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Purpose: To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber., Methods and Materials: 227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector., Results: Calibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R 2 values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose., Conclusion: In vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: To evaluate the feasibility, efficacy and safety of stereotactic ablative radiotherapy (SABR) to the primary tumor and lymph nodes in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who are ineligible for or refused concomitant chemoradiation., Materials and Methods: In accordance with the PRISMA and MOOSE guidelines, a systematic review with meta-analysis was conducted. The study included reports that assessed the outcomes of SABR treatment in patients with LA-NSCLC. Studies evaluating SBRT as a boost following primary radiotherapy were excluded. The primary outcomes measured were local control (LC) and overall survival (OS). The secondary endpoint was the incidence of severe toxicity (grades 3-5). A meta-regression analysis was performed to explore the relationship between LC, OS, and severe toxicity. The Biologically Effective Dose (BED) was analyzed as a continuous variable. Statistical significance was defined as a p-value < 0.05., Results: A total of seven studies (3 prospective and 4 retrospective studies) involving 268 patients (SBRT to primary and lymph nodes) were included in the analysis. The pooled 1-year LC rate was 80 % (95 % CI: 63-94 %), and the factors significantly associated with LC were BEDGy10 (p = 0.005) and neoadjuvant chemotherapy (p = 0.005). The 1-year and 2-year OS rates were 74 % (95 % CI: 58-90 %) and 55 % (95 % CI: 34-76 %), respectively. Meta-regression analysis indicated a linear relationship between OS and LC, with a 0.7 % increase in OS for each 1 % improvement in LC (p = 0.005). The pooled rate of grade 3 acute toxicity was 5 % (95 % CI: 1-10 %), and the rate of grade 5 toxicity was 1.7 % (95 % CI: 0-3 %)., Conclusion: Promising results (LC and OS) with limited toxicity (feasibility) using SABR in LA-NSCLC warrant further research, emphasizing the need for larger, well-designed trials for further validation of the approach., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FYM reports previous consulting fee from Elekta and honoraria from Astra Zeneca, both outside the current work., (Copyright © 2024. Published by Elsevier B.V.)

Background: Stereotactic ablative radiation therapy (SBRT) is an emerging treatment option for primary renal cell carcinoma (RCC), particularly in patients who are unsuitable for surgery. The aim of this review is to assess the effect of increasing the biologically equivalent dose (BED) via various radiation fractionation regimens on clinical outcomes., Methods: A literature search was conducted in PubMed (Medline), EMBASE, and the Cochrane Library for studies published up to October 2023. Studies reporting on patients with localized RCC receiving SBRT were included to determine its effectiveness on local control, progression-free survival, and overall survival. A random effects model was used to meta-regress clinical outcomes relative to the BED for each study and heterogeneity was assessed by I 2 ., Results: A total of 724 patients with RCC from 22 studies were included, with a mean age of 72.7 years (range: 44.0-81.0). Local control was excellent with an estimate of 99 % (95 %CI: 97-100 %, I 2  = 19 %), 98 % (95 %CI: 96-99 %, I 2  = 8 %), and 94 % (95 %CI: 90-97 %, I 2  = 11 %) at one year, two years, and five years respectively. No definitive association between increasing BED and local control, progression-free survival and overall survival was observed. No publication bias was observed., Conclusions: A significant dose response relationship between oncological outcomes and was not identified, and excellent local control outcomes were observed at the full range of doses. Until new evidence points otherwise, we support current recommendations against routine dose escalation beyond 25-26 Gy in one fraction or 42-48 Gy in three fractions, and to consider de-escalation or compromising target coverage if required to achieve safe organ at risk doses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RG: institutional grant funding- Astellas, TerSera. Honoraria: Bayer, Tolmar, Knight, TerSera. SR: Institutional grant funding – Astra Zeneca, Knight therapeutics. Honoraria – Bayer, Astra Zeneca, Tersera, Sanofi, Verity pharma., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The objective of this study is to determine the outcomes and toxicities of patients with malignant pleural mesothelioma (MPM) treated with stereotactic body radiotherapy (SBRT)., Materials and Methods: Data were extracted from an institutional tumor registry for patients diagnosed with mesothelioma and treated with SBRT. Kaplan-Meier and Cox regression analyses were employed to determine local control (LC) and overall survival (OS)., Results: Forty-four patients with 59 total treated tumors from December 2006 to April 2022 were identified. Fifty-one (86.4 %) cases had oligoprogressive disease (five sites or less). The median prescription dose delivered was 3000 cGy in 5 fractions (range: 2700-6000 cGy in 3-8 fractions). Fifty-one (86.4 %) tumors were in the pleura, 4 (6.8 %) spine, 2 (3.4 %) bone, 1 (1.7 %) brain, and 1 (1.7 %) pancreas. The median follow-up from SBRT completion for those alive at last follow-up was 28 months (range: 14-52 months). The most common toxicities were fatigue (50.8 %), nausea (22.0 %), pain flare (15.3 %), esophagitis (6.8 %), dermatitis (6.8 %), and pneumonitis (5.1 %). There were no grade ≥ 3 acute or late toxicities. There were 2 (3.4 %) local failures, one of the pleura and another of the spine. One-year LC was 92.9 % (95 % CI: 74.6-98.2 %) for all lesions and 96.3 % (95 % CI: 76.5-99.5 %) for pleural tumors. One-year LC was 90.9 % (95 % CI: 68.1-97.6 %) for epithelioid tumors and 92.1 % (95 % CI: 72.1-98.0 %) for oligoprogressive tumors. One-year OS from time of SBRT completion was 36.4 % (95 % CI: 22.6-50.3 %). On multivariable analysis, KPS was the lone significant predictor for OS (p = 0.029)., Conclusions: Our single-institutional experience on patients with MPM suggests that SBRT is safe with a low toxicity profile and potentially achieve good local control., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jacob Y. Shin-No conflicts of interest to disclose. Michael Offin-Dr. Offin has consulted regarding oncology drug development with Novartis, Jazz, and PharmaMar; and has received honorarium from Targeted Oncology, OncLive, and the American Society for Radiation Oncology. Charles B. Simone II-Dr. Simone II reported receiving honoraria from Varian Medical Systems outside the submitted work. Zhigang Zhang-No conflicts of interest to disclose. Annemarie F. Shepherd-Dr. Shepherd reported having stock or stock options in Doximity and ArcellX. Abraham J. Wu-Dr. Wu reported receiving grants from CivaTech Oncology; receiving personal fees from MoreHealth, AstraZeneca, and Nanovi; receiving travel expenses from AlphaTau; and serving on the scientific advisory board of Simphotek outside the submitted work. Narek Shaverdian-Dr. Shaverdian reported receiving research funding from Novartis outside the submitted work. Daphna Y. Gelblum-No conflicts of interest to disclose. Daniel R. Gomez-Dr. Gomez reported receiving grants from Merck, AstraZeneca, Varian Medical Systems, and Bristol Myers Squibb during the conduct of the study and receiving personal fees from Bristol Myers Squibb, Reflexsion, Merck, Medscape, Vindico, US Oncology, MedLearning Group, AstraZeneca, GRAIL, Medtronic, Johnson & Johnson, and Varian Medical Systems outside the submitted work. Jennifer L. Sauter-Dr. Sauter reported having stock or stock options in Chemed Corporation, Merck & Co., Inc., Pfizer, Inc., and Thermo Fisher Scientific. Michelle S. Ginsberg-No conflicts of interest to disclose. Prasad S. Adusumilli-Dr. Adusumilli is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, ImmPACT Bio, Johnson & Johnson, and Outpace Bio; declares having patents, royalties, and intellectual property on mesothelin-targeted CAR and other T-cell therapies, which have been licensed to ATARA Biotherapeutics, issued patent method for detection of cancer cells using virus, and pending patent applications on PD-1–dominant negative receptor, wireless pulse oximetry device, and on an exvivo malignant pleural effusion culture system. Memorial Sloan Kettering Cancer Center (MSK) has licensed intellectual property related to mesothelin-targeted CARs and T-cell therapies to ATARA Biotherapeutics and has associated financial interests. Valerie W. Rusch-Dr. Rusch reported receiving grants from the National Institutes of Health (NIH)/National Cancer Institute, during the conduct of the study; grants from Genelux, Inc.; grants from Genentech, other from DaVinci Surgery; nonfinancial support from Bristol Myers Squibb; and personal fees from the NIH/Coordinating Center For Clinical Trials, outside the submitted work. Marjorie G. Zauderer-In the last 3 years, Dr. Zauderer has received consulting fees from Curis, Ikena, Takeda, GlaxoSmithKline, and Novocure and honoraria for CME content from PER, Medscape, and Research to Practice. Memorial Sloan Kettering receives research funding from the Department of Defense, the National Institutes of Health, MedImmune, Precog, GlaxoSmithKline, Epizyme, Polaris, Sellas Life Sciences, Bristol Myers Squibb, Millenium/Takeda, Curis, and Atara for research conducted by Dr. Zauderer. Dr. Zauderer serves as Chair of the Board of Directors of the Mesothelioma Applied Research Foundation, uncompensated. Andreas Rimner-Dr. Rimner has consulted regarding oncology drug development with AstraZeneca, Merck, Boehringer Ingelheim, and Cybrexa; has received honorarium from MoreHealth and ResearchToPractice; has served on a scientific advisory board of Merck; and has received grants from Varian Medical Systems, Boehringer Ingelheim, Pfizer, AstraZeneca, and Merck., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: This study aimed to compare SBRT and cEBRT for treating spinal metastases through a systematic review and meta-analysis of randomized controlled trials (RCTs)., Methods: PubMed, EMBASE and Cochrane Library were searched up to 6 May 2023 for RCTs comparing SBRT and cEBRT for spinal metastases. Overall and complete pain response, local progression, overall survival, quality of life and adverse events were extracted. Data were pooled using random-effects models. Results were reported as risk ratios (RRs) for dichotomous outcomes, and hazard ratios (HRs) for time-to-event outcomes, along with their 95% confidence intervals (CIs). Heterogeneity was evaluated using the I 2 statistic., Results: Three RCTs were identified involving 642 patients. No differences were seen in overall pain response comparing SBRT and cEBRT (RR at 3 months: 1.12, 95% CI, 0.74-1.70, p = 0.59; RR at 6 months: 1.29, 95% CI, 0.97-1.72, p = 0.08). Only two of three studies presented complete pain response data. SBRT demonstrated a statistically significant improvement in complete pain response compared to cEBRT (RR at 3 months: 2.52; 95% CI, 1.58-4.01; P < 0.0001; RR at 6 months: 2.48; 95% CI, 1.23-4.99; P = 0.01). There were no significant differences in local progression and overall survival. Adverse events were similar, except for any grade radiation dermatitis, which was significantly lower in SBRT arm (RR 0.17, 95% CI 0.03-0.96, P = 0.04)., Conclusion: SBRT is a safe treatment option for spine metastases. It may provide better complete pain response compared to cEBRT. Additional trials are needed to determine the potential benefits of SBRT in specific patient subsets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background/purpose: Stereotactic body radiation therapy (SBRT) is standard for patients with inoperable early-stage NSCLC. We hypothesized that SBRT for sarcoma pulmonary metastases would achieve high rates of local control with acceptable toxicity and that patients with oligometastatic disease may achieve prolonged survival following SBRT., Materials/methods: This retrospective review included consecutive patients at our institution treated with SBRT for sarcoma pulmonary metastases. Cumulative incidence of local failure (LF) was estimated using a competing risks framework., Results: We identified 66 patients treated to 95 pulmonary metastases with SBRT. The median follow-up from the time of SBRT was 36 months (95% CI 34 - 53 months). The cumulative incidence of LF at 12 and 24 months was 3.1% (95% CI 0.9 - 10.6%) and 7.4% (95% CI 4.0% - 13.9%), respectively. The 12- and 24-month overall survival was 74% (95% CI 64 - 86%) and 49% (38 - 63%), respectively. Oligometastatic disease, intrathoracic only disease, and performance status were associated with improved survival on univariable analysis. Three patients had grade 2 pneumonitis, and one patient had grade 2 esophagitis. No patients had ≥ grade 3+ toxicities., Conclusion: To the best of our knowledge, this is the largest series of patients treated with SBRT for pulmonary sarcoma metastases. We observed that SBRT offers an effective alternative to surgical resection with excellent local control and low proportions of toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: We present efficacy and toxicity outcomes among patients with chordoma treated on the Proton Collaborative Group prospective registry., Methods: Consecutive chordoma patients treated between 2010-2018 were evaluated. One hundred fifty patients were identified, 100 had adequate follow-up information. Locations included base of skull (61%), spine (23%), and sacrum (16%). Patients had a performance status of ECOG 0-1 (82%) and median age of 58 years. Eighty-five percent of patients underwent surgical resection. The median proton RT dose was 74 Gy (RBE) (range 21-86 Gy (RBE)) using passive scatter proton RT (PS-PBT) (13%), uniform scanning proton RT (US-PBT) (54%) and pencil beam scanning proton RT (PBS-PBT) (33%). Rates of local control (LC), progression-free survival (PFS), overall survival (OS) and acute and late toxicities were assessed., Results: 2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively. LC did not differ based on surgical resection (p = 0.61), though this is likely limited by most patients having undergone a prior resection. Eight patients experienced acute grade 3 toxicities, most commonly pain (n = 3), radiation dermatitis (n = 2), fatigue (n = 1), insomnia (n = 1) and dizziness (n = 1). No grade ≥ 4 acute toxicities were reported. No grade ≥ 3 late toxicities were reported, and most common grade 2 toxicities were fatigue (n = 5), headache (n = 2), CNS necrosis (n = 1), and pain (n = 1)., Conclusions: In our series, PBT achieved excellent safety and efficacy outcomes with very low rates of treatment failure. CNS necrosis is exceedingly low (<1%) despite the high doses of PBT delivered. Further maturation of data and larger patient numbers are necessary to optimize therapy in chordoma., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To investigate the dosimetric characteristics between an advanced proton pencil beam scanning (PBS) Bragg peak FLASH technique and conventional PBS planning technique in lung tumors. To evaluate the "FLASHness" of single-field in a multiple-field delivery scheme for a hypofractionation regimen and move a step forward to clinical application., Methods: Single-energy PBS Bragg peak FLASH treatment plans were optimized based on a novel Bragg peak tracking technique to enable Bragg peaks to stop at the distal edge of the target. Inverse treatment planning using multiple-field optimization (MFO) can achieve sufficient FLASH dose rate and intensity-modulated proton therapy (IMPT)-equivalent dosimetric quality. The dose rate of organs-at-risk (OARs) and the target were calculated under FLASH machine parameters. A group of 10 consecutive lung SBRT patients was optimized to 34 Gy/fraction using a standard treatment of PBS technique with multiple energy layers as references to the Bragg peak plans. The dosimetric quality was compared between Bragg peak FLASH and conventional plans based on RTOG0915 dose metrics. FLASH dose rate ratios (V 40Gy/s ) were calculated as a metric of the FLASH-sparing effect., Results: For higher dose thresholds, the Bragg peak plans achieved greater V 40Gy/s FLASH coverage for all major OARs. The V40Gy/s was close to 100% for all OARs when the dose thresholds were > 5 Gy for full plan and single beam evaluations. The less "FLASHness" region was associated with a low dose distribution, mainly occurring in the PBS field penumbra region. The conventional IMPT treatment plans yielded slightly superior target dose uniformity with a D 2% (%) of 108.02% versus that of Bragg peak 300 MU plans of 111.81% (p < 0.01) and that of Bragg peak 1200 MU plans of 115.95% (p < 0.01). No significant difference in dose metrics was found between Bragg peak and IMPT treatment plans for the spinal cord, esophagus, heart, or lung-GTV (all p > 0.05)., Conclusion: Hypofractionated lung Bragg peak plans can maintain comparable plan quality to conventional PBS while achieving sufficient FLASH dose rate coverage for major OARs for each field under the multiple-field delivery scheme. The novel Bragg peak FLASH technique has the potential to enhance lung cancer planning treatment outcomes compared to standard PBS treatment techniques., (Copyright © 2022 Elsevier B.V. All rights reserved.)

4D multi-image-based (4D MIB ) optimization is a form of robust optimization where different uncertainty scenarios, due to anatomy variations, are considered via multiple image sets (e.g., 4DCT). In this review, we focused on providing an overview of different 4D MIB optimization implementations, introduced various frameworks to evaluate the robustness of scanned particle therapy affected by breathing motion and summarized the existing evidence on the necessity of using 4D MIB optimization clinically. Expected potential benefits of 4D MIB optimization include more robust and/or interplay-effect-resistant doses for the target volume and organs-at-risk for indications affected by anatomical variations (e.g., breathing, peristalsis, etc.). Although considerable literature is available on the research and technical aspects of 4D MIB , clinical studies are rare and often contain methodological limitations, such as, limited patient number, motion amplitude, motion and delivery time structure considerations, number of repeat CTs, etc. Therefore, the data are not conclusive. In addition, multiple studies have found that robust 3D optimized plans result in dose distributions within the set clinical tolerances and, therefore, are suitable for a treatment of moving targets with scanned particle therapy. We, therefore, consider the clinical necessity of 4D MIB optimization, when treating moving targets with scanned particle therapy, as still to be demonstrated., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The impact of peripheral blood immune measures and radiation-induced lymphopenia on outcomes in non-small cell lung cancer (NSCLC) patients treated with concurrent chemoradiation (cCRT) and immune check point inhibition (ICI) has yet to be fully defined., Methods: Stage III NSCLC patients treated with cCRT and ≥1 dose of durvalumab across a cancer center were examined. Peripheral blood counts were assessed pre-cCRT, during cCRT and at the start of ICI. These measures and risk-scores from two published models estimating radiation dose to immune-bearing organs were tested for association with disease control., Results: We assessed 113 patients treated with cCRT and a median of 8.5 months of durvalumab. Median PFS was 29 months (95% CI 18-35 months). A lower pre-cCRT ALC (HR: 0.51 (95% CI: 0.32-0.82), p = 0.02) and a higher pre-cCRT ANC (HR: 1.14 (1.06-1.23), p = 0.005) were associated with poor PFS. Neither ALC nadir, ALC at ICI start, ANC at ICI start or the normalized change in ALC from pre-cCRT to nadir were significantly associated with PFS (p = 0.07-0.49). Also, risk scores from the two radiation-dose models were not associated with PFS (p = 0.14, p = 0.21) but were so with the ALC Nadir (p = 0.001, p = 0.002). A higher pre-cCRT NLR was the strongest predictor for PFS (HR: 1.09 (1.05-1.14), p = 0.0001). The 12-month PFS in patients with the bottom vs. top NLR tertile was 84% vs 46% (p = 0.000004)., Conclusions: Baseline differences in peripheral immune cell populations are associated with disease outcomes in NSCLC patients treated with cCRT and ICI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Thor: No COI to report A. F. Shepard: Reports honoraria from ASCO. I. Preeshagul: Reports serving ono advisory board for Pfizer and AstraZeneca. M. Offin: Reports advisory role for PharMar, Novartis and Targeted Oncology. Reports honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. D. Y. Gelblum: No COI to report. A. J. Wu: Reports research support from CivaTech Oncology, Inc., non-financial support from AlphaTau Medical, personal fees from MoreHealth, and personal fees from AstraZeneca. A. Apte: No COI to report. C. B. Simone II: Reports honoraria from Varian Medical Systems. M. D. Hellmann: Reports personal fees from Genentech, grants, personal fees and non-financial support from Bristol Myers Squibb, personal fees from Merck, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and equity from Shattuck Labs, personal fees and equity from Immunai, personal fees from Nektar, personal fees from Blueprint Medicines. In addition, Dr. Hellmann has a pending patent Determinants of Cancer Response to Immunotherapy by PD-1 Blockade (PCT/US2015/062208) licensed to PGDx. A. Rimner: Reports grants from Varian Medical Systems, grants from Boehringer Ingelheim, grants from Pfizer, grants and personal fees from AstraZeneca, grants and personal fees from Merck, personal fees from Research to Practice, personal fees from Cybrexa, non-financial support from Philips/Elekta, personal fees from MoreHealth. J. E. Chaft: Reports both research funding and consulting roles with Bristol-Myers Squibb, Merck, Genentech and AstraZeneca. D. R. Gomez: Reports honoraria from Merck, BMS, AstraZeneca, Reflexion, Medscape, Vindico, US Oncology, and Varian. Reports research support from Merck, BMS, AstraZeneca, and Varian. Serves on advisory board for AstraZeneca. J. Deasy: No COI to report. N. Shaverdian: Reports research funding from Novartis., (Published by Elsevier B.V.)

Objectives: Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy., Materials and Methods: Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy., Results: A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm 3 (STD 561 cm 3 ). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p < 0.001), and a moderate correlation between tumor volume and serum fibulin-3 levels (r = 0.36, p = 0.014). Twenty-eight patients in the immunotherapy trial had longitudinal serologic and radiographic data. Fold-changes in SMRP and fibulin-3 did not show significant correlations with modified RECIST measurements., Conclusions: Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally., (Copyright © 2021. Published by Elsevier B.V.)

Radiation therapy (RT) plays an important role in the curative treatment of a variety of thoracic malignancies. However, delivery of tumoricidal doses with conventional photon-based RT to thoracic tumors often presents unique challenges. Extraneous dose deposited along the entrance and exit paths of the photon beam increases the likelihood of significant acute and delayed toxicities in cardiac, pulmonary, and gastrointestinal structures. Furthermore, safe dose-escalation, delivery of concomitant systemic therapy, or reirradiation of a recurrent disease are frequently not feasible with photon RT. In contrast, protons have distinct physical properties that allow them to deposit a high irradiation dose in the target, while leaving a negligible exit dose in the adjacent organs at risk. Proton beam therapy (PBT), therefore, can reduce toxicities with similar antitumor effect or allow for dose escalation and enhanced antitumor effect with the same or even lower risk of adverse events, thus potentially improving the therapeutic ratio of the treatment. For thoracic malignancies, this favorable dose distribution can translate to decreases in treatment-related morbidities, provide more durable disease control, and potentially prolong survival. This review examines the evolving role of PBT in the treatment of thoracic malignancies and evaluates the data supporting its use., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Recent evidence suggests that patients with malignant pleural mesothelioma (MPM) undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT)., Materials and Methods: Preoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007-2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN., Results: Of 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60 % and 38 % respectively. The number of PILN on preoperative CT did not predict metastasis (p = 0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p = 0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist., Conclusions: CT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: Concurrent chemoradiation (cCRT) and durvalumab is standard therapy for patients with unresectable stage III non-small-cell lung cancers (NSCLC). Data is limited on outcomes with this regimen outside of clinical trials. Local-regional control rates remain undefined., Materials and Methods: We reviewed patients with stage III unresectable NSCLCs treated between November 2017 and February 2019 with cCRT and ≥1 dose of durvalumab. We examined 12-month progression-free-survival (PFS), overall-survival (OS), toxicities, and the incidence and pattern of local-regional and metastatic failures., Results: Sixty-two patients (median follow-up 12 months) with median age of 66 years of which 73% had stage IIIB (n = 33) or IIIC (n = 12) disease started durvalumab a median of 1.5 months from the end of cCRT and were treated with a median of 8 months of durvalumab. Common reasons for stopping durvalumab included disease progression (32%, 20/62) and toxicity (24%, 15/62). The estimated 12-month PFS and OS were 65% (95% CI: 51-79%) and 85% (95% CI: 75-95%), respectively. The cumulative 12-month incidence of local-regional and distant failures were 18% (95% CI: 5.9-30%) and 30% (95% CI: 16.3-44.5%), respectively. Among patients with distant metastatic disease (n = 17), 47% had oligometastatic disease. High tumor mutation burden (≥8.8 mt/Mb) or PD-L1 (≥1% or PD-L1 ≥ 50%) did not predict improved PFS., Conclusions: Outcomes with cCRT and durvalumab in practice align with the PACIFIC trial. A substantial minority of patients are candidates for metastasis-directed therapies at progression. Local regional outcomes appear improved to historical data of cCRT alone., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic., Methods: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC., Results: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided., Conclusion: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Radiation remains an important component of mesothelioma treatment in 2018. Its use as a treatment modality continues to evolve as the technology for planning and delivery continues to improve. Use of radiation to improve local control in the involved hemithorax has been a common adjuvant treatment post extrapleural pneumonectomy for many years. Modern treatment options with advanced planning techniques including protons and intensity modulated radiation therapy lead to new potential options for treatment post lung-sparing surgery or in the unresectable setting. Presentations and discussions on the implementation of these strategies for palliation, treatment of oligometastatic recurrence or unresectable disease were the focus of a session dedicated to the role of radiation therapy at the 14 th International Conference of the International Mesothelioma Interest Group and are reviewed in this article. Preclinical data to better understand how to integrate radiation and the delivery of novel systemic therapy approached like check point inhibitors are also presented., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: The lymphangitic carcinomatosis (LC) pattern of metastatic malignancy is associated with a poor prognosis but is currently not well defined in malignant pleural mesothelioma (MPM). Here, we report the incidence and prognostic significance of the radiographic development of LC in MPM following extended pleurectomy/decortication (EPD)., Methods: Consecutive patients with biopsy-proven MPM undergoing EPD with intraoperative photodynamic therapy (PDT) at our institution from 2008 to 2014 were included in this retrospective study. Patients without available post-surgical clinical or imaging data for direct review were excluded. CT images were reviewed by an experienced, board-certified thoracic radiologist and confirmed by consensus review. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan Meier methodology. Hazard ratios were compared with a cox proportional hazard model., Results: 44 patients underwent EPD with PDT during the study period and had available clinical and imaging data. During the follow-up period (median 34 months), 17 patients (39%) developed LC at a median of 10 months after surgery (IQR 5-21 months). 16 of the 17 patients who developed LC (94%) died during the follow-up period, compared to 17 of the 27 who did not develop LC (63%). OS for the LC versus non-LC group was 53% versus 93% at 1 year and 18% versus 67% at 3 years. LC was significantly associated with a lower OS (HR 4.07; 95% confidence interval 1.44-11.48; p = 0.008). PFS for the LC group versus non-LC group was 8 months (IQR 5-9 months) compared to 17 months (IQR 11-24 months) (p < 0.001)., Conclusion: LC is a common form of failure in MPM following EPD and is associated with a poor prognosis. Thus, further studies are warranted to determine if any evidence of preoperative LC should be an absolute contraindication to EPD and may warrant an EPP or no surgery at all., (Copyright © 2019. Published by Elsevier B.V.)

Background and Purpose: Radiation pneumonitis (RP) is a radiotherapy dose-limiting toxicity for locally advanced non-small cell lung cancer (LA-NSCLC). Prior studies have proposed relevant dosimetric constraints to limit this toxicity. Using machine learning algorithms, we performed analyses of contributing factors in the development of RP to uncover previously unidentified criteria and elucidate the relative importance of individual factors., Materials and Methods: We evaluated 32 clinical features per patient in a cohort of 203 stage II-III LA-NSCLC patients treated with definitive chemoradiation to a median dose of 66.6 Gy in 1.8 Gy daily fractions at our institution from 2008 to 2016. Of this cohort, 17.7% of patients developed grade ≥2 RP. Univariate analysis was performed using trained decision stumps to individually analyze statistically significant predictors of RP and perform feature selection. Applying Random Forest, we performed multivariate analysis to assess the combined performance of important predictors of RP., Results: On univariate analysis, lung V20, lung mean, lung V10 and lung V5 were found to be significant RP predictors with the greatest balance of specificity and sensitivity. On multivariate analysis, Random Forest (AUC = 0.66, p = 0.0005) identified esophagus max (20.5%), lung V20 (16.4%), lung mean (15.7%) and pack-year (14.9%) as the most common primary differentiators of RP., Conclusions: We highlight Random Forest as an accurate machine learning method to identify known and new predictors of symptomatic RP. Furthermore, this analysis confirms the importance of lung V20, lung mean and pack-year as predictors of RP while also introducing esophagus max as an important RP predictor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: This study sought to develop and validate a nomogram to predict cerebrovascular disease (CVD) among patients with brain necrosis after radiotherapy for nasopharyngeal carcinoma (NPC)., Materials and Methods: A total of 346 eligible patients with brain necrosis after radiotherapy for NPC were divided into a training set (n = 231) and a validation set (n = 115). A multivariate Cox proportional hazards regression model was used to select the significant variables for CVD prediction in the training set. Then, a nomogram was developed based on the regression model. The performance of the nomogram was assessed with respect to discrimination and calibration. All patients were classified into high- or low-risk groups based on the risk scores derived from the nomogram. Moreover, a decision curve analysis was performed with the combined training and validation sets to evaluate the clinical usefulness of the nomogram., Results: Four significant predictors were identified: hypertension, statin treatment, serum level of high-density lipoprotein, and interval between radiotherapy and brain necrosis. The nomogram incorporating these four predictors showed favorable calibration and discrimination regarding the training set, with a C-index of 0.763 (95% CI, 0.694 to 0.832), which was confirmed using the validation set (C-index 0.768; 95% CI, 0.675 to 0.861). Furthermore, the nomogram successfully stratified patients into high- and low-risk groups. The decision curve indicated that our nomogram was clinically useful., Conclusion: The nomogram showed favorable predictive accuracy for CVD among patients with brain necrosis after radiotherapy for NPC and might aid in clinical decision making., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: To predict treatment response and survival of NSCLC patients receiving stereotactic body radiation therapy (SBRT), we develop an unsupervised machine learning method for stratifying patients and extracting meta-features simultaneously based on imaging data., Material and Methods: This study was performed based on an 18 F-FDG-PET dataset of 100 consecutive patients who were treated with SBRT for early stage NSCLC. Each patient's tumor was characterized by 722 radiomic features. An unsupervised two-way clustering method was used to identify groups of patients and radiomic features simultaneously. The groups of patients were compared in terms of survival and freedom from nodal failure. Meta-features were computed for building survival models to predict survival and free of nodal failure., Results: Differences were found between 2 groups of patients when the patients were clustered into 3 groups in terms of both survival (p = 0.003) and freedom from nodal failure (p = 0.038). Average concordance measures for predicting survival and nodal failure were 0.640±0.029 and 0.664±0.063 respectively, better than those obtained by prediction models built upon clinical variables (p < 0.04)., Conclusions: The evaluation results demonstrate that our method allows us to stratify patients and predict survival and freedom from nodal failure with better performance than current alternative methods., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Life expectancy of patients with limited-stage small cell lung cancer (LS-SCLC) continues to rise; thus, characterization of long-term toxicities is essential. Although there are emerging data linking cardiac irradiation doses with survival for non-small cell lung cancer, there are currently minimal data on cardiac-specific mortality (CSM) in LS-SCLC. The goal of this investigation was to evaluate CSM between left- and right-sided cases., Methods: The Surveillance, Epidemiology, and End Results database was queried for stage I-III primary SCLC patients receiving radiotherapy; CSM was compared between left- and right-sided diseases. Accounting for mortality from other causes, Gray's test compared cumulative incidences of CSM between both groups. Multiple multivariate models examined the independent effect of laterality on CSM, including the Fine and Gray competing risk model and the Cox proportional hazards model., Results: Of 19,692 patients, 7991 (41%) were left-sided and 11,701 (59%) were right-sided. Left-sided patients experienced significantly higher CSM overall (3.3% vs. 2.6%, p = 0.004). Laterality was an independent predictor of CSM in the overall population in the Fine and Gray competing risk model (p = 0.006) as well as the Cox proportional hazards model (p = 0.007). The overall hazard ratio for CSM by disease laterality was 1.27 (95% confidence interval, 1.08-1.50). Laterality had no statistical association with non-cardiac mortality in the Fine and Gray competing risk model (p = 0.130)., Conclusions: Although causation between radiotherapy and CSM in LS-SCLC cannot be stated based on these data, we encourage clinical attentiveness to cardiac-sparing radiotherapy for LS-SCLC, along with further investigation evaluating dosimetric correlates for cardiotoxicity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial., Methods: For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions., Results: The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ., Conclusion: On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: This study of a large, contemporary national database evaluated postoperative outcomes and overall survival (OS) for malignant pleural mesothelioma (MPM) by facility volume., Methods: The National Cancer Database was queried for newly-diagnosed non-metastatic MPM undergoing definitive surgery (extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D)). Patients were dichotomized into those receiving therapy at a high-volume facility (HVF), defined a priori at the 90th percentile of case volume, with all others categorized as lower-volume facilities (LVFs). Statistics included multivariable logistic regression, Kaplan-Meier analysis, propensity-matching, and multivariable Cox proportional hazards modeling. Sensitivity analysis varied the dichotomized HVF-LVF cutoff and evaluated effects on postoperative outcomes and OS., Results: Of 1307 patients, 621 (48%) were treated at LVFs and 686 (52%) at HVFs. HVFs were more often in the Middle/South Atlantic regions, and less likely in New England, South, and Midwest. Notably, 75% of procedures at HVFs were P/Ds, versus 84% at LVFs (p < 0.001). Patients treated at HVFs experienced shorter length of postoperative hospitalization (p = 0.035), lower 30-day readmission rates (4.6% vs. 6.1%, p = 0.021), and lower 90-day mortality rates (10.0% vs. 14.6%, p = 0.029). Median OS for respective groups were 18 versus 15 months (p = 0.010), which were not significant following propensity-matching (p = 0.540). On multivariable analysis, facility volume did not independently predict for OS. Sensitivity analyses confirmed the postoperative outcomes and OS findings., Conclusions: This is the largest investigation to date assessing facility volume and outcomes following surgery for MPM. Although no independent effects on OS were observed, postoperative outcomes were more favorable at HVFs. These findings have implications for postoperative management, patient counseling, referring providers, and cost-effectiveness., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Contrary to prevailing notions of uniform efficacy regarding stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC), a recent report has indicated increased risk of local failure for squamous cell carcinoma (SCC). As those data have not been corroborated by other studies, we performed a multi-institutional analysis to evaluate the influence of histology on post-SBRT outcomes., Materials and Methods: Records from 152 consecutive patients who received SBRT for primary early-stage NSCLC at two academic medical centers were retrospectively assessed. Primary comparison was between SCC and adenocarcinoma. Patient outcomes including actuarial recurrences and overall survival were calculated using the Kaplan-Meier method. Univariable and multivariable logistic regression analyses addressed associated factors., Results: At a median follow-up of 44 months, patients with SCC had an increased risk of local, (hazard ratio (HR) (95% confidence interval (CI)): 1.69 (1.05-2.73), p = 0.032), regional (HR (95% CI): 2.03 (1.24-3.33), p = 0.005), and distant failure (HR (95% CI): 1.71 (1.06-2.77), p = 0.036). Median times to local (32 m vs 50m, p = 0.023), regional (26 m vs 50 m, p = 0.011), and distant (26 m vs 50 m, p = 0.024) failure were all significantly reduced in SCC histology. SCC histology was also independently associated with an increased risk for death (HR: 1.80 (1.10-2.94), p = 0.019) and had a 5-yr overall survival of 26%, versus 41% for adenocarcinoma (p = 0.016)., Conclusions: This multi-institutional analysis corroborates that SCC histology is independently predictive for local, regional, and distant recurrence and worse overall survival. Future data are needed to determine if treatment paradigms should differ by histology for early stage NSCLC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The benefit of invasive mediastinal nodal staging (IMNS) in addition to positron emission tomography-computed tomography (PET/CT) is undefined for early stage non-small cell lung cancer (NSCLC). This multi-institutional investigation aimed to evaluate outcomes and patterns of failure in patients staged with PET/CT with or without additional IMNS., Methods: Two academic centers assessed all consecutive patients staged with PET/CT for early-stage, primary lung NSCLC (cT1-2aN0M0) treated with SBRT. Local recurrence-free survival (LRFS), nodal recurrence-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling addressed factors associated with outcomes., Results: Overall, 180 patients (199 lesions) were staged with PET/CT alone and 56 patients (58 lesions) underwent additional IMNS. Among patients receiving IMNS, 52 (93%) underwent EBUS and 4 (7%) underwent mediastinoscopy. At a median follow-up of 33.5 months (range, 1.9-80.9 months), there was no significant difference in LRFS (37 vs. 47 months, p=0.309), NRFS (34 vs. 42 months p=0.370), DMFS (36 vs. 47 months, p=0.234) or OS (37 vs. 47 months, p=0.236) between patients undergoing PET/CT-only versus PET/CT+IMNS staging, respectively. Receipt of IMNS did not correlate with any outcome on either univariate or multivariate analysis (p>0.05). Patterns of failure in both groups were similar, including crude isolated nodal failure rates (8% PET/CT-only versus 14% PET+IMNS group, p=0.202)., Conclusions: Patients undergoing IMNS had similar survival and patterns of recurrence as those receiving PET/CT alone. Further study, ideally prospectively, is needed to determine which subgroups might benefit from IMNS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Clinical decision support systems are a growing class of tools with the potential to impact healthcare. This study investigates the construction of a decision support system through which clinicians can efficiently identify which previously approved historical treatment plans are achievable for a new patient to aid in selection of therapy., Material and Methods: Treatment data were collected for early-stage lung and postoperative oropharyngeal cancers treated using photon (lung and head and neck) and proton (head and neck) radiotherapy. Machine-learning classifiers were constructed using patient-specific feature-sets and a library of historical plans. Model accuracy was analyzed using learning curves, and historical treatment plan matching was investigated., Results: Learning curves demonstrate that for these datasets, approximately 45, 60, and 30 patients are needed for a sufficiently accurate classification model for radiotherapy for early-stage lung, postoperative oropharyngeal photon, and postoperative oropharyngeal proton, respectively. The resulting classification model provides a database of previously approved treatment plans that are achievable for a new patient. An exemplary case, highlighting tradeoffs between the heart and chest wall dose while holding target dose constant in two historical plans is provided., Conclusions: We report on the first artificial-intelligence based clinical decision support system that connects patients to past discrete treatment plans in radiation oncology and demonstrate for the first time how this tool can enable clinicians to use past decisions to help inform current assessments. Clinicians can be informed of dose tradeoffs between critical structures early in the treatment process, enabling more time spent on finding the optimal course of treatment for individual patients., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: The black population remains underrepresented in clinical trials despite reports suggesting greater incidence and deaths from locally advanced non-small cell lung cancer (NSCLC). We determined outcomes for black and non-black patients in a well-annotated cohort treated with either definitive chemoradiation (CRT; bimodality) or CRT followed by surgery (trimodality therapy)., Materials and Methods: A retrospective analysis of 355 stage III NSCLC patients treated with curative intent at the University of Maryland, Medical Center, between January 2000-December 2013 was performed. The Kaplan-Meier approach and the Cox proportional hazards models were used to analyze overall survival (OS) and freedom-from-recurrence (FFR) in black and non-black patients. The chi-square test was used to compare categorical variables., Results: Black patients comprised 42% of the cohort and were more likely to be younger (p<0.0001), male (p=0.030), single (p<0.0001), reside in lower household income zipcodes (p<0.0001), have an Eastern Cooperative Oncology Group (ECOG) performance status >0 (p<0.001), and less likely to undergo surgery (p<0.0001). With a median follow-up of 15 months for all patients and 89 months for surviving patients (range:1-186 months), median OS times for black and non-black patients were 22 and 24 months, respectively (p=0.698). FFR rates were also comparable between the two groups (p=0.468). Surgery improved OS in both cohorts. Race was not a significant predictor for OS or FFR even when adjusted for other factors., Conclusions: We found similar oncologic outcomes in black and non-black NSCLC patients when treated with curative intent in a comprehensive cancer center setting, despite epidemiologic differences in presentation and receipt of care. Future efforts to improve outcomes in black patients could focus on addressing modifiable social disparities., (Copyright © 2017. Published by Elsevier B.V.)

Background: The importance of the thoracic radiation therapy (TRT) dose has not been clearly defined in extensive stage small-cell lung cancer (ES-SCLC) and it is unclear whether improved TRT dose translates into a survival benefit., Methods: 306 patients with ES-SCLC were retrospectively reviewed, of which 170 received IMRT/CRT fractionation RT after ChT, and 136 received chemotherapy (ChT) alone. We adopted the time-adjusted BED (tBED) for effective dose fractionation calculation. Due to the nonrandomized nature of this study, we compared the ChT+RT with ChT groups that matched on possible confounding variables., Results: Patients achieved 2-year OS, PFS and LC rates of 19.7%, 10.7% and 28.4%, respectively. After propensity score matching, (113 cases for each group), the rates of OS, PFS and LC at 2 years were 21.4%, 7.7% and 34.5% for ChT+TRT, and 10.3% (p<0.001), 4.6% (p<0.001) and 6.3% for ChT only (p<0.001), respectively. Among propensity score matching patients, 56 cases for each group received the high dose (tBED>50 Gy) TRT and received low dose (tBED≤50 Gy) TRT. Two-year OS, PFS and LC rates were 32.3%, 15.3% and 47.1% for the high dose compared with 17.0% (p<0.001), 12.9% (p=0.097) and 34.7% (p=0.029) for low dose radiotherapy., Conclusions: TRT added to ChT improved ES-SCLC patient OS. High dose TRT improved OS over lower doses. Our results suggest that high-dose thoracic radiation therapy may be a reasonable consideration in select patients with ES-SCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Reirradiation (reRT) for locoregional recurrences poses unique challenges and risks; re-treatment using proton beam radiotherapy (PBT) could prove advantageous. Assessing clinical outcomes and toxicity profiles, this systematic review comprehensively evaluated available evidence regarding PBT reRT. Fourteen original investigations across central nervous system (CNS) (n=6), head/neck (H&N) (n=4), lung (n=2), and gastrointestinal (n=2) malignancies were analyzed. PBT for recurrent uveal melanoma achieved 5-year eye retention of 55%; for chordomas, reRT afforded a 2-year local control and overall survival (OS) of 85% and 80%, respectively. Multiple PBT reRT studies for adult gliomas illustrate no grade ≥3 toxicities. Two pediatric CNS tumor studies demonstrated the safety and efficacy of reRT, with one total grade 3 toxicity and achievement of longer-term OS. PBT for H&N malignancies shows appropriate local/locoregional control and favorable toxicity profiles versus historical photon-based methods, including low (9-10%) rates of feeding tube placement. PBT for recurrent lung cancer can achieve favorable survival with expected toxicities/complications of reRT, especially with concurrent chemotherapy and centrally located recurrences. Lastly, PBT reRT in gastrointestinal malignancies induced very few high-grade complications. Hence, based on the limited existing data, PBT is a notably safe reRT modality for effective salvage of recurrent disease. Institutional experiences must continue to be reported: dosimetric correlations, late toxicities, and advanced PBT techniques., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Proton reirradiation for sarcoma has not been previously described. We hypothesized that this strategy would provide favorable toxicity and survival outcomes., Material and Methods: Patients with soft tissue sarcoma in a previously-irradiated field were enrolled on a prospective trial of proton reirradiation. The primary endpoint was provider-reported acute toxicity. Secondary endpoints included late toxicities, local control, and overall survival., Results: 23 patients underwent proton reirradiation. Median time between radiation courses was 40.7months (range 10-272). No grade 4-5 toxicities were observed. One patient (4%) experienced acute grade 3 dysphagia. Common grade 2 acute toxicities were fatigue (26%), anorexia (17%), and urinary incontinence (13%). There were two grade 3 late wound infections (10%) and one grade 3 late wound complication (5%). Grade 2 late complications included lymphedema (10%), fracture (5%), and fibrosis (5%). At a median follow-up of 36months, the 3-year cumulative incidence of local failure was 41% (95% CI [20-63%]). Median overall survival and progression-free survival were 44 and 29months, respectively. In extremity patients, amputation was spared in 7/10 (70%)., Conclusions: Proton reirradiation of recurrent/secondary soft tissue sarcomas is well tolerated. While longer follow-up is needed, early survival outcomes in this high-risk population are encouraging., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: We aimed to report trends in stereotactic body radiation therapy (SBRT) utilization, dose prescriptions, and chemotherapy administration for stage I small cell lung cancer (SCLC) in the United States., Materials and Methods: The National Cancer Data Base (NCDB) was used to identify patients with cT1-2 N0 SCLC treated with SBRT between 2004 and 2013. Trends in SBRT use and dose prescription were analyzed over time. Multivariable logistic regression was used to determine factors associated with the administration of chemotherapy with SBRT. The Kaplan-Meier method was used to estimate overall survival., Results: Of 9265 patients with clinical stage I SCLC who were examined for initial treatment allocation, 285 were treated with SBRT and represented the subject of the primary analysis. SBRT utilization increased from 2004 (0.4% of all stage I patients diagnosed that year) to 2013 (6.4%). During this same time period, definitive surgical management also increased from 14.9% of all patients in 2004 to 28.5% in 2013. The median SBRT biologically effective dose (BED 10 ) was 112.5Gy (range, 72-290) and only 33 out of 285 (11.6%) received a BED 10 <100Gy. Nearly half of all patients (130/285, 45.6%) received chemotherapy, with 42.7% of those patients receiving their chemotherapy prior to SBRT. On multivariable logistic regression, only age<75 (the median) vs. ≥75years (OR 4.97, 95% CI 2.96-8.35, p<0.001) and year of diagnosis 2004-2008 vs. 2009-2013 (OR 2.58, 95% CI 1.27-5.26, p=0.009) were predictive of chemotherapy use with SBRT. After median follow up of 45 months, the median survival was 23.5 months., Conclusions: Our findings suggest that SBRT utilization for stage I SCLC has increased between 2004 and 2013, highlighting the need for additional research to validate the feasibility of this management approach for inoperable patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Radiation is an important modality in treatment of thymic tumors. However, toxicity may reduce its overall benefit. We hypothesized that double-scattering proton beam therapy (DS-PT) can achieve excellent local control with limited toxicity in patients with thymic malignancies., Methods and Materials: Patients with thymoma or thymic carcinoma treated with DS-PT between 2011 and 2015 were prospectively analyzed for toxicity and patterns of failure on an IRB-approved study., Results: Twenty-seven consecutive patients were evaluated. Patients were a median of 56 years and had thymoma (85%). They were treated with definitive (22%), salvage (15%) or adjuvant (63%) DS-PT to a median of 61.2/1.8 Gy [CGE]. No patient experienced grade ⩾3 toxicity. Acute grade 2 toxicities included dermatitis (37%), fatigue (11%), esophagitis (7%), and pneumonitis (4%). Late grade 2 toxicity was limited to a single patient with chronic dyspnea. At a median follow-up of 2 years, 100% local control was achieved. Three-year regional control, distant control, and overall survival rates were 96% (95% CI 76-99%), 74% (95% CI 41-90%), and 94% (95% CI 63-99%), respectively., Conclusions: This is the first cohort and prospective series of proton therapy to treat thymic tumors, demonstrating low rates of early toxicity and excellent initial outcomes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hyperthermia has long been used for cancer treatment, either alone or in combination with chemotherapy, radiation therapy, or both. Its efficacy and versatility continue to be well demonstrated in randomized trials across a number of primary cancers, but barriers to its widespread adoption persist including effective delivery and verification systems. This article describes hyperthermia, details its biological mechanisms of action and immunological effects, and summarizes select preclinical data and key clinical trials combining hyperthermia with standard cancer treatments. Current challenges and emerging technologies that have the potential to make this translational therapy more accessible to a greater number of patients are also described., (Published by Elsevier Ireland Ltd.)

Radiation therapy has long played a major role in the treatment of gynecological malignancies. There is increasing interest in the utility of intensity-modulated radiotherapy (IMRT) and its application to treat gynecological malignancies. Herein, we review the state-of-the-art use of IMRT for gynecological malignancies and report how it is being used alone as well as in combination with chemotherapy in both the adjuvant and definitive settings. Based on dosimetric and clinical evidence, IMRT can reduce gastrointestinal, genitourinary, and hematological toxicities compared with 3D-conformal radiotherapy for gynecologic malignancies. We discuss how these attributes of IMRT may lead to improvements in disease outcomes by allowing for dose escalation of radiation therapy, intensification of chemotherapy, and limiting toxicity-related treatment breaks. Currently accruing trials investigating pelvic IMRT for cervical and endometrial cancers are discussed., (Published by Elsevier Ireland Ltd.)

Background and Purpose: Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN., Materials and Methods: Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n=40 plans) and dose-volume histograms were generated., Results: The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p=0.020) and mean doses to the contralateral parotid gland (p=0.049) and larynx (p=0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p<0.002 for both) and brainstem (p<0.002 for both) and mean doses to the larynx (p<0.002 for both) and ipsilateral (p=0.004 IMRT, p=0.050 adaptive) and contralateral (p<0.002 IMRT, p=0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT., Conclusions: Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage., (Published by Elsevier Ireland Ltd.)