under various conditions.RESULTS: The optimized five-mm, seven-mm, and ten-mm models had beamlet widths of 5.1 mm, 7.2 mm, and 10.1 mm2 and dose rates of 3574 Gy/C, 6351 Gy/C and 10015 Gy/C respectively. The reduction in dose rate for smaller beamlet widths is a result of both increased collimation and source occlusion. For the simulation of all beamlets in water, the scanning magnet calibration reduced the offset between the collimator channels and beam centroids from 2.9+-1.9 mm to 0.01 +- 0.03mm. A slight reduction in dose rate of approximately 2% per degree of scanning angle was observed. Based on a back-of-envelope dose rate formalism, SPHINX in conjunction with next-generation linear accelerators has the potential to achieve substantially higher dose rates than conventional MLC based delivery, with delivery of an intensity modulated 100*100 mm2 field achievable in 0.9 to 10.6 s depending on the beamlet widths used.CONCLUSIONS: Bayesian optimization was coupled with Monte Carlo modelling to generate SPHINX geometries for various beamlet widths. A complete Monte Carlo simulation for one of these designs was developed, including electron beam transport of all beamlets through scanning magnets, X-ray production and collimation, and dose in water. These results demonstrate that SPHINX is a promising candidate for sculpting radiation dose with no moving parts, and has the potential to vastly improve both the speed and robustness of radiotherapy delivery. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mp.15887

  View details for PubMedID 35904020

• 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

• Bayesian Optimization of a Novel Intensity Modulated X-Ray Source Whelan, B., Keall, P., Perl, J., Wang, J., Trovati, S., Tantawi, S., Fahrig, R., Maxim, P., Shumail, M., Loo, B. WILEY. 2022: E320

  View details for Web of Science ID 000808579201032

• TopasOpt: An Open-Source Library for Optimization with Topas Monte Carlo Whelan, B., Loo, B., Keall, P. WILEY. 2022: E307-E308

  View details for Web of Science ID 000808579201005

• Calibration and Validation of a Real-Time Oximeter for FLASH-RT Experiments Liang, K., Pratx, G., Manjappa, R., Ha, B., Liu, C., Melemenidis, S., Rao, J., Loo, B. WILEY. 2022: E521-E522

  View details for Web of Science ID 000808579202043

• 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

• Detection of Recurrence After Thoracic Stereotactic Ablative Radiotherapy Using FDG-PET-CT. Clinical lung cancer Sodji, Q. H., Harris, J. P., Quon, A., Modlin, L. A., Lau, B., Jiang, A., Trakul, N., Maxim, P. G., Diehn, M., Loo, B. W., Hiniker, S. M. 2022

  Abstract

  INTRODUCTION/BACKGROUND: Differentiating local recurrence (LR) from post-treatment changes following stereotactic ablative radiotherapy (SABR) for thoracic tumors is challenging. We sought to evaluate the performance of FDG-PET-CT in distinguishing recurrence from post-radiation changes in patients with stage I-II non-small cell lung cancer (NSCLC) treated with SABR.MATERIALS AND METHODS: We performed a retrospective review of patients with stage I-II NSCLC treated with SABR and subsequently followed with surveillance FDG-PET-CT scans from 2004 to 2014. The radiology reports were coded as 0 or 1 if minimally or substantially concerning for LR, respectively, and correlated with outcome. Prognostic factors for false-positive FDG-PET-CT were assessed using logistic regression models.RESULTS: We identified 145 patients meeting inclusion criteria for the retrospective analysis. Amongst the 39 (26.9%) patients with FDG-PET-CT scans concerning for LR 3 to 24 months after treatment, 14 were confirmed to have LR. Thus, the positive predictive value (PPV) of FDG-PET-CT in identifying LR was 36% (14/39). Factors associated with a false-positive scan included concerning FDG-PET-CT at the earliest post-treatment time point (3 months) (odds ratio 0.67, P= .04) and older age (odds ratio 2.3, P= .02).CONCLUSION: Our analysis indicates that the PPV of a concerning FDG-PET-CT after SABR for early-stage NSCLC is relatively low, especially at early post-treatment timepoints, but accuracy is improving over time with institutional experience.

  View details for DOI 10.1016/j.cllc.2022.01.006

  View details for PubMedID 35246393

• Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., D'Amico, T. A., DeCamp, M., Dilling, T. J., Dowell, J., Gettinger, S., Grotz, T. E., Gubens, M. A., Hegde, A., Lackner, R. P., Lanuti, M., Lin, J., Loo, B. W., Lovly, C. M., Maldonado, F., Massarelli, E., Morgensztern, D., Ng, T., Otterson, G. A., Pacheco, J. M., Patel, S. P., Riely, G. J., Riess, J., Schild, S. E., Shapiro, T. A., Singh, A. P., Stevenson, J., Tam, A., Tanvetyanon, T., Yanagawa, J., Yang, S. C., Yau, E., Gregory, K., Hughes, M. 2022; 20 (5): 497-530

  Abstract

  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

  View details for DOI 10.6004/jnccn.2022.0025

  View details for PubMedID 35545176

• Ultra-high dose rate electron beams and the FLASH effect: from preclinical evidence to a new radiotherapy paradigm. Medical physics Schüler, E., Acharya, M., Montay-Gruel, P., Loo, B. W., Vozenin, M. C., Maxim, P. G. 2022

  Abstract

  In their seminal paper from 2014, Fauvadon et al. coined the term FLASH irradiation to describe ultra-high-dose-rate irradiation with dose rates greater than 40 Gy/s, which results in delivery times of fractions of a second. The experiments presented in that paper were performed with a high-dose-per-pulse 4.5-MeV electron beam, and the results served as the basis for the modern-day field of FLASH radiation therapy (RT). In this article, we review the studies that have been published after those early experiments, demonstrating the robust effects of FLASH RT on normal tissue sparing in preclinical models. We also outline the various irradiation parameters that have been used. Although the robustness of the biological response has been established, the mechanisms behind the FLASH effect are currently under investigation in a number of laboratories. However, differences in the magnitude of the FLASH effect between experiments in different labs have been reported. Reasons for these differences even within the same animal model are currently unknown, but likely has to do with the marked differences in irradiation parameter settings used. Here we show that these parameters are often not reported, which complicates large multi-study comparisons. For this reason, we propose a new standard for beam parameter reporting and discuss a systematic path to the clinical translation of FLASH radiation therapy. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/mp.15442

  View details for PubMedID 34997969

• Acute and Late Esophageal Toxicity Following Stereotactic Ablative Radiotherapy to Thoracic Tumors near or Abutting the Esophagus. International journal of radiation oncology, biology, physics Sodji, Q. H., Ko, R., von Eyben, R., Owen, S. G., Capaldi, D. P., Bush, K., Binkley, M. S., Alrowais, F., Pickthorn, B., Maxim, P. G., Gensheimer, M. F., Diehn, M., Loo, B. W. 1800

  Abstract

  PURPOSE: To evaluate the incidence of acute and late esophageal toxicity in patients with thoracic tumors near or abutting the esophagus treated with stereotactic ablative radiotherapy (SABR).METHODS AND MATERIALS: Among patients with thoracic tumors treated with SABR, we identified those with tumors near or abutting the esophagus. Using the linear-quadratic model with an alpha/SS ratio of 10, we determined the correlation between dosimetric parameters and esophageal toxicity graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.RESULTS: Out of 2200 patients treated with thoracic SABR, 767 patients were analyzable for esophageal dosimetry. We identified 55 patients with tumors near the esophagus (52 evaluable for esophagitis grade), 28 with PTV overlapping the esophagus. Median follow-up and overall survival were 16 and 23 months respectively. Thirteen patients (25%) developed temporary grade 2 acute esophageal toxicity, 11 (85%) of whom had PTV overlapping the esophagus. Symptoms resolved within 1-3 months in 12 patients, and 6 months in all patients. No grade 3-5 toxicity was observed. Only 3 patients (6%) developed late or persistent grade 2 dysphagia or dyspepsia of uncertain relationship to SABR. Cumulative incidence of acute esophagitis was 15% and 25% at 14 days and 60 days respectively. Acute toxicity correlated on univariate analysis with esophageal Dmax, D1cc, D2cc, Dmax/Dprescription and whether the PTV was overlapping the esophagus. Esophageal Dmax (BED10) < 62 Gy, D1cc (BED10) < 48 Gy, D2cc (BED10) < 43 Gy, and Dmax/Dprescription < 85% was associated with <20% risk of grade 2 acute esophagitis. Only 2 local recurrences occurred.CONCLUSIONS: Although 25% of patients with tumors near the esophagus developed acute esophagitis (39% of those with PTV overlapping the esophagus), these toxicities were all grade 2 and all temporary. This suggests the safety and efficacy of thoracic SABR for tumors near or abutting the esophagus when treating with high conformity and sharp dose gradients.

  View details for DOI 10.1016/j.ijrobp.2021.12.008

  View details for PubMedID 34942312

• Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer. Molecular cancer therapeutics Eggold, J. T., Chow, S., Melemenidis, S., Wang, J., Natarajan, S., Loo, P. E., Manjappa, R., Viswanathan, V., Kidd, E. A., Engleman, E., Dorigo, O., Loo, B. W., Rankin, E. B. 2021

  Abstract

  Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise, however current clinical trials are limited by modest response rates. Radiation therapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. While ultra-high dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, the immunomodulatory properties of FLASH irradiation remain unknown. Here we demonstrate that single high dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared to conventional irradiation, FLASH irradiation increased intratumoral T cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T cell infiltration and enhance the efficacy of alphaPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

  View details for DOI 10.1158/1535-7163.MCT-21-0358

  View details for PubMedID 34866044

• Deep Learning Based Identification and Segmentation of Lung Tumors on Computed Tomography Images. International journal of radiation oncology, biology, physics Kashyap, M., Panjwani, N., Hasan, M. A., Huang, C., Bush, K., Dong, P., Zaky, S. S., Chin, A. L., Vitzthum, L., Loo, B. W., Diehn, M., Xing, L., Gensheimer, M. F. 2021; 111 (3S): e92-e93

  Abstract

  PURPOSE/OBJECTIVE(S): Rapid and accurate estimation of tumor burden in biomedical images is essential for precisely monitoring cancer progression and assessing therapeutic response. The ability to detect and segment tumors using an automated approach is a key part of this task. Despite recent advances from deep learning, lung tumor delineation remains challenging, particularly when the tumor bounding box is not provided to the model. We hypothesized that clinical radiation oncology contours could supply a large enough dataset of 3D tumor segmentations to enable more accurate models. We developed and validated a deep learning-based model to identify and segment primary and metastatic lung tumors on computed tomography (CT) images.MATERIALS/METHODS: We curated a dataset consisting of CT images and clinical segmentations of 1,916 lung tumors in 1,504 patients who received radiation treatment for one or more primary or metastatic lung tumors. Segmentation quality was independently verified by a radiation oncologist using a custom web application. This dataset was used to train two 3D U-Net convolutional neural networks with varying model properties: one using high-resolution and small input volumes, and one using low-resolution and large input volumes. Models were ensembled together during validation. Performance was evaluated using an external held-out test set of CT images and segmentations from 59 patients with a single primary or metastatic lung tumor, treated at a separate clinical site. This test set consisted of 50 primary lung cancers and 9 metastases. To benchmark model performance against physicians, the test set was also contoured by two additional radiation oncologists.RESULTS: Median tumor volume in the external test set was 80.48 cubic centimeters (interquartile range [IQR]: 14.40 to 177.65). The segmentations generated by the ensembled model produced a mean Dice coefficient of 0.62 (IQR: 0.47 to 0.85) on the test set. The sensitivity for detecting a tumor, as defined by correctly predicting at least one voxel within a ground truth tumor, was 93.2%, and the Dice coefficient for the scans with correctly identified lesions was 0.67 (IQR: 0.53 to 0.85). In comparison, the mean interobserver Dice coefficient for the three physicians on the test set was 0.76 (IQR: 0.70 to 0.84). We observed strong correlation between physician-determined tumor size and model-predicted tumor size (Pearson correlation, r = 0.69, P < 0.0001).CONCLUSION: An end-to-end deep learning-based model was able to identify and segment lung tumors in a completely automated fashion, with near-expert level performance. Such models could soon be useful for clinical contouring and automatic quantification of tumor burden.

  View details for DOI 10.1016/j.ijrobp.2021.07.476

  View details for PubMedID 34702000

• Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E435

  View details for Web of Science ID 000715803800895

• Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents. International journal of radiation oncology, biology, physics 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. 2021; 111 (3S): e423

  Abstract

  PURPOSE/OBJECTIVE(S): Hemoptysis is a rare but potentially fatal toxicity associated with thoracic stereotactic ablative radiotherapy (SABR). Prior studies have suggested that vascular endothelial growth factor inhibitors (VEGFI) may potentiate the risk for pulmonary hemorrhage in patients treated with SABR for centrally located lung tumors. To what degree the risk of toxicity varies by timing of therapies or tumor location is uncertain. The purpose of this study is to evaluate the combined toxicity of VEGFIs and SABR for peripheral, central, or ultra-central tumors.MATERIALS/METHODS: We evaluated patients with primary or metastatic lung tumors treated with SABR between 2008 and 2018 at a single institution. Baseline patient, tumor and treatment characteristics were evaluated. Pulmonary bleeding events were graded using CTCAE version 5.0. Rates of a grade three or higher (G3+) or any ipsilateral pulmonary hemorrhage at three years were estimated using the Kaplan-Meier method. We compared rates of bleeding by tumor location, treatment with a VEGFI, sequence of therapy and VEGFI within 90 days of SABR using the log-rank test.RESULTS: This retrospective cohort study included a total of 925 pulmonary tumors treated with SABR in 691 patients. There were 44 patients treated with a VEGFI (bevacizumab, sorafenib, pazopanib, sunitinib or ramucirumab), with the majority receiving bevacizumab (n = 38, 86.3%). Among those treated with a VEGFI, the median interval between VEGFI therapy and SABR was 16 weeks, ranging from zero days to 3.7 years, with 15 (34.0%) patients treated within 90 days of SABR. Patients were treated with SABR to peripheral (738, 79.8%), central (137, 14.8%) and ultra-central (50, 5.4%) locations with a median BED10 of 87.5 Gy. Median follow-up was 32.2 months for the overall cohort and 46.4 months for VEGFI patients. The rate of G3+ hemorrhage was significantly higher in patients treated with a VEGFI (7.3 vs 0.8%, P < 0.01). The rate of any grade hemorrhage did not significantly vary between groups (9.4 vs 2.7%, P = 0.1). When stratified by location, both central/ultra-central tumors (21.1 vs 3.2%, P = 0.03) and peripheral tumors (3.4 vs 0.1%, P = 0.03) had increased rates of G3+ hemorrhage when treated with a VEGFI. Among patients treated with SABR and VEGFI, there was no significant difference in rates of hemorrhage when the interval was > or ≤ 90 days (12.0 vs 0.0%, P = 0.17). Similarly, there was no significant difference between rates of G3+ hemorrhage when VEGFI was given before (12.9%), after (8.3%), or before and after SABR (0.0%).CONCLUSION: VEGFI therapy was associated with an increased rate of high-grade hemorrhage in patients undergoing SABR to pulmonary tumors. Rates of high-grade hemorrhage were increased with VEGFI for both central/ultra-central and peripheral tumors although the absolute rate was low for peripheral tumors. While limited by low sample size and event rate, there was no correlation observed between interval or sequence of VEGFI and SABR and rate of high-grade hemorrhage.

  View details for DOI 10.1016/j.ijrobp.2021.07.1208

  View details for PubMedID 34701419

• Development of a Smartphone-Based Virtual Reality Platform for Radiation Oncology Patient Education Blomain, E., Capaldi, D. P., Panjwani, N., Skinner, L., Loo, B. W. ELSEVIER SCIENCE INC. 2021: E156

  View details for Web of Science ID 000715803800288

• Validation of a Novel Cone-Less Set-up for Electron FLASH Radiation Delivery on a Clinical-Use Linear Accelerator Wu, Y. F., No, H. J., Manjappa, R., Skinner, L., Yu, S. J., Lau, B., Surucu, M., Schueler, E., Bush, K., Graves, E. E., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2021: S139

  View details for Web of Science ID 000715803801616

• Feasibility of Clinically Practical Ultra-High Dose Rate (FLASH) Radiation Delivery by a Reversible Configuration of a Standard Clinical-Use Linear Accelerator No, H. J., Wu, Y. F., Manjappa, R., Skinner, L., Lau, B., Melemenidis, S., Yu, S. J., Surucu, M., Schueler, E., Bush, K., Graves, E. E., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2021: S32

  View details for Web of Science ID 000715803801402

• Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC) Marar, M., Bryant, A. K., Nalawade, V., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Murphy, J. D., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E447

  View details for Web of Science ID 000715803800920

• Deep Learning Based Identification and Segmentation of Lung Tumors on Computed Tomography Images Kashyap, M., Panjwani, N., Hasan, M. A., Huang, C., Bush, K., Dong, P., Zaky, S. S., Chin, A. L., Vitzthum, L., Loo, B. W., Diehn, M., Xing, L., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2021: E92-E93

  View details for Web of Science ID 000715803800145

• A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR) Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2021: S89-S90

  View details for Web of Science ID 000715803801515

• Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC). International journal of radiation oncology, biology, physics Marar, M., Bryant, A. K., Nalawade, V., Das, M., Jr, B. W., Diehn, M., Chin, A. L., Murphy, J. D., Vitzthum, L. 2021; 111 (3S): e447

  Abstract

  PURPOSE/OBJECTIVE(S): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.MATERIALS/METHODS: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.RESULTS: The observational cohort included N = 433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).CONCLUSION: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation.

  View details for DOI 10.1016/j.ijrobp.2021.07.1262

  View details for PubMedID 34701476

• 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

• Development of a Smartphone-Based Virtual Reality Platform for Radiation Oncology Patient Education. International journal of radiation oncology, biology, physics Blomain, E., Capaldi, D. P., Panjwani, N., Skinner, L., Loo, B. W. 2021; 111 (3S): e156

  Abstract

  PURPOSE/OBJECTIVE(S): Navigating cancer care is a major life stressor and negative determinant of cancer patient quality of life and potentially patient satisfaction. Patient education has been shown to ameliorate these negative outcomes, but this has proven difficult in the field of radiation oncology. One obstacle for effective patient education in radiation oncology is the inherent difficulty of explaining a visual spatial treatment paradigm using traditional verbal or written teaching aids. However, existing visual patient education platforms are lacking in key areas including fidelity to patient experience, cost, scalability and generalizability. In that context, the present study presents a cheap, immersive, realistic, and scalable smartphone-based virtual reality interface where patients can learn about and visually experience their treatment from anywhere using almost any modern smartphone.MATERIALS/METHODS: We utilized a Ricoh Theta V 360-degree camera to capture immersive spherical still images and videos of various parts of the patient experience, including simulation, Klarity mask-making, and the treatment vault. Images and videos were uploaded and processed in the Google environment (Google Photos and YouTube, respectively). The smartphone-based virtual reality experience was accomplished using various IOS and android devices attached to inexpensive Google Cardboard-compatible headsets. Separately, the VR experience was tested on an Oculus Quest 2 device as well.RESULTS: Images and videos were quick and easy to obtain (initial proof-of-concept was accomplished within 3 hours), and the approach was tractable for even those with limited audiovisual experience. The immersive images and videos were subjectively tested and validated by multiple investigators on the Oculus Platform as well as the Google Cardboard Platform using both IOS and Android devices as reliably representing the chosen aspect of treatment. The overall cost required to add the VR equipment to any existing smartphone was under $15 using commercially-available components.CONCLUSION: The present study describes a VR-based radiation oncology patient education experience that is inexpensive and modular to nearly any institution or clinical scenario. The already nominal cost can potentially be driven lower by 3D printing or similar customization. Moreover, patients can engage the simulation from anywhere with minimal assistance needed. The present proof-of-concept study has the potential to increase patient quality of life, treatment compliance and satisfaction all while reducing stress. Furthermore, the current global pandemic underscores the need for remote education resources both now and in the future. To these ends, this approach is currently being prospectively validated for impact on patient knowledge, satisfaction, stress and quality of life endpoints.

  View details for DOI 10.1016/j.ijrobp.2021.07.621

  View details for PubMedID 34700803

• Validation of a Novel Cone-Less Set-up for Electron FLASH Radiation Delivery on a Clinical-Use Linear Accelerator. International journal of radiation oncology, biology, physics Wu, Y. F., No, H. J., Manjappa, R., Skinner, L., Yu, S. J., Lau, B., Surucu, M., Schueler, E., Bush, K., Graves, E. E., Maxim, P. G., Loo, B. W. 2021; 111 (3S): S139

  Abstract

  PURPOSE/OBJECTIVE(S): Ultra-high dose rate (FLASH) radiotherapy (RT) at ≥40 Gray per second has been shown preclinically to achieve improved normal tissue sparing while maintaining tumor control similar to that of conventional dose-rate RT. Many published FLASH-RT delivery models are inaccessible for widespread use and/or not applicable for clinical translation. We previously described a model for reversible configuration of a clinical linear accelerator (LINAC) that can deliver 16-18 MeV electron FLASH-RT at source-to-surface distances (SSDs) < 95 cm. However, it precludes the use of a standard electron cone. This proof-of-concept study will characterize the beam profiles from a novel cone-less set-up, to verify its feasibility as a widely accessible method of electron FLASH-RT delivery for the intention of clinical treatment.MATERIALS/METHODS: This novel set-up employs a flat 25 * 25 cm applicator with custom cut-outs that lies within the accessory mount at 66.6 cm SSD of a standard treatment delivery system. We tested a 10 * 10 cm circular field size at a target distance of 80 cm SSD (selected to maintain FLASH dose rates). Radiographic film and an IC Profiler were used to evaluate penumbra width, beam flatness, symmetry, and percentage depth dose (PDD). FLASH-RT was delivered in 20 pulses with 3 independent measurements each using film and the profiler. This was compared to a conventional 16 MeV beam using a standard cone with a 10 * 10 cm field size at 100 cm SSD.RESULTS: Our novel cone-less FLASH set-up achieved a beam profile that was similar to the conventional electron set-up. Respectively, for the cone-less and conventional set-up, measured at a standardized depth of half R85, penumbra width was 1.13 cm and 1.15 cm, and uniformity index was 0.72 and 0.74 (defined as the ratio of the areas inside the 90% and 50% isodose lines); measured at a standardized depth of R95, flatness (defined as the maximum dose deviation from the central axis at a specific depth over an area confined within lines 2 cm inside the geometric edge of fields) was 1.5% and 4.1%, beam diameter containing dose > 80% of the central axis was 10.6 cm and 9.6 cm, and symmetry (defined as the maximum dose difference between any two symmetric points about the central axis in the flat portion of the beam, as a percentage of central dose) was 2.24% and 2.20%. PDD values for the cone-less set-up at Dmax, R95, R85, and R50 were, respectively, 3.1, 4.1, 5.3, and 6.8 cm.CONCLUSION: We have developed a novel cone-less set-up that allows for the delivery of electron FLASH-RT utilizing a clinical LINAC at practical SSDs and verified that its beam profiles are clinically feasible. Further work will be done to characterize additional SSDs and field sizes, along with the addition of a custom skin collimator to further shape the beam. This will pave the way for practical treatment using electron FLASH-RT to a host of oncologic indications, including cutaneous malignancies and partial breast irradiation in the future.

  View details for DOI 10.1016/j.ijrobp.2021.07.314

  View details for PubMedID 34700478

• A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR). International journal of radiation oncology, biology, physics Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. 2021; 111 (3S): S89-S90

  Abstract

  PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.

  View details for DOI 10.1016/j.ijrobp.2021.07.212

  View details for PubMedID 34700657

• Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. 2021; 111 (3S): e435

  Abstract

  PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.

  View details for DOI 10.1016/j.ijrobp.2021.07.1235

  View details for PubMedID 34701446

• The Nordic-HILUS Trial: Ultracentral Lung Stereotactic Ablative Radiotherapy and a Narrow Therapeutic Window. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Rosenberg, S. A., Mak, R., Kotecha, R., Loo, B. W., Senan, S. 2021; 16 (10): e79-e80

  View details for DOI 10.1016/j.jtho.2021.06.030

  View details for PubMedID 34561039

• 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

• Local Recurrence Outcomes of Colorectal Cancer Oligometastases Treated With Stereotactic Ablative Radiotherapy. American journal of clinical oncology Benson, K. R., Sandhu, N., Zhang, C., Ko, R., Toesca, D. A., Lee, P. E., Von Eyben, R., Diehn, M., Gensheimer, M., Maxim, P. G., Bush, K., Loo, B. W., Soltys, S. G., Pollom, E. L., Chang, D. T. 2021

  Abstract

  PURPOSE: The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR).MATERIALS AND METHODS: We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk.RESULTS: The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using alpha/beta ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively).CONCLUSIONS: CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.

  View details for DOI 10.1097/COC.0000000000000864

  View details for PubMedID 34534143

• Radiological tumor classification across imaging modality and histology. Nature machine intelligence Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schönlieb, C. B., Price, S. J., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021; 3: 787-798

  Abstract

  Radiomics refers to the high-throughput extraction of quantitative features from radiological scans and is widely used to search for imaging biomarkers for prediction of clinical outcomes. Current radiomic signatures suffer from limited reproducibility and generalizability, because most features are dependent on imaging modality and tumor histology, making them sensitive to variations in scan protocol. Here, we propose novel radiological features that are specially designed to ensure compatibility across diverse tissues and imaging contrast. These features provide systematic characterization of tumor morphology and spatial heterogeneity. In an international multi-institution study of 1,682 patients, we discover and validate four unifying imaging subtypes across three malignancies and two major imaging modalities. These tumor subtypes demonstrate distinct molecular characteristics and prognoses after conventional therapies. In advanced lung cancer treated with immunotherapy, one subtype is associated with improved survival and increased tumor-infiltrating lymphocytes compared with the others. Deep learning enables automatic tumor segmentation and reproducible subtype identification, which can facilitate practical implementation. The unifying radiological tumor classification may inform prognosis and treatment response for precision medicine.

  View details for DOI 10.1038/s42256-021-00377-0

  View details for PubMedID 34841195

  View details for PubMedCentralID PMC8612063

• Radiological tumour classification across imaging modality and histology NATURE MACHINE INTELLIGENCE Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schonlieb, C., Price, S., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021

  View details for DOI 10.1038/s42256-021-00377-0

  View details for Web of Science ID 000685037800005

• Definition and assessment of high risk in patients considered for lobectomy for stage I non-small cell lung cancer: The American Association for Thoracic Surgery expert panel consensus document. The Journal of thoracic and cardiovascular surgery Writing Committee, Pennathur, A., Brunelli, A., Criner, G., Keshavarz, H., Mazzone, P., Walsh, G., Luketich, J., Liptay, M., Wafford, E., Murthy, S., Marshall, M. B., Tong, B., Lanuti, M., Wolf, A., Pettiford, B., Loo, B., Merritt, R., Rocco, G., Schuchert, M., Varghese, T., Swanson, S. J., AATS Clinical Practice Standards Committee: Thoracic Surgery 2021

  Abstract

  OBJECTIVE: Lobectomy is a standard treatment for stage I non-small cell lung cancer, but a significant proportion of patients are considered at high risk for complications, including mortality, after lobectomy and might not be candidates. Identifying who is at risk is important and in evolution. The objective of The American Association for Thoracic Surgery Clinical Practice Standards Committee expert panel was to review important considerations and factors in assessing who is at high risk among patients considered for lobectomy.METHODS: The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an expert panel that developed an expert consensus document after systematic review of the literature. The expert panel generated a priori a list of important risk factors in the determination of high risk for lobectomy. A survey was administered, and the expert panel was asked to grade the relative importance of each risk factor. Recommendations were developed using discussion and a modified Delphi method.RESULTS: The expert panel survey identified the most important factors in the determination of high risk, which included the need for supplemental oxygen because of severe underlying lung disease, low diffusion capacity, the presence of frailty, and the overall assessment of daily activity and functional status. The panel determined that factors, such as age (as a sole factor), were less important in risk assessment.CONCLUSIONS: Defining who is at high risk for lobectomy for stage I non-small cell lung cancer is challenging, but remains critical. There was impressive strong consensus on identification of important factors and their hierarchical ranking of perceived risk. The panel identified several key factors that can be incorporated in risk assessment. The factors are evolving and as the population ages, factors such as neurocognitive function and frailty become more important. A minimally invasive approach becomes even more critical in this older population to mitigate risk. The determination of risk is a clinical decision and judgement, which should also take into consideration patient perspectives, values, preferences, and quality of life.

  View details for DOI 10.1016/j.jtcvs.2021.07.030

  View details for PubMedID 34716030

• Constrained by Constraints, or Manacled by Margin Mandates? International journal of radiation oncology, biology, physics Loo, B. W., Pham, D. 2021; 110 (2): 264-266

  View details for DOI 10.1016/j.ijrobp.2020.11.031

  View details for PubMedID 33989569

• An IOS Surface Audiovisual Biofeedback Smartphone Application for Respiratory Monitoring in Radiation Oncology Nano, T., Hirata, E., Blomain, E., Skinner, L., Prionas, N., Loo, B., Capaldi, D. WILEY. 2021

  View details for Web of Science ID 000673145403271

• NRG-RTOG 1106/ACRIN 6697: A phase IIR trial of standard versus adaptive (mid-treatment PET-based) chemoradiotherapy for stage III NSCLC-Results and comparison to NRG-RTOG 0617 (non-personalized RT dose escalation). Kong, F., Hu, C., Ten Haken, R., Xiao, Y., Matuszak, M., Hirsh, V., Pryma, D. A., Siegel, B. A., Gelblum, D. Y., Hayman, J., Robinson, C., Loo, B. W., Videtic, G. M., Faria, S., Ferguson, C., Dunlap, N. E., Kundapur, V., Paulus, R., Bradley, J. D., Machtay, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.8548

  View details for Web of Science ID 000708120604262

• Local Control After Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lee, P., Loo Jr, B. W., Biswas, T., Ding, G. X., El Naqa, I. M., Jackson, A., Kong, F., LaCouture, T., Miften, M., Solberg, T., Tome, W. A., Tai, A., Yorke, E., Li, X. 2021; 110 (1): 160-171

  View details for DOI 10.1016/j.ijrobp.2019.03.045

  View details for Web of Science ID 000717463600013

• Ultra-high dose rate (FLASH) irradiation does not alter microhomology mediated recombination under varying oxygen tension when compared to standard clinical dose rates. Barghouth, P., Ollivier, J., Montay-Gruel, P., Loo, B. W., Vozenin, M., Limoli, C., Frock, R. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600046

• Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer. Moding, E. J., Liu, Y., Hui, A. B., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z., Das, M., Ramchandran, K. J., Padda, S. K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600097

• Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D., Yoo, C., Kurtz, D. M., Owen, S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600087

• Implementing New Paradigms for Delivering Radiation Therapy in the Clinic Loo, B. ELSEVIER SCIENCE INC. 2021: S67

  View details for Web of Science ID 000631349600016

• Randomized Phase II Trial (RTOG1106) on Midtreatment PET/CT Guided Adaptive Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer Kong, F., Hu, C., Machtay, M., Matuszak, M., Xiao, Y., Ten Haken, R., Hirsh, V., Pryma, D., Siegel, B. A., Gelblum, D., Hayman, J., Robinson, C., Loo, B., Videtic, G., Faria, S. L., Ferguson, C., Dunlap, N., Kundapu, V., Paulus, R., Curran, W., Bradley, J. ELSEVIER SCIENCE INC. 2021: S104–S105

  View details for Web of Science ID 000631349600076

• Multicellular spheroids as in vitro models of oxygen depletion during FLASH irradiation. International journal of radiation oncology, biology, physics Khan, S., Bassenne, M., Wang, J., Manjappa, R., Melemenidis, S., Breitkreutz, D. Y., Maxim, P. G., Xing, L., Loo, B. W., Pratx, G. 2021

  Abstract

  PURPOSE: The differential response of normal and tumor tissues to ultra-high dose rate radiation (FLASH) has raised new hope for treating solid tumors but, to date, the mechanism remains elusive. One leading hypothesis is that FLASH radiochemically depletes oxygen from irradiated tissues faster than it is replenished through diffusion. The purpose of this study is to investigate these effects within hypoxic multicellular tumor spheroids, through simulations and experiments.MATERIALS AND METHODS: Physicobiological equations were derived to model (i) the diffusion and metabolism of oxygen within spheroids; (ii) its depletion through reactions involving radiation-induced radicals; and (iii) the increase in radioresistance of spheroids, modeled according to the classical oxygen enhancement ratio and linear-quadratic response. These predictions were then tested experimentally in A549 spheroids exposed to electron irradiation at conventional (0.075 Gy/s) or FLASH (90 Gy/s) dose rates. Clonogenic survival, cell viability, and spheroid growth were scored post-radiation. Clonogenic survival of two other cell lines was also investigated.RESULTS: The existence of a hypoxic core in unirradiated tumor spheroids is predicted by simulations and visualized by fluorescence microscopy. Upon FLASH irradiation, this hypoxic core transiently expands, engulfing a large number of well-oxygenated cells. In contrast, oxygen is steadily replenished during slower conventional irradiation. Experimentally, clonogenic survival was around 3-fold higher in FLASH-irradiated spheroid compared to conventional irradiation, but no significant difference was observed for well-oxygenated 2D-cultured cells. This differential survival is consistent with the predictions of the computational model. FLASH irradiation of spheroids resulted in a dose-modifying factor of around 1.3 for doses above 10 Gy.CONCLUSION: Tumor spheroids can be used as a model to study FLASH irradiation in vitro . The improved survival of tumor spheroids receiving FLASH radiation confirms that ultra-fast radiochemical oxygen depletion and its slow replenishment are critical components of the FLASH effect.

  View details for DOI 10.1016/j.ijrobp.2021.01.050

  View details for PubMedID 33545301

• NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. Journal of the National Comprehensive Cancer Network : JNCCN Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., D'Amico, T. A., Dilling, T. J., Dowell, J., Gettinger, S., Gubens, M. A., Hegde, A., Hennon, M., Lackner, R. P., Lanuti, M., Leal, T. A., Lin, J., Loo, B. W., Lovly, C. M., Martins, R. G., Massarelli, E., Morgensztern, D., Ng, T., Otterson, G. A., Patel, S. P., Riely, G. J., Schild, S. E., Shapiro, T. A., Singh, A. P., Stevenson, J., Tam, A., Yanagawa, J., Yang, S. C., Gregory, K. M., Hughes, M. 2021; 19 (3): 254–66

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

  View details for DOI 10.6004/jnccn.2021.0013

  View details for PubMedID 33668021

• A robotically assisted 3D printed quality assurance lung phantom for Calypso. Physics in medicine and biology Capaldi, D. P., Skinner, L. B., Dubrowski, P. n., Zhang, H. n., Xing, L. n., Chuang, C. F., Loo, B. W., Bush, K. K., Fahimian, B. P., Yu, A. S. 2021

  Abstract

  Purpose:Radiation dose delivered to targets located near the upper-abdomen or in the thorax are significantly affected by respiratory-motion. Relatively large-margins are commonly added to compensate for this motion, limiting radiation-dose-escalation. Internal-surrogates of target motion, such as a radiofrequency (RF) tracking system, i.e. Calypso® System, are used to overcome this challenge and improve normal-tissue sparing. RF tracking systems consist of implanting transponders in the vicinity of the tumor to be tracked using radiofrequency-waves. Unfortunately, although the manufacture provides a universal quality-assurance (QA) phantom, QA-phantoms specifically for lung-applications are limited, warranting the development of alternative solutions to fulfil the tests mandated by AAPM's TG142. Accordingly, our objective was to design and develop a motion-phantom to evaluate Calypso for lung-applications that allows the Calypso® Beacons to move in different directions to better simulate true lung-motion.Methods and Materials:A Calypso lung QA-phantom was designed, and 3D-printed. The design consists of three independent arms where the transponders were attached. A pinpoint-chamber with a buildup-cap was also incorporated. A 4-axis robotic arm was programmed to drive the motion-phantom to mimic breathing. After acquiring a four-dimensional-computed-tomography (4DCT) scan of the motion-phantom, treatment-plans were generated and delivered on a Varian TrueBeam® with Calypso capabilities. Stationary and gated-treatment plans were generated and delivered to determine the dosimetric difference between gated and non-gated treatments. Portal cine-images were acquired to determine the temporal-accuracy of delivery by calculating the difference between the observed versus expected transponders locations with the known speed of the transponders' motion.Results:Dosimetric accuracy is better than TG142 tolerance of 2%. Temporal accuracy is greater than, TG142 tolerance of 100ms for beam-on, but less than 100ms for beam-hold.Conclusions:The robotic QA-phantom designed and developed in this study provides an independent phantom for performing Calypso lung-QA for commissioning and acceptance testing of Calypso for lung treatments.

  View details for DOI 10.1088/1361-6560/abebaa

  View details for PubMedID 33657537

• Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Ganti, A. K., Loo, B. W., Bassetti, M., Blakely, C., Chiang, A., D'Amico, T. A., D'Avella, C., Dowlati, A., Downey, R. J., Edelman, M., Florsheim, C., Gold, K. A., Goldman, J. W., Grecula, J. C., Hann, C., Iams, W., Iyengar, P., Kelly, K., Khalil, M., Koczywas, M., Merritt, R. E., Mohindra, N., Molina, J., Moran, C., Pokharel, S., Puri, S., Qin, A., Rusthoven, C., Sands, J., Santana-Davila, R., Shafique, M., Waqar, S. N., Gregory, K. M., Hughes, M. 1800; 19 (12): 1441-1464

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

  View details for DOI 10.6004/jnccn.2021.0058

  View details for PubMedID 34902832

• Durvalumab for Patients with Stage III EGFR-Mutated Non-Small Cell Lung Cancer Receiving Definitive Chemoradiotherapy Aredo, J. V., Hellyer, J. A., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Loo, B. W., Diehn, M., Wakelee, H. A. ELSEVIER SCIENCE INC. 2021: S15

  View details for Web of Science ID 000610079600029

• Durvalumab for Stage III EGFR-Mutated Non-Small Cell Lung Cancer After Definitive Chemoradiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Mambetsariev, I. n., Hellyer, J. A., Amini, A. n., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Naidoo, J. n., Abuali, T. n., Salgia, R. n., Loo, B. W., Diehn, M. n., Han, S. S., Wakelee, H. A. 2021

  Abstract

  In 2018, durvalumab was FDA approved as consolidation immunotherapy for patients with stage III non-small cell lung cancer (NSCLC) after definitive chemoradiotherapy (CRT). Whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab due to progression and five due to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and 8 completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKI). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank P=0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 months) compared to CRT and durvalumab or CRT alone (log-rank P=0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction and/or consolidation EGFR TKIs further investigated as definitive treatment.

  View details for DOI 10.1016/j.jtho.2021.01.1628

  View details for PubMedID 33588109

• An automated optimization strategy to design collimator geometry for small field radiation therapy systems. Physics in medicine and biology Wang, J. n., Wang, L. n., Maxim, P. G., Loo, B. W. 2021

  Abstract

  To develop an automated optimization strategy to facilitate collimator design for small-field radiotherapy systems.We developed an objective function that links the dose profile characteristics (FWHM, penumbra, and central dose rate) and the treatment head geometric parameters (collimator thickness/radii, source-to-distal-collimator distance[SDC]) for small-field radiotherapy systems. We performed optimization using a downhill simplex algorithm. We applied this optimization strategy to a linac-based radiosurgery system to determine the optimal geometry of four pencil-beam collimators to produce 5, 10, 15, and 20mm diameter photon beams (from a 6.7MeV, 2.1mmFWHM electron beam). Two different optimizations were performed to prioritize minimum penumbra or maximum central dose rate for each beam size. We compared the optimized geometric parameters and dose distributions to an existing clinical system (CyberKnife).When minimum penumbra was prioritized, using the same collimator thickness and SDC (40cm) as a CyberKnife system, the optimized collimator upstream and downstream radii agreed with the CyberKnife system within 3-14%, the optimized output factors agreed within 0-8%, and the optimized transverse and percentage depth dose profiles matched those of the CyberKnife with the penumbras agreeing within 2%. However, when maximum dose rate was prioritized, allowing both the collimator thickness and SDC to change, the central dose rate for larger collimator sizes (10, 15, 20mm) could be increased by about 1.5-2 times at the cost of 1.5-2 times larger penumbras. No further improvement in central dose rate for the 5mm beam size could be achieved.We developed an automated optimization strategy to design the collimator geometry for small-field radiation therapy systems. Using this strategy, the penumbra-prioritized dose distribution and geometric parameters agree well with the CyberKnife system as an example, suggesting that this system was designed to prioritize sharp penumbra. This represents proof-of-principle that an automated optimization strategy may apply to more complex collimator designs with multiple optimization parameters.

  View details for DOI 10.1088/1361-6560/abeba9

  View details for PubMedID 33657538

• Effects of ultra-high dose rate FLASH irradiation on the tumor microenvironment in Lewis lung carcinoma: role of myosin light chain. International journal of radiation oncology, biology, physics Kim, Y., Gwak, S., Hong, B., Oh, J., Choi, H., Kim, M. S., Oh, D., Lartey, F., Rafat, M., Schuler, E., Kim, H., von Eyben, R., Weissman, I. L., Koch, C. J., Maxim, P. G., Loo, B. W., Ahn, G. 2020

  Abstract

  PURPOSE: To investigate whether the vascular collapse in tumors by conventional dose rate (CONV) irradiation (IR) would also occur by the ultra-high dose rate FLASH IR.METHODS AND MATERIALS: Lewis lung carcinoma (LLC) were subcutaneously implanted in mice followed by CONV or FLASH IR at 15 Gy. Tumors were harvested at 6 or 48 hr post-IR and stained for CD31, phosphorylated myosin-light chain (p-MLC), gammaH2AX, intracellular reactive oxygen species (ROS), or immune cells such as myeloid and CD8alpha T cells. Cell lines were irradiated with CONV IR for Western blot analyses. ML-7 was intraperitoneally administered daily to LLC-bearing mice for 7 days prior to 15 Gy CONV IR. Tumors were similarly harvested and analyzed as above.RESULTS: By immunostaining, we observed that CONV IR at 6 hr post-IR resulted in constricted vessel morphology, increased expression of phosphorylated myosin light chain (p-MLC), and much higher numbers of gammaH2AX (surrogate marker for DNA double strand break)-positive cells in tumors, which were not observed with FLASH IR. Mechanistically, we found that MLC activation by reactive oxygen species (ROS) is unlikely since FLASH IR produced significantly higher ROS than CONV IR in tumors. In vitro studies demonstrated that ML-7, an inhibitor of MLC kinase abrogated IR-induced gammaH2AX formation and disappearance kinetics. Lastly, we observed that CONV IR when combined with ML-7 produced some effects similar to FLASH IR including the reduction in the vasculature collapse, fewer gammaH2AX-positive cells, and increased immune cell influx to the tumors.CONCLUSIONS: FLASH IR produced novel changes in the tumor microenvironment that were not observed with CONV IR. We believe that MLC activation in tumors may be responsible for some of those microenvironmental changes differentially regulated between CONV and FLASH IR.

  View details for DOI 10.1016/j.ijrobp.2020.11.012

  View details for PubMedID 33186615

• Cardiac Toxicities and Outcomes Following Stereotactic Ablative Radiation to Thoracic Cancers Obeid, J. P., Natarajan, J. M., Ko, R., Jani, K., Sodji, Q., Merriott, D. J., Pickthorn, W., Bush, K., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2020: E158–E159

  View details for Web of Science ID 000582521500355

• Pre-Treatment Lung FDG-PET Uptake is Correlated with Radiologic Lung Fibrosis after Stereotactic Ablative Radiotherapy (SABR) Ross, J. B., Merriott, D. J., Alhumaid, S., Schueler, E., Ko, R., Bush, K., Maxim, P. G., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2020: E155

  View details for Web of Science ID 000582521500346

• Parametric Response Mapping as an Imaging Biomarker for Regional Ventilation in Stereotactic Ablative Radiotherapy Capaldi, D. P., Binkley, M. S., Ko, R., Xing, L., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2020: E359

  View details for Web of Science ID 000582521501276

• FLASH Irradiation Of Avascular Tumor Spheroids Khan, S., Bassenne, M., Wang, J., Manjappa, R., Loo, B. W., Pratx, G. ELSEVIER SCIENCE INC. 2020: E558

  View details for Web of Science ID 000582521502042

• Combination total abdominal ultra-rapid flash irradiation and PD-1 inhibition provides enhanced tumor burden control in a preclinical ovarian cancer model Chow, S., Eggold, J., Levy, K., Wang, J., Manjappa, R., Dorigo, O., Loo, B., Rankin, E. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2020: 103

  View details for DOI 10.1016/j.ygyno.2020.05.102

  View details for Web of Science ID 000579556200210

• FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice Natarajan, S., Levy, K., Wang, J., Chow, S., Eggold, J., Loo, P., Manjappa, R., Lartey, F. M., Schuler, E., Skinner, L., Rafat, M., Ko, R., Kim, A., Al Rawi, D., von Eyben, R., Dorigo, O., Casey, K. M., Graves, E. E., Bush, K., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-5351

  View details for Web of Science ID 000590059306341

• Total abdominal ultra-rapid FLASH irradiation enhances the efficacy of PD-1 inhibition in preclinical models of ovarian cancer Chow, S., Eggold, J. T., Levy, K., Wang, J., Manjappa, R., Breitkreutz, D. Y., Yu, A. S., Bush, K., Dorigo, O., Loo, B. W., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-5357

  View details for Web of Science ID 000590059306346

• Ultrarapid total abdominal FLASH irradiation in a preclinical model of ovarian cancer. Levy, K., Wang, J., Eggold, J., Natarajan, S., Maxim, P., Loo, B., Rankin, E. AMER ASSOC CANCER RESEARCH. 2020: 49

  View details for Web of Science ID 000546013300059

• Initial Steps Towards A Clinical FLASH Radiotherapy System: Pediatric Whole Brain Irradiation with 40 MeV Electrons Breitkreutz, D., Shumail, M., Bush, K., Tantawi, S., Maxim, P., Loo, B. WILEY. 2020: E799

  View details for Web of Science ID 000699864000563

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

  Abstract

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

  View details for DOI 10.1016/j.jtcvs.2020.03.171

  View details for PubMedID 32798022

• A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction. Moding, E. J., Esfahani, M., Nabet, B., Liu, Y., Chabon, J. J., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z. X., Das, M., Ramchandran, K., Padda, S., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303378

• KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D. S., Yoo, C., Kurtz, D., Owen, S., Backhus, L., Berry, M. F., Shrager, J. B., Ramchandran, K., Padda, S., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303348

• Integrating genomic features for non-invasive early lung cancer detection. Nature Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y. J., Nesselbush, M. C., Co Ting Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020; 580 (7802): 245-251

  Abstract

  Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

  View details for DOI 10.1038/s41586-020-2140-0

  View details for PubMedID 32269342

• Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer. Nature cancer Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Yoo, C. H., Gojenola, L., Jones, C. D., He, J., Qiao, Y., Xu, T., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1 (2): 176-183

  Abstract

  Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

  View details for DOI 10.1038/s43018-019-0011-0

  View details for PubMedID 34505064

  View details for PubMedCentralID PMC8425388

• Impact of Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) on Anesthesia Use, Payer Charges, and Treatment Time in Pediatric Patients. Practical radiation oncology Balazy, K. E., Gutkin, P. M., Skinner, L., von Eyben, R., Fowler, T., Pinkham, D. W., Rodriguez, S., Maxim, P. G., Donaldson, S. S., Loo, B. W., Bush, K., Hiniker, S. M. 2020

  Abstract

  PURPOSE: Pediatric radiotherapy requires optimal immobilization that often necessitates daily anesthesia. To decrease anesthesia use, we implemented a novel XXX system which projects video onto a radiolucent screen within the child's line of vision to provide attentional diversion. We investigated its reduction on anesthesia use, payer charges, and treatment time, as well as its impact on radiation delivery.METHODS AND MATERIALS: A 6-year retrospective analysis was performed among children undergoing radiotherapy (n=224), 3 years before and 3 after introduction of XXX. The frequency of anesthesia use before and after XXX implementation, as well as radiotherapy treatment times were compared. The number of spared anesthesia treatments allowed for a charge to payer analysis. To document lack of surface dose perturbation by XXX, a phantom craniospinal treatment course was delivered both with and without XXX. Additionally, an ion chamber course was delivered to document changes to dose at depth.RESULTS: More children were able to avoid anesthesia use entirely in the post-XXX cohort, compared to the pre-XXX cohort (73.2% vs 63.4%, p=0.03) and fewer required anesthesia for each treatment (18.8% vs 33%; p = 0.03). XXX introduction reduced anesthesia use for all ages studied. Treatment time per session was reduced by 38% using XXX compared to anesthesia. There were 326 fewer anesthesia sessions delivered over three years after XXX was introduced, with an estimated savings of > $500,000. OSLDs revealed a small increase in dose of 0.8%-9.5% with XXX, while the use of a thermomolded face mask increased skin dose as much as 58%.CONCLUSIONS: XXX introduction decreased anesthesia use in children undergoing radiotherapy; more avoided anesthesia entirely, and fewer needed it for every treatment. This resulted in a reduction in treatment time, and savings of nearly $550,000 in approximately 3 years, with minimal perturbation of radiotherapy dose delivery.

  View details for DOI 10.1016/j.prro.2019.12.009

  View details for PubMedID 31935524

• Initial Steps Towards a Clinical FLASH Radiotherapy System: Pediatric Whole Brain Irradiation with 40 MeV Electrons at FLASH Dose Rates. Radiation research Breitkreutz, D. Y., Shumail, M. n., Bush, K. K., Tantawi, S. G., Maxim, P. G., Loo, B. W. 2020

  Abstract

  In this work, we investigated the delivery of a clinically acceptable pediatric whole brain radiotherapy plan at FLASH dose rates using two lateral opposing 40-MeV electron beams produced by a practically realizable linear accelerator system. The EGSnrc Monte Carlo software modules, BEAMnrc and DOSXYZnrc, were used to generate whole brain radiotherapy plans for a pediatric patient using two lateral opposing 40-MeV electron beams. Electron beam phase space files were simulated using a model of a diverging beam with a diameter of 10 cm at 50 cm SAD (defined at brain midline). The electron beams were collimated using a 10-cm-thick block composed of 5 cm of aluminum oxide and 5 cm of tungsten. For comparison, a 6-MV photon plan was calculated with the Varian AAA algorithm. Electron beam parameters were based on a novel linear accelerator designed for the PHASER system and powered by a commercial 6-MW klystron. Calculations of the linear accelerator's performance indicated an average beam current of at least 6.25 μA, providing a dose rate of 115 Gy/s at isocenter, high enough for cognition-sparing FLASH effects. The electron plan was less homogenous with a homogeneity index of 0.133 compared to the photon plan's index of 0.087. Overall, the dosimetric characteristics of the 40-MeV electron plan were suitable for treatment. In conclusion, Monte Carlo simulations performed in this work indicate that two lateral opposing 40-MeV electron beams can be used for pediatric whole brain irradiation at FLASH dose rates of 115 Gy/s and serve as motivation for a practical clinical FLASH radiotherapy system, which can be implemented in the near future.

  View details for DOI 10.1667/RADE-20-00069.1

  View details for PubMedID 32991725

• Evaluating the Reproducibility of Mouse Anatomy under Rotation in a Custom Immobilization Device for Conformal FLASH Radiotherapy. Radiation research Ko, R. B., Soto, L. A., von Eyben, R. n., Melemenidis, S. n., Rankin, E. B., Maxim, P. G., Graves, E. E., Loo, B. W. 2020

  Abstract

  The observation of an enhanced therapeutic index for FLASH radiotherapy in mice has created interest in practical laboratory-based FLASH irradiators. To date, systems capable of 3D conformal FLASH irradiation in mice have been lacking. We are developing such a system, incorporating a high-current linear accelerator to produce a collimated X-ray beam in a stationary beamline design, rotating the mouse about a longitudinal axis to achieve conformal irradiation from multiple beam directions. The purpose of this work was to evaluate the reproducibility of mouse anatomy under rotation at speeds compatible with conformal FLASH delivery. Three short-hair mice and two hairless mice were immobilized under anesthesia in body weight-specific contoured plastic molds, and subjected to three rotational (up to 3 revolutions/s) and two non-rotational movement interventions. MicroCT images were acquired before and after each intervention. The displacements of 11 anatomic landmarks were measured on the image pairs. The displacement of the anatomical landmarks with any of the interventions was 0.5 mm or less for 92.4% of measurements, with a single measurement out of 275 (11 landmarks × 5 interventions × 5 mice) reaching 1 mm. There was no significant difference in the displacements associated with rotation compared to those associated with moving the immobilized mouse in and out of a scanner or with leaving the mouse in place for 5 min with no motion. There were no significant differences in displacements between mice with or without hair, although the analysis is limited by small numbers, or between different anatomic landmarks. These results show that anatomic reproducibility under rotation speed corresponding to FLASH irradiation times appears to be compatible with conformal/stereotactic irradiation in mice.

  View details for DOI 10.1667/RADE-20-00095

  View details for PubMedID 32857849

• Predicting per-lesion local recurrence in locally advanced non-small cell lung cancer following definitive radiation therapy using pre- and mid-treatment metabolic tumor volume. Radiation oncology (London, England) Binkley, M. S., Koenig, J. L., Kashyap, M. n., Xiang, M. n., Liu, Y. n., Sodji, Q. n., Maxim, P. G., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2020; 15 (1): 114

  Abstract

  We evaluated whether pre- and mid-treatment metabolic tumor volume (MTV) predicts per lesion local recurrence (LR) in patients treated with definitive radiation therapy (RT, dose≥60 Gy) for locally advanced non-small cell lung cancer (NSCLC).We retrospectively reviewed records of patients with stage III NSCLC treated from 2006 to 2018 with pre- and mid-RT PET-CT. We measured the MTV of treated lesions on the pre-RT (MTVpre) and mid-RT (MTVmid) PET-CT. LR was defined per lesion as recurrence within the planning target volume. Receiver operating characteristic (ROC) curves, cumulative incidence rates, and uni- and multivariable (MVA) competing risk regressions were used to evaluate the association between MTV and LR.We identified 111 patients with 387 lesions (112 lung tumors and 275 lymph nodes). Median age was 68 years, 69.4% were male, 46.8% had adenocarcinoma, 39.6% had squamous cell carcinoma, and 95.5% received concurrent chemotherapy. Median follow-up was 38.7 months. 3-year overall survival was 42.3%. 3-year cumulative incidence of LR was 26.8% per patient and 11.9% per lesion. Both MTVpre and MTVmid were predictive of LR by ROC (AUC = 0.71 and 0.76, respectively) and were significantly associated with LR on MVA (P = 0.004 and P = 7.1e-5, respectively). Among lesions at lower risk of LR based on MTVpre, higher MTVmid was associated with LR (P = 0.001).Per-lesion, larger MTVpre and MTVmid predicted for increased risk of LR. MTVmid was more highly predictive of LR than MTVpre and if validated may allow for further discrimination of high-risk lesions at mid-RT informing dose painting strategies.

  View details for DOI 10.1186/s13014-020-01546-y

  View details for PubMedID 32429982

• Early response evaluation using primary tumor and nodal imaging features to predict progression-free survival of locally advanced non-small cell lung cancer. Theranostics Zhang, N., Liang, R., Gensheimer, M. F., Guo, M., Zhu, H., Yu, J., Diehn, M., Loo, B. W., Li, R., Wu, J. 2020; 10 (25): 11707–18

  Abstract

  Prognostic biomarkers that can reliably predict early disease progression of non-small cell lung cancer (NSCLC) are needed for identifying those patients at high risk for progression, who may benefit from more intensive treatment. In this work, we aimed to identify an imaging signature for predicting progression-free survival (PFS) of locally advanced NSCLC. Methods: This retrospective study included 82 patients with stage III NSCLC treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were performed. They were randomly placed into two groups: training cohort (n=41) and testing cohort (n=41). All primary tumors and involved lymph nodes were delineated. Forty-five quantitative imaging features were extracted to characterize the tumors and involved nodes at baseline and mid-treatment as well as differences between two scans performed at these two points. An imaging signature was developed to predict PFS by fitting an L1-regularized Cox regression model. Results: The final imaging signature consisted of three imaging features: the baseline tumor volume, the baseline maximum distance between involved nodes, and the change in maximum distance between the primary tumor and involved nodes measured at two time points. According to multivariate analysis, the imaging model was an independent prognostic factor for PFS in both the training (hazard ratio [HR], 1.14, 95% confidence interval [CI], 1.04-1.24; P = 0.003), and testing (HR, 1.21, 95% CI, 1.10-1.33; P = 0.048) cohorts. The imaging signature stratified patients into low- and high-risk groups, with 2-year PFS rates of 61.9% and 33.2%, respectively (P = 0.004 [log-rank test]; HR, 4.13, 95% CI, 1.42-11.70) in the training cohort, as well as 43.8% and 22.6%, respectively (P = 0.006 [log-rank test]; HR, 3.45, 95% CI, 1.35-8.83) in the testing cohort. In both cohorts, the imaging signature significantly outperformed conventional imaging metrics, including tumor volume and SUVmax value (C-indices: 0.77-0.79 for imaging signature, and 0.53-0.73 for conventional metrics). Conclusions: Evaluation of early treatment response by combining primary tumor and nodal imaging characteristics may improve the prediction of PFS of locally advanced NSCLC patients.

  View details for DOI 10.7150/thno.50565

  View details for PubMedID 33052242

• FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation. Radiation research Soto, L. A., Casey, K. M., Wang, J. n., Blaney, A. n., Manjappa, R. n., Breitkreutz, D. n., Skinner, L. n., Dutt, S. n., Ko, R. B., Bush, K. n., Yu, A. S., Melemenidis, S. n., Strober, S. n., Englemann, E. n., Maxim, P. G., Graves, E. E., Loo, B. W. 2020

  Abstract

  Radiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.

  View details for DOI 10.1667/RADE-20-00090

  View details for PubMedID 32853385

• Patient motion tracking for non-isocentric and non-coplanar treatments via fixed frame-of-reference 3D camera. Journal of applied clinical medical physics Gasparyan, S. n., Ko, K. n., Skinner, L. B., Ko, R. B., Loo, B. W., Fahimian, B. P., Yu, A. S. 2020

  Abstract

  As C-arm linac radiation therapy evolves toward faster, more efficient delivery, and more conformal dosimetry, treatments with increasingly complex couch motions are emerging. Monitoring the patient motion independently of the couch motion during non-coplanar, non-isocentric, or dynamic couch treatments is a key bottleneck to their clinical implementation. The goal of this study is to develop a prototype real-time monitoring system for unconventional beam trajectories to ensure a safe and accurate treatment delivery.An in-house algorithm was developed for tracking using a couch-mounted three-dimensional (3D) depth camera. The accuracy of patient motion detection on the couch was tested on a 3D printed phantom created from the body surface contour exported from the treatment planning system. The technique was evaluated against a commercial optical surface monitoring system with known phantom displacements of 3, 5, and 7 mm in lateral, longitudinal, and vertical directions by placing a head phantom on a dynamic platform on the treatment couch. The stability of the monitoring system was evaluated during dynamic couch trajectories, at speeds between 10.6 and 65 cm/min.The proposed monitoring system agreed with the ceiling mounted optical surface monitoring system in longitudinal, lateral, and vertical directions within 0.5 mm. The uncertainty caused by couch vibration increased with couch speed but remained sub-millimeter for speeds up to 32 cm/min. For couch speeds of 10.6, 32.2, and 65 cm/min, the uncertainty ranges were 0.27- 0.73 mm, 0.15-0.87 mm, and 0.28-1.29 mm, respectively.By mounting a 3D camera in the same frame-of-reference as the patient and eliminating dead spots, this proof of concept demonstrates real-time patient monitoring during couch motion. For treatments with non-coplanar beams, multiple isocenters, or dynamic couch motion, this provides additional safety without additional radiation dose and avoids some of the complexity and limitations of room mounted systems.

  View details for DOI 10.1002/acm2.12842

  View details for PubMedID 32107845

• KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer discovery Binkley, M. S., Jeon, Y. J., Nesselbush, M. n., Moding, E. J., Nabet, B. Y., Almanza, D. n., Kunder, C. n., Stehr, H. n., Yoo, C. H., Rhee, S. n., Xiang, M. n., Chabon, J. J., Hamilton, E. n., Kurtz, D. M., Gojenola, L. n., Owen, S. G., Ko, R. B., Shin, J. H., Maxim, P. G., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M. n., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. n. 2020

  Abstract

  Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

  View details for DOI 10.1158/2159-8290.CD-20-0282

  View details for PubMedID 33071215

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2020.03.028

  View details for PubMedID 32298811

• Novel Radiation Therapy Paradigms and Immunomodulation: Heresies and Hope. Seminars in radiation oncology Dutt, S. n., Ahmed, M. M., Loo, B. W., Strober, S. n. 2020; 30 (2): 194–200

  Abstract

  Radiation therapy benefits the majority of patients across the spectrum of cancer types. However, both local and distant tumor recurrences limit its clinical success. While departing from the established tenet of fractionation in clinical radiotherapy, ablative-intensity hypofractionated radiotherapy, especially stereotactic radiosurgery and stereotactic ablative radiotherapy, has emerged as an alternative paradigm achieving unprecedented rates of local tumor control. Direct tumor cell killing has been assumed to be the primary therapeutic mode of action of such ablative radiation. But with increasing recognition that tumor responses also depend on the immunostimulatory or immunosuppressive status of the tumor microenvironment, the immunologic effect of ablative radiotherapy is emerging as a key contributor to antitumor response. More recently, novel radiation modalities, such as spatially fractionated radiotherapy and ultrahigh dose rate FLASH irradiation, that venture even further from conventional paradigms have shown promise of increasing the therapeutic index of radiation therapy with the potential of immunomodulation. Here, we review the immunomodulatory impact of novel radiation therapy paradigms, heretofore considered radiobiological heresies, a deeper understanding of which is imperative to realizing fully their potential for more curative cancer therapy.

  View details for DOI 10.1016/j.semradonc.2019.12.006

  View details for PubMedID 32381299

• Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer NATURE CANCER Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Gojenola, L., Jones, C. D., He, J., Qiao, Y., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo Jr., B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1: 176–183

  View details for DOI 10.1038/s43018-019-0011-0

• Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice. Scientific reports Levy, K. n., Natarajan, S. n., Wang, J. n., Chow, S. n., Eggold, J. T., Loo, P. E., Manjappa, R. n., Melemenidis, S. n., Lartey, F. M., Schüler, E. n., Skinner, L. n., Rafat, M. n., Ko, R. n., Kim, A. n., H Al-Rawi, D. n., von Eyben, R. n., Dorigo, O. n., Casey, K. M., Graves, E. E., Bush, K. n., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B. 2020; 10 (1): 21600

  Abstract

  Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

  View details for DOI 10.1038/s41598-020-78017-7

  View details for PubMedID 33303827

• Non-Small Cell Lung Cancer, Version 1.2020 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Wood, D. E., Aggarwal, C., Aisner, D. L., Akerley, W., Bauman, J. R., Bharat, A., Bruno, D. S., Chang, J. Y., Chirieac, L. R., D'Amico, T. A., Dilling, T. J., Dobelbower, M., Gettinger, S., Govindan, R., Gubens, M. A., Hennon, M., Horn, L., Lackner, R. P., Lanuti, M., Leal, T. A., Lin, J., Loo, B. W., Martins, R. G., Otterson, G. A., Patel, S. P., Reckamp, K. L., Riely, G. J., Schild, S. E., Shapiro, T. A., Stevenson, J., Swanson, S. J., Tauer, K. W., Yang, S. C., Gregory, K., Hughes, M. 2019; 17 (12): 1464–72

  Abstract

  The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."

  View details for DOI 10.6004/jnccn.2019.0059

  View details for Web of Science ID 000500944300007

  View details for PubMedID 31805526

• Deep segmentation networks predict survival of non-small cell lung cancer. Scientific reports Baek, S., He, Y., Allen, B. G., Buatti, J. M., Smith, B. J., Tong, L., Sun, Z., Wu, J., Diehn, M., Loo, B. W., Plichta, K. A., Seyedin, S. N., Gannon, M., Cabel, K. R., Kim, Y., Wu, X. 2019; 9 (1): 17286

  Abstract

  Non-small-cell lung cancer (NSCLC) represents approximately 80-85% of lung cancer diagnoses and is the leading cause of cancer-related death worldwide. Recent studies indicate that image-based radiomics features from positron emission tomography/computed tomography (PET/CT) images have predictive power for NSCLC outcomes. To this end, easily calculated functional features such as the maximum and the mean of standard uptake value (SUV) and total lesion glycolysis (TLG) are most commonly used for NSCLC prognostication, but their prognostic value remains controversial. Meanwhile, convolutional neural networks (CNN) are rapidly emerging as a new method for cancer image analysis, with significantly enhanced predictive power compared to hand-crafted radiomics features. Here we show that CNNs trained to perform the tumor segmentation task, with no other information than physician contours, identify a rich set of survival-related image features with remarkable prognostic value. In a retrospective study on pre-treatment PET-CT images of 96 NSCLC patients before stereotactic-body radiotherapy (SBRT), we found that the CNN segmentation algorithm (U-Net) trained for tumor segmentation in PET and CT images, contained features having strong correlation with 2- and 5-year overall and disease-specific survivals. The U-Net algorithm has not seen any other clinical information (e.g. survival, age, smoking history, etc.) than the images and the corresponding tumor contours provided by physicians. In addition, we observed the same trend by validating the U-Net features against anextramural data set provided by Stanford Cancer Institute. Furthermore, through visualization of the U-Net, we also found convincing evidence that the regions of metastasis and recurrence appear to match with the regions where the U-Net features identified patterns that predicted higher likelihoods of death. We anticipate our findings will be a starting point for more sophisticated non-intrusive patient specific cancer prognosis determination. For example, the deep learned PET/CT features can not only predict survival but also visualize high-risk regions within or adjacent to the primary tumor and hence potentially impact therapeutic outcomes by optimal selection of therapeutic strategy or first-line therapy adjustment.

  View details for DOI 10.1038/s41598-019-53461-2

  View details for PubMedID 31754135

• TOTAL ABDOMINAL ULTRA-RAPID FLASH IRRADIATION DEMONSTRATES DECREASED GASTROINTESTINAL TOXICITY COMPARED TO CONVENTIONAL TOTAL ABDOMINAL IRRADIATION IN MICE Levy, K., Eggold, J., Rafat, M., Schuler, E., Shehade, H., Fregoso, D., Vilches-Moure, J., Koong, A., Maxim, P., Loo, B. W., Rankin, E. AMER ASSOC CANCER RESEARCH. 2019: 182

  View details for Web of Science ID 000497337700109

• The Real-World Risk of Brain Metastases in Stage 3 Lung Cancer Patients in the Era of PET and MRI Staging Ko, R., Therkelsen, K., Von Eyben, R., Neal, J., Loo, B., Nagpal, S. ELSEVIER SCIENCE INC. 2019: S585–S586

  View details for Web of Science ID 000492162203144

• Circulating Tumor DNA Changes During Chemoradiation for Lung Cancer Predict Patient Outcomes Moding, E. J., Nabet, B. Y., Liu, Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Binkley, M. S., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z., Das, M., Ramchandran, K. J., Padda, S., Neal, W., Wakelee, H. A., Gensheimer, M. F., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2019: S113

  View details for DOI 10.1016/j.ijrobp.2019.06.610

  View details for Web of Science ID 000485671502643

• Lessons Learned From Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients PRACTICAL RADIATION ONCOLOGY Gay, H. A., Santiago, R., Gil, B., Remedios, C., Montes, P. J., Lopez-Araujo, J., Chevere, C. M., Imbert, W. S., White, J., Arthur, D. W., Horton, J. K., Jagsi, R., Rabinovich, R., Beriwal, S., Viswanathan, A., Erickson, B. A., Rengan, R., Palma, D., Loo, B. W., Kavanaugh, J. A., Bradley, J., Yom, S. S., Harari, P. M., Burnett, O. 2019; 9 (5): 305–21

  View details for DOI 10.1016/j.prro.2019.03.007

  View details for Web of Science ID 000483978300015

• Symptomatic Cardiac Events in Patients with Lung Tumors Near The Heart Treated with Stereotactic Ablative Radiotherapy (SABR): A Single Institution Experience Ko, R. B., Jani, K., Sodji, Q., Merriott, D. J., Pickthorn, W., Bush, K., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2019: S148

  View details for DOI 10.1016/j.ijrobp.2019.06.151

  View details for Web of Science ID 000485671503008

• Influence of Dose and Fractionation on Radiologic Lung Fibrosis after Stereotactic Ablative Radiotherapy (SABR) Ross, J. B., Ross, J. B., Merriott, D. J., Alhumaid, S., Schueler, E., Ko, R. B., Bush, K., Maxim, P. G., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2019: E527–E528

  View details for DOI 10.1016/j.ijrobp.2019.06.2430

  View details for Web of Science ID 000485671501498

• Investigating and Validating Metabolic Tumor Volume As a Prognostic Factor for Local Recurrence in Early Stage Lung Cancer Binkley, M. S., Stehr, H., Moding, E. J., Owen, S. G., Ko, R., Maxim, P. G., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2019: E497

  View details for DOI 10.1016/j.ijrobp.2019.06.1407

  View details for Web of Science ID 000485671501426

• Lessons Learned from Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients Gay, H. A., Santiago, R., Gil, B., Remedios, C., Montes-Garcia, P. J., Lopez Araujo, J., Chevere, C. M., Imbert, W. S., White, J. R., Arthur, D. W., Horton, J. K., Jagsi, R., Rabinovitch, R. A., Beriwal, S., Viswanathan, A. N., Erickson, B. A., Rengan, R., Palma, D. A., Loo, B. W., Kavanaugh, J., Bradley, J. D., Yom, S. S., Harari, P. M., Burnett, O. L. ELSEVIER SCIENCE INC. 2019: E612–E613

  View details for DOI 10.1016/j.ijrobp.2019.06.1137

  View details for Web of Science ID 000485671501699

• Outcomes of Oligometastatic Colorectal Cancer treated with Stereotactic Ablative Radiotherapy Benson, K., Sandhu, N., Zhang, C., Ko, R. B., Toesca, D. S., Von Eyben, R., Diehn, M., Bush, K., Maxim, P. G., Gensheimer, M. F., Soltys, S. G., Loo, B. W., Pollom, E., Chang, D. T. ELSEVIER SCIENCE INC. 2019: E161–E162

  View details for DOI 10.1016/j.ijrobp.2019.06.2134

  View details for Web of Science ID 000485671500365

• Radiotherapy and Immunotherapy-Shining Further Together. JAMA oncology Walker, J., Loo, B. W. 2019

  View details for DOI 10.1001/jamaoncol.2019.1448

  View details for PubMedID 31294751

• PHASER: A platform for clinical translation of FLASH cancer radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Maxim, P. G., Tantawi, S. G., Loo, B. W. 2019

  Abstract

  Pluridirectional high-energy agile scanning electronic radiotherapy (PHASER) is next-generation medical linac technology for ultra-rapid highly conformal image-guided radiation, fast enough to "freeze" physiological motion, affording improved accuracy, precision, and potentially superior FLASH radiobiological therapeutic index. Designed for compactness, economy, and clinical efficiency, it is also intended to address barriers to global access to curative radiotherapy.

  View details for DOI 10.1016/j.radonc.2019.05.005

  View details for PubMedID 31178058

• The Promise of FLASH Koong, A., Pollard-Larkin, J., Dong, L., Loo, B. WILEY. 2019: E395

  View details for Web of Science ID 000471277703001

• Mortality of lung cancer as a second primary malignancy: A population-based cohort study CANCER MEDICINE Deng, L., Hardardottir, H., Song, H., Xiao, Z., Jiang, C., Wang, Q., Valdimarsdottir, U., Cheng, H., Loo, B. W., Lu, D. 2019; 8 (6): 3269–77

  View details for DOI 10.1002/cam4.2172

  View details for Web of Science ID 000474292100054

• FLT-PET-CT for the Detection of Disease Recurrence After Stereotactic Ablative Radiotherapy or Hyperfractionation for Thoracic Malignancy: A Prospective Pilot Study. Frontiers in oncology Hiniker, S. M., Sodji, Q., Quon, A., Gutkin, P. M., Arksey, N., Graves, E. E., Chin, F. T., Maxim, P. G., Diehn, M., Loo, B. W. 2019; 9: 467

  Abstract

  Differentiating local recurrence from post-treatment changes on PET scans following stereotactic ablative radiotherapy (SABR) or hyperfractionation for lung tumors is challenging. We performed a prospective pilot study of 3-deoxy-3-[18F]-fluorothymidine (FLT)-PET-CT in patients with equivocal post-radiation FDG-PET-CT to assess disease recurrence. Methods: We prospectively enrolled 10 patients, 9 treated with SABR and 1 with hyperfractionated external beam radiotherapy for thoracic malignancy with subsequent equivocal follow-up FDG-PET-CT, to undergo FLT-PET-CT prior to biopsy or serial imaging. FLT-PET scans were interpreted by a radiologist with experience in reading FLT-PET-CT and blinded to the results of any subsequent biopsy or imaging. Results: Of the 10 patients enrolled, 8 were evaluable after FLT-PET-CT. Based on the FLT-PET-CT, a blinded radiologist accurately predicted disease recurrence vs. inflammatory changes in 7 patients (87.5%). The combination of higher lesion SUVmax and higher ratio of lesion SUVmax to SUVmax of mediastinal blood pool was indicative of recurrence. Qualitative assessment of increased degree of focality of the lesion also appears to be indicative of disease recurrence. Conclusion: Adjunctive FLT-PET-CT imaging can complement FDG-PET-CT scan in distinguishing post-treatment radiation changes from disease recurrence in thoracic malignancies. These findings support the investigation of FLT-PET-CT in a larger prospective study.

  View details for DOI 10.3389/fonc.2019.00467

  View details for PubMedID 31214507

  View details for PubMedCentralID PMC6555304

• Conical beam geometry intensity-modulated radiation therapy. Physics in medicine and biology Schueler, E., Wang, L., Loo, B., Maxim, P. G. 2019

  Abstract

  Most commonly in radiation therapy, treatments are delivered in a co-planar geometry. Numerous advantages have been reported of adding non-coplanar beams to the treatment plan. The aim of this study was to compare current state-of-the-art VMAT and CyberKnife treatment plans to that of a novel linac design developed at Stanford which utilizes a static conical beam arrangement that allows the inclusion of a full ring diagnostic CT with shared isocenter with the treatment beams.&#13; &#13; Four clinical cases, prostate, lung, head/neck, and pediatric brain, were selected and treatment plans were generated with 45o or 60o (to the longitudinal axis of the patient ) conical beam IMRT and compared with co-planar 90o VMAT plans. Double cone, with beams entering from both superior and inferior directions, and single cone geometries were evaluated. Plans were optimized in RayStation using an in-house developed script to minimize operator bias between the different techniques. Non-coplanar CyberKnife IMRT plans for the pediatric and prostate case were optimized separately in MultiPlan and compared to conical geometry plans. &#13; &#13; In the prostate case, increased mean dose to the rectum (2.3-3.7 Gy) and bladder (9.5-14.5 Gy) but decreased dose to the femoral heads (femurs) (7.1-10 Gy) were found with the conical arrangement compared to 90o VMAT. Only minor dosimetric differences were found in the lung case, while selective sparing of organs at risk was found with 45o or 60o conical arrangement in the pediatric brain and head/neck cases. For the prostate case, a reduction in mean doses to the bladder and rectum of 6% (2 Gy) and 18% (5.2 Gy), respectively, was found when comparing the CyberKnife to the 60o conical plan, in favor of the CyberKnife plan, but with an increase in integral dose and reduced conformity. An increase in integral dose and reduced conformity was also found for the pediatric brain case when comparing CyberKnife and 60o conical plan. Minor benefits were found with double cone compared to single cone geometry.&#13; &#13; Comparable treatment plan quality could be achieved between conical beam arrangement and 90o (coplanar) VMAT and CyberKnife (non-coplanar) IMRT, demonstrating the promise of this novel beam geometry. The use of this beam geometry allows volumetric image-guidance with full ring imaging and a common isocenter for simultaneous treatment and imaging. &#13.

  View details for DOI 10.1088/1361-6560/ab246f

  View details for PubMedID 31125980

• Preclinical testing of ultra-rapid FLASH total abdominal irradiation demonstrates survival benefit and decreased gastrointestinal toxicity compared to conventional external beam radiation. Levy, K., Rafat, M., Schueler, E., Eggold, J., Wang, J., Casey, K., Koong, A., Maxim, P., Loo, B. W., Rankin, E. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.3092

  View details for Web of Science ID 000487345805026

• ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer. Moding, E. J., Liu, Y., Nabet, B., Chabon, J. J., Chaudhuri, A., Hui, A. B., He, J., Qiao, Y., Heymach, J., Tsao, A. S., Liao, Z. X., Gomez, D., Ramchandran, K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2547

  View details for Web of Science ID 000487345804497

• SABR-COMET: harbinger of a new cancer treatment paradigm LANCET Loo, B. W., Diehn, M. 2019; 393 (10185): 2013–14

  View details for DOI 10.1016/S0140-6736(19)30278-8

  View details for Web of Science ID 000468112000006

• Mortality of lung cancer as a second primary malignancy: A population-based cohort study. Cancer medicine Deng, L., Hardardottir, H., Song, H., Xiao, Z., Jiang, C., Wang, Q., Valdimarsdottir, U., Cheng, H., Loo, B. W., Lu, D. 2019

  Abstract

  Lung cancer as a second primary malignancy (lung-2) is increasingly common, but its prognosis is poorly understood. This study aims to examine the overall and cancer-specific survival of patients diagnosed with lung-2 compared to lung-1. Primary lung cancer patients diagnosed from 1988 to 2014 in the Surveillance, Epidemiology, and End Results (SEER) program were included. Lung-2 was identified in patients with a previous diagnosis of nonlung primary malignancy in SEER. Hazard ratios (HRs) of overall and lung cancer-specific mortality were estimated among patients with lung-2 compared to lung-1, adjusting for age and calendar period at diagnosis, sex, race, socioeconomic status, tumor stage, histology, tumor grade, and treatment. A total of 679541 and 85758 patients were identified as lung-1 and lung-2, respectively. Compared to lung-1, patients with lung-2 were more likely to be diagnosed at localized stage, with smaller primary tumor, and treated with surgery. Lung-2 patients were at lower risk of lung cancer-specific mortality in the first 5years (HR, 0.77; 95% CI, 0.76-0.78 at <1year; HR, 0.87; 95% CI, 0.86-0.89 from 1 to <5years) but at higher risk thereafter (HR, 1.32; 95% CI, 1.27-1.37 from 5 to 10years), independent of tumor characteristics and cancer treatment. Similar pattern was found for overall mortality, although the survival benefit was restricted to the first year after diagnosis. Patients diagnosed with lung-2 face a favorable lung cancer-specific survival within the early period after diagnosis. A conservative approach to manage lung-2 solely based on malignancy history is not supported.

  View details for PubMedID 30993899

• Lessons Learned from Hurricane Maria in Puerto Rico: Practical Measures to Mitigate the Impact of a Catastrophic Natural Disaster on Radiation Oncology Patients. Practical radiation oncology Gay, H. A., Santiago, R., Gil, B., Remedios, C., Montes, P. J., Lopez-Araujo, J., Chevere, C. M., Imbert, W. S., White, J., Arthur, D. W., Horton, J. K., Jagsi, R., Rabinovich, R., Beriwal, S., Viswanathan, A., Erickson, B. A., Rengan, R., Palma, D., Loo, B. W., Kavanaugh, J. A., Bradley, J., Yom, S. S., Harari, P. M., Lee Burnett, O. 3. 2019

  View details for PubMedID 30999000

• HyTEC: Organ-Specific Paper Thoracic: Lung TCP. International journal of radiation oncology, biology, physics Lee, P., Loo, B. W., Biswas, T., Ding, G. X., El Naqa, I. M., Jackson, A., Kong, F., LaCouture, T., Miften, M., Solberg, T., Tome, W. A., Tai, A., Yorke, E., Li, X. A. 2019

  Abstract

  PURPOSE: Numerous dose and fractionation schedules have been used to treat medically inoperable stage I Non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR). We evaluated published experiences with SBRT to determine local control (LC) rates as a function of SBRT dose.METHODS: One hundred sixty published articles reporting LC rates following SBRT for stage I NSCLC were identified. Quality of the series was assessed by evaluating the number of patients in the study, homogeneity of the dose regimen, length of follow-up time, and reporting of LC. Clinical data including 1, 2, 3, and 5 year tumor control probabilities for T1, T2, and combined T1 and T2 stage as a function of the biological effective dose were fitted to the linear quadratic (LQ), Universal survival curve (USC), and regrowth models.RESULTS: Forty-six studies met inclusion criteria. As measured by the goodness of fit chi2/ndf, with ndf as the number of degrees of freedom, none of the models were ideal fits for the data. Of the three models, the regrowth model provides the best fit to the clinical data. For the regrowth model, the fitting yielded an alpha/beta ratio of approximately 25 Gy for T1 tumors, 19 Gy for T2 tumors, and 21 Gy for T1 and T2 combined. In order to achieve the maximal LC rate, the predicted physical dose schemes when prescribed at the periphery of the planning target volume (PTV) are 43 +/- 1 Gy in 3 fractions, 47 +/- 1 Gy in 4 fractions, and 50 +/- 1 Gy in 5 fractions for combined T1 and T2 tumors.CONCLUSION: Early stage NSCLC is radioresponsive when treated with SBRT/SABR. A steep dose-response relationship exists with high rates of durable LC when physical doses of 43-50 Gy are delivered in 3-5 fractions.

  View details for PubMedID 30954520

• Increases in Serial Pretreatment 18F-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy. Advances in radiation oncology Prionas, N. D., von Eyben, R., Yi, E., Aggarwal, S., Shaffer, J., Bazan, J., Eastham, D., Maxim, P. G., Graves, E. E., Diehn, M., Gensheimer, M. F., Loo, B. W. 2019; 4 (2): 429–37

  Abstract

  Purpose: Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR).Methods and Materials: Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort.Results: A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P=.10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P=.07). MTGR greater than 0.04mL/d was prognostic of decreased survival in discovery (P=.048) and validation cohorts (P<.01).Conclusions: MTGR greater than 0.04mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.

  View details for PubMedID 31011689

• Increases in Serial Pretreatment F-18-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy ADVANCES IN RADIATION ONCOLOGY Prionas, N. D., von Eyben, R., Yi, E., Aggarwal, S., Shaffer, J., Bazan, J., Eastham, D., Maxim, P. G., Graves, E. E., Diehn, M., Gensheimer, M. F., Loo, B. W. 2019; 4 (2): 429–37

  View details for DOI 10.1016/j.adro.2018.11.006

  View details for Web of Science ID 000516858500027

• Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Simmons, D. A., Lartey, F. M., Schüler, E. n., Rafat, M. n., King, G. n., Kim, A. n., Ko, R. n., Semaan, S. n., Gonzalez, S. n., Jenkins, M. n., Pradhan, P. n., Shih, Z. n., Wang, J. n., von Eyben, R. n., Graves, E. E., Maxim, P. G., Longo, F. M., Loo, B. W. 2019

  Abstract

  To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation.We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay.At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3.Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors.

  View details for DOI 10.1016/j.radonc.2019.06.006

  View details for PubMedID 31253467

• The use of texture-based radiomics CT analysis to predict outcomes in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy BRITISH JOURNAL OF RADIOLOGY Starkov, P., Aguilera, T. A., Golden, D., Shultz, D. B., Trakul, N., Maxim, P. G., Quynh-Thu Le, Loo, B. W., Diehn, M., Depeursinge, A., Rubin, D. L. 2019; 92 (1094)

  View details for DOI 10.1259/bjr.20180228

  View details for Web of Science ID 000456614000006

• Stereotactic Ablative Radiotherapy for Central and Ultra-Central Lung Tumors. Therapeutic radiology and oncology Chaudhuri, A. A., Chen, K. n., Diehn, M. n., Loo, B. W. 2019; 3

  Abstract

  Stereotactic ablative radiotherapy (SABR) has emerged as a standard-of-care treatment for patients with early stage non-small cell lung cancer (NSCLC) who are poor surgical candidates. Current evidence supports the consensus that lung SABR with BED ≥100 Gy leads to high local tumor control, and that the treatment is generally well-tolerated when applied to peripheral lung tumors. However, several studies present conflicting evidence for the treatment of central and ultra-central lung tumors, with some showing superb outcomes and others showing concerning rates of morbidity and mortality. Therefore, treatment of central and especially ultra-central lung tumors with SABR remains controversial. In this review, we aim to present the existing evidence for SABR treatment of central and ultra-central lung tumors and delineate the factors that could lead to significant toxicity.

  View details for DOI 10.21037/tro.2019.05.01

  View details for PubMedID 33880444

  View details for PubMedCentralID PMC8054989

• Cost Analysis of Audiovisual-Assisted Therapeutic Ambiance in Radiation Therapy (AVATAR) Aided Omission of Anesthesia in Radiation for Pediatric Malignancies. Practical radiation oncology McClelland, S. n., Overton, K. W., Overshiner, B. n., Bush, K. n., Loo, B. W., Skinner, L. B., Watson, G. A., Holmes, J. A., Hiniker, S. M., Maxim, P. G. 2019

  View details for DOI 10.1016/j.prro.2019.09.011

  View details for PubMedID 31574319

• Predictors of Respiratory Decline Following Stereotactic Ablative Radiotherapy to Multiple Lung Tumors. Clinical lung cancer Moding, E. J., Liang, R. n., Lartey, F. M., Maxim, P. G., Sung, A. n., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2019

  Abstract

  Stereotactic ablative radiotherapy (SABR) is highly effective at controlling early stage primary lung cancer and lung metastases. Although previous studies have suggested that treating multiple lung tumors with SABR is safe, post-treatment changes in respiratory function have not been analyzed in detail.We retrospectively identified patients with 2 or more primary lung cancers or lung metastases treated with SABR and analyzed clinical outcomes and predictors of toxicity. We defined a composite respiratory decline endpoint to include increased oxygen requirement, increased dyspnea scale, or death from respiratory failure not owing to disease progression.A total of 86 patients treated with SABR to 203 lung tumors were analyzed. A total of 21.8% and 41.8% of patients developed composite respiratory decline at 2 and 4 years, respectively. When accounting for intrathoracic disease progression, 12.7% of patients developed composite respiratory decline at 2 years. Of the patients, 7.9% experienced grade 2 or greater radiation pneumonitis. No patient- or treatment-related factor predicted development of respiratory decline. The median overall survival was 46.9 months, and the median progression-free survival was 14.8 months. The cumulative incidence of local failure was 9.7% at 2 years.Although our results confirm that SABR is an effective treatment modality for patients with multiple lung tumors, we observed a high rate of respiratory decline after treatment, which may be owing to a combination of treatment and disease effects. Future studies may help to determine ways to avoid pulmonary toxicity from SABR.

  View details for DOI 10.1016/j.cllc.2019.05.015

  View details for PubMedID 31377143

• Stressed out: DNA damage delivered at ultrahigh dose rates reduces cellular stress and apoptosis Al Rawi, D. H., Rafat, M., Vemireddy, S., Maxim, P., Loo, B. W. AMER SOC CELL BIOLOGY. 2018

  View details for Web of Science ID 000505772704094

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

  Abstract

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

  View details for PubMedID 30457885

• A Quantitative CT Imaging Signature Predicts Survival and Complements Established Prognosticators in Stage I Non-Small Cell Lung Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lee, J., Li, B., Cui, Y., Sun, X., Wu, J., Zhu, H., Yu, J., Gensheimer, M. F., Loo, B. W., Diehn, M., Li, R. 2018; 102 (4): 1098–1106

  View details for DOI 10.1016/j.ijrobp.2018.01.006

  View details for Web of Science ID 000447789700056

• F-18-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated With Highly Conformal Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Qian, Y., Von Eyben, R., Liu, Y., Chin, F. T., Miao, Z., Apte, S., Carter, J. N., Binkley, M. S., Pollom, E. L., Harris, J. P., Prionas, N. D., Kissel, M., Simmons, A., Diehn, M., Shultz, D. B., Brown, J., Maxim, P. G., Koong, A. C., Graves, E. E., Loo Jr, B. W. 2018; 102 (4): 1183–92

  View details for DOI 10.1016/j.ijrobp.2018.03.045

  View details for Web of Science ID 000447789700063

• Analysis of Circulating Tumor DNA Kinetics during Stereotactic Ablative Radiation Therapy for Non-Small Cell Lung Cancer Chen, E. L., Chaudhuri, A. A., Nabet, B. Y., Chabon, J. J., Merriott, D. J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2018: E676

  View details for DOI 10.1016/j.ijrobp.2018.07.1826

  View details for Web of Science ID 000447811602078

• Radiologic Quantification and Predictors of Lung Fibrosis after Stereotactic Ablative Radiation Therapy(SABR) Ross, J. B., Schueler, E., Ko, R., Bush, K., Maxim, P. G., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2018: E703

  View details for DOI 10.1016/j.ijrobp.2018.07.1890

  View details for Web of Science ID 000447811602141

• Esophagitis in Patients Treated with Thoracic Stereotactic Ablative Radiation Therapy (SABR) to Tumors within 2 cm of the Esophagus Quaovi, S., Ko, R., Bush, K., Binkley, M. S., Pickthorn, W., Maxim, P. G., Gensheimer, M. F., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2018: E666

  View details for DOI 10.1016/j.ijrobp.2018.07.1802

  View details for Web of Science ID 000447811602055

• Predicting Per-Lesion Local Recurrence in Locally Advanced Lung Cancer using Metabolic Tumor Volume on Pre- and Mid-Radiation FDG-PET Binkley, M. S., Koenig, J. L., Sodji, Q., Maxim, P. G., Diehn, M., Loo, B. W., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2018: E674

  View details for DOI 10.1016/j.ijrobp.2018.07.1820

  View details for Web of Science ID 000447811602073

• Pulmonary Interstitial Lymphography and Patterns of Recurrence after Stereotactic Ablative Radiation Therapy(SABR) of Lung Tumors Ko, R. B., Abelson, J. A., Kothary, N., Fleischmann, D., Hofmann, L., Hovsepian, D., Louie, J. D., Hwang, G., Sze, D. H., Kielar, K., Maxim, P. G., Le, Q. T., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2018: E689

  View details for DOI 10.1016/j.ijrobp.2018.07.1856

  View details for Web of Science ID 000447811602108

• Invasive nodal evaluation prior to stereotactic ablative radiation for non-small cell lung cancer LUNG CANCER Harris, J. P., Nwachukwu, C., Qian, Y., Pollom, E., Loo, B. W., Das, M., Diehn, M. 2018; 124: 76–85

  View details for DOI 10.1016/j.lungcan.2018.07.033

  View details for Web of Science ID 000448100600012

• NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018. Journal of the National Comprehensive Cancer Network : JNCCN Kalemkerian, G. P., Loo, B. W., Akerley, W., Attia, A., Bassetti, M., Boumber, Y., Decker, R., Dobelbower, M. C., Dowlati, A., Downey, R. J., Florsheim, C., Ganti, A. K., Grecula, J. C., Gubens, M. A., Hann, C. L., Hayman, J. A., Heist, R. S., Koczywas, M., Merritt, R. E., Mohindra, N., Molina, J., Moran, C. A., Morgensztern, D., Pokharel, S., Portnoy, D. C., Rhodes, D., Rusthoven, C., Santana-Davila, R., Williams, C. C., Hoffmann, K. G., Hughes, M. 2018; 16 (10): 1171–82

  Abstract

  The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."

  View details for DOI 10.6004/jnccn.2018.0079

  View details for PubMedID 30323087

• The Future of Stereotactic Ablative Radiotherapy (SABR) Loo, B. ELSEVIER SCIENCE INC. 2018: S283–S284

  View details for DOI 10.1016/j.jtho.2018.08.169

  View details for Web of Science ID 000454014500156

• Invasive nodal evaluation prior to stereotactic ablative radiation for non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Harris, J. P., Nwachukwu, C., Qian, Y., Pollom, E., Loo, B. W., Das, M., Diehn, M. 2018; 124: 76–85

  Abstract

  INTRODUCTION: Invasive nodal evaluation (INE) is used to improve staging for early stage non-small cell lung cancer (NSCLC), including when stereotactic ablative radiation (SABR) is used. Consensus guidelines from the NCCN recommend performing INE for patients with T2N0 tumors and considering INE for those with T1N0 tumors. We reasoned that if INE results in significant stage migration in the form of substantially fewer patients with occult nodal involvement, then patients treated with SABR who do not undergo INE should have worse overall survival (OS).METHODS: Patients diagnosed 2004-2014 with stage T1-2N0M0 NSCLC and treated with SABR were identified from the National Cancer Database. Factors associated with INE were determined using mixed effects logistic regression. We tested for an association between INE and OS for patients diagnosed 2004-2013 using mixed effects proportional hazards regression methods.RESULTS: 24,603 SABR patients were identified. 6% of the 19,322 patients with T1 tumors and 9% of the 5281 patients with T2 tumors had INE. Median OS was 2.8 years for the no-INE group and 2.7 years for the INE group (log-rank P=0.69). No significant association was observed between the use of INE and OS in the univariate analysis (HR 1.02, 95% CI 0.94-1.11) or the multivariate analysis (HR 0.94, 95% CI 0.86-1.02). These findings were confirmed using propensity score matched and instrumental variable analysis. On subgroup analysis, INE was associated with a non-significant trend for improved OS in patients with T2 tumors (HR 0.87, 95% CI 0.76-1.00) but not T1 tumors (HR 0.98, 95% CI 0.88-1.09).CONCLUSIONS: Despite current NCCN recommendations, the rate of INE was low for patients with stage T1 or T2 tumors. While omitting INE represents a compromise in the completeness of nodal evaluation, we found that it was not associated with a detriment in overall survival.

  View details for PubMedID 30268484

• Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer Findings From the NRG Oncology RTOG 0618 Trial JAMA ONCOLOGY Timmerman, R. D., Paulus, R., Pass, H. I., Gore, E. M., Edelman, M. J., Galvin, J., Straube, W. L., Nedzi, L. A., McGarry, R. C., Robinson, C. G., Schiff, P. B., Chang, G., Loo, B. W., Bradley, J. D., Choy, H. 2018; 4 (9): 1263–66

  Abstract

  Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear.To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection.Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non-small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014.The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks.Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points.Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively.As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer.ClinicalTrials.gov Identifier: NCT00551369.

  View details for PubMedID 29852037

  View details for PubMedCentralID PMC6117102

• Changing the global radiation therapy paradigm RADIOTHERAPY AND ONCOLOGY Pistenmaa, D. A., Dosanjh, M., Amaldi, U., Jaffray, D., Zubizarreta, E., Holt, K., Lievens, Y., Pipman, Y., Coleman, C., Workshop Participants 2018; 128 (3): 393–99

  View details for DOI 10.1016/j.radonc.2018.05.025

  View details for Web of Science ID 000444505600001

  View details for PubMedID 29921460

• Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer CLINICAL LUNG CANCER Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H., Neal, J. W., Diehn, M., Loo, B. W., Gensheimer, M. F. 2018; 19 (5): E581–E588

  View details for DOI 10.1016/j.cllc.2018.04.003

  View details for Web of Science ID 000442538700007

• NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018. Journal of the National Comprehensive Cancer Network : JNCCN Ettinger, D. S., Aisner, D. L., Wood, D. E., Akerley, W., Bauman, J., Chang, J. Y., Chirieac, L. R., D'Amico, T. A., Dilling, T. J., Dobelbower, M., Govindan, R., Gubens, M. A., Hennon, M., Horn, L., Lackner, R. P., Lanuti, M., Leal, T. A., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Patel, S. P., Reckamp, K., Riely, G. J., Schild, S. E., Shapiro, T. A., Stevenson, J., Swanson, S. J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2018; 16 (7): 807–21

  Abstract

  The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

  View details for DOI 10.6004/jnccn.2018.0062

  View details for PubMedID 30006423

• Chest wall dose reduction using noncoplanar volumetric modulated arc radiation therapy for lung stereotactic ablative radiation therapy PRACTICAL RADIATION ONCOLOGY Yu, A. S., Maxim, P. G., Loo, B. W., Gensheimer, M. F. 2018; 8 (4): E199–E207

  View details for DOI 10.1016/j.prro.2017.12.005

  View details for Web of Science ID 000436836900004

• Feasibility of a Novel Conical Beans Arrangement in Radiation Therapy Schueler, E., Wang, L., Loo, B., Maxim, P. WILEY. 2018: E127

  View details for Web of Science ID 000434978000025

• Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer Chaudhuri, A. A., Nabet, B. Y., Merriott, D. J., Jin, M., Chen, E. L., Chabon, J. J., Newman, A. M., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H., Das, M., Padda, S. K., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2018: E1–E2

  View details for Web of Science ID 000432447200003

• Biological effects by the next generation of ultra-fast dose rate ionizing radiation 'FLASH' Kim, H., Hong, B., Shueler, E., Rafat, M., Maxim, P., Loo, B. J., Ahn, G. ELSEVIER IRELAND LTD. 2018: S301

  View details for Web of Science ID 000437723401179

• A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans. Academic radiology Pinkham, D. W., Negahdar, M., Yamamoto, T., Mittra, E., Diehn, M., Nair, V. S., Keall, P. J., Maxim, P. G., Loo, B. W. 2018

  Abstract

  RATIONALE AND OBJECTIVES: The objective of this study was to assess the feasibility of single-inhalation xenon-enhanced computed tomography (XeCT) to provide clinically practical, high-resolution pulmonary ventilation imaging to clinics with access to only a single-energy computed tomography scanner, and to reduce the subject's overall exposure to xenon by utilizing a higher (70%) concentration for a much shorter time than has been employed in prior studies.MATERIALS AND METHODS: We conducted an institutional review board-approved prospective feasibility study of XeCT for 15 patients undergoing thoracic radiotherapy. For XeCT, we acquired two breath-hold single-energy computed tomography images of the entire lung with a single inhalation each of 100% oxygen and a mixture of 70% xenon and 30% oxygen, respectively. A video biofeedback system for coached patient breathing was used to achieve reproducible breath holds. We assessed the technical success of XeCT acquisition and side effects. We then used deformable image registration to align the breath-hold images with each other to accurately subtract them, producing a map of lung xenon distribution. Additionally, we acquired ventilation single-photon emission computed tomography-computed tomography (V-SPECT-CT) images for 11 of the 15 patients. For a comparative analysis, we partitioned each lung into 12 sectors, calculated the xenon concentration from the Hounsfield unit enhancement in each sector, and then correlated this with the corresponding V-SPECT-CT counts.RESULTS: XeCT scans were tolerated well overall, with a mild (grade 1) dizziness as the only side effect in 5 of the 15 patients. Technical failures in five patients occurred because of inaccurate breathing synchronization with xenon gas delivery, leaving seven patients analyzable for XeCT and single-photon emission computed tomography correlation. Sector-wise correlations were strong (Spearman coefficient >0.75, Pearson coefficient >0.65, P value <.002) for two patients for whom ventilation deficits were visibly pronounced in both scans. Correlations were nonsignificant for the remaining five who had more homogeneous XeCT ventilation maps, as well as strong V-SPECT-CT imaging artifacts attributable to airway deposition of the aerosolized imaging agent. Qualitatively, XeCT demonstrated higher resolution and no central airway deposition artifacts compared to V-SPECT-CT.CONCLUSIONS: In this pilot study, single-breath XeCT ventilation imaging was generally feasible for patients undergoing thoracic radiotherapy, using an imaging protocol that is clinically practical and potentially widely available. In the future, the xenon delivery failures can be addressed by straightforward technical improvements to the patient biofeedback coaching system.

  View details for PubMedID 29606339

• Optimal imaging surveillance after stereotactic ablative radiation therapy for early-stage non-small cell lung cancer: Findings of an International Delphi Consensus Study PRACTICAL RADIATION ONCOLOGY Nguyen, T. K., Senan, S., Bradley, J. D., Franks, K., Giuliani, M., Guckenberger, M., Landis, M., Loo, B. W., Louie, A. V., Onishi, H., Schmidt, H., Timmerman, R., Videtic, G. M., Palma, D. A. 2018; 8 (2): E71–E78

  Abstract

  Imaging after stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer can detect recurrences and second primary lung cancers; however, the optimal follow-up practice of these patients remains unclear. We sought to establish consensus recommendations for surveillance after SABR.International opinion leaders in thoracic radiation oncology and radiology were invited to participate (n = 31), with 11 accepting (9 radiation oncologists, 2 radiologists). Consensus-building was achieved using a 3-round Delphi process. Participants rated their agreement/disagreement with statements using a 5-point Likert scale. An a priori threshold of ≥75% agreement/disagreement was required for consensus.A 100% response rate was achieved and final consensus statements were approved by all participants. The consensus statements were: (1.1) thoracic computed tomography (CT) scans should be ordered routinely in follow-up; (1.2) if there is a suspicion for local recurrence (LR), fludeoxyglucose positron emission tomography/CT scans are strongly recommended. Otherwise, there is limited evidence to guide routine use of fludeoxyglucose positron emission tomography /CT; (1.3) CT imaging is not recommended at 6 weeks, but is recommended at months 3, 6, and 12 in year 1 and then every 6 months in year 2 and annually in years 3 through 5; (1.4) after 5 years, CT imaging should continue, although no consensus was reached regarding the frequency. (2.1) Response Evaluation Criteria in Solid Tumors 1.1 criteria are not sufficient for detecting LR; (2.2) a formal scoring system, informed by validated data, should be used to classify high-risk imaging features predictive of LR; (2.3) CT findings suspicious for LR include: infiltration into adjacent structures, bulging margins, sustained growth, mass-like growth, spherical growth, craniocaudal growth, and loss of air bronchograms. (3) Salvage therapy without pathologic confirmation of recurrence is acceptable if imaging findings are highly suspicious and a biopsy is not safe/feasible or if an attempted biopsy was nondiagnostic.These guidelines provide international expert consensus on areas of uncertainty in the management of early-stage non-small cell lung cancer patients after SABR.

  View details for PubMedID 29291965

• A Quantitative CT Imaging Signature Predicts Survival and Complements Established Prognosticators in Stage I Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Lee, J. n., Li, B. n., Cui, Y. n., Sun, X. n., Wu, J. n., Zhu, H. n., Yu, J. n., Gensheimer, M. F., Loo, B. W., Diehn, M. n., Li, R. n. 2018

  Abstract

  Prognostic biomarkers are needed to guide the management of early-stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers.We retrospectively analyzed data of stage I NSCLC in 8 cohorts. On the basis of an analysis of 39 computed tomography (CT) features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n = 117) and tested it in an external cohort (n = 88). A third cohort of 89 patients with CT and gene expression data was used to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from 5 gene expression cohorts (n = 639) and built a composite signature by integrating with the cell-cycle progression (CCP) score and clinical variables.An imaging signature consisting of a pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (P = .0005 and P = .0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate < 0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival when we adjusted for known prognostic factors (hazard ratio, 1.81; 95% confidence interval, 1.34-2.44; P < .0001) and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (P < .01) regarding concordance index (0.70 vs 0.62-0.63).The proposed CT imaging signature reflects fundamental biological differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction.

  View details for PubMedID 29439884

• Line-Enhanced Deformable Registration of Pulmonary Computed Tomography Images Before and After Radiation Therapy With Radiation-Induced Fibrosis TECHNOLOGY IN CANCER RESEARCH & TREATMENT King, M., Sensakovic, W. F., Maxim, P., Diehn, M., Loo, B. W., Xing, L. 2018; 17

  View details for DOI 10.1177/1533034617749419

  View details for Web of Science ID 000429305700016

• Line-Enhanced Deformable Registration of Pulmonary Computed Tomography Images Before and After Radiation Therapy With Radiation-Induced Fibrosis. Technology in cancer research & treatment King, M., Sensakovic, W. F., Maxim, P., Diehn, M., Loo, B. W., Xing, L. 2018; 17: 1533034617749419

  Abstract

  PURPOSE: The deformable registration of pulmonary computed tomography images before and after radiation therapy is challenging due to anatomic changes from radiation fibrosis. We hypothesize that a line-enhanced registration algorithm can reduce landmark error over the entire lung, including the irradiated regions, when compared to an intensity-based deformable registration algorithm.MATERIALS: Two intensity-based B-spline deformable registration algorithms of pre-radiation therapy and post-radiation therapy images were compared. The first was a control intensity-based algorithm that utilized computed tomography images without modification. The second was a line enhancement algorithm that incorporated a Hessian-based line enhancement filter prior to deformable image registration. Registrations were evaluated based on the landmark error between user-identified landmark pairs and the overlap ratio.RESULTS: Twenty-one patients with pre-radiation therapy and post-radiation therapy scans were included. The median time interval between scans was 1.2 years (range: 0.3-3.3 years). Median landmark errors for the line enhancement algorithm were significantly lower than those for the control algorithm over the entire lung (1.67 vs 1.83 mm; P < .01), as well as within the 0 to 5 Gy (1.40 vs 1.57; P < .01) and >5 Gy (2.25 vs 3.31; P < .01) dose intervals. The median lung mask overlap ratio for the line enhancement algorithm (96.2%) was greater than that for the control algorithm (95.8%; P < .01). Landmark error within the >5 Gy dose interval demonstrated a significant inverse relationship with post-radiation therapy fibrosis enhancement after line enhancement filtration (Pearson correlation coefficient = -0.48; P = .03).CONCLUSION: The line enhancement registration algorithm is a promising method for registering images before and after radiation therapy.

  View details for PubMedID 29343206

• 18F-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated With Highly Conformal Radiation Therapy. International journal of radiation oncology, biology, physics Qian, Y. n., Von Eyben, R. n., Liu, Y. n., Chin, F. T., Miao, Z. n., Apte, S. n., Carter, J. N., Binkley, M. S., Pollom, E. L., Harris, J. P., Prionas, N. D., Kissel, M. n., Simmons, A. n., Diehn, M. n., Shultz, D. B., Brown, J. M., Maxim, P. G., Koong, A. C., Graves, E. E., Loo, B. W. 2018

  Abstract

  Tumor hypoxia contributes to radiation resistance. A noninvasive assessment of tumor hypoxia would be valuable for prognostication and possibly selection for hypoxia-targeted therapies. 18F-pentafluorinated etanidazole (18F-EF5) is a nitroimidazole derivative that has demonstrated promise as a positron emission tomography (PET) hypoxia imaging agent in preclinical and clinical studies. However, correlation of imageable hypoxia by 18F-EF5 PET with clinical outcomes after radiation therapy remains limited.Our study prospectively enrolled 28 patients undergoing radiation therapy for localized lung or other tumors to receive pretreatment 18F-EF5 PET imaging. Depending on the level of 18F-EF5 tumor uptake, patients underwent functional manipulation of tumor oxygenation with either carbogen breathing or oral dichloroacetate followed by repeated 18F-EF5 PET. The hypoxic subvolume of tumor was defined as the proportion of tumor voxels exhibiting higher 18F-EF5 uptake than the 95th percentile of 18F-EF5 uptake in the blood pool. Tumors with a hypoxic subvolume ≥ 10% on baseline 18F-EF5 PET imaging were classified as hypoxic by imaging. A Cox model was used to assess the correlation between imageable hypoxia and clinical outcomes after treatment.At baseline, imageable hypoxia was demonstrated in 43% of all patients (12 of 28), including 6 of 16 patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy and 6 of 12 patients with other cancers. Carbogen breathing was significantly associated with decreased imageable hypoxia, while dichloroacetate did not result in a significant change under our protocol conditions. Tumors with imageable hypoxia had a higher incidence of local recurrence at 12 months (30%) than those without (0%) (P < .01).Noninvasive hypoxia imaging by 18F-EF5 PET identified imageable hypoxia in about 40% of tumors in our study population. Local tumor recurrence after highly conformal radiation therapy was higher in tumors with imageable hypoxia.

  View details for PubMedID 29859786

• Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer. Clinical lung cancer Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H. n., Neal, J. W., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2018

  Abstract

  Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

  View details for PubMedID 29759331

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

  Abstract

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

  View details for PubMedID 28830717

• Practical workflow for rapid prototyping of radiation therapy positioning devices PRACTICAL RADIATION ONCOLOGY Gensheimer, M. F., Bush, K., Juang, T., Herzberg, B., Villegas, M., Maxim, P. G., Diehn, M., Loo, B. W. 2017; 7 (6): 442–45

  View details for PubMedID 28668669

• Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA Chabon, J., Chaudhuri, A., Azad, T., Kurtz, D., Stehr, H., Liu, C. L., Martin, J., Merriott, D., Carter, J., Ayers, K., Mansfield, A., Jen, J., Ren, H., West, R., Nair, V., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1851

  View details for DOI 10.1016/j.jtho.2017.09.560

  View details for Web of Science ID 000463860800456

• Comparison of Circulating Tumor DNA Analysis and Surveillance Imaging After Treatment for Localized Lung Cancer Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A., Stehr, H., Azad, T. D., Carter, J. N., Merriott, D. J., Liu, C. L., Kurtz, D. M., Gensheimer, M. F., Shrager, J. B., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S114

  View details for DOI 10.1016/j.ijrobp.2017.06.269

  View details for Web of Science ID 000411559107060

• Impact of Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) on Anesthesia Use, Cost, and Time in Pediatric Patients Balazy, K. E., Hiniker, S. M., Bush, K., Fowler, T. L., White, E. C., Rodriquez, S., Maxim, P. G., Donaldson, S. S., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E564–E565

  View details for DOI 10.1016/j.ijrobp.2017.06.1957

  View details for Web of Science ID 000411559104221

• Single-Arm Phase 2 Study of Stereotactic Body Radiation Therapy (SBRT) Concurrent with Nelfinavir for Solid Tumor Oligometastases Terezakis, S. A., Herman, J., Hu, C., Yan, J., Di Pasquale, S., McIntyre, R., Kim, H., Loo, B. W., Hales, R. K., Tran, P. T. ELSEVIER SCIENCE INC. 2017: S221

  View details for DOI 10.1016/j.ijrobp.2017.06.544

  View details for Web of Science ID 000411559108023

• Safety and Efficacy of Stereotactic Ablative Radiotherapy (SABR) to Multiple (3 or More) Lung Tumors Moding, E. J., Maxim, P. G., Diehn, M., Loo, B. W., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2017: E482

  View details for DOI 10.1016/j.ijrobp.2017.06.1756

  View details for Web of Science ID 000411559104024

• Outcomes of Moderately Hypofractionated Intensity-Modulated Thoracic Radiotherapy with Concurrent Chemotherapy for Treatment of Non-Small Cell Lung Cancer Xiang, M., Gensheimer, M. F., Maxim, P. G., Wakelee, H. A., Neal, J. W., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E504

  View details for DOI 10.1016/j.ijrobp.2017.06.1806

  View details for Web of Science ID 000411559104073

• Mid-radiation Therapy PET/CT for Prognostication and Detection of Early Progression in Patients With Stage III Non-small Cell Lung Cancer Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C. N., Eclov, N., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q. T., Hara, W., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E456

  View details for DOI 10.1016/j.ijrobp.2017.06.1695

  View details for Web of Science ID 000411559103253

• Radiogenomic Analysis of a Peritumoral CT Image Feature and Its Prognostic Value in Early Stage NSCLC Lee, J., Cui, Y., Gensheimer, M. F., Loo, B. W., Diehn, M., Li, R. ELSEVIER SCIENCE INC. 2017: S48

  View details for DOI 10.1016/j.ijrobp.2017.06.122

  View details for Web of Science ID 000411559106186

• Lesion Response to Stereotactic Body Radiation Therapy Concurrent With Nelfinavir for Solid Tumor Oligometastases Yan, J., Tran, P. T., Hu, C., McIntyre, R., Di Pasquale, S., Kim, H., Loo, B. W., Hales, R. K., Herman, J., Terezakis, S. A. ELSEVIER SCIENCE INC. 2017: E529

  View details for Web of Science ID 000411559104135

• Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer Merriott, D. J., Chaudhuri, A. A., Jin, M., Chabon, J. J., Newman, A., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H. R., Das, M., Padda, S., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S20–S21

  View details for DOI 10.1016/j.ijrobp.2017.06.061

  View details for Web of Science ID 000411559106127

• Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Merriott, D. J., Carter, J. N., Azad, T. D., Padda, S., Gensheimer, M. F., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1–S2

  View details for DOI 10.1016/j.ijrobp.2017.06.021

  View details for Web of Science ID 000411559106087

• Normal Tissue Constraints for Abdominal and Thoracic Stereotactic Body Radiotherapy. Seminars in radiation oncology Pollom, E. L., Chin, A. L., Diehn, M., Loo, B. W., Chang, D. T. 2017; 27 (3): 197-208

  Abstract

  Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung.

  View details for DOI 10.1016/j.semradonc.2017.02.001

  View details for PubMedID 28577827

• Stereotactic Ablative Radiotherapy for Early-Stage Lung Cancer. Seminars in radiation oncology Shah, J. L., Loo, B. W. 2017; 27 (3): 218-228

  Abstract

  The rising incidence of early-stage lung cancer, particularly in medically inoperable patients, is anticipated because of the implementation of early detection strategies and population aging in the United States and worldwide. This mandates the development of noninvasive curative treatment approaches for this disease. Stereotactic ablative radiotherapy (SABR) has recently emerged as a standard of care for early-stage lung cancer in medically inoperable patients who cannot safely tolerate surgical lobectomy, the established standard for operable patients. Further experience has demonstrated key principles with this highly conformal and dose-intensive radiation technique, including the need for sufficiently high biologically effective dose to achieve optimal local control, dose-fractionation modifications needed to treat centrally located tumors safely, and individualization of treatment based on tumor size, location, and other factors. SABR requires particular technical expertise including a nuanced understanding of dose prescription and calculation and appropriate management of tumor and organ motion. Progress continues as increasing experience with and data on SABR in selected cohorts of medically operable patients suggest comparable oncologic outcomes and a more favorable toxicity profile that challenges the historical standard of care for broader patient populations.

  View details for DOI 10.1016/j.semradonc.2017.03.001

  View details for PubMedID 28577829

• Conical Beam Geometry in Radiation Therapy Schueler, E., Loo, B., Maxim, P. WILEY. 2017: 3209

  View details for Web of Science ID 000426452604155

• Delivery of Ultra-Rapid Flash Radiation Therapy and Demonstration of Normal Tissue Sparing After Abdominal Irradiation of Mice Loo, B. W., Schuler, E., Lartey, F. M., Rafat, M., King, G. J., Trovati, S., Koong, A. C., Maxim, P. G. ELSEVIER SCIENCE INC. 2017: E16

  View details for DOI 10.1016/j.ijrobp.2017.02.101

  View details for Web of Science ID 000403079100049

• A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer LUNG CANCER Harris, J. P., Patel, M. I., Loo, B. W., Wakelee, H. A., Diehn, M. 2017; 108: 173–82

  Abstract

  In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach.Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged ≥65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach.1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide.Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.

  View details for PubMedID 28625632

• A Method for the Generation of Treatment Plans for a Novel X-Ray Target and Collimation System (SPHINX) Trovati, S., Schueler, E., King, G., Hynning, E., Loo, B., Maxim, P. WILEY. 2017

  View details for Web of Science ID 000426452601080

• Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung. Radiotherapy and oncology Binkley, M. S., King, M. T., Shrager, J. B., Bush, K., Chaudhuri, A. A., Popat, R., Gensheimer, M. F., Maxim, P. G., Henry Guo, H., Diehn, M., Nair, V. S., Loo, B. W. 2017; 123 (2): 270-275

  Abstract

  To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV).Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ΔFEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved ΔFEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ΔFEV1/FEV1pre (R(2)=0.25, p=0.03).After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.

  View details for DOI 10.1016/j.radonc.2017.03.021

  View details for PubMedID 28460826

• Pilot study of F-18-FSPG vs F-18-FDG PET imaging for response assessment in cancer Park, S., Hatami, N., Rutledge, O., Koglin, N., Loo, B., Fan, A., Mittra, E. SOC NUCLEAR MEDICINE INC. 2017

  View details for Web of Science ID 000404949900118

• Optimal Radiation Therapy for Small Cell Lung Cancer. Current treatment options in oncology Gensheimer, M. F., Loo, B. W. 2017; 18 (4): 21-?

  Abstract

  Radiation therapy plays an important role in the management of both limited stage and extensive stage small cell lung cancer. For limited stage disease, there has been a trend toward reduced size of thoracic radiation fields, which has the potential to reduce toxicity. FDG-PET staging helps make this possible by more accurately identifying areas of nodal and metastatic involvement. Trials have demonstrated similar outcomes using a range of radiation fractionation schedules, allowing flexibility in individualizing treatment. Using advanced radiation therapy techniques such as intensity-modulated radiation therapy, it may be possible to deliver fewer, higher dose fractions and achieve similar results to the hyperfractionated regimen. For extensive stage disease, consolidative thoracic radiation therapy after chemotherapy was recently shown to improve overall survival in certain patient subsets. Prophylactic cranial irradiation continues to play an important role in management of all stages of small cell lung cancer. Debate continues about the neurocognitive effects of this treatment, and whether MRI surveillance is an acceptable alternative. Strategies such as hippocampal avoidance may reduce the cognitive effects of prophylactic cranial irradiation in the future. Finally, in the last few years stereotactic ablative radiation therapy followed by chemotherapy has emerged as a promising treatment for stage I small cell lung cancer. This radiation treatment is usually given over 1-5 fractions and appears to provide a good rate of local control with a low rate of serious toxicity.

  View details for DOI 10.1007/s11864-017-0467-z

  View details for PubMedID 28391424

• Non-Small Cell Lung Cancer, Version 5.2017 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Wood, D. E., Aisner, D. L., Akerley, W., Bauman, J., Chirieac, L. R., D'Amico, T. A., DeCamp, M. M., Dilling, T. J., Dobelbower, M., Doebele, R. C., Govindan, R., Gubens, M. A., Hennon, M., Horn, L., Komaki, R., Lackner, R. P., Lanuti, M., Leal, T. A., Leisch, L. J., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Reckamp, K., Riely, G. J., Schild, S. E., Shapiro, T. A., Stevenson, J., Swanson, S. J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2017; 15 (4): 504-535

  Abstract

  This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

  View details for Web of Science ID 000399398700009

  View details for PubMedID 28404761

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

  Abstract

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

  View details for DOI 10.1002/mp.12233

  View details for PubMedID 28339108

• Sinoatrial node dysfunction after stereotactic ablative radiation therapy in the chest Qian, Y., Dudley, S., Kumar, K., Chaudhuri, A., Chin, A., Harris, J., Prionas, N., Nwachukwu, C., Bagshaw, H., Pollom, E. L., Ben Durkee, Shultz, D., Gensheimer, M. F., Diehn, M., Loo, B. W. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for Web of Science ID 000443300500123

• Tumor control probability modeling for stereotactic body radiation therapy of early-stage lung cancer using multiple bio-physical models. Radiotherapy and oncology Liu, F., Tai, A., Lee, P., Biswas, T., Ding, G. X., El Naqa, I., Grimm, J., Jackson, A., Kong, F. S., LaCouture, T., Loo, B., Miften, M., Solberg, T., Li, X. A. 2017; 122 (2): 286-294

  Abstract

  This work is to analyze pooled clinical data using different radiobiological models and to understand the relationship between biologically effective dose (BED) and tumor control probability (TCP) for stereotactic body radiotherapy (SBRT) of early-stage non-small cell lung cancer (NSCLC). The clinical data of 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP from 46 selected studies were collected for SBRT of NSCLC in the literature. The TCP data were separated for Stage T1 and T2 tumors if possible, otherwise collected for combined stages. BED was calculated at isocenters using six radiobiological models. For each model, the independent model parameters were determined from a fit to the TCP data using the least chi-square (χ(2)) method with either one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately. The fits to the clinic data yield consistent results of large α/β ratios of about 20Gy for all models investigated. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1Gy physical dose at isocenters per fraction (⩽5 fractions) to achieve the optimal TCP when compared to the T1 tumors. In conclusion, this systematic analysis of a large set of published clinical data using different radiobiological models shows that local TCP for SBRT of early-stage NSCLC has strong dependence on BED with large α/β ratios of about 20Gy. The six models predict that a BED (calculated with α/β of 20) of 90Gy is sufficient to achieve TCP⩾95%. Among the models considered, the regrowth model leads to a better fit to the clinical data.

  View details for DOI 10.1016/j.radonc.2016.11.006

  View details for PubMedID 27871671

• Dynamic CT imaging of volumetric changes in pulmonary nodules correlates with physical measurements of stiffness. Radiotherapy and oncology Lartey, F. M., Rafat, M., Negahdar, M., Malkovskiy, A. V., Dong, X., Sun, X., Li, M., Doyle, T., Rajadas, J., Graves, E. E., Loo, B. W., Maxim, P. G. 2017; 122 (2): 313-318

  Abstract

  A major challenge in CT screening for lung cancer is limited specificity when distinguishing between malignant and non-malignant pulmonary nodules (PN). Malignant nodules have different mechanical properties and tissue characteristics ('stiffness') from non-malignant nodules. This study seeks to improve CT specificity by demonstrating in rats that measurements of volumetric ratios in PNs with varying composition can be determined by respiratory-gated dynamic CT imaging and that these ratios correlate with direct physical measurements of PN stiffness.Respiratory-gated MicroCT images acquired at extreme tidal volumes of 9 rats with PNs from talc, matrigel and A549 human lung carcinoma were analyzed and their volumetric ratios (δ) derived. PN stiffness was determined by measuring the Young's modulus using atomic force microscopy (AFM) for each nodule excised immediately after MicroCT imaging.There was significant correlation (p=0.0002) between PN volumetric ratios determined by respiratory-gated CT imaging and the physical stiffness of the PNs determined from AFM measurements.We demonstrated proof of concept that PN volume changes measured non-invasively correlate with direct physical measurements of stiffness. These results may translate clinically into a means of improving the specificity of CT screening for lung cancer and/or improving individual prognostic assessments based on lung tumor stiffness.

  View details for DOI 10.1016/j.radonc.2016.11.019

  View details for PubMedID 27989402

  View details for PubMedCentralID PMC5319913

• Initial clinical outcomes of audiovisual-assisted therapeutic ambience in radiation therapy (AVATAR). Practical radiation oncology Hiniker, S. M., Bush, K., Fowler, T., White, E. C., Rodriguez, S., Maxim, P. G., Donaldson, S. S., Loo, B. W. 2017

  Abstract

  Radiation therapy is an important component of treatment for many childhood cancers. Depending upon the age and maturity of the child, pediatric radiation therapy often requires general anesthesia for immobilization, position reproducibility, and daily treatment delivery. We designed and clinically implemented a radiation therapy-compatible audiovisual system that allows children to watch streaming video during treatment, with the goal of reducing the need for daily anesthesia through immersion in video.We designed an audiovisual-assisted therapeutic ambience in radiation therapy (AVATAR) system using a digital media player with wireless streaming and pico projector, and a radiolucent display screen positioned within the child's field of view to him or her with sufficient entertainment and distraction for the duration of serial treatments without the need for daily anesthesia. We piloted this system in 25 pediatric patients between the ages of 3 and 12 years. We calculated the number of fractions of radiation for which this system was used successfully and anesthesia avoided and compared it with the anesthesia rates reported in the literature for children of this age.Twenty-three of 25 patients (92%) were able to complete the prescribed course of radiation therapy without anesthesia using the AVATAR system, with a total of 441 fractions of treatment administered when using AVATAR. The median age of patients successfully treated with this approach was 6 years. Seven of the 23 patients were initially treated with daily anesthesia and were successfully transitioned to use of the AVATAR system. Patients and families reported an improved treatment experience with the use of the AVATAR system compared with anesthesia.The AVATAR system enables a high proportion of children to undergo radiation therapy without anesthesia compared with reported anesthesia rates, justifying continued development and clinical investigation of this technique.

  View details for DOI 10.1016/j.prro.2017.01.007

  View details for PubMedID 28242188

• Metabolic tumor volume predicts overall survival and local control in patients with stage III non-small cell lung cancer treated in ACRIN 6668/RTOG 0235 EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Bazan, J. G., Duan, F., Snyder, B. S., Horng, D., Graves, E. E., Siegel, B. A., Machtay, M., Loo, B. W. 2017; 44 (1): 17-24

  Abstract

  To determine whether higher pre-treatment metabolic tumor volume (tMTV-pre) is associated with worse overall survival (OS) in patients with inoperable NSCLC treated with definitive chemoradiation (CRT).This is a secondary analysis of the American College of Radiology Imaging Network (ACRIN) 6668/Radiation Therapy Oncology Group 0235 trial. Pre-treatment PET scans were performed on ACRIN-qualified scanners. Computer-aided MTV measurement was performed using RT_Image. Kaplan-Meier curves and Cox proportional hazards regression models were used to assess the association between tMTV and OS.Of the 250 patients enrolled on the study, 230 were evaluable for tMTV-pre. Patients with MTV-pre >32 mL (median value) vs. ≤32 mL had worse median OS (14.8 vs. 29.7 months, p < 0.001). As a continuous variable, higher tMTV-pre (per 10-mL increase) remained associated with worse OS (HR = 1.03, p < 0.001) after controlling for other variables. A significant interaction between radiation dose and tMTV-pre occurred for OS (p = 0.002), demonstrating that the negative prognostic impact of tMTV-pre decreased as radiotherapy dose increased. Among patients with tMTV-pre ≤32 mL, there was no difference in survival according to radiotherapy dose delivered (p = 0.694). However, median OS was inferior in patients with tMTV-pre >32 mL who received ≤60 Gy compared with those who received 61-69 Gy or ≥70 Gy (p = 0.001).Higher tMTV-pre is associated with significantly worse OS in inoperable stage III NSCLC treated with definitive CRT. Our findings suggest that for patients with large tMTV-pre, achieving a therapeutic radiation dose may help maximize OS. Prospective studies are needed to confirm this finding.

  View details for DOI 10.1007/s00259-016-3520-4

  View details for Web of Science ID 000389242200004

  View details for PubMedCentralID PMC5121029

• Chest wall dose reduction using noncoplanar volumetric modulated arc radiation therapy for lung stereotactic ablative radiation therapy. Practical radiation oncology Yu, A. S., Maxim, P. G., Loo, B. W., Gensheimer, M. F. 2017

  Abstract

  Stereotactic ablative radiation therapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using noncoplanar volumetric modulated arc radiation therapy (VMAT) to reduce chest wall dose from lung SABR.Twenty lung SABR VMAT plans in which the chest wall volume receiving 30 Gy or higher (V30) exceeded 30 mL were replanned by noncoplanar VMAT with opposite 15° couch kicks. Dosimetric parameters including chest wall V30 and V40; lung V5, V10, V20, and mean dose; Paddick high-dose conformity index; intermediate-dose conformity index; and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t test was used to evaluate the difference of the dosimetric parameters between coplanar 1 arc (cVMAT1), coplanar 2 arcs (cVMAT2), and noncoplanar two arcs (nVMAT2) plans; differences with P < .05 were considered statistically significant.V30 and V40 for chest wall were reduced on average by 20% ± 9% and 15% ± 11% (mean ± standard deviation) from cVMAT2 plans to nVMAT2 plans (P < .01 for both comparisons) and by 8% ± 7% and 16% ± 13% from cVMAT1 plans to cVMAT2 plans (P < .003 for both comparisons). The differences in lung mean dose were <0.2 Gy among cVMAT1, cVMAT2, and nVMAT2. There were no significant differences in lung V5, V10, and V20. On average, the number of MU increased 14% for nVMAT2 compared with cVMAT2. The Paddick high-dose conformity indexes were 0.88 ± 0.03, 0.89 ± 0.04, and 0.91 ± 0.03, and intermediate-dose conformity indexes were 3.88 ± 0.49, 3.80 ± 0.44 and 3.51 ± 0.38 for cVMAT1, cVMAT2, and nVMAT2, respectively.We found that noncoplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.

  View details for PubMedID 29452868

• Fdg Pet-CT Suvmax And Circulating Tumor Microemboli Identify Recurrence In Patients With Non-Small Cell Lung Cancer Nair, V. S., Carlsson, F., Carlsson, A., Jamali, M., Keu, K., Vasanawala, M., Shrager, J., Loo, B. W., Horng, G., Kuschner, W., Gambhir, S. S., Kuhn, P. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372500266

• Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer Chaudhuri, A., Lovejoy, A., Chabon, J., Newman, A., Stehr, H., Say, C., Carter, J., Zhou, L., West, R., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S445

  View details for Web of Science ID 000413055801024

• Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors. Practical radiation oncology Qian, Y. n., Zhu, H. n., Pollom, E. L., Durkee, B. Y., Chaudhuri, A. A., Gensheimer, M. F., Diehn, M. n., Shultz, D. B., Loo, B. W. 2017

  Abstract

  Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR.We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right-sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR.Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity.While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies.

  View details for PubMedID 28669706

• Stressed out: DNA damage delivered at ultrahigh dose rates reduces cellular stress and apoptosis. Al-Rawi, D. H., Rafat, M., Vemireddy, S., Schuler, E., Maxim, P., Loo, B. W., King, G. AMER SOC CELL BIOLOGY. 2017

  View details for Web of Science ID 000426664301528

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for PubMedID 28899864

• Prognostic value and molecular correlates of a CT image-based quantitative pleural contact index in early stage NSCLC. European radiology Lee, J. n., Cui, Y. n., Sun, X. n., Li, B. n., Wu, J. n., Li, D. n., Gensheimer, M. F., Loo, B. W., Diehn, M. n., Li, R. n. 2017

  Abstract

  To evaluate the prognostic value and molecular basis of a CT-derived pleural contact index (PCI) in early stage non-small cell lung cancer (NSCLC).We retrospectively analysed seven NSCLC cohorts. A quantitative PCI was defined on CT as the length of tumour-pleura interface normalised by tumour diameter. We evaluated the prognostic value of PCI in a discovery cohort (n = 117) and tested in an external cohort (n = 88) of stage I NSCLC. Additionally, we identified the molecular correlates and built a gene expression-based surrogate of PCI using another cohort of 89 patients. To further evaluate the prognostic relevance, we used four datasets totalling 775 stage I patients with publically available gene expression data and linked survival information.At a cutoff of 0.8, PCI stratified patients for overall survival in both imaging cohorts (log-rank p = 0.0076, 0.0304). Extracellular matrix (ECM) remodelling was enriched among genes associated with PCI (p = 0.0003). The genomic surrogate of PCI remained an independent predictor of overall survival in the gene expression cohorts (hazard ratio: 1.46, p = 0.0007) adjusting for age, gender, and tumour stage.CT-derived pleural contact index is associated with ECM remodelling and may serve as a noninvasive prognostic marker in early stage NSCLC.• A quantitative pleural contact index (PCI) predicts survival in early stage NSCLC. • PCI is associated with extracellular matrix organisation and collagen catabolic process. • A multi-gene surrogate of PCI is an independent predictor of survival. • PCI can be used to noninvasively identify patients with poor prognosis.

  View details for PubMedID 28786009

• Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance CANCER DISCOVERY Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Diana Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2017; 7 (1): 86-101

  Abstract

  Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

  View details for DOI 10.1158/2159-8290.CD-16-0127

  View details for Web of Science ID 000396017700024

  View details for PubMedCentralID PMC5222718

• Thermal limits on MV x-ray production by bremsstrahlung targets in the context of novel linear accelerators. Medical physics Wang, J. n., Trovati, S. n., Borchard, P. M., Loo, B. W., Maxim, P. G., Fahrig, R. n. 2017; 44 (12): 6610–20

  Abstract

  To study the impact of target geometrical and linac operational parameters, such as target material and thickness, electron beam size, repetition rate, and mean current on the ability of the radiotherapy treatment head to deliver high-dose-rate x-ray irradiation in the context of novel linear accelerators capable of higher repetition rates/duty cycle than conventional clinical linacs.The depth dose in a water phantom without a flattening filter and heat deposition in an x-ray target by 10 MeV pulsed electron beams were calculated using the Monte-Carlo code MCNPX, and the transient temperature behavior of the target was simulated by ANSYS. Several parameters that affect both the dose distribution and temperature behavior were investigated. The target was tungsten with a thickness ranging from 0 to 3 mm and a copper heat remover layer. An electron beam with full width at half maximum (FWHM) between 0 and3 mm and mean current of 0.05-2 mA was used as the primary beam at repetition rates of 100, 200, 400, and 800 Hz.For a 10 MeV electron beam with FWHM of 1 mm, pulse length of 5 μs, by using a thin tungsten target with thickness of 0.2 mm instead of 1 mm, and by employing a high repetition rate of 800 Hz instead of 100 Hz, the maximum dose rate delivered can increase two times from 0.57 to 1.16 Gy/s. In this simple model, the limiting factor on dose rate is the copper heat remover's softening temperature, which was considered to be 500°C in our study.A high dose rate can be obtained by employing thin targets together with high repetition rate electron beams enabled by novel linac designs, whereas the benefit of thin targets is marginal at conventional repetition rates. Next generation linacs used to increase dose rate need different target designs compared to conventional linacs.

  View details for PubMedID 28983960

  View details for PubMedCentralID PMC5734638

• A 3-D Riesz-Covariance Texture Model for Prediction of Nodule Recurrence in Lung CT IEEE TRANSACTIONS ON MEDICAL IMAGING Cirujeda, P., Cid, Y. D., Muller, H., Rubin, D., Aguilera, T. A., Loo, B. W., Diehn, M., Binefa, X., Depeursinge, A. 2016; 35 (12): 2620-2630

  Abstract

  This paper proposes a novel imaging biomarker of lung cancer relapse from 3-D texture analysis of CT images. Three-dimensional morphological nodular tissue properties are described in terms of 3-D Riesz-wavelets. The responses of the latter are aggregated within nodular regions by means of feature covariances, which leverage rich intra- and inter- variations of the feature space dimensions. When compared to the classical use of the average for feature aggregation, feature covariances preserve spatial co-variations between features. The obtained Riesz-covariance descriptors lie on a manifold governed by Riemannian geometry allowing geodesic measurements and differentiations. The latter property is incorporated both into a kernel for support vector machines (SVM) and a manifold-aware sparse regularized classifier. The effectiveness of the presented models is evaluated on a dataset of 110 patients with non-small cell lung carcinoma (NSCLC) and cancer recurrence information. Disease recurrence within a timeframe of 12 months could be predicted with an accuracy of 81.3-82.7%. The anatomical location of recurrence could be discriminated between local, regional and distant failure with an accuracy of 78.3-93.3%. The obtained results open novel research perspectives by revealing the importance of the nodular regions used to build the predictive models.

  View details for DOI 10.1109/TMI.2016.2591921

  View details for Web of Science ID 000391547700011

  View details for PubMedID 27429433

• Hypofractionated Intensity-Modulated Radiotherapy for Patients With Non-Small-Cell Lung Cancer. Clinical lung cancer Pollom, E. L., Qian, Y., Durkee, B. Y., von Eyben, R., Maxim, P. G., Shultz, D. B., Gensheimer, M., Diehn, M., Loo, B. W. 2016; 17 (6): 588-594

  Abstract

  Alternative treatment regimens are needed for patients with non-small cell lung cancer (NSCLC) who cannot receive definitive treatment with concurrent chemoradiotherapy, surgery, or stereotactic ablative radiotherapy (SABR).We report survival, patterns of failure and toxicity outcomes for patients with NSCLC who were not eligible for surgical resection, concurrent chemoradiotherapy, or SABR and underwent hypofractionated intensity-modulated radiotherapy (IMRT). Kaplan-Meier survival analysis was used to evaluate the progression-free and overall survival. Competing risk analysis was used to evaluate in-field, locoregional, and distant failure.A total of 42 patients treated to 52.5 to 60 Gy in 15 fractions were included. Most of the patients had metastatic or recurrent disease (64%) and a relatively large, centrally located tumor burden (74%). The median follow-up period was 13 months (interquartile range, 6-18 months). All patients received the total prescribed dose. The median survival was 15.1 months. The overall and progression-free survival rates at 1 year were 63% and 22.5%, respectively. The pattern of failure was predominantly distant, with only 2% of patients experiencing isolated in-field recurrence. The cumulative incidence of in-field failure at 6 and 12 months was 2.5% (95% confidence interval, 0.4%-15.6%) and 16.1% (95% confidence interval, 7.5%-34.7%), respectively. The risk of esophageal toxicity was associated with the esophageal mean dose, maximal point dose, and dose to the 5 cm(3) volume. The risk of pneumonitis was associated with the lung mean dose and volume receiving 18 Gy.Hypofractionated IMRT without concurrent chemotherapy provides favorable rates of local control and survival for well-selected patients with NSCLC who cannot tolerate standard definitive therapy.

  View details for DOI 10.1016/j.cllc.2016.05.024

  View details for PubMedID 27378172

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

  Abstract

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

  View details for DOI 10.1002/hed.24454

  View details for PubMedID 27043927

• Patterns of Failure After Hypofractionated Intensity Modulated Radiation Therapy for Patients With Non-Small Cell Lung Cancer Qian, Y., Pollom, E., Durkee, B. Y., von Eyben, R., Gensheimer, M. F., Shultz, D. B., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E422–E423

  View details for DOI 10.1016/j.ijrobp.2016.06.1692

  View details for Web of Science ID 000387655803354

• CAPP-Seq Circulating Tumor DNA Analysis for Early Detection of Tumor Progression After Definitive Radiation Therapy for Lung Cancer Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Say, C., Aggarwal, S., Carter, J. N., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2016: S41–S42

  View details for DOI 10.1016/j.ijrobp.2016.06.112

  View details for Web of Science ID 000387655804429

• Remotely Preplanned Stereotactic Ablative Radiation Therapy Using Rapid Prototyping of Immobilization Devices Gensheimer, M. F., Bush, K., Juang, T., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E680

  View details for DOI 10.1016/j.ijrobp.2016.06.2330

  View details for Web of Science ID 000387655804245

• Effectiveness of Radiation Therapy for Low- to Intermediate-Grade Neuroendocrine Tumors Carter, J. N., Aggarwal, S., Radish, K., Allen, J. R., Koong, A. C., Chang, D. T., Loo, B. W., Diehn, M., Kunz, P. L., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2016: E202–E203

  View details for DOI 10.1016/j.ijrobp.2016.06.1100

  View details for Web of Science ID 000387655802495

• Regional Ventilation Predicts Change in Pulmonary Function After Stereotactic Ablative Radiation Therapy of Lung Tumors Binkley, M. S., King, M., Bush, K., Shrager, J. B., Chaudhuri, A. A., Popat, R., Maxim, P. G., Guo, H. H., Diehn, M., Nair, V. S., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E456–E457

  View details for DOI 10.1016/j.ijrobp.2016.06.1776

  View details for Web of Science ID 000387655803435

• Intratumor Partitioning of Serial Computed Tomography and FDG Positron Emission Tomography Images Identifies High-Risk Tumor Subregions and Predicts Patterns of Failure in Non-Small Cell Lung Cancer After Radiation Therapy 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Wu, J., Gensheimer, M. F., Dong, X., Rubin, D. L., Napel, S., Diehn, M., Loo, B. W., Li, R. ELSEVIER SCIENCE INC. 2016: S100–S100

  View details for Web of Science ID 000387655804563

• Early-Stage Non-Small Cell Lung Cancer: Quantitative Imaging Characteristics of (18)F Fluorodeoxyglucose PET/CT Allow Prediction of Distant Metastasis. Radiology Wu, J., Aguilera, T., Shultz, D., Gudur, M., Rubin, D. L., Loo, B. W., Diehn, M., Li, R. 2016; 281 (1): 270-278

  Abstract

  Purpose To identify quantitative imaging biomarkers at fluorine 18 ((18)F) positron emission tomography (PET) for predicting distant metastasis in patients with early-stage non-small cell lung cancer (NSCLC). Materials and Methods In this institutional review board-approved HIPAA-compliant retrospective study, the pretreatment (18)F fluorodeoxyglucose PET images in 101 patients treated with stereotactic ablative radiation therapy from 2005 to 2013 were analyzed. Data for 70 patients who were treated before 2011 were used for discovery purposes, while data from the remaining 31 patients were used for independent validation. Quantitative PET imaging characteristics including statistical, histogram-related, morphologic, and texture features were analyzed, from which 35 nonredundant and robust features were further evaluated. Cox proportional hazards regression model coupled with the least absolute shrinkage and selection operator was used to predict distant metastasis. Whether histologic type provided complementary value to imaging by combining both in a single prognostic model was also assessed. Results The optimal prognostic model included two image features that allowed quantification of intratumor heterogeneity and peak standardized uptake value. In the independent validation cohort, this model showed a concordance index of 0.71, which was higher than those of the maximum standardized uptake value and tumor volume, with concordance indexes of 0.67 and 0.64, respectively. The prognostic model also allowed separation of groups with low and high risk for developing distant metastasis (hazard ratio, 4.8; P = .0498, log-rank test), which compared favorably with maximum standardized uptake value and tumor volume (hazard ratio, 1.5 and 2.0, respectively; P = .73 and 0.54, log-rank test, respectively). When combined with histologic types, the prognostic power was further improved (hazard ratio, 6.9; P = .0289, log-rank test; and concordance index, 0.80). Conclusion PET imaging characteristics associated with distant metastasis that could potentially help practitioners to tailor appropriate therapy for individual patients with early-stage NSCLC were identified. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016151829

  View details for PubMedID 27046074

• Experimental Platform for Ultra-high Dose Rate FLASH Irradiation of Small Animals Using a Clinical Linear Accelerator. International journal of radiation oncology, biology, physics Schüler, E., Trovati, S., King, G., Lartey, F., Rafat, M., Villegas, M., Praxel, A. J., Loo, B. W., Maxim, P. G. 2016

  Abstract

  A key factor limiting the effectiveness of radiation therapy is normal tissue toxicity, and recent preclinical data have shown that ultra-high dose rate irradiation (>50 Gy/s, "FLASH") potentially mitigates this effect. However, research in this field has been strongly limited by the availability of FLASH irradiators suitable for small animal experiments. We present a simple methodologic approach for FLASH electron small animal irradiation with a clinically available linear accelerator (LINAC).We investigated the FLASH irradiation potential of a Varian Clinac 21EX in both clinical mode and after tuning of the LINAC. We performed detailed FLUKA Monte Carlo and experimental dosimetric characterization at multiple experimental locations within the LINAC head.Average dose rates of ≤74 Gy/s were achieved in clinical mode, and the dose rate after tuning exceeded 900 Gy/s. We obtained 220 Gy/s at 1-cm depth for a >4-cm field size with 90% homogeneity throughout a 2-cm-thick volume.We present an approach for using a clinical LINAC for FLASH irradiation. We obtained dose rates exceeding 200 Gy/s after simple tuning of the LINAC, with excellent dosimetric properties for small animal experiments. This will allow for increased availability of FLASH irradiation to the general research community.

  View details for DOI 10.1016/j.ijrobp.2016.09.018

  View details for PubMedID 27816362

• The impact of audiovisual biofeedback on 4D functional and anatomic imaging: Results of a lung cancer pilot study. Radiotherapy and oncology Yang, J., Yamamoto, T., Pollock, S., Berger, J., Diehn, M., Graves, E. E., Loo, B. W., Keall, P. J. 2016; 120 (2): 267-272

  Abstract

  The impact of audiovisual (AV) biofeedback on four dimensional (4D) positron emission tomography (PET) and 4D computed tomography (CT) image quality was investigated in a prospective clinical trial (NCT01172041).4D-PET and 4D-CT images of ten lung cancer patients were acquired with AV biofeedback (AV) and free breathing (FB). The 4D-PET images were analyzed for motion artifacts by comparing 4D to 3D PET for gross tumor volumes (GTVPET) and maximum standardized uptake values (SUVmax). The 4D-CT images were analyzed for artifacts by comparing normalized cross correlation-based scores (NCCS) and quantifying a visual assessment score (VAS). A Wilcoxon signed-ranks test was used for statistical testing.The impact of AV biofeedback varied widely. Overall, the 3D to 4D decrease of GTVPET was 1.2±1.3cm(3) with AV and 0.6±1.8cm(3) for FB. The 4D-PET increase of SUVmax was 1.3±0.9 with AV and 1.3±0.8 for FB. The 4D-CT NCCS were 0.65±0.27 with AV and 0.60±0.32 for FB (p=0.08). The 4D-CT VAS was 0.0±2.7.This study demonstrated a high patient dependence on the use of AV biofeedback to reduce motion artifacts in 4D imaging. None of the hypotheses tested were statistically significant. Future development of AV biofeedback will focus on optimizing the human-computer interface and including patient training sessions for improved comprehension and compliance.

  View details for DOI 10.1016/j.radonc.2016.05.016

  View details for PubMedID 27256597

• Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study. International journal of radiation oncology, biology, physics Wu, J., Gensheimer, M. F., Dong, X., Rubin, D. L., Napel, S., Diehn, M., Loo, B. W., Li, R. 2016; 95 (5): 1504-1512

  Abstract

  To develop an intratumor partitioning framework for identifying high-risk subregions from (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer.In this institutional review board-approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treated with radiation therapy. A novel, intratumor partitioning method was developed, based on a 2-stage clustering process: first at the patient level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP).Three spatially distinct subregions were identified within each tumor that were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI of 0.66-0.67. When restricting the analysis to patients with stage III disease (n=32), the same subregion achieved an even higher CI of 0.75 (hazard ratio 3.93, log-rank P=.002) for predicting OS, and a CI of 0.76 (hazard ratio 4.84, log-rank P=.002) for predicting OFP. In comparison, conventional imaging markers, including tumor volume, maximum standardized uptake value, and metabolic tumor volume using threshold of 50% standardized uptake value maximum, were not predictive of OS or OFP, with CI mostly below 0.60 (log-rank P>.05).We propose a robust intratumor partitioning method to identify clinically relevant, high-risk subregions in lung cancer. We envision that this approach will be applicable to identifying useful imaging biomarkers in many cancer types.

  View details for DOI 10.1016/j.ijrobp.2016.03.018

  View details for PubMedID 27212196

• NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016. Journal of the National Comprehensive Cancer Network Ettinger, D. S., Wood, D. E., Akerley, W., Bazhenova, L. A., Borghaei, H., Camidge, D. R., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Dilling, T., Dobelbower, M., Govindan, R., Hennon, M., Horn, L., Jahan, T. M., Komaki, R., Lackner, R. P., Lanuti, M., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Schild, S. E., Shapiro, T. A., Sharma, N., Swanson, S. J., Stevenson, J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2016; 14 (7): 825-836

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

  View details for PubMedID 27407123

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

  Abstract

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

  View details for DOI 10.1016/j.radonc.2016.05.007

  View details for PubMedID 27267049

• SU-D-207B-05: Robust Intra-Tumor Partitioning to Identify High-Risk Subregions for Prognosis in Lung Cancer. Medical physics Wu, J., Gensheimer, M., Dong, X., Rubin, D., Napel, S., Diehn, M., Loo, B., Li, R. 2016; 43 (6): 3349-?

  View details for DOI 10.1118/1.4955673

  View details for PubMedID 28046308

• Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC. Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D., Chabon, J. J., Scherer, F., Stehr, H., Liu, C., Bratman, S., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500

  View details for Web of Science ID 000404711506257

• Randomized phase II study of preoperative chemoradiotherapy (CRT) plus /-Panitumumab (P) followed by consolidation chemotherapy (C) in potentially operable locally advanced (stage Ma, N2+) non -small cell lung cancer (LANSCLC): Nrg oncology/RTOG 0839. Edelman, M. J., Hu, C., Le, Q., Donington, J., D'Souza, W. D., Dicker, A., Loo, B. W., Gore, E., Videtic, G. M., Evans, N. R., Leach, J., Diehn, M., Feigenberg, S. J., Chen, Y., Bradley, J. D. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.8510

  View details for Web of Science ID 000404711505242

• Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555

  Abstract

  High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

  View details for DOI 10.1038/nbt.3520

  View details for PubMedID 27018799

• Assessment of the quality of very high-energy electron radiotherapy planning RADIOTHERAPY AND ONCOLOGY Palma, B., Bazalova-Carter, M., Hardemark, B., Hynning, E., Qu, B., Loo, B. W., Maxim, P. G. 2016; 119 (1): 154-158

  Abstract

  To assess the quality of very-high energy electron (VHEE) scanning pencil beam radiation therapy in relation to state-of-the-art volumetric modulated arc therapy (VMAT) and to determine the extent of its application.We planned five clinical cases with VHEE scanning pencil beams of 100 and 120MeV, equally distributed in a coplanar arrangement around the patient. The clinical cases included acoustic neuroma, and liver, lung, esophagus, and anal cancer cases. We performed Monte Carlo (MC) dose calculations and we optimized the dose in a research version of RayStation. VHEE plan performance was compared against clinically delivered VMAT.With equal target coverage, mean doses to organs at risk (OARs) were on average 22% lower for the VHEE plans compared to the VMAT plans. Dose conformity was equal or superior compared to the VMAT plans and integral dose to the body was in average 14% (9-22%) lower for the VHEE plans.The dosimetric advantages of VHEE as demonstrated for a variety of clinical cases, combined with the theoretical ultra fast treatment delivery, afford VHEE scanning pencil beam radiotherapy a suitable and potentially superior alternative for cancer radiotherapy.

  View details for DOI 10.1016/j.radonc.2016.01.017

  View details for Web of Science ID 000375822700027

  View details for PubMedID 26898508

• Tracheal Diverticulum Following Paratracheal Hypofractionated Radiotherapy in the Setting of Prior and Subsequent Bevacizumab CUREUS Chaudhuri, A. A., Chen, J., Carter, J. N., Binkley, M. S., Kumar, K. A., Dudley, S. A., Sung, A. W., Loo, B. W. 2016; 8 (4)

  View details for DOI 10.7759/cureus.578

  View details for Web of Science ID 000453611400028

• Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation. International journal of radiation oncology, biology, physics Binkley, M. S., Hiniker, S. M., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W., Shultz, D. B. 2016; 94 (4): 808-815

  Abstract

  We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation.We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/β = 2 for spinal cord; α/β = 3 for other critical structures).We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm(3); n=1), esophagus (1 cm(3); n=10), trachea (1 cm(3); n=11), heart (1 cm(3); n=9), aorta (1 cm(3); n=16), superior vena cava (1 cm(3); n=12), brachial plexus (0.2 cm(3); n=2), vagus nerve (0.2 cm(3); n=7), sympathetic trunk (0.2 cm(3); n=4), chest wall (30 cm(3); n=12), and proximal bronchial tree (1 cm(3); n=17). Cumulative dose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm(3) range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm(3) range: 35.0-117.2 Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm(3) range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm(3) = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm(3) = 130.8 Gy). No grade ≥4 toxicity was observed.Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

  View details for DOI 10.1016/j.ijrobp.2015.12.007

  View details for PubMedID 26831903

• NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016. Journal of the National Comprehensive Cancer Network Ettinger, D. S., Wood, D. E., Akerley, W., Bazhenova, L. A., Borghaei, H., Camidge, D. R., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Dilling, T. J., Dobelbower, M. C., Govindan, R., Hennon, M., Horn, L., Jahan, T. M., Komaki, R., Lackner, R. P., Lanuti, M., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Schild, S. E., Shapiro, T. A., Sharma, N., Stevenson, J., Swanson, S. J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2016; 14 (3): 255-264

  Abstract

  These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

  View details for PubMedID 26957612

• CT ventilation functional image-based IMRT treatment plans are comparable to SPECT ventilation functional image-based plans. Radiotherapy and oncology Kida, S., Bal, M., Kabus, S., Negahdar, M., Shan, X., Loo, B. W., Keall, P. J., Yamamoto, T. 2016; 118 (3): 521-527

  Abstract

  To investigate the hypothesis that CT ventilation functional image-based IMRT plans designed to avoid irradiating highly-functional lung regions are comparable to single-photon emission CT (SPECT) ventilation functional image-based plans.Three IMRT plans were created for eight thoracic cancer patients using: (1) CT ventilation functional images, (2) SPECT ventilation functional images, and (3) anatomic images (no functional images). CT ventilation images were created by deformable image registration of 4D-CT image data sets and quantitative analysis. The resulting plans were analyzed for the relationship between the deviations of CT-functional plan metrics from anatomic plan metrics (ΔCT-anatomic) and those of SPECT-functional plans (ΔSPECT-anatomic), and moreover for agreements of various metrics between the CT-functional and SPECT-functional plans.The relationship between ΔCT-anatomic and ΔSPECT-anatomic was strong (e.g., R=0.94; linear regression slope 0.71). The average differences and 95% limits of agreement between the CT-functional and SPECT-functional plan metrics (except for monitor units) for various structures were mostly less than 1% and 2%, respectively.This study demonstrated a reasonable agreement between the CT ventilation functional image-based IMRT plans and SPECT-functional plans, suggesting the potential for CT ventilation imaging to serve as a surrogate for SPECT ventilation in functional image-guided radiotherapy.

  View details for DOI 10.1016/j.radonc.2016.02.019

  View details for PubMedID 26922488

• Severe Chest Wall Toxicity From Cryoablation in the Setting of Prior Stereotactic Ablative Radiotherapy CUREUS Chaudhuri, A. A., Binkley, M. S., Aggarwal, S., Qian, Y., Carter, J. N., Shah, R., Loo, B. W. 2016; 8 (2)

  View details for DOI 10.7759/cureus.477

  View details for Web of Science ID 000453610500005

• Tracheal Diverticulum Following Paratracheal Hypofractionated Radiotherapy in the Setting of Prior and Subsequent Bevacizumab. Cure¯us Chaudhuri, A. A., Chen, J. J., Carter, J. N., Binkley, M. S., Kumar, K. A., Dudley, S. A., Sung, A. W., Loo, B. W. 2016; 8 (4)

  Abstract

  We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions (70 Gy equivalent dose in 2 Gy fractions). The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy.

  View details for DOI 10.7759/cureus.578

  View details for PubMedID 27226939

• Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors. Radiation oncology Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. 2016; 11 (1): 40-?

  Abstract

  Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 ≥4.1 % TLV).Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2)  = 0.52-0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R (2)  = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted.We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

  View details for DOI 10.1186/s13014-016-0616-8

  View details for PubMedID 26975700

• CONCEPTUAL LAYOUT FOR AWAFER-SCALE DIELECTRIC LASER ACCELERATOR England, R. J., Noble, R. J., Fahimian, B., Loo, B., Abel, E., Hanuka, A., Schachter, L., Hogan, M. J. AMER INST PHYSICS. 2016

  View details for DOI 10.1063/1.4965631

  View details for Web of Science ID 000389510300042

• Stereotactic Arrhythmia Radioablation (STAR) of Ventricular Tachycardia: A Treatment Planning Study. Cure¯us Wang, L., Fahimian, B., Soltys, S. G., Zei, P., Lo, A., Gardner, E. A., Maguire, P. J., Loo, B. W. 2016; 8 (7)

  Abstract

  The first stereotactic arrhythmia radioablation (STAR) of ventricular tachycardia (VT) was delivered at Stanford on a robotic radiosurgery system (CyberKnife® G4) in 2012. The results warranted further investigation of this treatment. Here we compare dosimetrically three possible treatment delivery platforms for STAR.The anatomy and target volume of the first treated patient were used for this study. A dose of 25 Gy in one fraction was prescribed to the planning target volume (PTV). Treatment plans were created on three treatment platforms: CyberKnife® G4 system with Iris collimator (Multiplan, V. 4.6)(Plan #1), CyberKnife® M6 system with InCise 2(TM) multileaf collimator (Multiplan V. 5.3)(Plan #2) and Varian TrueBeam(TM) STx with HD 120(TM) MLC and 10MV flattening filter free (FFF) beam (Eclipse planning system, V.11) (Plan #3 coplanar and #4 noncoplanar VMAT plans). The four plans were compared by prescription isodose line, plan conformity index, dose gradient, as well as dose to the nearby critical structures. To assess the delivery efficiency, planned monitor units (MU) and estimated treatment time were evaluated.Plans #1-4 delivered 25 Gy to the PTV to the 75.0%, 83.0%, 84.3%, and 84.9% isodose lines and with conformity indices of 1.19, 1.16, 1.05, and 1.05, respectively. The dose gradients for plans #1-4 were 3.62, 3.42, 3.93, and 3.73 with the CyberKnife® MLC plan (Plan #2) the best, and the TrueBeam(TM) STx co-planar plan (Plan #3) the worst. The dose to nearby critical structures (lung, stomach, bowel, and esophagus) were all well within tolerance. The MUs for plans #1-4 were 27671, 16522, 6275, and 6004 for an estimated total-treatment-time/beam-delivery-time of 99/69, 65/35, 37/7, and 56/6 minutes, respectively, under the assumption of 30 minutes pretreatment setup time. For VMAT gated delivery, a 40% duty cycle, 2400MU/minute dose rate, and an extra 10 minutes per extra arc were assumed.Clinically acceptable plans were created with all three platforms. Plans with MLC were considerably more efficient in MU. CyberKnife® M6 with InCise 2(TM) collimator provided the most conformal plan (steepest dose drop-off) with significantly reduced MU and treatment time. VMAT plans were most efficient in MU and delivery time. Fluoroscopic image guidance removes the need for additional fiducial marker placement; however, benefits may be moderated by worse dose gradient and more operator-dependent motion management by gated delivery.

  View details for DOI 10.7759/cureus.694

  View details for PubMedID 27570715

  View details for PubMedCentralID PMC4996541

• Severe Chest Wall Toxicity From Cryoablation in the Setting of Prior Stereotactic Ablative Radiotherapy. Cure¯us Chaudhuri, A. A., Binkley, M. S., Aggarwal, S., Qian, Y., Carter, J. N., Shah, R., Loo, B. W. 2016; 8 (2)

  Abstract

  We present the case of a 42-year-old woman with metastatic synovial sarcoma of parotid origin, treated definitively with chemoradiation, who subsequently developed oligometastatic disease limited to the lungs. She underwent multiple left and right lung wedge resections and left lower lobectomy, followed by right lower lobe stereotactic ablative radiotherapy (SABR), 54 Gy in three fractions to a right lower lobe lesion abutting the chest wall. Two years later, she was treated with cryoablation for a separate right upper lobe nodule abutting the chest wall. Two months later, she presented with acute shortness of breath, pleuritic chest pain, decreased peripheral blood O2 saturation, and productive cough. A computed tomography (CT) scan demonstrated severe chest wall necrosis in the area of recent cryoablation that, in retrospect, also received a significant radiation dose from her prior SABR. This case demonstrates that clinicians should exercise caution in using cryoablation when treating lung tumors abutting a previously irradiated chest wall. Note: Drs. Loo and Shah contributed equally as co-senior authors.

  View details for DOI 10.7759/cureus.477

  View details for PubMedID 27004154

  View details for PubMedCentralID PMC4780688

• Outcomes of Modestly Hypofractionated Radiation for Lung Tumors: Pre- and Mid-Treatment Positron Emission Tomography-Computed Tomography Metrics as Prognostic Factors. Clinical lung cancer Harris, J. P., Chang-Halpenny, C. N., Maxim, P. G., Quon, A., Graves, E. E., Diehn, M., Loo, B. W. 2015; 16 (6): 475-485

  Abstract

  Modestly hypofractionated radiation therapy (HypoRT; 60-66 Gy in 3-Gy fractions) allows patients with locally advanced thoracic tumors and poor performance status to complete treatment within a shorter period without concurrent chemotherapy. We evaluated the outcomes and imaging prognostic factors of HypoRT.We retrospectively reviewed the data from all patients with primary and metastatic intrathoracic tumors treated with HypoRT from 2006 to 2012. We analyzed the survival and toxicity outcomes, including overall survival (OS), progression-free survival (PFS), local recurrence (LR), and distant metastasis. We also evaluated the following tumor metrics in an exploratory analysis: gross tumor volume (GTV), maximum standardized uptake value (SUVMax), and metabolic tumor volume using a threshold of ≥ 50% of the SUVMax (MTV50%) or the maximum gradient of fluorine-18 fluorodeoxyglucose uptake (MTVEdge). We assessed the association of these metrics and their changes from before to mid-RT using positron emission tomography-computed tomography (PET-CT) with OS and PFS.We identified 29 patients, all with pre-RT and 20 with mid-RT PET-CT scans. The median follow-up period was 15 months. The 2-year overall and non-small-cell lung cancer-only rate for OS, PFS, and LR, was 59% and 59%, 52% and 41%, and 27% and 32%, respectively. No grade ≥ 3 toxicities developed. The median decrease in GTV, SUVMax, and MTVEdge was 11%, 24%, and 18%, respectively. Inferior OS was associated with a larger pre-RT MTVEdge (P = .005) and pre-RT MTV50% (P = .007). Inferior PFS was associated with a larger mid-RT SUVMax (P = .003).These findings add to the growing body of data demonstrating promising outcomes and limited toxicity with HypoRT. The pre- and mid-RT PET-CT metrics could be useful for prognostic stratification in future clinical trials.

  View details for DOI 10.1016/j.cllc.2015.01.007

  View details for PubMedID 25770888

• Anatomic optimization of lung tumor stereotactic ablative radiation therapy. Practical radiation oncology Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Shultz, D. B., Loo, B. W., Maxim, P. G. 2015; 5 (6): e607-13

  Abstract

  The purpose of this study was to demonstrate that anatomic optimization through selection of the degree of breath hold that yields the largest separation between the target and nearby organ at risk could result in dosimetrically superior treatment plans.Thirty patients with 41 plans were included in this planned secondary analysis of a prospective trial. Fifteen plans were created for treatment with use of natural end exhale (NEE), and 26 plans used deep inspiration breath hold (DIBH). To evaluate whether the original plan was dosimetrically optimal, we replanned treatment using the opposite respiratory state with the same beam configuration as the original plan. A treatment plan was deemed superior if it met protocol constraints when the other did not. If both plans met or violated the constraints, the plans were deemed equivalent.Of the 26 plans originally planned with DIBH and replanned with NEE, 3 plans were dosimetrically superior with NEE, 1 plan was dosimetrically superior with DIBH, and 22 plans were dosimetrically equivalent. Of the 15 plans originally planned with NEE, 4 plans were dosimetrically superior with NEE, 2 plans were dosimetrically superior with DIBH, and 9 plans were dosimetrically equivalent.For 10 of 41 plans, planning with 1 respiratory state was superior. To obtain uniformly optimal plans, individual anatomic optimization would be needed.

  View details for DOI 10.1016/j.prro.2015.05.008

  View details for PubMedID 26231596

• First In-Human Stereotactic Arrhythmia Radioablation (STAR) of Ventricular Tachycardia: Dynamic Tracking Delivery Analysis and Implications Fahimian, B. P., Loo, B. W., Soltys, S. G., Zei, P., Lo, A. T., Maguire, P. J., Gardner, E., Wang, L. ELSEVIER SCIENCE INC. 2015: E466–E467

  View details for DOI 10.1016/j.ijrobp.2015.07.1738

  View details for Web of Science ID 000373215301232

• Imaging Based Parameters Associated With Disease Progression of Early-Stage NSCLC Treated With Surgical Resection Wang, A., von Eyben, R., Loo, B. W., Diehn, M., Shrager, J. B., Maxim, P. G., Guo, H. H., Burt, B., Shultz, D. B. ELSEVIER SCIENCE INC. 2015: E414

  View details for DOI 10.1016/j.ijrobp.2015.07.1603

  View details for Web of Science ID 000373215301101

• Time Course and Predictive Factors for Lung Volume Reduction Following Stereotactic Ablative Radiation Therapy (SABR) of Lung Tumors Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2015: E424

  View details for DOI 10.1016/j.ijrobp.2015.07.1628

  View details for Web of Science ID 000373215301125

• Pruritus as a Paraneoplastic Symptom of Thymoma JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Shrager, J. B., Riess, J. W., Pagtama, J. Y., Tisch, A. J., Kwong, B. Y., Liang, Y., Schwartz, E. J., Loo, B. W., Neal, J. W., Hardy, R., Wakelee, H. A. 2015; 10 (11): E110-E112

  View details for DOI 10.1097/JTO.0000000000000623

  View details for PubMedID 26536199

• Optimization of an on-board imaging system for extremely rapid radiation therapy. Medical physics Cherry Kemmerling, E. M., Wu, M., Yang, H., Maxim, P. G., Loo, B. W., Fahrig, R. 2015; 42 (11): 6757-?

  Abstract

  Next-generation extremely rapid radiation therapy systems could mitigate the need for motion management, improve patient comfort during the treatment, and increase patient throughput for cost effectiveness. Such systems require an on-board imaging system that is competitively priced, fast, and of sufficiently high quality to allow good registration between the image taken on the day of treatment and the image taken the day of treatment planning. In this study, three different detectors for a custom on-board CT system were investigated to select the best design for integration with an extremely rapid radiation therapy system.Three different CT detectors are proposed: low-resolution (all 4×4 mm pixels), medium-resolution (a combination of 4×4 mm pixels and 2×2 mm pixels), and high-resolution (all 1×1 mm pixels). An in-house program was used to generate projection images of a numerical anthropomorphic phantom and to reconstruct the projections into CT datasets, henceforth called "realistic" images. Scatter was calculated using a separate Monte Carlo simulation, and the model included an antiscatter grid and bowtie filter. Diagnostic-quality images of the phantom were generated to represent the patient scan at the time of treatment planning. Commercial deformable registration software was used to register the diagnostic-quality scan to images produced by the various on-board detector configurations. The deformation fields were compared against a "gold standard" deformation field generated by registering initial and deformed images of the numerical phantoms that were used to make the diagnostic and treatment-day images. Registrations of on-board imaging system data were judged by the amount their deformation fields differed from the corresponding gold standard deformation fields--the smaller the difference, the better the system. To evaluate the registrations, the pointwise distance between gold standard and realistic registration deformation fields was computed.By most global metrics (e.g., mean, median, and maximum pointwise distance), the high-resolution detector had the best performance but the medium-resolution detector was comparable. For all medium- and high-resolution detector registrations, mean error between the realistic and gold standard deformation fields was less than 4 mm. By pointwise metrics (e.g., tracking a small lesion), the high- and medium-resolution detectors performed similarly. For these detectors, the smallest error between the realistic and gold standard registrations was 0.6 mm and the largest error was 3.6 mm.The medium-resolution CT detector was selected as the best for an extremely rapid radiation therapy system. In essentially all test cases, data from this detector produced a significantly better registration than data from the low-resolution detector and a comparable registration to data from the high-resolution detector. The medium-resolution detector provides an appropriate compromise between registration accuracy and system cost.

  View details for DOI 10.1118/1.4934377

  View details for PubMedID 26520765

• Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial. International journal of radiation oncology, biology, physics Westover, K. D., Loo, B. W., Gerber, D. E., Iyengar, P., Choy, H., Diehn, M., Hughes, R., Schiller, J., Dowell, J., Wardak, Z., Sher, D., Christie, A., Xie, X., Corona, I., Sharma, A., Wadsworth, M. E., Timmerman, R. 2015; 93 (1): 72-81

  Abstract

  Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC.Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy.Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59).Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.

  View details for DOI 10.1016/j.ijrobp.2015.05.004

  View details for PubMedID 26279026

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2015.04.004

  View details for Web of Science ID 000357900600024

  View details for PubMedID 26025776

• 3D Riesz-wavelet based Covariance descriptors for texture classification of lung nodule tissue in CT. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Cirujeda, P., Muller, H., Rubin, D., Aguilera, T. A., Loo, B. W., Diehn, M., Binefa, X., Depeursinge, A. 2015; 2015: 7909-7912

  Abstract

  In this paper we present a novel technique for characterizing and classifying 3D textured volumes belonging to different lung tissue types in 3D CT images. We build a volume-based 3D descriptor, robust to changes of size, rigid spatial transformations and texture variability, thanks to the integration of Riesz-wavelet features within a Covariance-based descriptor formulation. 3D Riesz features characterize the morphology of tissue density due to their response to changes in intensity in CT images. These features are encoded in a Covariance-based descriptor formulation: this provides a compact and flexible representation thanks to the use of feature variations rather than dense features themselves and adds robustness to spatial changes. Furthermore, the particular symmetric definite positive matrix form of these descriptors causes them to lay in a Riemannian manifold. Thus, descriptors can be compared with analytical measures, and accurate techniques from machine learning and clustering can be adapted to their spatial domain. Additionally we present a classification model following a "Bag of Covariance Descriptors" paradigm in order to distinguish three different nodule tissue types in CT: solid, ground-glass opacity, and healthy lung. The method is evaluated on top of an acquired dataset of 95 patients with manually delineated ground truth by radiation oncology specialists in 3D, and quantitative sensitivity and specificity values are presented.

  View details for DOI 10.1109/EMBC.2015.7320226

  View details for PubMedID 26738126

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2015.02.016

  View details for PubMedID 26068491

• Analysis of Long-Term 4-Dimensional Computed Tomography Regional Ventilation After Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS King, M. T., Maxim, P. G., Diehn, M., Loo, B. W., Xing, L. 2015; 92 (3): 683-690

  Abstract

  To determine whether regional ventilation, as measured using 4-dimensional computed tomography (4D-CT), declines after radiation therapy (RT).We analyzed pretreatment 4D-CT scans associated with 2 RT courses. We quantified regional pulmonary function over equivalent dose in 2 Gy (EQD2α/β=3) intervals of 0 to 5 Gy, 5 to 20 Gy, 20 to 40 Gy, and >40 Gy using percentile-normalized intensity-based (VentInt) and Jacobian-based (VentJac) ventilation metrics. We modeled the impact of dose on mean ventilation (Vent¯) and regional tidal volume (rTV: tidal volume [TV] within a dose interval normalized to total lung TV). We also identified clinical and dosimetric factors that affected regional ventilation changes (ΔVent¯ and ΔrTV) after RT for the >20 Gy dose interval.After RT, Vent¯Int exhibited statistically significant dose-dependent declines within the 20 to 40 Gy (-5.0%; P=.03) and >40 Gy (-6.8%; P<.01) intervals. Vent¯Jac exhibited a declining trend after RT only for the >40 Gy interval (-4.6%; P=.07). Factors associated with ΔVent¯Int for the >20 Gy dose interval included airway stenosis progression (P=.03) and gross tumor volume (P=.09). Both rTVInt and rTVJac were associated with small (<2%) but significant declines after RT for 20 to 40 Gy and >40 Gy intervals. Factors associated with declining rTVInt (P<.05) for the >20 Gy dose interval included airway stenosis progression, greater V20 (volume of lung receiving >20 Gy), and smaller fraction of emphysema in V20. The association between the absence of chronic obstructive pulmonary disease and declining rTV trended toward significance (P=.09).Regional ventilation, as measured using 4D-CT, demonstrates a dose-dependent decline after RT. Our results support the use of 4D-CT ventilation imaging for monitoring regional pulmonary function change after RT.

  View details for DOI 10.1016/j.ijrobp.2015.02.037

  View details for Web of Science ID 000355636800032

  View details for PubMedID 25936813

• Stereotactic ablative radiotherapy (SABR) for treatment of central and ultra-central lung tumors LUNG CANCER Chaudhuri, A. A., Tang, C., Binkley, M. S., Jin, M., Wynne, J. F., von Eyben, R., Hara, W. Y., Trakul, N., Loo, B. W., Diehn, M. 2015; 89 (1): 50-56

  Abstract

  Treatment of central and ultra-central lung tumors with stereotactic ablative radiotherapy (SABR) remains controversial due to risks of treatment-related toxicities compared with peripheral tumors. Here we report our institution's experience in treating central and ultra-central lung tumor patients with SABR.We retrospectively reviewed outcomes in 68 patients with single lung tumors, 34 central and 34 peripheral, all treated with SABR consisting of 50 Gy in 4-5 fractions. Tumor centrality was defined per the RTOG 0813 protocol. We defined "ultra-central" tumors as those with GTV directly abutting the central airway.Median follow-up time was 18.4 months and median overall survival was 38.1 months. Two-year overall survival was similar between ultra-central, central, and peripheral NSCLC (80.0% vs. 63.2% vs. 86.6%, P=0.62), as was 2-year local failure (0% vs. 10.0% vs. 16.3%, P=0.64). Toxicity rates were low and comparable between the three groups, with only two cases of grade 3 toxicity (chest wall pain), and one case of grade 4 toxicity (pneumonitis) observed. Patients with ultra-central tumors experienced no symptomatic toxicities over a median follow-up time of 23.6 months. Dosimetric analysis revealed that RTOG 0813 central airway dose constraints were frequently not achieved in central tumor treatment plans, but this did not correlate with increased toxicity rate.Patients with central and ultra-central lung tumors treated with SABR (50 Gy in 4-5 fractions) experienced few toxicities and good outcomes, similar to patients with peripheral lung tumors.

  View details for DOI 10.1016/j.lungcan.2015.04.014

  View details for Web of Science ID 000356546300010

  View details for PubMedID 25997421

• TU-CD-304-01: FEATURED PRESENTATION and BEST IN PHYSICS (THERAPY): Trajectory Modulated Arc Therapy: Development of Novel Arc Delivery Techniques Integrating Dynamic Table Motion for Extended Volume Treatments. Medical physics Chin, E., Otto, K., Hoppe, R., Million, L., Loo, B., Koong, A., Xing, L., Hsu, A., Fahimian, B. 2015; 42 (6): 3598-?

  Abstract

  Integration of coordinated robotic table motion with inversely-planned arc delivery has the potential to resolve table-top delivery limitations of large-field treatments such as Total Body Irradiation (TBI), Total Lymphoid Irradiation (TLI), and Cranial-Spinal Irradiation (CSI). We formulate the foundation for Trajectory Modulated Arc Therapy (TMAT), and using Varian Developer Mode capabilities, experimentally investigate its practical implementation for such techniques.A MATLAB algorithm was developed for inverse planning optimization of the table motion, MLC positions, and gantry motion under extended-SSD geometry. To maximize the effective field size, delivery trajectories for TMAT TBI were formed with the table rotated at 270° IEC and dropped vertically to 152.5cm SSD. Preliminary testing of algorithm parameters was done through retrospective planning analysis. Robotic delivery was programmed using custom XML scripting on the TrueBeam Developer Mode platform. Final dose was calculated using the Eclipse AAA algorithm. Initial verification of delivery accuracy was measured using OSLDs on a solid water phantom of varying thickness.A comparison of DVH curves demonstrated that dynamic couch motion irradiation was sufficiently approximated by static control points spaced in intervals of less than 2cm. Optimized MLC motion decreased the average lung dose to 68.5% of the prescription dose. The programmed irradiation integrating coordinated table motion was deliverable on a TrueBeam STx linac in 6.7 min. With the couch translating under an open 10cmx20cm field angled at 10°, OSLD measurements along the midline of a solid water phantom at depths of 3, 5, and 9cm were within 3% of the TPS AAA algorithm with an average deviation of 1.2%.A treatment planning and delivery system for Trajectory Modulated Arc Therapy of extended volumes has been established and experimentally demonstrated for TBI. Extension to other treatment techniques such as TLI and CSI is readily achievable through the developed platform. Grant Funding by Varian Medical Systems.

  View details for DOI 10.1118/1.4925570

  View details for PubMedID 26128865

• TU-AB-201-06: Evaluation of Electromagnetically Guided High- Dose Rate Brachytherapy for Ablative Treatment of Lung Metastases. Medical physics Pinkham, D. W., Shultz, D., Loo, B. W., Sung, A., Diehn, M., Fahimian, B. P. 2015; 42 (6): 3595-?

  Abstract

  The advent of electromagnetic navigation bronchoscopy has enabled minimally invasive access to peripheral lung tumors previously inaccessible by optical bronchoscopes. As an adjunct to Stereotactic Ablative Radiosurgery (SABR), implantation of HDR catheters can provide focal treatments for multiple metastases and sites of retreatments. The authors evaluate a procedure to deliver ablative doses via Electromagnetically-Guided HDR (EMG-HDR) to lung metastases, quantify the resulting dosimetry, and assess its role in the comprehensive treatment of lung cancer.A retrospective study was conducted on ten patients, who, from 2009 to 2011, received a hypo-fractionated SABR regimen with 6MV VMAT to lesions in various lobes ranging from 1.5 to 20 cc in volume. A CT visible pathway was delineated for EM guided placement of an HDR applicator (catheter) and dwell times were optimized to ensure at least 98% prescription dose coverage of the GTV. Normal tissue doses were calculated using inhomogeneity corrections via a grid-based Boltzmann solver (Acuros_BV_1.5.0).With EMG-HDR, an average of 83% (+/-9% standard deviation) of each patient's GTV received over 200% of the prescription dose, as compared to SABR where the patients received an average maximum dose of 125% (+/-5%). EMG-HDR enabled a 59% (+/-12%) decrease in the aorta maximum dose, a 63% (+/-26%) decrease in the spinal cord max dose, and 57% (+/-23%) and 70% (+/-17%) decreases in the volume of the body receiving over 50% and 25% of the prescription dose, respectively.EMG-HDR enables delivery of higher ablative doses to the GTV, while concurrently reducing surrounding normal tissue doses. The single catheter approach shown here is limited to targets smaller than 20 cc. As such, the technique enables ablation of small lesions and a potentially safe and effective retreatment option in situations where external beam utility is limited by normal tissue constraints.

  View details for DOI 10.1118/1.4925544

  View details for PubMedID 26128845

• SU-E-T-514: Investigating the Dose Distributions of Equiangular Spaced Noncoplanar Beams. Medical physics Mitchell, T., Maxim, P., Hadsell, M., Loo, B. 2015; 42 (6): 3453-?

  Abstract

  It has been demonstrated that the use of noncoplanar beams in radiation therapy may Result in dose distributions that are comparable or better than standard coplanar beams [Pugachev, 2001]. A radiation therapy system designed with a noncoplanar beam geometry could allow for a full ring diagnostic quality imaging system to be placed around the patient. Additionally, if the noncoplanar beams were fixed in number and in their angle with respect to the patient's axial plane, then both treatment and imaging could be achieved concurrently without the need for moving parts, which could greatly reduce treatment times. For such a system to be designed, it is necessary to determine the appropriate number of beams and the beam angles to achieve optimal dose distributions. For simplicity, the beam angles are assumed to be equiangular in the patient's axial plane, and only the beam angle with respect to the axial plane are varied. This study aims to investigate the dose distributions produced by equiangular noncoplanar beams for multiple beam numbers and beam angles, and to compare these dose distributions with distributions achieved in coplanar volumetric arc therapy (VMAT).Dose distributions produced by noncoplanar beams were calculated using the Varian Eclipse treatment planning system by varying the gantry, collimator, and couch angles to simulate the noncoplanar delivery method. Noncoplanar intensity-modulated (NC-IMRT) beams using 8, 12, and 16 beams with angles varying from 45 degrees to 54 with respect to the patient's axial plane were studied.The NC-IMRT beams produced dose distributions comparable to VMAT plans for a number of treatment sites, and were capable of meeting similar dose-volume histogram constraints.This study has demonstrated that a noncoplanar beam delivery method with fixed beam numbers and beam angles is capable of delivering dose distributions comparable to VMAT plans currently in use.

  View details for DOI 10.1118/1.4924876

  View details for PubMedID 26128177

• Stereotactic ablative radiotherapy for the treatment of refractory cardiac ventricular arrhythmia. Circulation. Arrhythmia and electrophysiology Loo, B. W., Soltys, S. G., Wang, L., Lo, A., Fahimian, B. P., Iagaru, A., Norton, L., Shan, X., Gardner, E., Fogarty, T., Maguire, P., Al-Ahmad, A., Zei, P. 2015; 8 (3): 748-750

  View details for DOI 10.1161/CIRCEP.115.002765

  View details for PubMedID 26082532

• TH-AB-304-04: Tumor Control Probability Modeling for Stereotactic Body Radiation Therapy of Early-Stage Lung Cancer Using Multiple Bio-Physical Models. Medical physics Liu, F., Tai, A., Lee, P., Biswas, T., Ding, G., El Naqa, I., Grimm, J., Jackson, A., Kong, F., LaCouture, T., Loo, B., Miften, M., Solberg, T., Li, X. 2015; 42 (6): 3701-?

  Abstract

  To analyze pooled clinical data using six radiobiological models and to understand the relationship between BED and TCP for SBRT of early-stage NSCLC.The clinical data of 1- , 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data from 46 studies were collected for SBRT of early stage (T1 and T2) NSCLC. The TCP data were separated for Stage T1 and T2 tumors if possible. BED was calculated at isocenters using six radiobiological models. Model parameters were determined from a fit to the TCP data using the least chi-square (χ2) method with one set of parameters regardless of tumor stages or two sets for T1 and T2 tumors separately.The fits to the clinic data yield consistent results of large α/β ratios of about 23 Gy for all models. The regrowth model that accounts for the tumor repopulation and heterogeneity leads to a better fit to the data, compared to other 5 models where the fits were indistinguishable between the models. The models based on the fitting parameters predict that the T2 tumors require about additional 1 Gy physical dose at isocenters per fraction (≤5 fractions) to achieve the optimal TCP when compared to the T1 tumors. Sample fractionation schemes were estimated based the determined model parameters for the regrowth model.A systematic analysis of a large set clinical data using six radiobiological models shows that local TCP for SBRT of early stage NSCLC has strong dependence on BED with large α/β ratios of about 23 Gy. The six models considered predict that a BED of 80 Gy is sufficient to achieve a 95% TCP. The regrowth model leads to better fit to the clinical data, the LQ model is the simplest and indistinguishable with remaining models. Sample fractionation regimens that can yield TCPs larger than 95% were estimated.

  View details for DOI 10.1118/1.4926119

  View details for PubMedID 26129419

• TU-G-BRA-04: Changes in Regional Lung Function Measured by 4D-CT Ventilation Imaging for Thoracic Radiotherapy. Medical physics Nakajima, Y., KADOYA, N., Kabus, S., Loo, B., Keall, P., Yamamoto, T. 2015; 42 (6): 3630-?

  Abstract

  To test the hypothesis: 4D-CT ventilation imaging can show the known effects of radiotherapy on lung function: (1) radiation-induced ventilation reductions, and (2) ventilation increases caused by tumor regression.Repeat 4D-CT scans (pre-, mid- and/or post-treatment) were acquired prospectively for 11 thoracic cancer patients in an IRB-approved clinical trial. A ventilation image for each time point was created using deformable image registration and the Hounsfield unit (HU)-based or Jacobian-based metric. The 11 patients were divided into two subgroups based on tumor volume reduction using a threshold of 5 cm(3). To quantify radiation-induced ventilation reduction, six patients who showed a small tumor volume reduction (<5 cm(3)) were analyzed for dose-response relationships. To investigate ventilation increase caused by tumor regression, two of the other five patients were analyzed to compare ventilation changes in the lung lobes affected and unaffected by the tumor. The remaining three patients were excluded because there were no unaffected lobes.Dose-dependent reductions of HU-based ventilation were observed in a majority of the patient-specific dose-response curves and in the population-based dose-response curve, whereas no clear relationship was seen for Jacobian-based ventilation. The post-treatment population-based dose-response curve of HU-based ventilation demonstrated the average ventilation reductions of 20.9±7.0% at 35-40 Gy (equivalent dose in 2-Gy fractions, EQD2), and 40.6±22.9% at 75-80 Gy EQD2. Remarkable ventilation increases in the affected lobes were observed for the two patients who showed an average tumor volume reduction of 37.1 cm(3) and re-opening airways. The mid-treatment increase in HU-based ventilation of patient 3 was 100.4% in the affected lobes, which was considerably greater than 7.8% in the unaffected lobes.This study has demonstrated that 4D-CT ventilation imaging shows the known effects of radiotherapy on lung function: radiation-induced ventilation reduction and ventilation increase caused by tumor regression, providing validation for 4D-CT ventilation imaging. This study was supported in part by a National Lung Cancer Partnership Young Investigator Research grant.

  View details for DOI 10.1118/1.4925754

  View details for PubMedID 26129054

• MO-FG-303-06: Evaluation of the Performance of Very High-Energy Electron (VHEE) Beams in Radiotherapy: Five Clinical Cases. Medical physics Palma, B., Bazalova-Carter, M., Hardemark, B., Hynning, E., Qu, B., Loo, B., Maxim, P. 2015; 42 (6): 3568-?

  Abstract

  To evaluate the performance of 100-120 MeV very-high energy electron (VHEE) scanning pencil beams to radiotherapy by means of Monte Carlo (MC) simulations.We selected five clinical cases with target sizes of 1.2 cm(3) to 990.4 cm(3). We calculated VHEE treatment plans using the MC EGSnrc code implemented in a MATLAB-based graphical user interface developed by our group. We generated phase space data for beam energies: 100 and 120 MeV and pencil beam spot sizes of 1, 3, and 5 mm at FWHM. The number of equidistant beams considered in this work was 16 or 32. Dose was calculated and then imported into a research version of RayStation where treatment plan optimization was performed. We compared the VHEE plans with the clinically delivered volumetric modulated arc therapy (VMAT) plan to evaluate VHEE plans performance.VHEE plans provided the same PTV coverage and dose homogeneity than VMAT plans for all the cases. In average, the mean dose to organs at risk (OARs) was 24% lower for the VHEE plans. The structures that benefited the most from using VHEE were: large bowel for the esophagus case, chest wall for the liver case, brainstem for the acoustic case, carina for the lung case, and genitalia for the anal case, with 23.7-34.6% lower dose. VHEE dose distributions were more conformal than VMAT solution as confirmed by conformity indices CI100 and CI50. Integral dose to the body was in average 19.6% (9.2%-36.5%) lower for the VHEE plans.We have shown that VHEE plans resulted in similar or superior dose distributions compared to clinical VMAT plans for five different cases and a wide range of target volumes, including a case with a small target (1.2 cm(3)), which represents a challenge for VMAT planning and might require the use of more complex non-coplanar VMAT plans. B Palma: None. M Bazalova: None. B Hardemark: Employee, RaySearch Laboratories AB. E Hynning: Employee, RaySearch Laboratories AB. B Qu: None. B Loo Jr.: Research support, RaySearch, Varian. P Maxim: Research support, RaySearch, Varian.

  View details for DOI 10.1118/1.4925419

  View details for PubMedID 26128721

• SU-F-207-13: Comparison of Four Dimensional Computed Tomography (4D CT) Versus Breath Hold Images to Determine Pulmonary Nodule Elasticity. Medical physics Negahdar, M., Loo, B., Maxim, P. 2015; 42 (6): 3544-?

  Abstract

  Elasticity may distinguish malignant from benign pulmonary nodules. To compare determining of malignant pulmonary nodule (MPN) elasticity from four dimensional computed tomography (4D CT) images versus inhale/exhale breath-hold CT images.We analyzed phase 00 and 50 of 4D CT and deep inhale and natural exhale of breath-hold CT images of 30 MPN treated with stereotactic ablative radiotherapy (SABR). The radius of the smallest MPN was 0.3 cm while the biggest one was 2.1 cm. An intensity based deformable image registration (DIR) workflow was applied to the 4D CT and breath-hold images to determine the volumes of the MPNs and a 1 cm ring of surrounding lung tissue (ring) in each state. Next, an elasticity parameter was derived by calculating the ratio of the volume changes of MPN (exhale:inhale or phase50:phase00) to that of a 1 cm ring of lung tissue surrounding the MPN. The proposed formulation of elasticity enables us to compare volume changes of two different MPN in two different locations of lung.The calculated volume ratio of MPNs from 4D CT (phase50:phase00) and breath-hold images (exhale:inhale) was 1.00±0.23 and 0.95±0.11, respectively. It shows the stiffness of MPN and comparably bigger volume changes of MPN in breath-hold images because of the deeper degree of inhalation. The calculated elasticity of MPNs from 4D CT and breath-hold images was 1.12±0.22 and 1.23±0.26, respectively. For five patients who have had two MPN in their lung, calculated elasticity of tumor A and tumor B follows same trend in both 4D CT and breath-hold images.We showed that 4D CT and breath-hold images are comparable in the ability to calculate the elasticity of MPN. This study has been supported by Department of Defense LCRP 2011 #W81XWH-12-1-0286.

  View details for DOI 10.1118/1.4925257

  View details for PubMedID 26128555

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

  Abstract

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

  View details for DOI 10.1118/1.4925515

  View details for PubMedID 26128812

• Non-Small Cell Lung Cancer, Version 6.2015. Journal of the National Comprehensive Cancer Network Ettinger, D. S., Wood, D. E., Akerley, W., Bazhenova, L. A., Borghaei, H., Camidge, D. R., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Dilling, T. J., Dobelbower, M. C., Govindan, R., Grannis, F. W., Horn, L., Jahan, T. M., Komaki, R., Krug, L. M., Lackner, R. P., Lanuti, M., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Schild, S. E., Shapiro, T. A., Swanson, S. J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2015; 13 (5): 515-524

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

  View details for PubMedID 25964637

• Non-Small Cell Lung Cancer, Version 6.2015 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Wood, D. E., Akerley, W., Bazhenova, L. A., Borghaei, H., Camidge, D. R., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Dilling, T. J., Dobelbower, M. C., Govindan, R., Grannis, F. W., Horn, L., Jahan, T. M., Komaki, R., Krug, L. M., Lackner, R. P., Lanuti, M., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Schild, S. E., Shapiro, T. A., Swanson, S. J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2015; 13 (5): 515-524

  Abstract

  These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

  View details for Web of Science ID 000354283800004

• Treatment planning for radiotherapy with very high-energy electron beams and comparison of VHEE and VMAT plans MEDICAL PHYSICS Bazalova-Carter, M., Qu, B., Palma, B., Hardemark, B., Hynning, E., Jensen, C., Maxim, P. G., Loo, B. W. 2015; 42 (5): 2615-2625

  Abstract

  The aim of this work was to develop a treatment planning workflow for rapid radiotherapy delivered with very high-energy electron (VHEE) scanning pencil beams of 60-120 MeV and to study VHEE plans as a function of VHEE treatment parameters. Additionally, VHEE plans were compared to clinical state-of-the-art volumetric modulated arc therapy (VMAT) photon plans for three cases.VHEE radiotherapy treatment planning was performed by linking EGSnrc Monte Carlo (MC) dose calculations with inverse treatment planning in a research version of RayStation. In order to study the effect of VHEE treatment parameters on VHEE dose distributions, a matlab graphical user interface (GUI) for calculation of VHEE MC pencil beam doses was developed. Through the GUI, pediatric case MC simulations were run for a number of beam energies (60, 80, 100, and 120 MeV), number of beams (13, 17, and 36), pencil beam spot (0.1, 1.0, and 3.0 mm) and grid (2.0, 2.5, and 3.5 mm) sizes, and source-to-axis distance, SAD (40 and 50 cm). VHEE plans for the pediatric case calculated with the different treatment parameters were optimized and compared. Furthermore, 100 MeV VHEE plans for the pediatric case, a lung, and a prostate case were calculated and compared to the clinically delivered VMAT plans. All plans were normalized such that the 100% isodose line covered 95% of the target volume.VHEE beam energy had the largest effect on the quality of dose distributions of the pediatric case. For the same target dose, the mean doses to organs at risk (OARs) decreased by 5%-16% when planned with 100 MeV compared to 60 MeV, but there was no further improvement in the 120 MeV plan. VHEE plans calculated with 36 beams outperformed plans calculated with 13 and 17 beams, but to a more modest degree (<8%). While pencil beam spacing and SAD had a small effect on VHEE dose distributions, 0.1-3 mm pencil beam sizes resulted in identical dose distributions. For the 100 MeV VHEE pediatric plan, OAR doses were up to 70% lower and the integral dose was 33% lower for VHEE compared to 6 MV VMAT. Additionally, VHEE conformity indices (CI100 = 1.09 and CI50 = 4.07) were better than VMAT conformity indices (CI100 = 1.30 and CI50 = 6.81). The 100 MeV VHEE lung plan resulted in mean dose decrease to all OARs by up to 27% for the same target coverage compared to the clinical 6 MV flattening filter-free (FFF) VMAT plan. The 100 MeV prostate plan resulted in 3% mean dose increase to the penile bulb and the urethra, but all other OAR mean doses were lower compared to the 15 MV VMAT plan. The lung case CI100 and CI50 conformity indices were 3% and 8% lower, respectively, in the VHEE plan compared to the VMAT plan. The prostate case CI100 and CI50 conformity indices were 1% higher and 8% lower, respectively, in the VHEE plan compared to the VMAT plan.The authors have developed a treatment planning workflow for MC dose calculation of pencil beams and optimization for treatment planning of VHEE radiotherapy. The authors have demonstrated that VHEE plans resulted in similar or superior dose distributions for pediatric, lung, and prostate cases compared to clinical VMAT plans.

  View details for DOI 10.1118/1.4918923

  View details for Web of Science ID 000354776800050

  View details for PubMedID 25979053

• ACR Appropriateness Criteria (R) Induction and Adjuvant Therapy for N2 Non-small-cell Lung Cancer AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Willers, H., Stinchcombe, T. E., Barriger, R. B., Chetty, I. J., Ginsburg, M. E., Kestin, L. L., Kumar, S., Loo, B. W., Movsas, B., Rimner, A., Rosenzweig, K. E., Videtic, G. M., Chang, J. Y. 2015; 38 (2): 197-205

  Abstract

  The integration of chemotherapy, radiation therapy (RT), and surgery in the management of patients with stage IIIA (N2) non-small-cell lung carcinoma is challenging. The American College of Radiology (ACR) Appropriateness Criteria Lung Cancer Panel was charged to update management recommendations for this clinical scenario. The Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. There is limited level I evidence to guide patient selection for induction, postoperative RT (PORT), or definitive RT. Literature interpretation is complicated by inconsistent diagnostic procedures for N2 disease, disease heterogeneity, and pooled analysis with other stages. PORT is an appropriate therapy following adjuvant chemotherapy in patients with incidental pN2 disease. In patients with clinical N2 disease who are potential candidates for a lobectomy, both definitive and induction concurrent chemotherapy/RT are appropriate treatments. In N2 patients who require a pneumonectomy, definitive concurrent chemotherapy/RT is most appropriate although induction concurrent chemotherapy/RT may be considered in expert hands. Induction chemotherapy followed by surgery +/- PORT may also be an option in N2 patients. For preoperative RT and PORT, 3-dimensional conformal techniques and intensity-modulated RT are most appropriate.

  View details for DOI 10.1097/COC.0000000000000154

  View details for Web of Science ID 000351770500013

  View details for PubMedID 25803563

• To SABR or not to SABR? Indications and contraindications for stereotactic ablative radiotherapy in the treatment of early-stage, oligometastatic, or oligoprogressive non-small cell lung cancer. Seminars in radiation oncology Shultz, D. B., Diehn, M., Loo, B. W. 2015; 25 (2): 78-86

  Abstract

  Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for early-stage non-small cell lung cancer. Although direct comparisons from randomized trials are not available, rates of both primary tumor control and distant metastasis are similar between SABR and surgery. Overall survival is lower after SABR compared with surgery, largely reflecting that a primary selection criterion for SABR has been medical inoperability because of decreased cardiopulmonary function and other comorbidities that lead to decreased survival independent of non-small cell lung cancer. Survival outcomes between SABR and surgery are much more similar in propensity-matched cohorts. Newer potential indications for SABR include treatment of operable patients; of oligometastatic lung cancer, in which SABR has emerged as an alternative to metastasectomy; and of oligoprogressive lung cancer, an attractive concept especially as improved personalized systemic therapies emerge, and prospective trials are currently being conducted in these settings. Although toxicity in modern series is low, SABR is clearly capable of producing fatal complications, and understanding the risk factors and approaches for mitigating them has been emerging in recent years. Thus, appropriate patient selection is a vital, evolving, and controversial topic.

  View details for DOI 10.1016/j.semradonc.2014.11.005

  View details for PubMedID 25771411

• Noninvasive pulmonary nodule elastometry by CT and deformable image registration. Radiotherapy and oncology Negahdar, M., Fasola, C. E., Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Fleischmann, D., Tian, L., Loo, B. W., Maxim, P. G. 2015; 115 (1): 35-40

  Abstract

  To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring.We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring.For all 30 tumors the Dice coefficient was 0.79±0.07 and 0.79±0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81±0.1. The elasticity of MPNs was 1.24±0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung.We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules.

  View details for DOI 10.1016/j.radonc.2015.03.015

  View details for PubMedID 25824979

• Comparison of film measurements and Monte Carlo simulations of dose delivered with very high-energy electron beams in a polystyrene phantom MEDICAL PHYSICS Bazalova-Carter, M., Liu, M., Palma, B., Dunning, M., McCormick, D., Hemsing, E., Nelson, J., Jobe, K., Colby, E., Koong, A. C., Tantawi, S., Dolgashev, V., Maxim, P. G., Loo, B. W. 2015; 42 (4): 1606-1613

  Abstract

  To measure radiation dose in a water-equivalent medium from very high-energy electron (VHEE) beams and make comparisons to Monte Carlo (MC) simulation results.Dose in a polystyrene phantom delivered by an experimental VHEE beam line was measured with Gafchromic films for three 50 MeV and two 70 MeV Gaussian beams of 4.0-6.9 mm FWHM and compared to corresponding MC-simulated dose distributions. MC dose in the polystyrene phantom was calculated with the EGSnrc/BEAMnrc and DOSXYZnrc codes based on the experimental setup. Additionally, the effect of 2% beam energy measurement uncertainty and possible non-zero beam angular spread on MC dose distributions was evaluated.MC simulated percentage depth dose (PDD) curves agreed with measurements within 4% for all beam sizes at both 50 and 70 MeV VHEE beams. Central axis PDD at 8 cm depth ranged from 14% to 19% for the 5.4-6.9 mm 50 MeV beams and it ranged from 14% to 18% for the 4.0-4.5 mm 70 MeV beams. MC simulated relative beam profiles of regularly shaped Gaussian beams evaluated at depths of 0.64 to 7.46 cm agreed with measurements to within 5%. A 2% beam energy uncertainty and 0.286° beam angular spread corresponded to a maximum 3.0% and 3.8% difference in depth dose curves of the 50 and 70 MeV electron beams, respectively. Absolute dose differences between MC simulations and film measurements of regularly shaped Gaussian beams were between 10% and 42%.The authors demonstrate that relative dose distributions for VHEE beams of 50-70 MeV can be measured with Gafchromic films and modeled with Monte Carlo simulations to an accuracy of 5%. The reported absolute dose differences likely caused by imperfect beam steering and subsequent charge loss revealed the importance of accurate VHEE beam control and diagnostics.

  View details for DOI 10.1118/1.4914371

  View details for Web of Science ID 000352273200015

  View details for PubMedID 25832051

• The relationship between serial [(18)?F]PBR06 PET imaging of microglial activation and motor function following stroke in mice. Molecular imaging and biology Lartey, F. M., Ahn, G., Ali, R., Rosenblum, S., Miao, Z., Arksey, N., Shen, B., Colomer, M. V., Rafat, M., Liu, H., Alejandre-Alcazar, M. A., Chen, J. W., Palmer, T., Chin, F. T., Guzman, R., Loo, B. W., Graves, E. 2014; 16 (6): 821-829

  Abstract

  Using [(18) F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [(18) F]PBR06 PET as a therapeutic assessment tool.Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI).The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI.[18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function.

  View details for DOI 10.1007/s11307-014-0745-0

  View details for PubMedID 24865401

• Non-Small Cell Lung Cancer, Version 1.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Wood, D. E., Akerley, W., Bazhenova, L. A., Borghaei, H., Camidge, D. R., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Dilling, T. J., Govindan, R., Grannis, F. W., Horn, L., Jahan, T. M., Komaki, R., Kris, M. G., Krug, L. M., Lackner, R. P., Lanuti, M., Lilenbaum, R., Lin, J., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Schild, S., Shapiro, T. A., Swanson, S. J., Tauer, K., Yang, S. C., Gregory, K., Hughes, M. 2014; 12 (12): 1738-1761

  Abstract

  This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

  View details for Web of Science ID 000346190900012

  View details for PubMedID 25505215

• Ultrasensitive Detection of Circulating Tumor DNA in Non-Small Cell Lung Cancer by Deep Sequencing Diehn, M., Bratman, S. V., Newman, A. M., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. ELSEVIER SCIENCE INC. 2014: S75

  View details for DOI 10.1016/j.ijrobp.2014.08.315

  View details for Web of Science ID 000346413500167

• Noninvasive Pulmonary Nodule Elastometry by CT and Deformable Image Registration Negahdar, M., Shultz, D. B., Eyben, R. V., Fasola, C., Yu, A. S., Tian, L., Fleischmann, D., Gable, L., Shan, X., Diehn, M., Loo, B. W., Maxim, P. G. ELSEVIER SCIENCE INC. 2014: S10

  View details for DOI 10.1016/j.ijrobp.2014.08.145

  View details for Web of Science ID 000346413500020

• Metabolic Tumor Volume Predicts Overall Survival in Patients With Stage III Non-Small Cell Lung Cancer Treated on ACRIN 6668/RTOG 0235 Bazan, J. G., Duan, F., Snyder, B. S., Horng, D., Graves, E. E., Siegel, B. A., Machtay, M., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S3–S4

  View details for DOI 10.1016/j.ijrobp.2014.08.027

  View details for Web of Science ID 000346413500007

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

  Abstract

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

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

  View details for PubMedID 25189484

  View details for PubMedCentralID PMC4216761

• Stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer. Journal of thoracic oncology Shultz, D. B., Filippi, A. R., Thariat, J., Mornex, F., Loo, B. W., Ricardi, U. 2014; 9 (10): 1426-1433

  Abstract

  An increasing body of experience suggests that oligometastasis represents a minimal metastatic state with the potential for cure or prolonged survival in selected patients treated with radical local therapy to all identified sites of disease. The main clinical scenarios managed by thoracic oncology specialists are pulmonary oligometastases from primary malignancies of other anatomic sites and primary lung cancer with oligometastases to lung or other organs. Surgery has been a mainstay of treatment in these situations, with remarkably favorable outcomes following pulmonary metastasectomy in well-selected patient cohorts. As with early stage lung cancer in patients who are medically inoperable, stereotactic ablative radiotherapy is emerging as a prominent local treatment option for oligometastatic disease. We review the role and clinical experience of stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer.

  View details for DOI 10.1097/JTO.0000000000000317

  View details for PubMedID 25170641

• Stereotactic Ablative Radiotherapy for Pulmonary Oligometastases and Oligometastatic Lung Cancer JOURNAL OF THORACIC ONCOLOGY Shultz, D. B., Filippi, A. R., Thariat, J., Mornex, F., Loo, B. W., Ricardi, U. 2014; 9 (10): 1426-1433

  Abstract

  An increasing body of experience suggests that oligometastasis represents a minimal metastatic state with the potential for cure or prolonged survival in selected patients treated with radical local therapy to all identified sites of disease. The main clinical scenarios managed by thoracic oncology specialists are pulmonary oligometastases from primary malignancies of other anatomic sites and primary lung cancer with oligometastases to lung or other organs. Surgery has been a mainstay of treatment in these situations, with remarkably favorable outcomes following pulmonary metastasectomy in well-selected patient cohorts. As with early stage lung cancer in patients who are medically inoperable, stereotactic ablative radiotherapy is emerging as a prominent local treatment option for oligometastatic disease. We review the role and clinical experience of stereotactic ablative radiotherapy for pulmonary oligometastases and oligometastatic lung cancer.

  View details for DOI 10.1097/JTO.0000000000000317

  View details for Web of Science ID 000344368000006

• Pulmonary Ventilation Imaging Based on 4-Dimensional Computed Tomography: Comparison With Pulmonary Function Tests and SPECT Ventilation Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Yamamoto, T., Kabus, S., Lorenz, C., Mittra, E., Hong, J. C., Chung, M., Eclov, N., To, J., Diehn, M., Loo, B. W., Keall, P. J. 2014; 90 (2): 414-422

  Abstract

  4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively.In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 ± 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01).An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging.

  View details for DOI 10.1016/j.ijrobp.2014.06.006

  View details for Web of Science ID 000341994400026

• Motion management during IMAT treatment of mobile lung tumors-A comparison of MLC tracking and gated delivery MEDICAL PHYSICS Falk, M., Pommer, T., Keall, P., Korreman, S., Persson, G., Poulsen, P., af Rosenschold, P. 2014; 41 (10): 101707

  Abstract

  To compare real-time dynamic multileaf collimator (MLC) tracking, respiratory amplitude and phase gating, and no compensation for intrafraction motion management during intensity modulated arc therapy (IMAT).Motion management with MLC tracking and gating was evaluated for four lung cancer patients. The IMAT plans were delivered to a dosimetric phantom mounted onto a 3D motion phantom performing patient-specific lung tumor motion. The MLC tracking system was guided by an optical system that used stereoscopic infrared (IR) cameras and five spherical reflecting markers attached to the dosimetric phantom. The gated delivery used a duty cycle of 35% and collected position data using an IR camera and two reflecting markers attached to a marker block.The average gamma index failure rate (2% and 2 mm criteria) was <0.01% with amplitude gating for all patients, and <0.1% with phase gating and <3.7% with MLC tracking for three of the four patients. One of the patients had an average failure rate of 15.1% with phase gating and 18.3% with MLC tracking. With no motion compensation, the average gamma index failure rate ranged from 7.1% to 46.9% for the different patients. Evaluation of the dosimetric error contributions showed that the gated delivery mainly had errors in target localization, while MLC tracking also had contributions from MLC leaf fitting and leaf adjustment. The average treatment time was about three times longer with gating compared to delivery with MLC tracking (that did not prolong the treatment time) or no motion compensation. For two of the patients, the different motion compensation techniques allowed for approximately the same margin reduction but for two of the patients, gating enabled a larger reduction of the margins than MLC tracking.Both gating and MLC tracking reduced the effects of the target movements, although the gated delivery showed a better dosimetric accuracy and enabled a larger reduction of the margins in some cases. MLC tracking did not prolong the treatment time compared to delivery with no motion compensation while gating had a considerably longer delivery time. In a clinical setting, the optical monitoring of the patients breathing would have to be correlated to the internal movements of the tumor.

  View details for DOI 10.1118/1.4896024

  View details for Web of Science ID 000343032400010

  View details for PubMedID 25281946

  View details for PubMedCentralID PMC4281086

• Pulmonary ventilation imaging based on 4-dimensional computed tomography: comparison with pulmonary function tests and SPECT ventilation images. International journal of radiation oncology, biology, physics Yamamoto, T., Kabus, S., Lorenz, C., Mittra, E., Hong, J. C., Chung, M., Eclov, N., To, J., Diehn, M., Loo, B. W., Keall, P. J. 2014; 90 (2): 414-422

  Abstract

  4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively.In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 ± 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01).An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging.

  View details for DOI 10.1016/j.ijrobp.2014.06.006

  View details for PubMedID 25104070

• Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

  Abstract

  Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

  View details for DOI 10.1016/j.ijrobp.2014.05.025

  View details for Web of Science ID 000341456500029

• Noninvasive Pulmonary Nodule Elastometry by CT and Deformable Image Registration Negahdar, M., Shultz, D. B., Eyben, R. V., Fasola, C., Yu, A. S., Tian, L., Fleischmann, D., Gable, L., Shan, X., Diehn, M., Loo, B. W., Maxim, P. G. ELSEVIER SCIENCE INC. 2014: S623–S624

  View details for DOI 10.1016/j.ijrobp.2014.05.1857

  View details for Web of Science ID 000342331402265

• Impact of Very Rapid Irradiation on Clonogenic Survival Rafat, M., Bazalova, M., Palma, B. A., Kozak, M. M., Jiang, D., Dunning, M., McCormick, D. J., Nelson, J. L., Hemsing, E., Lartey, F. M., Graves, E. E., Koong, A. C., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S790

  View details for DOI 10.1016/j.ijrobp.2014.05.2283

  View details for Web of Science ID 000342331403079

• Impact of Optimally-Gated PET on Tumor Localization and Quantification Lee, K., Loo, B. W., Diehn, M., Atwood, T. F., Hristov, D. H. ELSEVIER SCIENCE INC. 2014: S795

  View details for Web of Science ID 000342331403092

• Optimization of Beam Parameters for Very High-Energy Electron Radiation Therapy: A Lung Cancer Case Palma, B. A., Bazalova, M., Bjoern, H., Hynning, E., Qu, B., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S933–S934

  View details for DOI 10.1016/j.ijrobp.2014.05.2641

  View details for Web of Science ID 000342331403435

• Treatment-Planning Study for Very High-Energy Electron Beam Radiation Therapy: Integral Dose Reduction for Pediatric Patients Bazalova, M., Qu, B., Palma, B., Hynning, E., Hardemark, B., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S935–S936

  View details for DOI 10.1016/j.ijrobp.2014.05.2647

  View details for Web of Science ID 000342331403441

• Relationship of Dose and TCP for SBRT of Lung Cancer as Analyzed From a Pooled 118 Studies Using a New Radiobiological Model Liu, F., Tai, A., Lee, P., Biswas, T., Ding, G. X., Naqa, I., Grimm, J., Kong, F., LaCouture, T. A., Loo, B. W., Miften, M., Solberg, T., Li, A. ELSEVIER SCIENCE INC. 2014: S189–S190

  View details for DOI 10.1016/j.ijrobp.2014.05.721

  View details for Web of Science ID 000342331400435

• Lung volume reduction after stereotactic ablative radiation therapy of lung tumors: potential application to emphysema. International journal of radiation oncology, biology, physics Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

  Abstract

  Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

  View details for DOI 10.1016/j.ijrobp.2014.05.025

  View details for PubMedID 25015205

• PRURITUS AS A PARANEOPLASTIC SYMPTOM OF THYMOMA Padda, S., Pagtama, J. Y., Tisch, A. H., Neal, J. W., Riess, J. W., Loo, B. W., Hardy, R., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S240–S241

  View details for Web of Science ID 000344627500044

• Circulating Tumor DNA Concentrations Reflect Metabolic Tumor Volume in NSCLC Modlin, L. A., Bratman, S. V., Newman, A. M., Eclov, N. W., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2014: S812

  View details for DOI 10.1016/j.ijrobp.2014.05.2342

  View details for Web of Science ID 000342331403138

• ACR Appropriateness Criteria® nonsurgical treatment for locally advanced non-small-cell lung cancer: good performance status/definitive intent. Oncology (Williston Park, N.Y.) Chang, J. Y., Kestin, L. L., Barriger, R. B., Chetty, I. J., Ginsburg, M. E., Kumar, S., Loo, B. W., Movsas, B., Rimner, A., Rosenzweig, K. E., Stinchcombe, T. E., Videtic, G. M., Willers, H. 2014; 28 (8): 706-?

  Abstract

  Concurrent chemotherapy/radiotherapy has been considered the standard treatment for patients with a good performance status and inoperable stage III non-small-cell lung cancer (NSCLC). Three-dimensional chemoradiation therapy and intensity-modulated radiation therapy have been reported to reduce toxicity and allow a dose escalation to 70 Gy and beyond. However, the Radiation Therapy Oncology Group 0617 trial recently showed that dose escalation from 60 Gy to 74 Gy with concurrent chemotherapy in stage III NSCLC was associated with higher toxicity and worse survival. A "one size fits all" treatment approach may need to be changed and adapted to each patient's particular disease and unique biologic/anatomic features, as well as the most appropriate radiotherapy modalities for that patient. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.

  View details for PubMedID 25140629

• Feasibility of a Table-Top Total Body Irradiation Technique using Robotic Couch Motion Chin, E., Otto, K., Hoppe, R., Hsu, A., Loo, B., Million, L., Xing, L., Fahimian, B. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2014: 15

  View details for DOI 10.1118/1.4894898

  View details for Web of Science ID 000341068100118

• Circulating Tumor Microemboli Diagnostics for Patients with Non-Small-Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Carlsson, A., Nair, V. S., Luttgen, M. S., Keu, K. V., Horng, G., Vasanawala, M., Kolatkar, A., Jamali, M., Iagaru, A. H., Kuschner, W., Loo, B. W., Shrager, J. B., Bethel, K., Hoh, C. K., Bazhenova, L., Nieva, J., Kuhn, P., Gambhir, S. S. 2014; 9 (8): 1111-1119

  Abstract

  Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation.First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group.We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002).CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.

  View details for PubMedID 25157764

• Feasibility and Potential Utility of Multicomponent Exhaled Breath Analysis for Predicting Development of Radiation Pneumonitis After Stereotactic Ablative Radiotherapy JOURNAL OF THORACIC ONCOLOGY More, J. M., Eclov, N. C., Chung, M. P., Wynne, J. F., Shorter, J. H., Nelson, D. D., Hanlon, A. L., Burmeister, R., Banos, P., Maxim, P. G., Loo, B. W., Diehn, M. 2014; 9 (7): 957-964

  Abstract

  In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors.Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade ≥2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters.Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development.The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

  View details for DOI 10.1097/JTO.0000000000000182

  View details for Web of Science ID 000338025600015

• Feasibility and potential utility of multicomponent exhaled breath analysis for predicting development of radiation pneumonitis after stereotactic ablative radiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Moré, J. M., Eclov, N. C., Chung, M. P., Wynne, J. F., Shorter, J. H., Nelson, D. D., Hanlon, A. L., Burmeister, R., Banos, P., Maxim, P. G., Loo, B. W., Diehn, M. 2014; 9 (7): 957-64

  Abstract

  In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors.Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade ≥2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters.Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development.The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

  View details for DOI 10.1097/JTO.0000000000000182

  View details for PubMedID 24926543

• Vagal and recurrent laryngeal neuropathy following stereotactic ablative radiation therapy in the chest. Practical radiation oncology Shultz, D. B., Trakul, N., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 4 (4): 272-278

  Abstract

  To identify clinical and dosimetric factors associated with vagus nerve (VN) and recurrent laryngeal nerve (RecLN) injury following stereotactic ablative radiation therapy (SABR) in the chest.We examined the clinical courses and SABR plans of 67 patients treated for T1 or T2 non-small cell lung cancer of the upper right or left lung, including 2 who developed vocal cord paresis (VCP) following treatment. After developing a contouring atlas for the VN and RecLN in the thorax, dose to those structures was retrospectively determined for each patient, and we identified 12 patients whose treatment imparted significant dose to either nerve and who were assessable for more than 12 months follow-up. Biologically effective doses using linear-quadratic (LQ) and linear quadratic-linear (LQ-L) modeling were correlated with VN and RecLN toxicity.Of 12 patients, 2 developed VCP. The first underwent repeat SABR and received a cumulative single fraction equivalent dose (alpha/beta = 3; SFED3) of 37.4 or 64.5 Gy to the VN and 13.7 or 15.3 Gy to the RecLN (by LQ or LQ-L modeling, respectively). This was the highest VN dose and fifth highest RecLN dose in the cohort. The second had rheumatoid arthritis and connective tissue disease and received a SFED3 of 16 Gy to the VN and 19.5 Gy to the RecLN (by both LQ and LQ-L modeling). This was in the upper tertile of VN and RecLN doses for the cohort.Following SABR for non-small cell lung cancer, VCP was associated with high cumulative dose to the VN in 1 patient and a moderately high dose to the VN and RecLN in another patient with rheumatoid arthritis and connective tissue disease. Particularly in the setting of reirradiation or connective tissue disease, potential toxicity to the VN or RecLN should be considered.

  View details for DOI 10.1016/j.prro.2013.08.005

  View details for PubMedID 25012837

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

  Abstract

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

  View details for DOI 10.1016/j.cllc.2013.12.011

  View details for PubMedID 24594400

• 4D-CT Ventilation Image-Based IMRT Plans Are Dosimetrically Comparable to SPECT Ventilation Image-Based Plans Kida, S., Bal, M., Kabus, S., Loo, B., Keall, P., Yamamoto, T. WILEY. 2014: 569

  View details for DOI 10.1118/1.4889666

  View details for Web of Science ID 000438759605324

• The Effect of Beam Parameters On Very High-Energy Electron Radiotherapy: A Planning Study Palma, B., Bazalova, M., Hardemark, B., Hynning, E., Qu, B., Loo, B., Maxim, P. WILEY. 2014: 111

  View details for DOI 10.1118/1.4894982

  View details for Web of Science ID 000438759601086

• The Effect of Beam Parameters On Very High-Energy Electron Radiotherapy: A Planning Study Palma, B., Bazalova, M., Hardemark, B., Hynning, E., Qu, B., Loo, B., Maxim, P. WILEY. 2014

  View details for DOI 10.1118/1.4887869

  View details for Web of Science ID 000439377700038

• Radiation Therapy with Very High-Energy Electron (VHEE) Beams in the Presence of Metal Implants Jensen, C., Palma, B., Qu, B., Maxim, P., Hardemark, B., Hynning, E., Loo, B., Bazalova, M. WILEY. 2014

  View details for DOI 10.1118/1.4888605

  View details for Web of Science ID 000436931100041

• Radiation Therapy with Very High-Energy Electron (VHEE) Beams in the Presence of Metal Implants Jensen, C., Palma, B., Qu, B., Maxim, P., Hardemark, B., Hynning, E., Loo, B., Bazalova, M. WILEY. 2014: 286–87

  Abstract

  To evaluate the efficacy of two noncommercial techniques for deep inspiration breathhold (DIBH) treatment of left-sided breast cancer (LSBC) using cine electronic portal imaging device (EPID) images.23,875 EPID images of 65 patients treated for LSBC at two different cancer treatment centers were retrieved. At the Milford Regional Cancer Center, DIBH stability was maintained by visual alignment of inroom lasers and patient skin tattoos (TAT). At the South Shore Hospital, a distance-measuring laser device (RTSSD) was implemented. For both centers,cine EPID images were acquired at least once per week during beam-on. Chest wall position relative to image boundary was measured and tracked over the course of treatment for every patient and treatment fraction for which data were acquired.Median intrabeam chest motion was 0.31 mm for the TAT method and 0.37 mm for the RTSSD method. The maximum excursions exceeded our treatment protocol threshold of 3 mm in 0.3% of cases (TAT) and 1.2% of cases (RTSSD). The authors did not observe a clinically significant difference between the two datasets.Both noncommercial techniques for monitoring the DIBH location provided DIBH stability within the predetermined treatment protocol parameters (<3 mm). The intreatment imaging offered by the EPID operating in cine mode facilitates retrospective analysis and validation of both techniques.

  View details for DOI 10.1118/1.4862835

  View details for Web of Science ID 000438759603034

  View details for PubMedID 24506621

  View details for PubMedCentralID PMC3977833

• Radiobiological Advantage of Very Rapid Irradiation Rafat, M., Bazalova, M., Palma, B., Kozak, M., Jiang, D., Dunning, M., McCormick, D., Nelson, J., Hemsing, E., Lartey, F., Graves, E., Koong, A., Maxim, P., Loo, B. WILEY. 2014: 95

  View details for DOI 10.1118/1.4889712

  View details for Web of Science ID 000438759601023

• Dynamic Treatment of Clinical Margins Beyond the PET-Avid Target in Emission Guided Radiation Therapy: A Retrospective Patient Study Nanduri, A., Fan, Q., Yang, J., Yamamoto, T., Graves, E., Loo, B., Mazin, S. WILEY. 2014: 571

  View details for DOI 10.1118/1.4889675

  View details for Web of Science ID 000438759605333

• Positron Emission Tomography (PET)-Guided Dynamic Lung Tumor Tracking for Cancer Radiotherapy: First Patient Simulations Yang, J., Yamamoto, T., Loo, B., Graves, E., Keall, P. WILEY. 2014: 522–23

  View details for DOI 10.1118/1.4889499

  View details for Web of Science ID 000438759605157

• Calibration-Free Combined KV/MV Short Scan CBCT Wu, M., Loo, B., Bazalova, M., Star-Lack, J., Fahrig, R. WILEY. 2014

  View details for DOI 10.1118/1.4889513

  View details for Web of Science ID 000438726000033

• FEATURED PRESENTATION - Treatment Planning Tool for Radiotherapy with Very High-Energy Electron Beams Bazalova, M., Qu, B., Hynning, E., Hardemark, B., Palma, B., Loo, B., Maxim, P. WILEY. 2014

  View details for DOI 10.1118/1.4889223

  View details for Web of Science ID 000438445400004

• Noninvasive and ultrasensitive quantitation of circulating tumor DNA by hybrid capture and deep sequencing. Bratman, S., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204749

• The effect of arm position on the dosimetry of thoracic stereotactic ablative radiation therapy using volumetric modulated arc therapy. Practical radiation oncology Shultz, D. B., Jang, S. S., Hanlon, A. L., Diehn, M., Loo, B. W., Maxim, P. G. 2014; 4 (3): 192-197

  Abstract

  Patient comfort and positioning stability may be improved in the arms down (AD) compared with the typical arms up (AU) position in thoracic stereotactic ablative radiation therapy (SABR). We compared plan quality for AD vs AU when using volumetric modulated arc therapy (VMAT), and evaluated the sensitivity of AD plans to arm positioning variability.We took plans of 14 patients with 17 lung tumors treated with thoracic SABR using VMAT in the AD position and simulated the same treatments in the AU position by re-optimizing after digitally removing the ipsilateral arm. To evaluate the sensitivity of AD plans to arm positioning variability, all plans were recalculated without re-optimization after assigning water density to the ipsilateral arm (AD-W) and then digitally shifting the arm 2.5 cm anterolaterally (AD-WS).Between AD and AU plans, statistically significant but clinically insignificant (all original planning constraints met) differences were found for the following parameters: mean planning target volume maximum dose, difference of 2.3% of prescription dose (P = .049); mean intermediate dose conformity index, difference of 0.27 (P = .012); median percent lung volume receiving a minimum of 10, 20, and 30 Gy (V10, V20, and V30), differences of 0.5%, 0.2%, and 0.1%, respectively (P = .040, .007, and .001); and median spinal cord maximum dose, difference of 33.5 cGy (P = .017). Similarly, between AD-W and AD-WS plans, statistically significant but clinically insignificant differences were found for median lung V20 and V30, difference of 0.0% for both (P = .034 and .016, by matched pair analysis).Our exploratory planning study suggests that when using VMAT for lung tumor SABR, AD and AU positioning achieve clinically equivalent plan quality, and AD plans are insensitive to relatively large variability in arm position.

  View details for DOI 10.1016/j.prro.2013.07.010

  View details for PubMedID 24766687

• An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 548-554

  Abstract

  Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

  View details for DOI 10.1038/nm.3519

  View details for PubMedID 24705333

• ACR Appropriateness Criteria((R)) Early-Stage Non-Small-Cell Lung Cancer AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Videtic, G. M., Chang, J. Y., Chetty, I. J., Ginsburg, M. E., Kestin, L. L., Kong, F. (., Lally, B. E., Loo, B. W., Movsas, B., Stinchcombe, T. E., Willers, H., Rosenzweig, K. E. 2014; 37 (2): 201-207

  Abstract

  Early-stage non-small-cell lung cancer (NSCLC) is diagnosed in about 15% to 20% of lung cancer patients at presentation. In order to provide clinicians with guidance in decision making for early-stage NSCLC patients, the American College of Radiology Appropriateness Criteria Lung Cancer Panel was recently charged with a review of the current published literature to generate up-to-date management recommendations for this clinical scenario. For patients with localized, mediastinal lymph node-negative NSCLC, optimal management should be determined by an expert multidisciplinary team. For medically operable patients, surgical resection is the standard of care, with generally no role for adjuvant therapies thereafter. For patients with medical comorbidities making them at high risk for surgery, there is emerging evidence demonstrating the availability of low toxicity curative therapies, such as stereotactic body radiotherapy, for their care. As a general statement, the American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

  View details for DOI 10.1097/COC.0000000000000013

  View details for Web of Science ID 000333713100019

  View details for PubMedID 25180631

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2013.12.010

  View details for PubMedID 24495591

• PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [F-18]PBR06 MOLECULAR IMAGING AND BIOLOGY Lartey, F. M., Ahn, G., Shen, B., Cord, K., Smith, T., Chua, J. Y., Rosenblum, S., Liu, H., James, M. L., Chernikova, S., Lee, S. W., Pisani, L. J., Tirouvanziam, R., Chen, J. W., Palmer, T. D., Chin, F. T., Guzman, R., Graves, E. E., Loo, B. W. 2014; 16 (1): 109-117

  Abstract

  The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [(18)F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([(18)F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model.Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography.[(18)F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [(18)F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET.[(18)F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.

  View details for DOI 10.1007/s11307-013-0664-5

  View details for PubMedID 23836504

• Investigating the feasibility of rapid MRI for image-guided motion management in lung cancer radiotherapy. BioMed research international Sawant, A., Keall, P., Pauly, K. B., Alley, M., Vasanawala, S., Loo, B. W., Hinkle, J., Joshi, S. 2014; 2014: 485067-?

  Abstract

  Cycle-to-cycle variations in respiratory motion can cause significant geometric and dosimetric errors in the administration of lung cancer radiation therapy. A common limitation of the current strategies for motion management is that they assume a constant, reproducible respiratory cycle. In this work, we investigate the feasibility of using rapid MRI for providing long-term imaging of the thorax in order to better capture cycle-to-cycle variations. Two nonsmall-cell lung cancer patients were imaged (free-breathing, no extrinsic contrast, and 1.5 T scanner). A balanced steady-state-free-precession (b-SSFP) sequence was used to acquire cine-2D and cine-3D (4D) images. In the case of Patient 1 (right midlobe lesion, ~40 mm diameter), tumor motion was well correlated with diaphragmatic motion. In the case of Patient 2, (left upper-lobe lesion, ~60 mm diameter), tumor motion was poorly correlated with diaphragmatic motion. Furthermore, the motion of the tumor centroid was poorly correlated with the motion of individual points on the tumor boundary, indicating significant rotation and/or deformation. These studies indicate that image quality and acquisition speed of cine-2D MRI were adequate for motion monitoring. However, significant improvements are required to achieve comparable speeds for truly 4D MRI. Despite several challenges, rapid MRI offers a feasible and attractive tool for noninvasive, long-term motion monitoring.

  View details for DOI 10.1155/2014/485067

  View details for PubMedID 24524077

  View details for PubMedCentralID PMC3913339

• Clinical implementation of intrafraction cone beam computed tomography imaging during lung tumor stereotactic ablative radiation therapy. International journal of radiation oncology, biology, physics Li, R., Han, B., Meng, B., Maxim, P. G., Xing, L., Koong, A. C., Diehn, M., Loo, B. W. 2013; 87 (5): 917-923

  Abstract

  To develop and clinically evaluate a volumetric imaging technique for assessing intrafraction geometric and dosimetric accuracy of stereotactic ablative radiation therapy (SABR).Twenty patients received SABR for lung tumors using volumetric modulated arc therapy (VMAT). At the beginning of each fraction, pretreatment cone beam computed tomography (CBCT) was used to align the soft-tissue tumor position with that in the planning CT. Concurrent with dose delivery, we acquired fluoroscopic radiograph projections during VMAT using the Varian on-board imaging system. Those kilovolt projections acquired during millivolt beam-on were automatically extracted, and intrafraction CBCT images were reconstructed using the filtered backprojection technique. We determined the time-averaged target shift during VMAT by calculating the center of mass of the tumor target in the intrafraction CBCT relative to the planning CT. To estimate the dosimetric impact of the target shift during treatment, we recalculated the dose to the GTV after shifting the entire patient anatomy according to the time-averaged target shift determined earlier.The mean target shift from intrafraction CBCT to planning CT was 1.6, 1.0, and 1.5 mm; the 95th percentile shift was 5.2, 3.1, 3.6 mm; and the maximum shift was 5.7, 3.6, and 4.9 mm along the anterior-posterior, left-right, and superior-inferior directions. Thus, the time-averaged intrafraction gross tumor volume (GTV) position was always within the planning target volume. We observed some degree of target blurring in the intrafraction CBCT, indicating imperfect breath-hold reproducibility or residual motion of the GTV during treatment. By our estimated dose recalculation, the GTV was consistently covered by the prescription dose (PD), that is, V100% above 0.97 for all patients, and minimum dose to GTV >100% PD for 18 patients and >95% PD for all patients.Intrafraction CBCT during VMAT can provide geometric and dosimetric verification of SABR valuable for quality assurance and potentially for treatment adaptation.

  View details for DOI 10.1016/j.ijrobp.2013.08.015

  View details for PubMedID 24113060

• 4D CT lung ventilation images are affected by the 4D CT sorting method. Medical physics Yamamoto, T., Kabus, S., Lorenz, C., Johnston, E., Maxim, P. G., Diehn, M., Eclov, N., Barquero, C., Loo, B. W., Keall, P. J. 2013; 40 (10): 101907-?

  Abstract

  Four-dimensional (4D) computed tomography (CT) ventilation imaging is a novel promising technique for lung functional imaging. The current standard 4D CT technique using phase-based sorting frequently results in artifacts, which may deteriorate the accuracy of ventilation imaging. The purpose of this study was to quantify the variability of 4D CT ventilation imaging due to 4D CT sorting.4D CT image sets from nine lung cancer patients were each sorted by the phase-based method and anatomic similarity-based method, designed to reduce artifacts, with corresponding ventilation images created for each method. Artifacts in the resulting 4D CT images were quantified with the artifact score which was defined based on the difference between the normalized cross correlation for CT slices within a CT data segment and that for CT slices bordering the interface between adjacent CT data segments. The ventilation variation was quantified using voxel-based Spearman rank correlation coefficients for all lung voxels, and Dice similarity coefficients (DSC) for the spatial overlap of low-functional lung volumes. Furthermore, the correlations with matching single-photon emission CT (SPECT) ventilation images (assumed ground truth) were evaluated for three patients to investigate which sorting method provides higher physiologic accuracy.Anatomic similarity-based sorting reduced 4D CT artifacts compared to phase-based sorting (artifact score, 0.45 ± 0.14 vs 0.58 ± 0.24, p = 0.10 at peak-exhale; 0.63 ± 0.19 vs 0.71 ± 0.31, p = 0.25 at peak-inhale). The voxel-based correlation between the two ventilation images was 0.69 ± 0.26 on average, ranging from 0.03 to 0.85. The DSC was 0.71 ± 0.13 on average. Anatomic similarity-based sorting yielded significantly fewer lung voxels with paradoxical negative ventilation values than phase-based sorting (5.0 ± 2.6% vs 9.7 ± 8.4%, p = 0.05), and improved the correlation with SPECT ventilation regionally.The variability of 4D CT ventilation imaging due to 4D CT sorting was moderate overall and substantial in some cases, suggesting that 4D CT artifacts are an important source of variations in 4D CT ventilation imaging. Reduction of 4D CT artifacts provided more physiologically convincing and accurate ventilation estimates. Further studies are needed to confirm this result.

  View details for DOI 10.1118/1.4820538

  View details for PubMedID 24089909

  View details for PubMedCentralID PMC3785523

• Simultaneous Tracking of Multiple Metastases Using FDG-PET Emission-Guided Radiation Therapy (EGRT) in a Breast Cancer Patient Fan, Q., Nanduri, A., Yang, J., Yamamoto, T., Loo, B., Graves, E., Zhu, L., Mazin, S. ELSEVIER SCIENCE INC. 2013: S95

  View details for DOI 10.1016/j.ijrobp.2013.06.246

  View details for Web of Science ID 000324503600233

• Lung Tumor Stereotactic Ablative Radiation Therapy With Individualized Anatomic Optimization Yu, S., Loo, B. W., Maxim, P. G. ELSEVIER SCIENCE INC. 2013: S737–S738

  View details for DOI 10.1016/j.ijrobp.2013.06.1955

  View details for Web of Science ID 000324503602596

• Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema Binkley, M. S., Shrager, J. B., Trakul, N., Leung, A. N., Popat, R., Atwood, T. F., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2013: S545–S546

  View details for DOI 10.1016/j.ijrobp.2013.06.1443

  View details for Web of Science ID 000324503602097

• Noninvasive and Ultrasensitive Quantitation of Circulating Tumor DNA by Hybrid Capture and Deep Sequencing Bratman, S. V., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H., Shrager, J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2013: S92

  View details for DOI 10.1016/j.ijrobp.2013.06.237

  View details for Web of Science ID 000324503600224

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

  View details for DOI 10.1016/j.prro.2012.09.003

  View details for Web of Science ID 000422340000020

• Adaptive Replanning Does Not Inherently Improve Dose to Pharyngeal Constrictors in Patients With Cancer of the Oropharynx Durkee, B. Y., Ognibene, G., Chen, C., Loo, B., Le, Q., Hara, W. ELSEVIER SCIENCE INC. 2013: S435

  View details for DOI 10.1016/j.ijrobp.2013.06.1147

  View details for Web of Science ID 000324503601520

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

  Abstract

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

  View details for DOI 10.1016/j.prro.2012.09.003

  View details for PubMedID 24674401

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

  Abstract

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

  View details for DOI 10.1016/j.amjoto.2013.03.007

  View details for PubMedID 23583094

• Toward a planning scheme for emission guided radiation therapy (EGRT): FDG based tumor tracking in a metastatic breast cancer patient MEDICAL PHYSICS Fan, Q., Nanduri, A., Yang, J., Yamamoto, T., Loo, B., Graves, E., Zhu, L., Mazin, S. 2013; 40 (8)

  Abstract

  Purpose: Emission guided radiation therapy (EGRT) is a new modality that uses PET emissions in real-time for direct tumor tracking during radiation delivery. Radiation beamlets are delivered along positron emission tomography (PET) lines of response (LORs) by a fast rotating ring therapy unit consisting of a linear accelerator (Linac) and PET detectors. The feasibility of tumor tracking and a primitive modulation method to compensate for attenuation have been demonstrated using a 4D digital phantom in our prior work. However, the essential capability of achieving dose modulation as in conventional intensity modulated radiation therapy (IMRT) treatments remains absent. In this work, the authors develop a planning scheme for EGRT to accomplish sophisticated intensity modulation based on an IMRT plan while preserving tumor tracking.Methods: The planning scheme utilizes a precomputed LOR response probability distribution to achieve desired IMRT planning modulation with effects of inhomogeneous attenuation and nonuniform background activity distribution accounted for. Evaluation studies are performed on a 4D digital patient with a simulated lung tumor and a clinical patient who has a moving breast cancer metastasis in the lung. The Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm. The IMRT plan is optimized for a planning target volume (PTV) that encompasses the tumor motion using the MOSEK package and a Pinnacle(3)™ workstation (Philips Healthcare, Fitchburg, WI) for digital and clinical patients, respectively. To obtain the emission data for both patients, the Geant4 application for tomographic emission (GATE) package and a commercial PET scanner are used. As a comparison, 3D and helical IMRT treatments covering the same PTV based on the same IMRT plan are simulated.Results: 3D and helical IMRT treatments show similar dose distribution. In the digital patient case, compared with the 3D IMRT treatment, EGRT achieves a 15.1% relative increase in dose to 95% of the gross tumor volume (GTV) and a 31.8% increase to 50% of the GTV. In the patient case, EGRT yields a 15.2% relative increase in dose to 95% of the GTV and a 20.7% increase to 50% of the GTV. The organs at risk (OARs) doses are kept similar or lower for EGRT in both cases. Tumor tracking is observed in the presence of planning modulation in all EGRT treatments.Conclusions: As compared to conventional IMRT treatments, the proposed EGRT planning scheme allows an escalated target dose while keeping dose to the OARs within the same planning limits. With the capabilities of incorporating planning modulation and accurate tumor tracking, EGRT has the potential to greatly improve targeting in radiation therapy and enable a practical and effective implementation of 4D radiation therapy for planning and delivery.

  View details for DOI 10.1118/1.4812427

  View details for Web of Science ID 000322735900013

  View details for PubMedID 23927305

  View details for PubMedCentralID PMC3732304

• Non-small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Govindan, R., Grannis, F. W., Grant, S. C., Horn, L., Jahan, T. M., Komaki, R., Kong, F. S., Kris, M. G., Krug, L. M., Lackner, R. P., Lennes, I. T., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pinder-Schenck, M. C., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Shapiro, T. A., Swanson, S. J., Tauer, K., Wood, D. E., Yang, S. C., Gregory, K., Hughes, M. 2013; 11 (6): 645-653

  Abstract

  These NCCN Guidelines Insights focus on the diagnostic evaluation of suspected lung cancer. This topic was the subject of a major update in the 2013 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer. The NCCN Guidelines Insights focus on the major updates in the NCCN Guidelines and discuss the new updates in greater detail.

  View details for PubMedID 23744864

• Thymomas and Thymic Carcinomas Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Riely, G. J., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Govindan, R., Grannis, F. W., Grant, S. C., Horn, L., Jahan, T. M., Komaki, R., (Spring) Kong, F., Kris, M. G., Krug, L. M., Lackner, R. P., Lennes, I. T., Loo, B. W., Martins, R., Otterson, G. A., Patel, J. D., Pinder-Schenck, M. C., Pisters, K. M., Reckamp, K., Rohren, E., Shapiro, T. A., Swanson, S. J., Tauer, K., Wood, D. E., Yang, S. C., Gregory, K., Hughes, M. 2013; 11 (5): 562-576

  Abstract

  Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.

  View details for Web of Science ID 000318752600007

  View details for PubMedID 23667206

• Developing a non-invasive, diagnostic test for stage I non-small cell lung cancer using circulating tumor cells. Luttgen, M. S., Keu, K., Nair, V. S., Horng, G., Vasanawala, M., Kolatkar, A., Carlsson, A., Sabouri, M., Loo, B. W., Shrager, J. B., Iagaru, A., Kuschner, W., Kuhn, P., Gambhir, S. S. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1538-7445.AM2013-3485

  View details for Web of Science ID 000331220602190

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

  Abstract

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

  View details for DOI 10.1120/jacmp.v14i2.4046

  View details for PubMedID 23470933

• Small Cell Lung Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kalemkerian, G. P., Akerley, W., Bogner, P., Borghaei, H., Chow, L. Q., Downey, R. J., Gandhi, L., Ganti, A. K., Govindan, R., Grecula, J. C., Hayman, J., Heist, R. S., Horn, L., Jahan, T., Koczywas, M., Loo, B. W., Merritt, R. E., Moran, C. A., Niell, H. B., O'Malley, J., Patel, J. D., Ready, N., Rudin, C. M., Williams, C. C., Gregory, K., Hughes, M. 2013; 11 (1): 78-98

  Abstract

  Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted.

  View details for Web of Science ID 000313575200011

  View details for PubMedID 23307984

• Metabolic Tumor Volume Predicts Disease Progression and Survival in Patients with Squamous Cell Carcinoma of the Anal Canal JOURNAL OF NUCLEAR MEDICINE Bazan, J. G., Koong, A. C., Kapp, D. S., Quon, A., Graves, E. E., Loo, B. W., Chang, D. T. 2013; 54 (1): 27-32

  Abstract

  PET imaging has become a useful diagnostic tool in patients with anal cancer. We evaluated the prognostic value of metabolic tumor volume (MTV) in patients with anal cancer treated with definitive chemoradiotherapy.Patients with anal cancer who underwent PET imaging for pretreatment staging or radiation therapy planning from 2003 to 2011 were included. PET parameters included MTV and maximum standardized uptake value (SUVmax). Total MTV (MTV-T) was defined as the sum of the volumes above a standardized uptake value 50% of the SUVmax within the primary tumor and involved nodes. Kaplan-Meier and Cox regression models were used to test for associations between metabolic or clinical endpoints and overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Results: Thirty-nine patients were included. Median follow-up for the cohort was 22 mo. Overall, 6 patients died and 9 patients had disease progression. The 2-y OS, PFS, and EFS for the entire cohort were 88%, 74%, and 69%, respectively. Higher MTV-T was associated with worse OS (P = 0.04), PFS (P = 0.004), and EFS (P = 0.002) on univariate analysis. Patients with an MTV greater than 26 cm(3) had worse PFS than did those with an MTV of 26 cm(3) or less (33% vs. 82%, P = 0.003). SUVmax was not prognostic for any outcome. Higher T classification (T3/T4 vs. T1/T2) was associated with worse PFS and EFS. When adjusting for T classification, MTV-T remained a significant predictor for PFS (P = 0.01) and EFS (P = 0.02).MTV-T yields prognostic information on PFS and EFS beyond that of established prognostic factors in patients with anal cancer.

  View details for DOI 10.2967/jnumed.112.109470

  View details for PubMedID 23236018

• An observational study of circulating tumor cells and (18)F-FDG PET uptake in patients with treatment-naive non-small cell lung cancer. PloS one Nair, V. S., Keu, K. V., Luttgen, M. S., Kolatkar, A., Vasanawala, M., Kuschner, W., Bethel, K., Iagaru, A. H., Hoh, C., Shrager, J. B., Loo, B. W., Bazhenova, L., Nieva, J., Gambhir, S. S., Kuhn, P. 2013; 8 (7)

  Abstract

  We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by (18)F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis.We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or "HD-CTCs"). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis.We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0-3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7-15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r = 0.27, p-value = 0.03) and not correlated with tumor diameter (r = 0.07; p-value = 0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease.CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease.

  View details for DOI 10.1371/journal.pone.0067733

  View details for PubMedID 23861795

  View details for PubMedCentralID PMC3702496

• The Optimal Use of Radiotherapy in Small Cell Lung Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Shultz, D. B., Grecula, J. C., Hayman, J., Diehn, M., Loo, B. W. 2013; 11 (1): 107-114

  View details for Web of Science ID 000313575200013

• American College of Chest Physicians and Society of Thoracic Surgeons Consensus Statement for Evaluation and Management for High-Risk Patients With Stage I Non-small Cell Lung Cancer CHEST Donington, J., Ferguson, M., Mazzone, P., Handy, J., Schuchert, M., Fernando, H., Loo, B., Lanuti, M., de Hoyos, A., Detterbeck, F., Pennathur, A., Howington, J., Landreneau, R., Silvestri, G. 2012; 142 (6): 1620-1635

  Abstract

  The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity.A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved.Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking.Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date.

  View details for DOI 10.1378/chest.12-0790

  View details for Web of Science ID 000312283800041

  View details for PubMedID 23208335

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

  Abstract

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

  View details for DOI 10.1016/j.lungcan.2012.08.016

  View details for PubMedID 23009727

• Reproducibility of Four-dimensional Computed Tomography-based Lung Ventilation Imaging ACADEMIC RADIOLOGY Yamamoto, T., Kabus, S., von Berg, J., Lorenz, C., Chung, M. P., Hong, J. C., Loo, B. W., Keall, P. J. 2012; 19 (12): 1554-1565

  Abstract

  A novel ventilation imaging method based on four-dimensional (4D) computed tomography (CT) has been applied to the field of radiation oncology. Understanding its reproducibility is a prerequisite for clinical applications. The purpose of this study was to quantify the reproducibility of 4D CT ventilation imaging over different days and the same session.Two ventilation images were created from repeat 4D CT scans acquired over the average time frames of 15 days for 6 lung cancer patients and 5 minutes for another 6 patients. The reproducibility was quantified using the voxel-based Spearman rank correlation coefficients for all lung voxels and Dice similarity coefficients (DSC) for the spatial overlap of segmented high-, moderate-, and low-functional lung volumes. Furthermore, the relationship between the variation in abdominal motion range as a measure of the depth of breathing and variation in ventilation was evaluated using linear regression.The voxel-based correlation between the two ventilation images was moderate on average (0.50 ± 0.15). The DSCs were also moderate for the high- (0.60 ± 0.08), moderate- (0.46 ± 0.06), and low-functional lung (0.58 ± 0.09). No patients demonstrated strong correlations. The relationship between the motion range variation and ventilation variation was found to be moderate and significant.We investigated the reproducibility of 4D CT ventilation imaging over the time frames of 15 days and 5 minutes and found that it was only moderately reproducible. Respiratory variation during 4D CT scans was found to deteriorate the reproducibility. Improvement of 4D CT imaging is necessary to increase the reproducibility of 4D CT ventilation imaging.

  View details for DOI 10.1016/j.acra.2012.07.006

  View details for PubMedID 22975070

• Cell-free DNA as a Biomarker of Residual Disease Following Radiation Therapy for Non-small Cell Lung Cancer 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Bratman, S. V., Eclov, N. C., Modlin, L. A., Neal, J., Loo, B. W., Wu, G., Richardson, K., Newman, A. M., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2012: S713–S713

  View details for Web of Science ID 000310542902315

• Improved Outcomes in Stage I NSCLC Patients Treated in the Stereotactic Ablative Radiation Therapy Era: A Population-based Analysis Trakul, N., Murphy, J. D., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2012: S608

  View details for DOI 10.1016/j.ijrobp.2012.07.1621

  View details for Web of Science ID 000310542902036

• Stereotactic Radiosurgery for Stage I NSCLC in Medically Inoperable Patients: A Prospective Multicenter Phase II Study Pennathur, A., Loo, B. W., Heron, D. E., Whyte, R. I., Zajac, A., Brachman, D., Gooding, W. E., Christie, N. A., Urschel, H. C., Luketich, J. D. ELSEVIER SCIENCE INC. 2012: S593–S594

  View details for DOI 10.1016/j.ijrobp.2012.07.1582

  View details for Web of Science ID 000310542901708

• Anatomic and Metabolic Predictors of Failure After Stereotactic Ablative Radiation Therapy for Non-small Cell Lung Cancer Shultz, D. B., Trakul, N., Abelson, J. A., Murphy, J. D., Lee, Q. T., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2012: S571–S572

  View details for DOI 10.1016/j.ijrobp.2012.07.1523

  View details for Web of Science ID 000310542901651

• Is Recontouring Organs-at-Risk (OAR) for Adaptive Radiation Therapy Plans for Locally Advanced Lung Cancer Necessary? A Preactivation Analysis From Radiation Therapy Oncology Group (RTOG) 1106 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Chen, W., Cui, Y., Kong, F., Machtay, M., Videtic, G., Loo, B., Gore, E., Galvin, J., Yu, Y., Xiao, Y. ELSEVIER SCIENCE INC. 2012: S602–S602

  View details for Web of Science ID 000310542902020

• Quantitative Evaluation of Impact Upon Tumor Control Probability (TCP) From Quality Assurance Criteria for Non-small Cell Lung Cancer From RTOG 1106 Study 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Chen, W., Cui, Y., Kong, F., Machtay, M., Videtic, G., Loo, B., Gore, E., Galvin, J., Yan, Y., Xiao, Y. ELSEVIER SCIENCE INC. 2012: S601–S601

  View details for Web of Science ID 000310542902018

• Acute Changes in Composition of Exhaled Breath Predict Radiation Pneumonitis Following Stereotactic Ablative Radiation Therapy 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) More, J. M., Eclov, N. C., Chung, M., Shorter, J. H., BURMEISTER, R., BANOS, P., Maxim, P., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2012: S155–S156

  View details for Web of Science ID 000310542900386

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

  View details for Web of Science ID 000310542900432

• Non-Small Cell Lung Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Ganti, A. K., Govindan, R., Grannis, F. W., Horn, L., Jahan, T. M., Jahanzeb, M., Kessinger, A., Komaki, R., Kong, F. (., Kris, M. G., Krug, L. M., Lennes, I. T., Loo, B. W., Martins, R., O'Malley, J., Osarogiagbon, R. U., Otterson, G. A., Patel, J. D., Pinder-Schenck, M. C., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Swanson, S. J., Wood, D. E., Yang, S. C., Hughes, M., Gregory, K. M. 2012; 10 (10): 1236-1271

  Abstract

  Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.

  View details for Web of Science ID 000309901900007

  View details for PubMedID 23054877

• Postchemoradiotherapy Positron Emission Tomography Predicts Pathologic Response and Survival in Patients With Esophageal Cancer 53rd Annual Meeting of the American-Society-of-Radiation-Oncology (ASTRO) Jayachandran, P., Pai, R. K., Quon, A., Graves, E., Krakow, T. E., La, T., Loo, B. W., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2012: 471–77

  Abstract

  To correlate the prechemoradiotherapy (CRT) and post-CRT metabolic tumor volume (MTV) on positron emission tomography (PET) scanning with the pathologic response and survival in patients receiving preoperative CRT for esophageal cancer.The medical records of 37 patients with histologically confirmed Stage I-IVA esophageal cancer treated with CRT with or without surgical resection were reviewed. Of the 37 patients, 21 received preoperative CRT (57%) and 16 received definitive CRT (43%). All patients had a pre-CRT and 32 had a post-CRT PET scan. The MTV was measured on the pre-CRT PET and post-CRT PET scan, respectively, using a minimum standardized uptake value (SUV) threshold x, where x = 2, 2.5, 3, or the SUV maximum × 50%. The total glycolytic activity (TGA(x)) was defined as the mean SUV × MTV(x). The MTV ratio was defined as the pre-CRT PET MTV/post-CRT MTV. The SUV ratio was defined similarly. A single pathologist scored the pathologic response using a tumor regression grade (TRG) scale.The median follow-up was 1.5 years (range, 0.4-4.9). No significant correlation was found between any parameters on the pre-CRT PET scan and the TRG or overall survival (OS). Multiple post-CRT MTV values and post-TGA values correlated with the TRG and OS; however, the MTV(2.5(Post)) and TGA(2.5(Post)) had the greatest correlation. The MTV(2) ratio correlated with OS. The maximum SUV on either the pre-CRT and post-CRT PET scans or the maximum SUV ratio did not correlate with the TRG or OS. Patients treated preoperatively had survival similar compared with those treated definitively with a good PET response (p = 0.97) and significantly better than that of patients treated definitively with a poor PET response (p < 0.0001).The maximum SUV was not a predictive or prognostic parameter. The MTV(2.5) and TGA(2.5) were useful markers for predicting the response and survival on the post-CRT PET scan. The MTV(2) ratio also correlated with survival. Post-CRT PET can potentially guide therapy after CRT.

  View details for DOI 10.1016/j.ijrobp.2011.12.029

  View details for PubMedID 22381904

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

  Abstract

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

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

  View details for PubMedID 22168251

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

  Abstract

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

  View details for DOI 10.1097/JTO.0b013e31825f22ce

  View details for Web of Science ID 000308073300024

  View details for PubMedID 22895143

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2011.10.071

  View details for PubMedID 22381907

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2011.10.022

  View details for PubMedID 22270168

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2012.03.006

  View details for PubMedID 22554582

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2011.10.023

  View details for PubMedID 22270174

• 4D-CT Lung Ventilation Images Vary with 4D-CT Sorting Techniques 54th Annual Meeting and Exhibition of the American-Association-of-Physicists-in-Medicine (AAPM) Yamamoto, T., Kabus, S., Lorenz, C., Johnston, E., Maxim, P., Loo, B., Keall, P. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2012: 3614–14

  Abstract

  4D-CT ventilation imaging is a novel promising technique for lung functional imaging and has potential as a biomarker for radiation pneumonitis, but has not been validated in human subjects. The current 4D- CT technique with phase-based sorting results in artifacts at an alarmingly high frequency (90%), which may introduce variations into ventilation calculations. The purpose of this study was to quantify the variability of 4D- CT ventilation imaging to 4D-CT sorting techniques.Two 4D-CT images were generated from the same data set by: (1) phase-based; (2) anatomic similarity- and abdominal displacement-based sorting for five patients. Two ventilation image sets (V_phase and V_anat) were then calculated by deformable image registration of peak-exhale and peak-inhale4D-CT images and quantification of regional volume change based on Hounsfield unit change. The variability of 4D-CT ventilation imaging wasquantified using the voxel-based Spearman rank correlation coefficients and Dice similarity coefficients (DSC) for the spatial overlap of segmented low- functional lung regions. The relationship between the abdominal motionrange variation and ventilation variation was also assessed using linearregression. Furthermore, the correlations between V_phase or V_anat and SPECT ventilation images (assumed ground-truth) were compared.In general, displacement- and anatomic similarity-based sorting reduced 4D- CT artifacts compared to phase-based sorting. The voxel-based correlationsbetween V_phase and V_anat were only moderate (range, 0.57-0.77). The DSCs for the low-functional lung regions were moderate to substantial (0.58-0.70). The relationship between the motion range variation and ventilation variation was strong on average (R2=0.79±0.25), suggesting that ventilation variations are related to 4D-CT artifacts. Vanat was found to improve correlations with SPECT ventilation images compared to V_phase.4D-CT ventilation images vary markedly with 4D-CT sorting techniques. 4D-CT artifacts should be considered as a significant source of variation in 4D-CT ventilation imaging during its validation. This study wassupported in part by NIH/NCI R01 93626. SK and CL are employees ofPhilips Research.

  View details for Web of Science ID 000308905804076

• Characterization of the Effect of 'Lung Detail' CT Reconstruction Algorithm On Radiation Therapy Dose Calculation Eclov, N., Loo, B., Graves, E., Maxim, P. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2012: 3693

  Abstract

  Precise tumor delineation is important in thoracic radiation therapy planning, and using a 'lung detail' computed tomography (CT) reconstruction algorithm can assist in visualizing the tumor. We seek to determine the dosimetric impact of utilizing a lung detail algorithm versus a standard algorithm on calculated dose in radiation treatment planning.Ten patients, with 12 tumors, were analyzed in this study. Two CT scans, one reconstructed using a standard algorithm and one using a lung detail algorithm, were generated for each of 12 lung tumors. Treatment plans were calculated for each CT scan, with 7 tumors receiving stereotactic ablative radiotherapy (SABR) and 5 receiving intensity-modulated radiation therapy (IMRT). The Hounsfield unit (HU) and dose values for each voxel of the planning tumor volume (PTV), esophagus, spinal cord, and contralateral lung in both the CT and dose images were exported to MATLAB. For each contour, the voxel-by-voxel differences in the HU and dose distributions between the two scans were analyzed along with dose-volume histogram (DVH) data.Despite changes in HU values, the voxel-by-voxel analysis showed a negligible shift in dose values. The mean differences in dose for PTV, esophagus, spinal cord, and contralateral lung ranged from -12.12 to 22.57, -2.21 to 7.40, -0.50 to 5.93, and -1.12 to 7.41 cGy, respectively. DVH comparisons demonstrated no meaningful difference between plans. The mean PTV, esophagus, spinal cord, and contralateral lung doses measured from the DVH shifted between plans an average of 3.5, 2.93, -0.6 and -0.35 cGy, respectively. These dose differences are all less than 1% of the dose prescribed to the tumor and are not measurable by current technology.The lung detail reconstruction algorithm, when applied to thoracic radiation treatment planning CT scans, can help precisely delineate tumor with negligible dosimetric impact.

  View details for PubMedID 28518919

• Lung Cancer Patient Feasibility Study for Emission Guided Radiation Therapy Mazin, S., Nanduri, A., Yang, J., Yamamoto, T., Loo, B., Graves, E. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2012: 3888–89

  View details for DOI 10.1118/1.4735873

  View details for Web of Science ID 000308905805333

• Monte Carlo Simulations and Experimental Validation of Rapid Dose Delivery with Very High-Energy Electron Beams Bazalova, M., Maxim, P., Tantawi, S., Colby, E., Koong, A., Loo, B. W. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2012: 3944

  View details for DOI 10.1118/1.4736098

  View details for Web of Science ID 000308905805557

• SU-D-BRB-01: 4D-CT Lung Ventilation Images Vary with 4D-CT Sorting Techniques. Medical physics Yamamoto, T., Kabus, S., Lorenz, C., Johnston, E., Maxim, P., Loo, B., Keall, P. 2012; 39 (6Part3): 3614

  Abstract

  4D-CT ventilation imaging is a novel promising technique for lung functional imaging and has potential as a biomarker for radiation pneumonitis, but has not been validated in human subjects. The current 4D- CT technique with phase-based sorting results in artifacts at an alarmingly high frequency (90%), which may introduce variations into ventilation calculations. The purpose of this study was to quantify the variability of 4D- CT ventilation imaging to 4D-CT sorting techniques.Two 4D-CT images were generated from the same data set by: (1) phase-based; (2) anatomic similarity- and abdominal displacement-based sorting for five patients. Two ventilation image sets (V_phase and V_anat) were then calculated by deformable image registration of peak-exhale and peak-inhale4D-CT images and quantification of regional volume change based on Hounsfield unit change. The variability of 4D-CT ventilation imaging wasquantified using the voxel-based Spearman rank correlation coefficients and Dice similarity coefficients (DSC) for the spatial overlap of segmented low- functional lung regions. The relationship between the abdominal motionrange variation and ventilation variation was also assessed using linearregression. Furthermore, the correlations between V_phase or V_anat and SPECT ventilation images (assumed ground-truth) were compared.In general, displacement- and anatomic similarity-based sorting reduced 4D- CT artifacts compared to phase-based sorting. The voxel-based correlationsbetween V_phase and V_anat were only moderate (range, 0.57-0.77). The DSCs for the low-functional lung regions were moderate to substantial (0.58-0.70). The relationship between the motion range variation and ventilation variation was strong on average (R2=0.79±0.25), suggesting that ventilation variations are related to 4D-CT artifacts. Vanat was found to improve correlations with SPECT ventilation images compared to V_phase.4D-CT ventilation images vary markedly with 4D-CT sorting techniques. 4D-CT artifacts should be considered as a significant source of variation in 4D-CT ventilation imaging during its validation. This study wassupported in part by NIH/NCI R01 93626. SK and CL are employees ofPhilips Research.

  View details for DOI 10.1118/1.4734673

  View details for PubMedID 28517394

• The Management of Patients With Stage IIIA Non-Small Cell Lung Cancer With N2 Mediastinal Node Involvement JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Martins, R. G., D'Amico, T. A., Loo, B. W., Pinder-Schenck, M., Borghaei, H., Chaft, J. E., Ganti, A. K., Kong, F. (., Kris, M. G., Lennes, I. T., Wood, D. E. 2012; 10 (5): 599-613

  Abstract

  Patients with stage IIIA non-small cell lung cancer, determined based on involvement of ipsilateral mediastinal lymph nodes, represent the most challenging management problem in this disease. Patients with this stage disease may have very different degrees of lymph node involvement. The pathologic confirmation of this involvement is a key step in the therapeutic decision. The difference in the degree of lymph node compromise has prognostic and treatment implications. Based on multiple considerations, patients can be treated with induction chemotherapy, chemoradiotherapy followed by surgery, or definitive chemoradiotherapy without surgery. Data derived from clinical trials have provided incomplete guidance for physicians and their patients. The best therapeutic plan is achieved through the multidisciplinary cooperation of a team specialized in lung cancer.

  View details for Web of Science ID 000303557700006

  View details for PubMedID 22570291

• Interim-treatment quantitative PET parameters predict progression and death among patients with hodgkin's disease RADIATION ONCOLOGY Tseng, D., Rachakonda, L. P., Su, Z., Advani, R., Horning, S., Hoppe, R. T., Quon, A., Graves, E. E., Loo, B. W., Tran, P. T. 2012; 7

  Abstract

  We hypothesized that quantitative PET parameters may have predictive value beyond that of traditional clinical factors such as the International Prognostic Score (IPS) among Hodgkin's disease (HD) patients.Thirty HD patients treated at presentation or relapse had staging and interim-treatment PET-CT scans. The majority of patients (53%) had stage III-IV disease and 67% had IPS ≥ 2. Interim-treatment scans were performed at a median of 55 days from the staging PET-CT. Chemotherapy regimens used: Stanford V (67%), ABVD (17%), VAMP (10%), or BEACOPP (7%). Hypermetabolic tumor regions were segmented semiautomatically and the metabolic tumor volume (MTV), mean standardized uptake value (SUV mean), maximum SUV (SUV max) and integrated SUV (iSUV) were recorded. We analyzed whether IPS, absolute value PET parameters or the calculated ratio of interim- to pre-treatment PET parameters were associated with progression free survival (PFS) or overall survival (OS).Median follow-up of the study group was 50 months. Six of the 30 patients progressed clinically. Absolute value PET parameters from pre-treatment scans were not significant. Absolute value SUV max from interim-treatment scans was associated with OS as determined by univariate analysis (p < 0.01). All four calculated PET parameters (interim/pre-treatment values) were associated with OS: MTV int/pre (p < 0.01), SUV mean int/pre (p < 0.05), SUV max int/pre (p = 0.01), and iSUV int/pre (p < 0.01). Absolute value SUV max from interim-treatment scans was associated with PFS (p = 0.01). Three calculated PET parameters (int/pre-treatment values) were associated with PFS: MTV int/pre (p = 0.01), SUV max int/pre (p = 0.02) and iSUV int/pre (p = 0.01). IPS was associated with PFS (p < 0.05) and OS (p < 0.01).Calculated PET metrics may provide predictive information beyond that of traditional clinical factors and may identify patients at high risk of treatment failure early for treatment intensification.

  View details for DOI 10.1186/1748-717X-7-5

  View details for PubMedID 22260710

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

  Abstract

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

  View details for DOI 10.1016/j.cllc.2011.05.001

  View details for PubMedID 21703935

• An automated method for comparing motion artifacts in cine four-dimensional computed tomography images. Journal of applied clinical medical physics Cui, G., Jew, B., Hong, J. C., Johnston, E. W., Loo, B. W., Maxim, P. G. 2012; 13 (6): 3838-?

  Abstract

  The aim of this study is to develop an automated method to objectively compare motion artifacts in two four-dimensional computed tomography (4D CT) image sets, and identify the one that would appear to human observers with fewer or smaller artifacts. Our proposed method is based on the difference of the normalized correlation coefficients between edge slices at couch transitions, which we hypothesize may be a suitable metric to identify motion artifacts. We evaluated our method using ten pairs of 4D CT image sets that showed subtle differences in artifacts between images in a pair, which were identifiable by human observers. One set of 4D CT images was sorted using breathing traces in which our clinically implemented 4D CT sorting software miscalculated the respiratory phase, which expectedly led to artifacts in the images. The other set of images consisted of the same images; however, these were sorted using the same breathing traces but with corrected phases. Next we calculated the normalized correlation coefficients between edge slices at all couch transitions for all respiratory phases in both image sets to evaluate for motion artifacts. For nine image set pairs, our method identified the 4D CT sets sorted using the breathing traces with the corrected respiratory phase to result in images with fewer or smaller artifacts, whereas for one image pair, no difference was noted. Two observers independently assessed the accuracy of our method. Both observers identified 9 image sets that were sorted using the breathing traces with corrected respiratory phase as having fewer or smaller artifacts. In summary, using the 4D CT data of ten pairs of 4D CT image sets, we have demonstrated proof of principle that our method is able to replicate the results of two human observers in identifying the image set with fewer or smaller artifacts.

  View details for DOI 10.1120/jacmp.v13i6.3838

  View details for PubMedID 23149777

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

  View details for DOI 10.1016/j.prro.2011.06.004

  View details for Web of Science ID 000422312600005

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

  Abstract

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

  View details for DOI 10.1016/j.prro.2011.06.004

  View details for PubMedID 24674033

• Malignant Pleural Mesothelioma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A., Cheney, R. T., Chirieac, L. R., D'Amico, T. A., Demmy, T. L., Ganti, A. K., Govindan, R., Grannis, F. W., Horn, L., Jahan, T. M., Jahanzeb, M., Kessinger, A., Komaki, R., Kong, F. (., Kris, M. G., Krug, L. M., Lennes, I. T., Loo, B. W., Martins, R., O'Malley, J., Osarogiagbon, R. U., Otterson, G. A., Patel, J. D., Pinder-Schenck, M., Pisters, K. M., Reckamp, K., Riely, G. J., Rohren, E., Swanson, S. J., Wood, D. E., Yang, S. C. 2012; 10 (1): 26-41

  View details for Web of Science ID 000299007500006

  View details for PubMedID 22223867

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

  Abstract

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

  View details for DOI 10.1016/j.radonc.2011.05.040

  View details for PubMedID 21665308

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2010.08.049

  View details for Web of Science ID 000296823600035

  View details for PubMedID 21543166

• RESPONSE TO "STEREOTACTIC ABLATIVE RADIOTHERAPY IN THE FRAMEWORK OF CLASSICAL RADIOBIOLOGY: RESPONSE TO DRS. BROWN, DIEHN, AND LOO." (INT J RADIAT ONCOL BIOL PHYS 2011;79:1599-1600) AND "INFLUENCE OF TUMOR HYPOXIA ON STEREOTACTIC ABLATIVE RADIOTHERAPY (SABR): RESPONSE TO DRS. MAYER AND TIMMERMAN." (INT J RADIATION ONCOL BIOL PHYS 2011;78:1600) REPLY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, M., Loo, B. W., Diehn, M., Carlson, D. J. 2011; 81 (4): 1194

  View details for DOI 10.1016/j.ijrobp.2011.05.023

  View details for Web of Science ID 000296823600043

• What the Diagnostic Radiologist Needs to Know about Radiation Oncology RADIOLOGY Terezakis, S. A., Heron, D. E., Lavigne, R. F., Diehn, M., Loo, B. W. 2011; 261 (1): 30-44

  Abstract

  Substantial technologic advances in radiation treatment planning and delivery have made possible exquisite tailoring of three-dimensional radiation dose distributions that conform to the tumor treatment volume while avoiding adjacent normal tissues. Although such highly precise treatment can increase the therapeutic ratio, it also introduces the potential that tumor extension outside the target is missed because it is unrecognized at the time of radiation treatment planning. As a result, accurate targeting of the tumor with radiation is of utmost importance to the radiation oncologist. Communication between diagnostic radiologists and radiation oncologists is essential, particularly given the subtleties that accompany image interpretation, to optimize the care of the cancer patient.

  View details for DOI 10.1148/radiol.11101688

  View details for Web of Science ID 000295039000006

  View details for PubMedID 21931140

• Molecular Imaging with C-11-PD153035 PET/CT Predicts Survival in Non-Small Cell Lung Cancer Treated with EGFR-TKI: A Pilot Study JOURNAL OF NUCLEAR MEDICINE Meng, X., Loo, B. W., Ma, L., Murphy, J. D., Sun, X., Yu, J. 2011; 52 (10): 1573-1579

  Abstract

  Outcomes are suboptimal when molecularly targeted therapies are used in patient populations unselected for the molecular target. This pilot study examines the correlation of PET using (11)C-labeled 4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline ((11)C-PD153035), an imaging biomarker of epidermal growth factor receptor (EGFR), with outcomes in patients with non-small cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor erlotinib.Patients with advanced chemotherapy-refractory NSCLC were prospectively enrolled on a trial of erlotinib at a dose of 150 mg daily and imaged by (11)C-PD153035 PET/CT at baseline, after 1-2 wk, and after 6 wk from the start of treatment. Overall survival and progression-free survival (OS and PFS, respectively) times were correlated with the (11)C-PD153035 standardized uptake value (SUV) at each of the imaging times.Twenty-one patients were enrolled. Follow-up to progression was complete in all patients and to death in 18 of 21. By Cox regression analysis, baseline maximum SUV correlated strongly with OS and PFS (hazard ratio = 0.40, P = 0.002, and hazard ratio = 0.044, P < 0.001, respectively) independent of histology. Patients with higher maximum SUV (≥median) survived more than twice as long as patients with lower maximum SUV (median OS = 11.4 vs. 4.6 mo, P = 0.002; PFS = 4.4 vs. 1.8 mo, P < 0.001). However, (11)C-PD153035 uptake on follow-up scans was less well correlated with survival.Our preliminary results suggest (11)C-PD153035 PET/CT may be a noninvasive and rapid method for identifying patients with refractory advanced NSCLC of adenocarcinoma or squamous histology likely to respond to the EGFR tyrosine kinase inhibitor but not for monitoring treatment response.

  View details for DOI 10.2967/jnumed.111.092874

  View details for Web of Science ID 000295537800016

  View details for PubMedID 21903741

• Stereotactic ablative radiotherapy (SABR) for lung cancer: What does the future hold? Journal of thoracic disease Loo, B. W. 2011; 3 (3): 150-152

  View details for DOI 10.3978/j.issn.2072-1439.2011.06.08

  View details for PubMedID 22263081

  View details for PubMedCentralID PMC3256516

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

  Abstract

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

  View details for DOI 10.1016/j.cllc.2011.06.003

  View details for PubMedID 21752720

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2010.04.037

  View details for PubMedID 20675070

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2010.04.031

  View details for PubMedID 20675073

• IN REGARD TO BROWN ET AL. (INT J RADIAT ONCOL BIOL PHYS 2010;78:323-327) REPLY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, J. M., Loo, B. W., Diehn, M., Carlson, D. J. 2011; 80 (5): 1605-1605

  View details for DOI 10.1016/j.ijrobp.2011.03.032

  View details for Web of Science ID 000293207600049

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2010.01.057

  View details for Web of Science ID 000290837100028

  View details for PubMedID 20646870

  View details for PubMedCentralID PMC2962876

• MID-RADIATION THERAPY PET CORRELATES WITH SURVIVAL IN LOCALLY ADVANCED NSCLC Loo, B. W., Chang, C., Hong, J., Wakelee, H., Quynh Thu Le, Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Diehn, M., Olson, M. LIPPINCOTT WILLIAMS & WILKINS. 2011: S694–S695

  View details for Web of Science ID 000208855803108

• THE FUTURE ROLE OF DIFFERENT SPECIALISTS IN MULTIMODALITY MEDICINE (LUNG CANCER) - RADIOTHERAPIST Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2011: S269

  View details for Web of Science ID 000208855801215

• USING DURING-RT PET TO INDIVIDUALIZE ADAPTIVE RT FOR PATIENTS WITH STAGE III NSCLC: A MULTICENTER PLANNING STUDY Kong, F., Xiao, Y., Machtay, M., Werner-Wasik, M., Videtic, G. M., Loo, B. W., Wagner, H., Gore, E. M., Varlotto, J., Faria, S., Dilling, T. J., Sun, A., Swanson, T., Wang, L., Galvin, J., Ten Haken, R. K., Bradley, J. LIPPINCOTT WILLIAMS & WILKINS. 2011: S834–S835

  View details for Web of Science ID 000208855803306

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

  Abstract

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

  View details for DOI 10.1097/JTO.0b013e31821517db

  View details for PubMedID 21774104

• Reducing 4D CT artifacts using optimized sorting based on anatomic similarity MEDICAL PHYSICS Johnston, E., Diehn, M., Murphy, J. D., Loo, B. W., Maxim, P. G. 2011; 38 (5): 2424-2429

  Abstract

  Four-dimensional (4D) computed tomography (CT) has been widely used as a tool to characterize respiratory motion in radiotherapy. The two most commonly used 4D CT algorithms sort images by the associated respiratory phase or displacement into a predefined number of bins, and are prone to image artifacts at transitions between bed positions. The purpose of this work is to demonstrate a method of reducing motion artifacts in 4D CT by incorporating anatomic similarity into phase or displacement based sorting protocols.Ten patient datasets were retrospectively sorted using both the displacement and phase based sorting algorithms. Conventional sorting methods allow selection of only the nearest-neighbor image in time or displacement within each bin. In our method, for each bed position either the displacement or the phase defines the center of a bin range about which several candidate images are selected. The two dimensional correlation coefficients between slices bordering the interface between adjacent couch positions are then calculated for all candidate pairings. Two slices have a high correlation if they are anatomically similar. Candidates from each bin are then selected to maximize the slice correlation over the entire data set using the Dijkstra's shortest path algorithm. To assess the reduction of artifacts, two thoracic radiation oncologists independently compared the resorted 4D datasets pairwise with conventionally sorted datasets, blinded to the sorting method, to choose which had the least motion artifacts. Agreement between reviewers was evaluated using the weighted kappa score.Anatomically based image selection resulted in 4D CT datasets with significantly reduced motion artifacts with both displacement (P = 0.0063) and phase sorting (P = 0.00022). There was good agreement between the two reviewers, with complete agreement 34 times and complete disagreement 6 times.Optimized sorting using anatomic similarity significantly reduces 4D CT motion artifacts compared to conventional phase or displacement based sorting. This improved sorting algorithm is a straightforward extension of the two most common 4D CT sorting algorithms.

  View details for DOI 10.1118/1.3577601

  View details for Web of Science ID 000290625700016

  View details for PubMedID 21776777

• Investigation of four-dimensional computed tomography-based pulmonary ventilation imaging in patients with emphysematous lung regions PHYSICS IN MEDICINE AND BIOLOGY Yamamoto, T., Kabus, S., Klinder, T., Lorenz, C., von Berg, J., Blaffert, T., Loo, B. W., Keall, P. J. 2011; 56 (7): 2279-2298

  Abstract

  A pulmonary ventilation imaging technique based on four-dimensional (4D) computed tomography (CT) has advantages over existing techniques. However, physiologically accurate 4D-CT ventilation imaging has not been achieved in patients. The purpose of this study was to evaluate 4D-CT ventilation imaging by correlating ventilation with emphysema. Emphysematous lung regions are less ventilated and can be used as surrogates for low ventilation. We tested the hypothesis: 4D-CT ventilation in emphysematous lung regions is significantly lower than in non-emphysematous regions. Four-dimensional CT ventilation images were created for 12 patients with emphysematous lung regions as observed on CT, using a total of four combinations of two deformable image registration (DIR) algorithms: surface-based (DIR(sur)) and volumetric (DIR(vol)), and two metrics: Hounsfield unit (HU) change (V(HU)) and Jacobian determinant of deformation (V(Jac)), yielding four ventilation image sets per patient. Emphysematous lung regions were detected by density masking. We tested our hypothesis using the one-tailed t-test. Visually, different DIR algorithms and metrics yielded spatially variant 4D-CT ventilation images. The mean ventilation values in emphysematous lung regions were consistently lower than in non-emphysematous regions for all the combinations of DIR algorithms and metrics. V(HU) resulted in statistically significant differences for both DIR(sur) (0.14 ± 0.14 versus 0.29 ± 0.16, p = 0.01) and DIR(vol) (0.13 ± 0.13 versus 0.27 ± 0.15, p < 0.01). However, V(Jac) resulted in non-significant differences for both DIR(sur) (0.15 ± 0.07 versus 0.17 ± 0.08, p = 0.20) and DIR(vol) (0.17 ± 0.08 versus 0.19 ± 0.09, p = 0.30). This study demonstrated the strong correlation between the HU-based 4D-CT ventilation and emphysema, which indicates the potential for HU-based 4D-CT ventilation imaging to achieve high physiologic accuracy. A further study is needed to confirm these results.

  View details for DOI 10.1088/0031-9155/56/7/023

  View details for Web of Science ID 000288506600026

  View details for PubMedID 21411868

• HYPOFRACTIONATION RESULTS IN REDUCED TUMOR CELL KILL COMPARED TO CONVENTIONAL FRACTIONATION FOR TUMORS WITH REGIONS OF HYPOXIA INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Carlson, D. J., Keall, P. J., Loo, B. W., Chen, Z. J., Brown, J. M. 2011; 79 (4): 1188-1195

  Abstract

  Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation.A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions.Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10(5) over a distance of 130 μm. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of ∼10(3) as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively.Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.

  View details for DOI 10.1016/j.ijrobp.2010.10.007

  View details for Web of Science ID 000288471500031

  View details for PubMedID 21183291

  View details for PubMedCentralID PMC3053128

• Four-dimensional computed tomography pulmonary ventilation images vary with deformable image registration algorithms and metrics MEDICAL PHYSICS Yamamoto, T., Kabus, S., Klinder, T., von Berg, J., Lorenz, C., Loo, B. W., Keall, P. J. 2011; 38 (3): 1348-1358

  Abstract

  A novel pulmonary ventilation imaging technique based on four-dimensional (4D) CT has advantages over existing techniques and could be used for functional avoidance in radiotherapy. There are various deformable image registration (DIR) algorithms and two classes of ventilation metric that can be used for 4D-CT ventilation imaging, each yielding different images. The purpose of this study was to quantify the variability of the 4D-CT ventilation to DIR algorithms and metrics.4D-CT ventilation images were created for 12 patients using different combinations of two DIR algorithms, volumetric (DIR(vol)) and surface-based (DIR(sur)), yielding two displacement vector fields (DVFs) per patient (DVF(voI) and DVF(sur)), and two metrics, Hounsfield unit (HU) change (V(HU)) and Jacobian determinant of deformation (V(Jac)), yielding four ventilation image sets (V(HU)(vol), V(HU)(sur), V(Jac)(voI), and V(Jac)(sur). First DVF(vol) and DVF(sur) were compared visually and quantitatively to the length of 3D displacement vector difference. Second, four ventilation images were compared based on voxel-based Spearman's rank correlation coefficients and coefficients of variation as a measure of spatial heterogeneity. V(HU)(vol) was chosen as the reference for the comparison.The mean length of 3D vector difference between DVF(vol) and DVF(sur) was 2.0 +/- 1.1 mm on average, which was smaller than the voxel dimension of the image set and the variations. Visually, the reference V(HU)(vol) demonstrated similar regional distributions with V(HU)(sur); the reference, however, was markedly different from V(Jac)(vol) and V((Jac)(sur). The correlation coefficients of V(HU)(vol) with V(HU)(sur), V(Jac)(vol) and V(Jac)(sur) were 0.77 +/- 0.06, 0.25 +/- 0.06 and 0.15 +/- 0.07, respectively, indicating that the metric introduced larger variations in the ventilation images than the DIR algorithm. The spatial heterogeneities for V(HU)(vol), 'V(HU)(sur), V(Jac)(vol), and V(Jac)(sur) were 1.8 +/- 1.6, 1.8 +/- 1.5 (p = 0. 85), 0.6 +/- 0.2 (p = 0.02), and 0.7 +/- 0.2 (p = 0.03), respectively, also demonstrating that the metric introduced larger variations.4D-CT pulmonary ventilation images vary widely with DIR algorithms and metrics. Careful physiologic validation to determine the appropriate DIR algorithm and metric is needed prior to its applications.

  View details for DOI 10.1118/1.3547719

  View details for Web of Science ID 000287879400022

  View details for PubMedID 21520845

• Stereotactic ablative radiotherapy: what's in a name? Practical Radiation Oncology BW Loo Jr, JY Chang, LA Dawson, BD Kavanagh, AC Koong, S Senan, RD Timmerman 2011; 1 (1): 38-39
• Stereotactic ablative radiotherapy: what's in a name? PRACTICAL RADIATION ONCOLOGY Loo, B. W., Chang, J. Y., Dawson, L. A., Kavanagh, B. D., Koong, A. C., Senan, S., Timmerman, R. D. 2011; 1 (1): 38–39

  View details for PubMedID 24673868

• An efficient protocol for the radiosynthesis of clinical grade F-18-EF5 Apte, S. D., Chin, F. T., Loo, B. W., Chang, D., Graves, E. E. WILEY-BLACKWELL. 2011: S408

  View details for Web of Science ID 000295901600408

• Stereotactic Radiosurgery for the Treatment of Stage I NSCLC in Medically Inoperable Patients: A Prospective Multicenter Phase II Study Pennathur, A., Whyte, R. I., Heron, D. E., Loo, B. W., Gooding, W. E., Brachman, D. G., Zajac, A., Urschel, H. D., Christie, N. A., Luketich, J. D. ELSEVIER SCIENCE INC. 2011: S81

  View details for DOI 10.1016/j.ijrobp.2011.06.164

  View details for Web of Science ID 000296411700160

• Postchemoradiotherapy Positron Emission Tomography for Predicting Survival in Patients with Esophageal Cancer Jayachandran, P., Krakow, T., La, T., Loo, B. W., Koong, A. C., Chang, D. T. ELSEVIER SCIENCE INC. 2011: S310

  View details for DOI 10.1016/j.ijrobp.2011.06.500

  View details for Web of Science ID 000296411700633

• Using during RT PET to Individualize Adaptive RT for Patients with Stage III NSCLC: A RTOG Planning Study Kong, F. P., Machtay, M., Videtic, G., Loo, B. W., Gore, E., Wagner, H., Varlotto, J., Faria, S., Dilling, T. J., Sun, A. ELSEVIER SCIENCE INC. 2011: S603

  View details for DOI 10.1016/j.ijrobp.2011.06.1133

  View details for Web of Science ID 000296411701317

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

  View details for Web of Science ID 000296411701294

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

  View details for Web of Science ID 000296411701270

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

  View details for Web of Science ID 000296411701321

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

  View details for Web of Science ID 000296411701313

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

  View details for Web of Science ID 000296411701268

• PET imaging of cerebral ischemia-induced neuroinflammation in mice using F-18-PBR06 Lartey, F. M., Ahn, G., Shen, B., Cord, K., Smith, T., Chua, J. Y., Rosenblum, S., Tirouvanziam, R., Palmer, T., Guzman, R., Chin, F. T., Graves, E., Loo, B. W. WILEY-BLACKWELL. 2011: S319–S319

  View details for Web of Science ID 000295901600319

• Motion Management and Image Guidance for Thoracic Tumor Radiotherapy: Clinical Treatment Programs IMRT IGRT SBRT- ADVANCES IN THE TREATMENT PLANNING AND DELIVERY OF RADIOTHERAPY Loo, B. W., Kavanagh, B. D., Meyer, J. L. 2011; 43: 271-291

  Abstract

  Managing target motion first requires understanding the nature of the motion characteristic of the tumor in the individual patient. It is important to have effective immobilization and patient training strategies to help reduce motion, and then to design appropriate margins and compensation for the residual motion that is quantified. Especially when considering complex, technically demanding treatments that require a degree of patient cooperation, careful patient selection is needed to ensure that the potential benefits of the treatment design are actually realized. Finally, accurate treatment hinges critically on verification - of overall positioning, of target and organ motion at the time of treatment, and of the performance of the selected treatment strategy. Properly selected imaging methods are central to this verification process. This discussion will present practical solutions for motion management and image guidance of radiotherapy for thoracic tumors, and most of these concepts are widely applicable to treatment of other tumor sites as well.

  View details for Web of Science ID 000292117400013

  View details for PubMedID 21625158

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

  Abstract

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

  View details for DOI 10.1002/hed.21406

  View details for PubMedID 20848427

• CyberKnife Stereotactic Ablative Radiotherapy for Lung Tumors TECHNOLOGY IN CANCER RESEARCH & TREATMENT Gibbs, I. C., Loo, B. W. 2010; 9 (6): 589-596

  Abstract

  Stereotactic ablative radiotherapy (SABR) has emerged as a promising treatment for early stage non-small cell lung cancer, particularly for patients unable to tolerate surgical resection. High rates of local tumor control have been demonstrated with acceptable toxicity and the practical advantage of a short course of treatment. The CyberKnife image-guided robotic radiosurgery system has unique technical characteristics that make it well suited for SABR of tumors that move with breathing, including lung tumors. We review the qualities of the CyberKnife platform for lung tumor SABR, and provide a summary of clinical data using this system specifically.

  View details for Web of Science ID 000284971100007

  View details for PubMedID 21070081

• STEREOTACTIC ABLATIVE RADIOTHERAPY SHOULD BE COMBINED WITH A HYPOXIC CELL RADIOSENSITIZER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, J. M., Diehn, M., Loo, B. W. 2010; 78 (2): 323-327

  Abstract

  To evaluate the effect of tumor hypoxia on the expected level of cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available hypoxic cell radiosensitizer.We have calculated the expected level of tumor cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor cells are hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on cell survival of adding the hypoxic cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor cell killing from the large radiation doses used in SABR.The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the hypoxic cell radiosensitizer etanidazole.

  View details for DOI 10.1016/j.ijrobp.2010.04.070

  View details for Web of Science ID 000282147000002

  View details for PubMedID 20832663

  View details for PubMedCentralID PMC2939040

• Alternatives to Surgery for Early Stage Non-Small Cell Lung Cancer-Ready for Prime Time? CURRENT TREATMENT OPTIONS IN ONCOLOGY Das, M., Abdelmaksoud, M. H., Loo, B. W., Kothary, N. 2010; 11 (1-2): 24-35

  Abstract

  Surgery is the standard of care for early stage non-small cell lung cancer (NSCLC), with lobectomy being the most oncologically sound resection. Medically inoperable patients and high-risk surgical candidates require effective alternatives to surgery; even operable patients may opt for less invasive options if they are proven to achieve similar outcomes to surgery. Minimally invasive local treatment modalities including dose-intensified conformal radiation therapy, most notably stereotactic ablative radiotherapy (SABR; also known as stereotactic body radiation therapy), and thermal ablation methods such as radiofrequency ablation (RFA) and microwave ablation (MWA) are emerging as promising treatment options whose roles in the treatment of early stage lung cancer are being defined. Early clinical experience and a rapidly growing body of prospective clinical trials, primarily in medically inoperable patients, are demonstrating encouraging effectiveness and safety outcomes in some cases approaching historical results with surgery. Given the very poor prognosis of the medically inoperable patient population, these alternatives to surgery, particularly SABR, are starting to be considered appropriate first-line therapy in properly selected patients, and prospective cooperative group trials to evaluate and optimize RFA and SABR in specific patient subsets are being conducted. For operable patients, prospective multi-center and cooperative groups trials of SABR are ongoing or completed, and international randomized trials of SABR vs. surgery have been initiated. Thus, promising alternatives to surgery for early stage NSCLC are ready for prime time evaluation in the setting of clinical trials, and participation in ongoing trials for both operable and medically inoperable patients is strongly encouraged.

  View details for DOI 10.1007/s11864-010-0119-z

  View details for PubMedID 20577833

• Stereotactic radiosurgery for stage I NSCLC in medically inoperable patients: A prospective multicenter study. Pennathur, A., Whyte, R. I., Zajac, A., Brachman, D. G., Gooding, W. E., Christie, N. A., Urschel, H. C., Loo, B. W., Heron, D. E., Luketich, J. D., Multictr Stereotactic Radiosurg AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.7080

  View details for Web of Science ID 000208852004623

• Stereotactic radiosurgery for stage I NSCLC in medically inoperable patients: A prospective multicenter phase II study Pennathur, A., Whyte, R. I., Zajac, A., Brachman, D. G., Gooding, W. E., Christie, N. A., Urschel, H. C., Loo, B. W., Heron, D. E., Luketich, J. D., Multictr Stereotactic Radiosurg AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.tps288

  View details for Web of Science ID 000208852002288

• Stereotactic body radiation therapy (stereotactic ablative radiotherapy) for stage I non-small cell lung cancer--updates of radiobiology, techniques, and clinical outcomes. Discovery medicine Hadziahmetovic, M., Loo, B. W., Timmerman, R. D., Mayr, N. A., Wang, J. Z., Huang, Z., Grecula, J. C., Lo, S. S. 2010; 9 (48): 411-417

  Abstract

  Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has emerged as one of the standard treatment options for stage I non-small cell lung cancer (NSCLC), mainly in medically inoperable patients. Its use has also been explored in operable patients. A large body of experience, either from retrospective studies or clinical trials, has been accumulated over the years and more is known about the radiobiology, cancer biology, technical aspects, clinical outcomes, and toxicities of SBRT. This article provides updates of these aspects of SBRT for stage I NSCLC.

  View details for PubMedID 20515609

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2009.04.006

  View details for PubMedID 19540068

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

  View details for Web of Science ID 000288775701202

• Esophageal Dose Tolerance in Stereotactic Body Radiotherapy Abelson, J. A., Murphy, J., Chang, S. D., Soltys, S. G., Le, Q., Loo, B. W., Gibbs, I. C. ELSEVIER SCIENCE INC. 2010: S267

  View details for DOI 10.1016/j.ijrobp.2010.07.636

  View details for Web of Science ID 000288775700576

• 4D-CT Pulmonary Ventilation Image-guided Radiotherapy Planning Is Significantly Influenced by Deformable Image Registration Algorithms and Metrics Yamamoto, T., Kabus, S., von Berg, J., Lorenz, C., Loo, B. W., Keall, P. J. ELSEVIER SCIENCE INC. 2010: S185

  View details for DOI 10.1016/j.ijrobp.2010.07.450

  View details for Web of Science ID 000288775700396

• A Prospective Multicenter Study of Stereotactic Radiosurgery for the Treatment of Stage I NSCLC in Medically Inoperable Patients Pennathur, A., Whyte, R. I., Heron, D. E., Loo, B. W., Brachman, D. G., Gooding, W. E., Zajac, A., Christie, N. A., Urschel, H. D., Luketich, J. D. ELSEVIER SCIENCE INC. 2010: S520–S521

  View details for DOI 10.1016/j.ijrobp.2010.07.1216

  View details for Web of Science ID 000288775701207

• Hypoxia Imaging for Image-Guided Radiotherapy MOLECULAR IMAGING FOR INTEGRATED MEDICAL THERAPY AND DRUG DEVELOPMENT Le, Q., Loo, B. W., Lee, N., Tamaki, N., Kuge, Y. 2010: 7–18

  View details for DOI 10.1007/978-4-431-98074-2_2

  View details for Web of Science ID 000271884900002

• Mid-treatment Metabolic Tumor Volume Predicts Progression and Death among Patients with Hodgkin's Disease 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiation-Oncology (ASTRO) Tseng, D., Rachakonda, L. P., Su, Z., Advani, R., Horning, S., Rosenberg, S. A., Hoppe, R. T., Quon, A., Graves, E. E., Loo, B. W., Tran, P. T. ELSEVIER SCIENCE INC. 2010: S546–S547

  View details for Web of Science ID 000288775701265

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

  View details for Web of Science ID 000288775701074

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

  View details for Web of Science ID 000288775701063

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

  View details for Web of Science ID 000288775701162

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

  View details for Web of Science ID 000288775700383

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

  View details for Web of Science ID 000288775701011

• Marked Tumor Response and Fatal Hemoptysis During Radiation for Lung Cancer in a Human Immunodeficiency Virus-Positive Patient Taking Nelfinavir JOURNAL OF THORACIC ONCOLOGY Chapman, C. H., Shen, J., Filion, E. J., Tran, P. T., Hara, W., Asuncion, A., Marko, D., Wakelee, H., Berry, G. J., Dimmick, K. W., Loo, B. W., Green, J. 2009; 4 (12): 1587-1589

  View details for PubMedID 20009915

• Re: "The safety and efficacy of robotic image-guided radiosurgery system treatment for intra- and extracranial lesions: A systematic review of the literature" [Radiotherapy and Oncology 89 (2009) 245-253] RADIOTHERAPY AND ONCOLOGY Gibbs, I. C., Levendag, P. C., Fariselli, L., Bondiau, P., Lartigau, E., Loo, B. W., Gagnon, G. J., Koong, A. 2009; 93 (3): 656-657

  View details for DOI 10.1016/j.radonc.2009.08.024

  View details for Web of Science ID 000272762900048

  View details for PubMedID 19748142

• Cooperative Group Research Efforts in Thoracic Malignancies 2009: A Review From the 10th Annual International Lung Cancer Congress CLINICAL LUNG CANCER Wakelee, H., Loo, B. W., Kernstine, K. H., Putnam, J. B., Edelman, M. J., Vokes, E. E., Schiller, J. H., Baas, P., Saijo, N., Adjei, A., Goss, G., Choy, H., Gandara, D. R. 2009; 10 (6): 395-404

  Abstract

  Critical advances in the treatment of patients with lung cancer have occurred in the past few years. The cooperative groups in North America and internationally have played crucial roles in these advances. The leaders of the groups meet on a regular basis to review the progress of their trials. However, they rarely have a chance to discuss all ongoing and planned trials, except at the annual Lung Cancer Congress held each June. This article captures this exchange from the 10th Annual Lung Cancer Congress held in June 2009. Exciting efforts are ongoing for all stages of non-small-cell lung cancer, small-cell lung cancer, and mesothelioma. A major focus of the groups at this time is a push toward more personalized medicine, as reflected in the selection criteria for many of the trials, along with planned correlates to better define populations most likely to benefit. Agents targeting the vascular endothelial growth factor (VEGF) pathway, including many tyrosine kinase inhibitors against the VEGF receptor, and those targeting the epidermal growth factor receptor pathway, are under extensive development with many combination trials ongoing.

  View details for DOI 10.3816/CLC.2009.n.075

  View details for PubMedID 19900856

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

  View details for Web of Science ID 000269496002262

• Four-dimensional computed tomography-based pulmonary ventilation imaging for adaptive functional guidance in radiotherapy Yamamoto, T., Kabus, S., von Berg, J., Lorenz, C., Mittra, E. S., Quon, A., Loo, B. W., Keall, P. J. LIPPINCOTT WILLIAMS & WILKINS. 2009: S959–S960

  View details for Web of Science ID 000269496002765

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

  View details for Web of Science ID 000269496002721

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

  View details for Web of Science ID 000269496002720

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2008.10.060

  View details for Web of Science ID 000268346100006

  View details for PubMedID 19289263

  View details for PubMedCentralID PMC2752334

• Safety and Efficacy of Percutaneous Fiducial Marker Implantation for Image-guided Radiation Therapy JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Kothary, N., Heit, J. J., Louie, J. D., Kuo, W. T., Loo, B. W., Koong, A., Chang, D. T., Hovsepian, D., Sze, D. Y., Hofmann, L. V. 2009; 20 (2): 235-239

  Abstract

  To evaluate the safety and technical success rate of percutaneous fiducial marker implantation in preparation for image-guided radiation therapy.From January 2003 to January 2008, we retrospectively reviewed 139 percutaneous fiducial marker implantations in 132 patients. Of the 139 implantations, 44 were in the lung, 61 were in the pancreas, and 34 were in the liver. Procedure-related major and minor complications were documented. Technical success was defined as implantation enabling adequate treatment planning and computed tomographic simulation.The major and minor complication rates were 5% and 17.3%, respectively. Pneumothorax after lung implantation was the most common complication. Pneumothoraces were seen in 20 of the 44 lung implantations (45%); a chest tube was required in only seven of the 44 lung transplantations (16%). Of the 139 implantations, 133 were successful; in six implantations (4.3%) the fiducial markers migrated and required additional procedures or alternate methods of implantation.Percutaneous implantation of fiducial marker is a safe and effective procedure with risks that are similar to those of conventional percutaneous organ biopsy.

  View details for DOI 10.1016/j.jvir.2008.09.026

  View details for PubMedID 19019700

• Stereotactic body radiotherapy for primary and oligometastatic cancers Community Oncology MT Spiotto, BW Loo Jr, DT Chang 2009; 6 (10): 456-462
• Metabolic Tumor Volume and Oropharynx Subsite as Prognostic Factors in Advanced Head and Neck Cancer Raben, D., Chen, C., Loo, B., Graves, E., Kavanagh, B. ELSEVIER SCIENCE INC. 2009: S412

  View details for DOI 10.1016/j.ijrobp.2009.07.943

  View details for Web of Science ID 000270573601380

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

  View details for Web of Science ID 000270573601456

• Post-Operative Radiation Therapy (PORT) in Completely Resected Non-Small-Cell Lung Cancer CURRENT TREATMENT OPTIONS IN ONCOLOGY Krupitskaya, Y., Loo, B. W. 2008; 9 (4-6): 343-356

  Abstract

  High-level evidence to guide the optimal postoperative management of patients with completely resected non-small-cell lung cancer (NSCLC) is lacking. Large randomized controlled trials have established postoperative chemotherapy as the standard of care for patients with pathologically involved lymph nodes. Recent retrospective and non-randomized studies provide evidence of the benefit of post-operative radiation therapy (PORT) in patients with mediastinal nodal involvement (N2 stage). A large multi-institutional randomized trial of PORT in this patient population is now underway. Based on currently available data, PORT may be considered for fit patients with completely resected NSCLC with N2 nodal involvement, preferably after completion of adjuvant chemotherapy. At this point, PORT is not recommended for patients with less than N2 nodal stage. Ideally, modern three-dimensional conformal radiation technique should be used, with attention to normal organ sparing, particularly lung and heart. Appropriate image guidance tools are encouraged to individualize treatment margins, account for breathing-induced motion, and minimize irradiation of normal tissues. The target volume should include at a minimum the bronchial stump, ipsilateral hilum, and involved nodal stations, and covering adjacent mediastinal nodal stations is recommended. A total dose of 50-54 Gy in 1.8-2 Gy fractions is appropriate.

  View details for DOI 10.1007/s11864-009-0090-8

  View details for Web of Science ID 000267146600010

  View details for PubMedID 19387842

• RETROSPECTIVE ANALYSIS OF ARTIFACTS IN FOUR-DIMENSIONAL CT IMAGES OF 50 ABDOMINAL AND THORACIC RADIOTHERAPY PATIENTS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Yamamoto, T., Langner, U., Loo, B. W., Shen, J., Keall, P. J. 2008; 72 (4): 1250-1258

  Abstract

  To quantify the type, frequency, and magnitude of artifacts in four-dimensional (4D) CT images acquired using a multislice cine method.Fifty consecutive patients who underwent 4D-CT scanning and radiotherapy for thoracic or abdominal cancers were included in this study. All the 4D-CT scans were performed on the GE multislice PET/CT scanner with the Varian Real-time Position Management system in cine mode. The GE Advantage 4D software was used to create 4D-CT data sets. The artifacts were then visually and quantitatively analyzed. We performed statistical analyses to evaluate the relationships between patient- or breathing-pattern-related parameters and the occurrence as well as magnitude of artifacts.It was found that 45 of 50 patients (90%) had at least one artifact (other than blurring) with a mean magnitude of 11.6 mm (range, 4.4-56.0 mm) in the diaphragm or heart. We also observed at least one artifact in 6 of 20 lung or mediastinal tumors (30%). Statistical analysis revealed that there were significant differences between several breathing-pattern-related parameters, including abdominal displacement (p < 0.01), for the subgroups of patients with and without artifacts. The magnitude of an artifact was found to be significantly but weakly correlated with the abdominal displacement difference between two adjacent couch positions (R = 0.34, p < 0.01).This study has identified that the frequency and magnitude of artifacts in 4D-CT is alarmingly high. Significant improvement is needed in 4D-CT imaging.

  View details for DOI 10.1016/j.ijrobp.2008.06.1937

  View details for Web of Science ID 000260592600040

  View details for PubMedID 18823717

  View details for PubMedCentralID PMC2583232

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2007.10.027

  View details for Web of Science ID 000255971100013

  View details for PubMedID 18164839

• Complications of ablative therapies in lung cancer CLINICAL LUNG CANCER Padda, S., Kothary, N., Donington, J., Cannon, W., Loo, B. W., Kee, S., Wakelee, H. 2008; 9 (2): 122-126

  Abstract

  Two cases of complications secondary to the use of microwave ablation (MWA) in non-small-cell lung cancer (NSCLC) are discussed herein. The first case involves a 62-year-old man with stage IB NSCLC who declined surgery and pursued MWA. Within 7 months, he had residual disease at the MWA treatment site, and surgery was performed. The patient was found to have pleural and chest wall involvement, making complete resection impossible. The second case involves an 86-year-old woman with a second local recurrence of NSCLC and previous treatment including surgery and chemoradiation therapy. She was initially a surgical candidate but declined surgery and pursued MWA. Within 6 months, she had residual disease at the MWA treatment site. A second MWA was performed, and she developed a large cavitary abscess at the MWA site and had subsequent clinical decline. Less invasive ablation therapies and stereotactic radiosurgery are being developed for patients with inoperable lung cancer. Because these modalities have recently been developed, trials that clearly show efficacy and survival benefit are yet to be completed. Ablation procedures can result in complications, including residual disease and cavitary lesions susceptible to infection. These cases highlight the caution that should still be observed when recommending lung ablation strategies and the importance of selecting appropriate patients.

  View details for PubMedID 18501100

• Initial evaluation of F-18-fluorothymidine (FLT) PET/CT scanning for primary pancreatic cancer EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Quon, A., Chang, S. T., Chin, F., Kamaya, A., Dick, D. W., Loo, B. W., Gambhir, S. S., Koong, A. C. 2008; 35 (3): 527-531

  Abstract

  The aim of this study was to evaluate the potential of (18)F-fluorothymidine (FLT) PET/CT for imaging pancreatic adenocarcinoma.This was a pilot study of five patients (four males, one female) with newly diagnosed and previously untreated pancreatic adenocarcinoma. Patients underwent FLT PET/CT, (18)F-fluorodeoxyglucose (FDG) PET/CT, and contrast-enhanced CT scanning before treatment. The presence of cancer was confirmed by histopathological analysis at the time of scanning in all five patients. The degree of FLT and FDG uptake at the primary tumor site was assessed using visual interpretation and semi-quantitative SUV analyses.The primary tumor size ranged from 2.5 x 2.8 cm to 3.5 x 7.0 cm. The SUV of FLT uptake within the primary tumor ranged from 2.1 to 3.1. Using visual interpretation, the primary cancer could be detected from background activity in two of five patients (40%) on FLT PET/CT. By comparison, FDG uptake was higher in each patient with a SUV range of 3.4 to 10.8, and the primary cancer could be detected from background in all five patients (100%).In this pilot study of five patients with primary pancreatic adenocarcinoma, FLT PET/CT scanning showed poor lesion detectability and relatively low levels of radiotracer uptake in the primary tumor.

  View details for DOI 10.1007/s00259-007-0630-z

  View details for Web of Science ID 000254402800010

  View details for PubMedID 17960376

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

  View details for Web of Science ID 000258805300356

• Metabolic tumor volume predicts overall survival in lung cancer patients treated definitively Lee, P., Bazan, J. G., Weerasuriya, D. K., Lavori, P. W., Quon, A., Le, Q., Loo, B. W. ELSEVIER SCIENCE INC. 2008: S462

  View details for DOI 10.1016/j.ijrobp.2008.06.1375

  View details for Web of Science ID 000258805301508

• Time interval to FDG PET/CT after mediastinal radiation impacts the dose response of pneumonitis related metabolic activity Teo, B. K., Abelson, J., Teo, A., Graves, E. E., Guerrero, T., Loo, B. W. ELSEVIER SCIENCE INC. 2008: S67–S68

  View details for DOI 10.1016/j.ijrobp.2008.06.919

  View details for Web of Science ID 000258805300152

• Salvage re-irradiation using intensity-modulated radiotherapy for squamous cell carcinoma of the head and neck Chin, R. K., Daly, M. E., Maxim, P. G., Loo, B. W., Le, Q. T., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S420

  View details for DOI 10.1016/j.ijrobp.2008.06.1329

  View details for Web of Science ID 000258805301414

• Good concordance between on-board imaging and an optically guided stereotactic positioning system for paranasal sinus and skull base radiotherapy Maxim, P. G., Hristov, D., Loo, B. W., Le, Q. ELSEVIER SCIENCE INC. 2008: S423

  View details for DOI 10.1016/j.ijrobp.2008.06.1337

  View details for Web of Science ID 000258805301422

• Intensity modulated radiotherapy for squamous cell carcinoma of the hypopharynx and larynx: Clinical outcomes and patterns of failure Daly, M. E., Le, Q. T., Loo, B. W., Maxim, P. G., Pinto, H. A., Colevas, A. D., Fee, W. E., Kaplan, M. J., Chang, D. T. ELSEVIER SCIENCE INC. 2008: S405–S406

  View details for DOI 10.1016/j.ijrobp.2008.06.1296

  View details for Web of Science ID 000258805301382

• Dose escalation feasible due to gating in lung cancer patients 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Luxion, G., Antony, J., Loo, B. W., Carlson, D., Maxim, P. G., Xing, L. ELSEVIER SCIENCE INC. 2008: S625–S625

  View details for Web of Science ID 000258805302301

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

  View details for Web of Science ID 000258805301520

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

  Abstract

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

  View details for Web of Science ID 000251561100008

  View details for PubMedID 17869025

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2007.04.036

  View details for PubMedID 17869659

• Respiratory gated beam delivery cannot facilitate margin reduction, unless combined with respiratory correlated image guidance Korreman, S., Juhler-Nottrup, T., Boyer, A., Loo, B., Pedersen, A. N., Specht, L., Nystroem, H. ELSEVIER IRELAND LTD. 2007: S87–S88

  View details for Web of Science ID 000251397500180

• RT_Image: An open-source tool for investigating PET in radiation oncology TECHNOLOGY IN CANCER RESEARCH & TREATMENT Graves, E. E., Quon, A., Loo, B. W. 2007; 6 (2): 111-121

  Abstract

  Positron emission tomography (PET) has emerged as a valuable imaging modality for the diagnosis and staging of cancer. However, despite evidence that PET may be useful for defining target volumes for radiation therapy, no standardized methodology for accomplishing this task exists. To facilitate the investigation of the utility of PET imaging in radiotherapy treatment planning and accelerate its integration into clinical radiation oncology, we have developed software for exploratory analysis and segmentation of functional imaging datasets. The application, RT_Image, allows display of multiple imaging datasets and associated three-dimensional regions-of-interest (ROIs) at arbitrary view angles and fields of view. It also includes semi-automated image segmentation tools for defining metabolically active tumor volumes that may aid creation of target volumes for treatment planning. RT_Image is DICOM compliant, permitting the transfer of imaging data and DICOM-RT structure sets between the application and treatment planning software. RT_Image has been used by radiation oncologists, nuclear medicine physicians, and radiation physicists to analyze over 200 PET datasets. Novel segmentation techniques have been implemented within this programming framework for therapy planning and for evaluation of molecular imaging-derived parameters as prognostic indicators. RT_Image represents a freely-available software base on which further investigations of the utlity of PET and molecular imaging in radiation oncology may be built. The development of tools such as this is critical in order to realize the potential of molecular imaging-guided radiation therapy.

  View details for Web of Science ID 000245969900007

  View details for PubMedID 17375973

• Impact of integrated PET/CT on variability of target volume delineation in rectal cancer TECHNOLOGY IN CANCER RESEARCH & TREATMENT Patel, D. A., Chang, S. T., Goodman, K. A., Quon, A., Thorndyke, B., Gambhir, S. S., McMillan, A., Loo, B. W., Koong, A. C. 2007; 6 (1): 31-36

  Abstract

  Several studies have demonstrated substantial variability among individual radiation oncologists in defining target volumes using computed tomography (CT). The objective of this study was to determine the impact of combined positron emission tomography and computed tomography (PET/CT) on inter-observer variability of target volume delineation in rectal cancer. We also compared the relative concordance of two PET imaging tracers, 18F-fluorodeoxyglucose (FDG) and 18F-fluorodeoxythymidine (FLT), against conventional computed tomography (CT). Six consecutive patients with locally advanced rectal cancer were enrolled onto an institutional protocol involving preoperative chemoradiotherapy and correlative studies including FDG- and FLT-PET scans acquired in the treatment position. Using these image data sets, four radiation oncologists independently delineated primary and nodal gross tumor volumes (GTVp and GTVn) for a hypothetical boost treatment. Contours were first defined based on CT alone with observers blinded to the PET images, then based on combined PET/CT. An inter-observer similarity index (SI), ranging from a value of 0 for complete disagreement to 1 for complete agreement of contoured voxels, was calculated for each set of volumes. For primary gross tumor volume (GTVp), the difference in estimated SI between CT and FDG was modest (CT SI = 0.77 vs. FDG SI = 0.81), but statistically significant (p = 0.013). The SI difference between CT and FLT for GTVp was also slight (FLT SI = 0.80) and marginally non-significant (p < 0.082). For nodal gross tumor volume, (GTVn), SI was significantly lower for CT based volumes with an estimated SI of 0.22 compared to an estimated SI of 0.70 for FDG-PET/CT (p < 0.0001) and an estimated SI of 0.70 for FLT-PET/CT (p < 0.0001). Boost target volumes in rectal cancer based on combined PET/CT results in lower inter-observer variability compared with CT alone, particularly for nodal disease. The use of FDG and FLT did not appear to be different from this perspective.

  View details for Web of Science ID 000244732600005

  View details for PubMedID 17241098

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

  Abstract

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

  View details for Web of Science ID 000243420900008

  View details for PubMedID 17204721

• Mid-treatment FDG-PET predicts disease progression in patients with non-small cell lung cancer Olson, M. R., Weerasuriya, D. K., Wakelee, H. A., Quon, A., Maxim, P. G., Le, Q., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: S504

  View details for DOI 10.1016/j.ijrobp.2007.07.1720

  View details for Web of Science ID 000249950201230

• Quantification of progression of non-small cell lung cancer in the interval between diagnostic and radiotherapy treatment planning PET scans Eastham, D. V., Weerasuriya, D., Wakelee, H., Quon, A., Maxim, P., Le, Q., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: S520–S521

  View details for DOI 10.1016/j.ijrobp.2007.07.1750

  View details for Web of Science ID 000249950201258

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

  Abstract

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

  View details for PubMedID 17409963

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2006.05.045

  View details for Web of Science ID 000240699500024

  View details for PubMedID 16965993

• Four-dimensional cone-beam computed tomography using an on-board imager MEDICAL PHYSICS Li, T., Xing, L., Munro, P., McGuinness, C., Chao, M., Yang, Y., Loo, B., Koong, A. 2006; 33 (10): 3825-3833

  Abstract

  On-board cone-beam computed tomography (CBCT) has recently become available to provide volumetric information of a patient in the treatment position, and holds promises for improved target localization and irradiation dose verification. The design of currently available on-board CBCT, however, is far from optimal. Its quality is adversely influenced by many factors, such as scatter, beam hardening, and intra-scanning organ motion. In this work we quantitatively study the influence of organ motion on CBCT imaging and investigate a strategy to acquire high quality phase-resolved [four-dimensional (4D)] CBCT images based on phase binning of the CBCT projection data. An efficient and robust method for binning CBCT data according to the patient's respiratory phase derived in the projection space was developed. The phase-binned projections were reconstructed using the conventional Feldkamp algorithm to yield 4D CBCT images. Both phantom and patient studies were carried out to validate the technique and to optimize the 4D CBCT data acquisition protocol. Several factors that are important to the clinical implementation of the technique, such as the image quality, scanning time, number of projections, and radiation dose, were analyzed for various scanning schemes. The general references drawn from this study are: (i) reliable phase binning of CBCT projections is accomplishable with the aid of external or internal marker and simple analysis of its trace in the projection space, and (ii) artifact-free 4D CBCT images can be obtained without increasing the patient radiation dose as compared to the current 3D CBCT scan.

  View details for DOI 10.1118/1.2349692

  View details for Web of Science ID 000241424100024

  View details for PubMedID 17089847

• 4D cone-beam CT (CBCT) using an on-board imager 48th Annual Meeting of the American-Association-of-Physicists-in-Medicine Li, T., Xing, L., Munro, P., Yang, Y., Loo, B., Koong, A. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2006: 2234–34

  View details for Web of Science ID 000238688502246

• Dosimetric impact by temporal changes of the GTV in head and neck cancers Maxim, P., Le, Q., Loo, B., Pawlicki, T. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2006: 2032

  View details for DOI 10.1118/1.2240830

  View details for Web of Science ID 000238688500250

• Dosimetric impact by temporal changes of the PTV in head in neck cancers 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Maxim, P. G., Tran, P., Hsu, A., Daly, M., Loo, B. W., Wu, R., Pawlicki, T., Le, Q. ELSEVIER SCIENCE INC. 2006: S638–S639

  View details for Web of Science ID 000241221602277

• Quantification of motion for different thoracic locations using 4DCT: Implications for radiation treatment planning Shirazi, H., Thorndyke, B., Maxim, P., Loo, B., Luxton, G., Le, Q. ELSEVIER SCIENCE INC. 2006: S477–S478

  View details for DOI 10.1016/j.ijrobp.2006.07.891

  View details for Web of Science ID 000241221601424

• Analysis of daily set-up error by on-board imaging and its implications for PTV margin expansion Olson, M. R., Cox, B., Wu, R., Le, Q., Koong, A., Loo, B. W. ELSEVIER SCIENCE INC. 2006: S634–S635

  View details for DOI 10.1016/j.ijrobp.2006.07.1177

  View details for Web of Science ID 000241221602271

• A dosimetric study of dynamic conformal arc therapy for lung cancer Cho, N. K., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2006: S687

  View details for DOI 10.1016/j.ijrobp.2006.07.1265

  View details for Web of Science ID 000241221602357

• Integrated analysis of pancreatic tumor motion using multiple image-guided modalities 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Cox, B., Ho, T., Thorndyke, B., Pawlicki, T., Loo, B., Xing, L., Goodman, K., Koong, A. ELSEVIER SCIENCE INC. 2006: S53–S54

  View details for Web of Science ID 000241221600091

• Deep inspiration breath-hold decreases dose to the left ventricle with whole breast or accelerated partial breast radiotherapy for left sided breast cancers Jarvis, L. A., Loo, B., Chang, W., Thorndyke, B., Maxim, P., Horst, K. ELSEVIER SCIENCE INC. 2006: S179

  View details for DOI 10.1016/j.ijrobp.2006.07.350

  View details for Web of Science ID 000241221600300

• Optical detection of tumors in vivo by visible light tissue oximetry TECHNOLOGY IN CANCER RESEARCH & TREATMENT Maxim, P. G., Carson, J. J., Benaron, D. A., Loo, B. W., Xing, L., Boyer, A. L., Friedland, S. 2005; 4 (3): 227-234

  Abstract

  Endoscopy is a standard procedure for identifying tumors in patients suspected of having gastrointestinal (G.I.) cancer. The early detection of G.I. neoplasms during endoscopy is currently made by a subjective visual inspection that relies to a high degree on the experience of the examiner. This process can be difficult and unreliable, as tumor lesions may be visually indistinguishable from benign inflammatory conditions and the surrounding mucosa. In this study, we evaluated the ability of local ischemia detection using visible light spectroscopy (VLS) to differentiate neoplastic from normal tissue based on capillary tissue oxygenation during endoscopy. Real-time data were collected (i) from human subjects (N = 34) monitored at various sites during endoscopy (enteric mucosa, malignant, and abnormal tissue such as polyps) and (ii) murine animal subjects with human tumor xenografts. Tissue oximetry in human subjects during endoscopy revealed a tissue oxygenation (StO2%, mean +/- SD) of 46 +/- 22% in tumors, which was significantly lower than for normal mucosal oxygenation (72 +/- 4%; P < or = 0.0001). No difference in tissue oxygenation was observed between normal and non-tumor abnormal tissues (P = N.S.). Similarly, VLS tissue oximetry for murine tumors revealed a mean local tumor oxygenation of 45% in LNCaP, 50% in M21, and 24% in SCCVII tumors, all significantly lower than normal muscle tissue (74%, P < 0.001). These results were further substantiated by positive controls, where a rapid real-time drop in tumor oxygenation was measured during local ischemia induced by clamping or epinephrine. We conclude that VLS tissue oximetry can distinguish neoplastic tissue from normal tissue with a high specificity (though a low sensitivity), potentially aiding the endoscopic detection of gastrointestinal tumors.

  View details for Web of Science ID 000229787600001

  View details for PubMedID 15896077

• Enhancing 4D PET through retrospective stacking 47th Annual Meeting of the American-Association-of-Physicists-in-Medicine Thorndyke, B., Schreibmann, E., Maxim, P., Loo, B., Boyer, A., Koong, A., Xing, L. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2005: 2096–96

  View details for Web of Science ID 000229908601310

• Effect of respiratory cycle irregularities on image quality in four-dimensional computed tomography 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Thorndyke, B., Xing, L., Graves, E., Loo, B. W. ELSEVIER SCIENCE INC. 2005: S506–S506

  View details for Web of Science ID 000232083301373

• Respiratory Gating during accelerated partial breast irradiation (APBI) permits reduced planning tumor volumes and improved normal tissue dose distributions Cox, B., Horst, K., Thorndyke, B., Loo, B., Maxim, P., Dirbas, F. ELSEVIER SCIENCE INC. 2005: S249

  View details for DOI 10.1016/j.ijrobp.2005.07.424

  View details for Web of Science ID 000232083300415

• Metabolic tumor burden predicts for disease progression in lung cancer Lee, P., Le, Q., Lavori, P. W., Quon, A., Graves, E., Loo, B. W. ELSEVIER SCIENCE INC. 2005: S387–S388

  View details for DOI 10.1016/j.ijrobp.2005.07.663

  View details for Web of Science ID 000232083301178

• Determining margin for target deformation and rotation in respiratory motion-tracked stereotactic radiosurgery of pancreatic cancer 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Loo, B. W., Thorndyke, B. R., Maxim, P. G., Ho, A., Goodman, K. A., Xing, L., Yang, G. P., Koong, A. C. ELSEVIER SCIENCE INC. 2005: S31–S31

  View details for Web of Science ID 000232083300056

• Left anterior descending coronary artery motion in deep inspiration breath-hold and free breathing using 4D-CT scanning: Potential impact on left-sided breast cancer radiotherapy Jarvis, L. A., Loo, B. W., Thorndyke, B. R., Horst, K. C. ELSEVIER SCIENCE INC. 2005: S491

  View details for DOI 10.1016/j.ijrobp.2005.07.836

  View details for Web of Science ID 000232083301350

• Results of a phase I dose escalation study using single fraction stereotactic radiosurgery (SFSR) for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. X., Ho, A., Cotrutz, C., Loo, B., Petrik, D., Wakelee, H., Kee, S. T., Whyte, R. I., Donington, J. S. ELSEVIER SCIENCE INC. 2005: S226–S226

  View details for Web of Science ID 000232083300377

• Implementation of molecular imaging-guided radiation therapy: Software development and validation Graves, E., Loo, B. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2004: 1892

  View details for Web of Science ID 000222259100842

• A method of target definition in PET-based radiotherapy planning 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Loo, B. W., Quon, A., Vasanawala, M. S., Le, Q., Graves, E. E. ELSEVIER SCIENCE INC. 2004: S602–S602

  View details for Web of Science ID 000223854700784

• Plasmablastic lymphoma presenting in a human immunodeficiency virus-negative patient: a case report ANNALS OF HEMATOLOGY Nguyen, D. D., Loo, B. W., Tillman, G., Natkunam, Y., Cao, T. M., Vaughan, W., Dorfman, R. F., Goffinet, D. R., Jacobs, C. D., Advani, R. H. 2003; 82 (8): 521-525

  Abstract

  Plasmablastic lymphoma (PBL), an aggressive non-Hodgkin's lymphoma that carries a poor prognosis, previously has been identified almost exclusively in patients infected with the human immunodeficiency virus (HIV). We present a case of a 42-year-old HIV-negative patient presenting with an isolated nasal cavity mass, the typical presentation for PBL. The patient was given systemic chemotherapy, central nervous system prophylaxis, and consolidative locoregional radiotherapy and achieved a complete clinical response. This case suggests PBL should be considered in HIV-negative patients with characteristic findings.

  View details for DOI 10.1007/s00277-003-0684-3

  View details for PubMedID 12783213

• A new sample preparation method for biological soft X-ray microscopy: nitrogen-based contrast and radiation tolerance properties of glycol methacrylate-embedded and sectioned tissue JOURNAL OF MICROSCOPY-OXFORD Loo, B. W., Sauerwald, I. M., Hitchcock, A. P., Rothman, S. S. 2001; 204: 69-86

  Abstract

  We describe the preparation of a biological tissue for imaging in a transmission soft X-ray microscope. Sections of exocrine pancreas embedded in glycol methacrylate polymer, an embedding medium widely used in visible light and electron microscopy, were examined. Contrast was based primarily on the nitrogen content of the tissue, and dual-wavelength imaging at the nitrogen K-shell absorption edge was used to map the distribution and provide quantitative densitometry of both the protein and embedding matrix components of the sample. The measurements were calibrated by obtaining the absorption spectrum of protein near the nitrogen edge. The contrast was consistent and reproducible, making possible the first large-scale X-ray microscopic study on sections of plastic-embedded soft tissue. At radiation doses of up to 10(8) Gray, much more than required for routine imaging, no distortion and little mass loss were observed. This sample preparation method should permit routine imaging of tissues in X-ray microscopes, previously a difficult task, as well as multimodal imaging (using visible light, X-ray, electron, and scanned probe microscopies) on the same sample.

  View details for Web of Science ID 000171285700009

  View details for PubMedID 11580815

• Automatic image acquisition, calibration and montage assembly for biological X-ray microscopy JOURNAL OF MICROSCOPY-OXFORD Loo, B. W., Meyer-Ilse, W., Rothman, S. S. 2000; 197: 185-201

  Abstract

  We describe a system for the automatic acquisition and processing of digital images in a high-resolution X-ray microscope, including the formation of large-field high-resolution image montages. A computer-controlled sample positioning stage provides approximate coordinates for each high-resolution subimage. Individual subimages are corrected to compensate for time-varying, non-uniform illumination and CCD-related artefacts. They are then automatically assembled into a montage. The montage assembly algorithm is designed to use the overlap between each subimage and multiple neighbours to improve the performance of the registration step and the fidelity of the result. This is accomplished by explicit use of recorded stage positions, optimized ordering of subimage insertion, and registration of subimages to the developing montage. Using this procedure registration errors are below the resolution limit of the microscope (43 nm). The image produced is a seamless, large-field montage at full resolution, assembled automatically without human intervention. Beyond this, it is also an accurate X-ray transmission map that allows the quantitative measurement of anatomical and chemical features of the sample. Applying these tools to a biological problem, we have conducted the largest X-ray microscopical study to date.

  View details for Web of Science ID 000085459300007

  View details for PubMedID 10652011

• Two- and three-dimensional segmentation for measurement of particles in the analysis of microscopic digital images of biological samples Conference on Three-Dimensional Microscopy - Image Acquisition and Processing III Loo, B. W., Parvin, B., Rothman, S. S. SPIE - INT SOC OPTICAL ENGINEERING. 1996: 209–215

  View details for Web of Science ID A1996BF46V00026

• High resolution microscopic imaging with x-rays: Technology and application to the biological sciences Wescon/95 - Microelectronics, Communications Technology, Producing Quality Products, Mobile and Portable Power, Emerging Technologies Loo, B. W., Rothman, S. S. I E E E. 1995: 668–672

  View details for Web of Science ID A1995BE64P00119

• X-RAY MICROTOMOGRAPHY - 3-DIMENSIONAL RECONSTRUCTION METHODS FOR X-RAY MICROSCOPY OF BIOLOGICAL SAMPLES 3-Dimensional Microscopy - Image Acquisition and Processing II Conference Loo, B. W., Brown, J. K., Rothman, S. S. SPIE - INT SOC OPTICAL ENGINEERING. 1995: 196–209

  View details for Web of Science ID A1995BC95B00024

• AN ENVIRONMENTAL SAMPLE CHAMBER FOR X-RAY MICROSCOPY JOURNAL OF MICROSCOPY-OXFORD Goncz, K. K., Batson, P., CIARLO, D., Loo, B. W., Rothman, S. S. 1992; 168: 101-110

  View details for Web of Science ID A1992JV21500010

• X-RAY STEREOMICROSCOPY - HIGH-RESOLUTION 3-D IMAGING OF HUMAN SPERMATOZOA IN AQUEOUS SUSPENSION WITH NATURAL CONTRAST JOURNAL OF MICROSCOPY-OXFORD Loo, B. W., Williams, S., Meizel, S., Rothman, S. S. 1992; 166: RP5-RP6

  View details for Web of Science ID A1992HW41100010

  View details for PubMedID 1625335

• An environmental sample chamber for x-ray microscopy J Microsc Goncz KK, Batson P, Ciarlo D, Loo BW Jr, Rothman SS 1992; 168: 101-110