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Introduction: Accelerated hypofractionated radiotherapy has gained increasing interest for locally advanced NSCLC, as it can potentially increase radiobiologically effective dose and reduce health care resource utilization. Nevertheless, there is sparse prospective evidence supporting routine use of accelerated hypofractionation with or without concurrent chemotherapy. For this reason, the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee conducted a systematic review of prospective studies of accelerated hypofractionation for locally advanced NSCLC., Methods: A systematic search was conducted on Ovid MEDLINE, Ovid EMBASE, Wiley Cochrane Library, and ClinicalTrials.gov for English publications from 2010 to 2024 for prospective clinical trials and registries investigating accelerated hypofractionated radiotherapy defined as more than 2 Gy delivered in 10 to 25 fractions for nonmetastatic locally advanced (stage III) NSCLC., Results: There were 33 prospective studies identified that met the criteria for inclusion. Of 14 prospective studies evaluating definitive accelerated hypofractionation (without concurrent chemotherapy), there were six prospective registries, seven phase 1 to 2 trials, and one phase 3 randomized clinical trial, with a median dose of 60 Gy delivered in a median of 16 fractions, median progression-free survival of 6.4 to 25 months, median survival of 6 to 34 months, and 0% to 8% severe grade ≥3 esophagitis. There were 19 studies evaluating accelerated hypofractionated chemoradiation with platinum doublet-based chemotherapy as the most common concurrent regimen. Of these accelerated hypofractionated chemoradiation studies, there were 18 phase 1 to 2 trials and one prospective registry with a median radiation dose of 61.6 Gy delivered in a median of 23 fractions, median progression-free survival of 10 to 25 months, median survival of 13 to 38 months, grade ≥3 esophagitis of 0% to 23.5%, and grade ≥3 pneumonitis of 0% to 11.8%., Conclusions: Despite the increasing use of accelerated hypofractionation for locally advanced NSCLC, the supporting randomized evidence remains sparse. Only one randomized clinical trial comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions without concurrent chemotherapy did not reveal the superiority of accelerated hypofractionation. Therefore, the use of accelerated hypofractionated radiotherapy should be approached with caution, using advanced radiation techniques, especially with concurrent chemotherapy or targeted agents. Accelerated hypofractionated radiotherapy should be carefully considered alongside other multidisciplinary options and be further investigated through prospective clinical trials., Competing Interests: Disclosure Dr. Chun is supported by grant R50CA275822 from the National Institutes of Health (content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health) and reports having financial relationships with AstraZeneca, Curio Science, Nektar Therapeutics, Elsevier, and the Binaytara Foundation. Dr. Bang reports receiving grant support from BC Cancer Foundation and having financial relationships with AstraZeneca and the International Association for the Study of Lung Cancer. Dr. Przybysz reports receiving grant funding from AstraZeneca and Astellas and having financial relationships with AstraZeneca, Astellas, UpToDate, and Guidepoint. Dr. Faivre-Finn reports receiving grant support from AstraZeneca, Merck, and Elekta. Dr. Badiyan reports receiving grant funding from AstraZeneca and having financial relationships with the RTOG Foundation, Elekta, and Reflexion. Dr. Bezjak reports having financial relationships with AstraZeneca and the Canadian Radiation Oncology Foundation. Dr. McDonald reports having financial relationships with AstraZeneca. Dr. Chua reports receiving grant support from the National Medical Research Council of Singapore and having financial relationships with Varian Medical Systems, AstraZeneca, Regeneron, Roche, Seagen, Merck Sharp & Dohme, and Takeda. Dr. Kong reports receiving grant support from Varian Medical and the Shenzhen Science and Technology Program and having financial relationships with AstraZeneca and Merck. Dr. Putora reports receiving grants from AstraZeneca, Takeda, and Bayer. Dr. Siva reports receiving grant support from the Cancer Council Victoria, Varian, Bayer, and Merck and having financial relationships with AstraZeneca, Roche, and Telix. Dr. Welliver reports receiving grant support from the United States Department of Defense and having financial relationships with Onclive and Eli Lilly. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC., Methods: The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed., Results: At 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with α/β = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005-1.022, p = 0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively)., Conclusions: In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: Most patients with lung cancer are elderly and poorly represented in randomized clinical trials. They are often undertreated because of concerns about their ability to tolerate aggressive treatment. We tested the hypothesis that elderly patients undergoing definitive lung radiation might tolerate treatment differently than younger patients., Methods: A total of 125 patients who underwent definitive lung radiotherapy were identified from a prospective institutional database (University of Michigan cohort). Logistic regression modeling was performed to assess the impact of age on esophagitis grade 2 or higher or grade 2 or higher and pneumonitis grade 3 or higher or grade 2 or higher, with adjustment for esophageal and lung dose, respectively, as well as for chemotherapy utilization, smoking status, and performance status. The analysis was validated in a large cohort of 691 patients from the Michigan Radiation Oncology Quality Consortium registry, an independent statewide prospective database., Results: In the University of Michigan cohort, multivariable regression models revealed a significant inverse correlation between age and rate of esophagitis for both toxicity levels, (adjusted OR = 0.93 for both models and 95% confidence intervals of 0.88-0.98 and 0.87-0.99), with areas under the curve of 0.747 and 0.721, respectively, demonstrating good fit. This same association was noted in the Michigan Radiation Oncology Quality Consortium cohort. There was no significant association between age and pneumonitis., Conclusions: There is a lower incidence of esophagitis with increasing age even after adjustment for use of chemotherapy. This is a novel finding in thoracic oncology. No age dependence was noted for pulmonary toxicity. The elderly are able to tolerate definitive thoracic radiation well and should be offered this option when clinically warranted., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib., Methods: Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10., Results: From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance., Conclusions: Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.

Introduction: We hypothesized that radiation-induced thoracic toxicity (RITT) of the lung, esophagus and pericardium share a similar mechanism, and aimed to examine whether genetic variation of transforming growth factor-beta1 (TGFβ1), tissue plasminogen activator (tPA) and angiotensin converting enzyme (ACE), are associated with RITT in patients with non-small-cell lung cancer (NSCLC)., Methods: Patients with stage I-III NSCLC were enrolled and received radiotherapy (RT). Blood samples were obtained pre-RT and at 4 to 5 weeks during RT, and plasma TGF-β1 was measured using an enzyme-linked immunosorbent assay. The DNA samples extracted from blood pre-RT were analyzed for the following frequent genetic variations: TGFβ1 509C/T, tPA -7351 C/T, and ACE I/D. RITT score was defined as the sum of radiation-induced toxicity grades in esophagus, lung, and pericardium., Results: Seventy-six NSCLC patients receiving definitive RT were enrolled. Patients with TGFβ1 509CC had higher mean grade of esophagitis (1.4 ± 0.2 versus 0.8 ± 0.2, p = 0.019) and RITT score (2.6 ± 0.3 versus 1.6 ± 0.3, p = 0.009) than T allele carriers. Although no significant relationship was observed between RITT and the tPA or ACE variants individually, patients with any high-risk alleles (tPA CC or ACE D or TGFβ1 509CC) had significantly higher grade of developing combined RITT (p < 0.001). Patients with TGFβ1 509CC had greater increase of plasma TGF β1 levels at 4 to 5 weeks during RT than T allele carriers did (CC 1.2 ± 0.2 versus T 0.7 ± 0.1, p = 0.047)., Conclusion: This exploratory study demonstrated that sensitivity of radiation toxicity may be determined by genomic factors associated with TGFβ1 and genes involved in TGFβ1 pathway.

Purpose: To identify new plasma proteomic markers before radiotherapy start to predict later grade ≥2 radiation-induced lung toxicity (RILT2)., Methods: Fifty-seven patients with non-small cell lung cancer received radiotherapy (RT) were eligible. Forty-eight patients with minimum follow-up of 1 year, nine with RILT2 with tumor stage matched to 39 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained within 2 weeks before radiotherapy. The plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography, and nano liquid chromatography electrospray ionization tandem mass spectrometry. Z scores and Bonferroni-adjusted p values for the two-sample mean comparison were used to identify the differential protein expression between patients with and without RILT2., Results: More than 200 proteins were identified and quantified. After excluding proteins that were not detected in at least 40% of the 48 patient samples, C4b-binding protein alpha chain and vitronectin had significantly higher (p < 0.001 and p = 0.02) expression levels in patients with RILT2 compared with patients without RILT2. These two proteins were validated by Western blot. Ingenuity pathway analysis revealed that they both play important roles in the inflammatory response and are associated with the known pathways of radiation-induced lung damage., Conclusions: This proteomic approach demonstrates new plasma protein biomarkers before treatment for future studies on RILT2 prediction.

Introduction: Perfusion (Q) single photon emission computed tomography (SPECT) has been used to divert dose away from higher-functioning lung during radiation therapy (RT) planning. This study aimed to (1) study regional lung function through coregistered pulmonary ventilation/perfusion (V/Q)-SPECT-CT and (2) classify these defects for its potential value in radiation planning in patients with non-small cell lung cancer (NSCLC)., Methods: Patients with stages I to III NSCLC requiring radiation-based therapy were eligible for this prospective study. V/Q-SPECT performed within 2 weeks before the start of radiation was interpreted by nuclear medicine physicians and then measured by a semiquantitative score. The potential mechanism of V and Q defects was analyzed; the potential impact of V/Q-SPECT over Q-SPECT alone was completed through classified applications (high-dose RT versus RT avoidance) during planning., Results: Images of 51 consecutive patients were analyzed. The V and Q defects were matched, reverse mismatched (V defect > Q defect), and mismatched (Q defect > V defect) in 61, 31, and 8% of patients, respectively. Tumor was the leading cause of the defects of ipsilateral lung in 73% of patients. The defect scores of the ipsilateral lung were greater in patients with central primaries than those with peripheral primaries for both V-SPECT (2.3 ± 1.1 versus 1.5 ± 0.8, p = 0.017) and Q-SPECT (2.2 ± 0.8 versus 1.4 ± 0.6, p = 0.000). The patients with chronic obstructive pulmonary disease had greater defect scores in contralateral lung for both V-SPECT (1.5 ± 0.7 versus 1.0 ± 0.8, p = 0.006) and Q-SPECT (1.4 ± 0.6 versus 1.0 ± 0.4, p = 0.010). On assessing the potential value of SPECT on RT plan, 39% of patients could have their RT plan when applying V/Q-SPECT rather than Q-SPECT alone., Conclusions: V/Q-SPECT provides a more comprehensive functional assessment, may provide additional value over Q-SPECT alone in assessing local pulmonary function, and guide RT plan decisions in patients with NSCLC.