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Background: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes., Methods: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete., Findings: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts., Interpretation: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted., Funding: National Cancer Institute., Competing Interests: Declaration of interests CJT is on the advisory board of Nanobiotix and Varian Medical, and received consultation fees and honorarium support from Varian Medical. AR received grants from Varian Medical, AstraZeneca, Merck, Boehringer Ingelheim, Pfizer, and the National Cancer Institute at the National Institutes of Health. DRG is a researcher with AstraZeneca, Bristol Myers Squibb, and Merck; is on the advisory board of Grail, Olympus, Johnson & Johnson, Varian Medical, and Medtronic; and served as a speaker for MedLearning Group. NYL is on the advisory board of Merck, Merck EMD, Nanobiotix, and Galera Therapeutics; and received consulting fees from Shanghai JoAnn Medical Technology, Yingming Consulting, and Varian Medical. NR received research support from Invitae. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: We evaluate the impact of post-operative 18-fluorodeoxyglucose positron emission tomography with computed tomography (PET/CT) for radiation planning on the detection of early recurrence (ER) and treatment outcomes in oral squamous cell carcinoma (OSCC)., Methods: We retrospectively reviewed the records of patients treated with post-operative radiation between 2005 and 2019 for OSCC at our institution. Extracapsular extension and positive surgical margins were classified as high risk features; pT3-4, node positivity, lymphovascular invasion, perineural invasion, tumor thickness >5 mm, and close surgical margins were considered intermediate risk features. Patients with ER were identified. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between baseline characteristics., Results: 391 patients with OSCC were treated with post-operative radiation. 237 (60.6%) patients underwent post-operative PET/CT planning vs. 154 (39.4%) who were planned with CT only. Patients screened with post-operative PET/CT were more likely to be diagnosed with ER than those planned with CT only (16.5 vs. 3.3%, p < 0.0001). Among patients with ER, those with intermediate features were more likely than those high risk features to undergo major treatment intensification, including re-operation, the addition of chemotherapy, or intensification of radiation by ≥ 10 Gy (91% vs. 9%, p < 0.0001). Post-operative PET/CT was associated with improved disease-free and overall survival for patients with intermediate risk features (IPTW log-rank p = 0.026 and p = 0.047, respectively) but not high risk features (IPTW log-rank p = 0.44 and p = 0.96)., Conclusions: Use of post-operative PET/CT is associated with increased detection of early recurrence. Among patients with intermediate risk features, this may translate to improved disease-free survival., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yao Yu: Travel: Elekta. Heiko Schoder: None. Kaveh Zakeri: None. Linda Chen: None. Jung Kang: None. Sean McBride: Consulting or Advisory: Janssen, Astra Zeneca; Research Funding: Genentech, AstraZeneca. C. Jillian Tsai: Honoraria: Varian Medical Inc; Consulting or Advisory: Varian Medical Systems. Daphna Gelblum: None. Jay Boyle: None. Jennifer R Cracchiolo: None. Marc A Cohen: None. Bhuvanesh Singh: None. Ian Ganly: None. Snehal Patel: Patent PCT/US2016/026717; equity in Summit Biomedical Imaging; patent US 10,016,238 B2 Apparatus; equity in ColdSteel Laser Inc; patent PCT/US2014/073053; patent PCT/US2015/065816 ; Patent PCT/US2016/066969. Loren Michel: Research Funding: Exelixis; Travel: Immunomedics. Lara Dunn: Consulting: Regeneron, CUE Biopharma, Merck; Research Funding: Regeneron, Eisai, CUE-101. Eric Sherman: Consulting: Cota Healthcare, Goldilocks, Eisai, Regeneron, UpToDate, Lilly, Blueprint Medicines; Research Funding: Plexxikon, Regeneron. David Pfister: Consulting or Advisory: Boehringer Ingelheim, Incyte; Research Funding: AstraZeneca, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, Eisai, Exelixis, Genentech/Roche, Hoopika Pharma, Lilly, Medimmune, MeiraGtx, Merck, Novartis, Regeneron. Richard Wong: None. Nadeem Riaz: Honoraria: PeerView; Consulting or Advisory: Mirati Therapeutics, Repare Therapeutics; Speakers Bureau: Illumina; Research Funding: Bristol Myers Squibb, Pfizer, Repare Therapeutics; Travel, Accommodations, Expenses: Varian Medical Systems. Nancy Lee: Consulting or Advisory: Merck, Pfizer, Merck Serono, Sanofi, Mirati Therapeutics, Roche/Genentech; Research Funding: AstraZeneca, Pfizer., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: KEAP1-NFE2L2-mutant NSCLCs are chemoradiation resistant and at high risk for local-regional failure (LRF) after concurrent chemoradiation (cCRT). To elucidate the impact of durvalumab on local-regional control, we evaluated LRF in patients with NSCLC treated with cCRT with and without durvalumab., Methods: Patients with stage III NSCLC treated with cCRT or cCRT and durvalumab who underwent tumor genomic profiling were evaluated. The incidence of LRF and outcomes of patients with and without KEAP1-NFE2L2-mutant tumors were evaluated., Results: We analyzed 120 consecutive patients (cCRT alone, n = 54; cCRT and durvalumab, n = 66). Patients treated with cCRT alone had significantly more LRF events compared with those treated with cCRT and durvalumab, with 12-month LRF incidence of 39% (95% confidence interval [CI]: 24%-54%) and 18% (95% CI: 8%-28%), respectively (p = 0.002). Among patients treated with cCRT alone and cCRT and durvalumab, 20 patients (37%) and 18 patients (27%), respectively, had KEAP1-NFE2L2-mutant tumors. In patients treated with cCRT alone, those with KEAP1-NFE2L2-mutant tumors had worse local-regional control (p = 0.015), and on multivariate analysis, KEAP1-NFE2L2 mutation predicted for LRF (hazard ratio = 3.9, 95% CI: 1.6-9.8, p = 0.003). Nevertheless, patients with and without KEAP1-NFE2L2-mutant tumors had similar LRF outcomes (p = 0.541) when treated with cCRT and durvalumab, and mutational status did not predict for LRF (p = 0.545). Among those with KEAP1-NFE2L2-mutant tumors, cCRT and durvalumab significantly reduced the incidence of LRF compared with cCRT alone: 12-month LRF incidence of 62% (95% CI: 40%-84%) versus 25% (95% CI: 4%-46%), respectively (p = 0.021)., Conclusions: Durvalumab after cCRT significantly improves local-regional control and reduces LRF in chemoradiation-resistant KEAP1-NFE2L2-mutant NSCLC tumors., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation pneumonitis (RP) is a common and potentially life-threatening toxicity from lung cancer radiation therapy. Data sets reporting RP rates after postoperative radiation therapy (PORT) have historically been small and with predominantly outdated field designs and radiation techniques. We examined a large cohort of patients in this context to assess the incidence and causes of RP in the modern era., Methods and Materials: We reviewed 285 patients with non-small cell lung cancer treated with PORT at our institution from May 2004 to January 2017. Complete dosimetric data and clinical records were reviewed and analyzed with grade 2 or higher RP as the endpoint (RP2+) (Common Terminology Criteria for Adverse Events v4.0). Patients were a median of 67 years old (range, 28-87), and most had pathologic stage III non-small cell lung cancer (91%) and received trimodality therapy (90%). Systematic dosimetric analyses using Dx increments of 5% and Vx increments of 2 Gy were performed to robustly evaluate dosimetric variables. Lung V 5 was also evaluated., Results: The incidence of RP2+ after PORT was 12.6%. Dosimetric factors most associated with RP2+ were total lungV 4 (hazard ratio [HR] 1.04, P < .001) and heart V 16 (HR 1.03, P = .001). On univariate analysis, the clinical factors of age (HR 1.05, P = .006) and carboplatin chemotherapy (HR 2.32, P = .012) were correlated with RP2+. On step-up multivariate analysis, only bivariate models remained significant, including lungV 5 (HR 1.037, P < .001) and age (HR 1.052, P = .011)., Conclusions: The incidence of RP after PORT is consistent with the literature. Factors correlated with RP include lung and heart doses, age, and carboplatin chemotherapy. These data also suggest that elderly patients may be more susceptible to lower doses of radiation to the lung. Based on these data, dose constraints to limit the risk of RP2+ to <5% in the setting of PORT include lungV 5 ≤65% in patients <65 years old and lungV 5 ≤36% in patients 65 years or older., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objectives: Patients with prior irradiated head and neck cancer (HNC) who are ineligible for definitive retreatment have limited local palliative options. We report the largest series of the use of the Quad Shot (QS) regimen as a last-line local palliative therapy., Materials and Methods: We identified 166 patients with prior HN radiation therapy (RT) treated with QS regimen (3.7 Gy twice daily over 2 consecutive days at 4 weeks intervals per cycle, up to 4 cycles). Palliative response defined by symptom(s) relief or radiographic tumor reduction, locoregional progression free survival (LPFS), overall survival (OS) and radiation-related toxicity were assessed., Results: Median age was 66 years. Median follow-up for all patients was 6.0 months and 9.7 months for living patients. Overall palliative response rate was 66% and symptoms improved in 60% of all patients. Predictors of palliative response were > 2 year interval from prior RT and 3-4 QS cycles. Median LPFS was 5.1 months with 1-year LPFS 17.7%, and median OS was 6.4 months with 1-year OS 25.3%. On multivariate analysis, proton RT, KPS > 70, presence of palliative response and 3-4 QS cycles were associated with improved LPFS and improved OS. The overall Grade 3 toxicity rate was 10.8% (n = 18). No Grade 4-5 toxicities were observed., Conclusion: Palliative QS is an effective last-line local therapy with minimal toxicity in patients with previously irradiated HNC. The administration of 3-4 QS cycles predicts palliative response, improved PFS, and improved OS. KPS > 70 and proton therapy are associated with survival improvements., 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 © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The optimal radiation dose for locally advanced non-small-cell lung cancer (NSCLC) is not known for patients who receive sequential chemoradiation (CRT) or definitive radiotherapy (RT) only. Our objective was to determine whether a benefit exists for radiation dose escalation for these patients., Materials and Methods: The patients included in our retrospective analysis had undergone RT for NSCLC from 2004 to 2013, had not undergone surgery, and received a dose ≥ 50.0 Gy. Patients who received concurrent CRT were excluded from the analysis, leaving 336 patients for analysis. The primary outcomes were overall survival (OS), local failure (LF), and distant failure (DF)., Results: On multivariate analysis, after adjusting for age, Karnofsky performance status, gross tumor volume, and treatment modality, patients treated with a radiation dose > 66 Gy had significantly improved OS compared with those treated with < 60 Gy (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.39-0.87; P = .008). After adjusting for smoking history and radiologic tumor size, patients treated with a radiation dose > 66 Gy had a significantly decreased risk of LF compared with those treated with < 60 Gy (HR, 0.59; 95% CI, 0.38-0.91; P = .02). The radiation dose was not an independent prognostic factor of DF on multivariate analysis., Conclusion: When controlling for tumor volume and/or dimensions and other independent prognostic factors, patients with locally advanced NSCLC who were not candidates for concurrent CRT benefited from a radiation dose > 66 Gy versus < 60 Gy with improved OS and reduced LF. An increased radiation dose did not appear to affect the incidence of DF., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Whether (18)F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) metrics predict outcome in limited-stage (LS) small-cell lung cancer (SCLC) has not been well established; most previous reports have only analyzed maximal standardized uptake values (SUVmax). We investigated multiple pretreatment PET metrics, including SUVmax, mean SUV (SUVmean), total lesion glycolysis, and metabolic tumor volume (MTV) in LS-SCLC patients undergoing chemoradiotherapy (CRT) and correlated them with survival and disease control outcomes., Patients and Methods: All patients received platinum-based chemotherapy and a median radiation dose of 45 Gy. Kaplan-Meier and competing-risks analyses were performed to assess the prognostic value of PET metrics with respect to overall survival (OS), distant failure (DF), disease-free survival (DFS), and locoregional failure (LRF). Univariate and multivariate analyses were performed to account for the effect of other clinical factors on outcomes., Results: A total of 120 patients with LS-SCLC had analyzable pre-CRT PET/CTs. The median follow up was 34 months. Median OS was 26.9 months. OS was 53.2% at 2 years and 33.1% at 5 years. SUVmax, SUVmean, MTV, and total lesion glycolysis of the primary tumor were not significantly associated with OS, LRF, and DFS on univariate analysis. MTV was significantly associated with DF (P = .024) on univariate but not multivariate analysis., Conclusion: This is the largest reported series to date evaluating the prognostic value of baseline PET metrics in LS-SCLC. Neither SUVmax nor other analyzed PET metrics demonstrated significant correlation with OS or LRF. MTV was correlated with DF and DFS, but this association was no longer significant after adjustment for other clinical factors. This analysis suggests that pretreatment PET scans, even with the use of advanced metrics, do not have independent prognostic value for outcomes in LS-SCLC patients after CRT., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) is associated with excess toxicity following treatment of central lung tumors. Risk-adapted fractionation appears to have mitigated this risk, but it remains unclear whether SBRT is safe for all tumors within the central lung zone, especially those abutting the proximal bronchial tree (PBT). We investigated the dependence of toxicity on tumor proximity to PBT and whether tumors abutting the PBT had greater toxicity than other central lung tumors after SBRT., Materials and Methods: A total of 108 patients receiving SBRT for central lung tumors were reviewed. Patients were classified based on closest distance from tumor to PBT. Primary endpoint was SBRT-related death. Secondary endpoints were overall survival, local control, and grade 3+ pulmonary adverse events. We compared tumors abutting the PBT to nonabutting and those ≤1 cm and >1 cm from PBT., Results: Median follow-up was 22.7 months. Median distance from tumor to PBT was 1.78 cm. Eighty-eight tumors were primary lung and 20 were recurrent or metastatic; 23% of tumors were adenocarcinoma and 71% squamous cell. Median age was 77.5 years. Median dose was 4500 cGy in 5 fractions prescribed to the 100% isodose line. Eighteen patients had tumors abutting the PBT, 4 of whom experienced SBRT-related death. No other patients experienced death attributed to SBRT. Risk of SBRT-related death was significantly higher for tumors abutting the PBT compared with nonabutting tumors (P < .001). Two patients with SBRT-related death received anti-vascular endothelial growth factor therapy and experienced pulmonary hemorrhage. Patients with tumors ≤1 cm from PBT had significantly more grade 3+ events than those with tumors >1cm from PBT (P = .014)., Conclusions: Even with risk-adapted fractionation, tumors abutting PBT are associated with a significant and differential risk of SBRT-related toxicity and death. SBRT should be used with particular caution in central-abutting tumors, especially in the context of anti-vascular endothelial growth factor therapy., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)