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Hypothesis: For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS)., Methods: In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%., Results: Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis., Conclusions: The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease., Competing Interests: Declaration of competing interest AC reports consulting fees from TibaRay. BL reports consulting fees from Beigene, honoraria from Mevion, leadership role in TibaRay. MD reports honoraria from AstraZeneca, Illumina, Genentech, Novartis, Griftstone oncology, Boehringer Ingelheim, Bristol Myers Squibb, leadership role in CiberMed and Foresight Diagnostics, stock in Griftstone Oncology. HW reports honoraria from IOBiotech and Mirati., (Copyright © 2024. Published by Elsevier Inc.)

Background: Randomized trials have found that patients with locoregionally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC) do not benefit from treatment deintensification, even among favorable risk groups. While various methods have been used to identify candidates for treatment deintensification, the optimal approach is unknown., Methods: We conducted a multi-institutional cohort study of 444 patients with previously untreated p16+ OPSCC undergoing definitive radiotherapy with or without systemic therapy between 2009-2022. We compared two approaches for identifying candidates for deintensification: (1) favorable vs. unfavorable risk, using NRG-HN005 eligibility criteria, and (2) low vs. high relative risk for cancer events, using the HNCIG predictive classifier ("omega score"). We tested differences in outcomes and systemic therapy allocation by risk group using multivariable Cox models, competing event models, and logistic regression, and compared characteristics of hypothetical deintensification trials using the two approaches. PFS events were defined as cancer recurrence (locoregional or distant) or death from any cause., Results: Median follow-up time was 52 months; 120 patients (27.0%) were favorable risk; a different 120 patients had low omega score; 28 patients (6.3%) met both criteria; 184 patients (41.4%) had discordant classification. On ordinal logistic regression, decreasing omega score was associated with a statistically significantly lower odds of receiving intensive therapy (normalized OR 0.37 per standard deviation; 95% CI: 0.24-0.57), with a greater magnitude than favorable risk group (OR 0.66; 95% CI: 0.44-0.99). Among patients receiving cisplatin and/or platinum-based induction (N=374), favorable risk was associated with significantly improved PFS (HR 0.59, 95% CI 0.36-0.99), whereas lower omega score was associated with a significantly decreased relative hazard for cancer events (RHR 0.18, 95% CI 0.070-0.46). In simulations, selecting patients with low omega scores increased the efficiency of hypothetical non-inferiority trials., Conclusions: Considering patients' relative risk for cancer events can help define optimal populations for treatment deintensification in p16+ OPSCC., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose relevant to this work., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Inflammatory bowel disease (IBD) has been considered a relative contraindication to radiation therapy (RT) because of the potential greater risk of RT-induced toxicities. This study aimed to assess acute toxicity outcomes in patients with IBD treated with abdominal/pelvic RT., Methods and Materials: After institutional review board approval, patients with IBD who received RT to the abdomen/pelvis were identified from an institutional research repository, and their electronic medical records were reviewed. The IBD cohort was matched 1:1 with controls according to all of the following: RT, gender, disease site, age, and year of RT. Acute toxicity was defined as toxicity occurring within 3 months of RT. Primary outcomes were assessed via univariable logistic regression models and the predicted probability of acute toxicity and acute gastrointestinal (GI) toxicity were plotted for the most significant covariates. IBD and control cohorts were compared on demographic and toxicity variables using χ 2 /Fisher exact tests and Kruskal-Wallis tests where appropriate., Results: We identified 62 patients with a median age of 64 years (IQR, 54-70 years) who received RT from 2006 to 2022. Patients were treated with intensity modulated RT (38; 61.3%), 3-dimensional conformal RT (12; 19.4%), and stereotactic body RT/brachytherapy (12; 19.4%). After RT, 28 (45.2%) and 23 (37.1%) patients experienced grade ≥2 acute (any) and acute GI toxicity, respectively. Higher overall RT dose and RT dose to small bowel were found to be significantly associated with increased risk of grade ≥2 acute toxicities (OR, 1.041 per unit Gy; 95% CI, 1.005-1.084; P = .034 and OR, 1.046; 95% CI, 1.018-1.082; P = .003, respectively). Between IBD and control cohorts, there were no significant differences in grade ≥2 acute (any) and acute GI toxicities (P = .710 and P = .704, respectively)., Conclusions: In patients with IBD treated with abdominal/pelvic RT for malignancy, RT was effective and well-tolerated. RT treatment planning should carefully consider the location(s) of IBD inflammation and dose to bowel structures, in particular, dose to the small bowel., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Positron emission tomography (PET)-guided radiation therapy is a novel tracked dose delivery modality that uses real-time PET to guide radiation therapy beamlets. The BIOGUIDE-X study was performed with sequential cohorts of participants to (1) identify the fluorodeoxyglucose (FDG) dose for PET-guided therapy and (2) confirm that the emulated dose distribution was consistent with a physician-approved radiation therapy plan., Methods and Materials: This prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (2-5 cm) in the lung or bone. For cohort I, a modified 3 + 3 design was used to determine the FDG dose that would result in adequate signal for PET-guided therapy. For cohort II, PET imaging data were collected on the X1 system before the first and last fractions among patients undergoing conventional stereotactic body radiation therapy. PET-guided therapy dose distributions were modeled on the patient's computed tomography anatomy using the collected PET data at each fraction as input to an "emulated delivery" and compared with the physician-approved plan., Results: Cohort I demonstrated adequate FDG activity in 6 of 6 evaluable participants (100.0%) with the first injected dose level of 15 mCi FDG. In cohort II, 4 patients with lung tumors and 5 with bone tumors were enrolled, and evaluable emulated delivery data points were collected for 17 treatment fractions. Sixteen of the 17 emulated deliveries resulted in dose distributions that were accurate with respect to the approved PET-guided therapy plan. The 17th data point was just below the 95% threshold for accuracy (dose-volume histogram score = 94.6%). All emulated fluences were physically deliverable. No toxicities were attributed to multiple FDG administrations., Conclusions: PET-guided therapy is a novel radiation therapy modality in which a radiolabeled tumor can act as its own fiducial for radiation therapy targeting. Emulated therapy dose distributions calculated from continuously acquired real-time PET data were accurate and machine-deliverable in tumors that were 2 to 5 cm in size with adequate FDG signal characteristics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Pancreatic stereotactic body radiation therapy (SBRT) is limited to gross tumor without elective coverage for subclinical disease. Given a better understanding of recurrence patterns, we hypothesized that the addition of elective nodal irradiation (ENI) to pancreatic SBRT would be tolerable and would decrease locoregional progression., Methods and Materials: We conducted a retrospective 1:2 propensity-matched cohort study to compare toxicity and locoregional progression among patients treated with pancreatic SBRT with or without ENI. In the SBRT + ENI cohort, an elective target volume was delineated per Radiation Therapy Oncology Group guidelines and treated to 25 Gy in 5 fractions alongside 40 Gy in 5 fractions to gross disease. The primary outcome was the cumulative incidence of locoregional progression, with death as a competing risk., Results: Among 135 candidate controls treated with SBRT alone, 100 were propensity-matched to 50 patients treated with SBRT + ENI. All patients completed SBRT. Median potential radiographic follow-up was 28 months. The incidence of late and serious acute toxicity was similar between matched cohorts. However, SBRT + ENI was associated with a statistically significant increase in acute grade 1 to 2 nausea (60% vs 20%, P < .001). The 24-month cumulative incidences of locoregional progression with and without ENI were 22.6% (95% confidence interval [CI], 10.0%-35.1%) versus 44.6% (95% CI, 34.8%-54.4%; multivariable-adjusted hazard ratio, 0.39; 95% CI, 0.18-0.87; P = .021). This was stable in sensitivity analyses of uniform prescription dose, multiagent chemotherapy, and resectability. There were fewer peripancreatic (0% vs 7%), porta hepatis (2% vs 7%), and peri-aortic/aortocaval (5% vs 12%) recurrences after SBRT + ENI, but no difference in survival., Conclusions: Pancreatic SBRT + ENI was tolerable and did not increase late or serious acute toxicity relative to a matched cohort undergoing SBRT alone, but did increase acute grade 1 to 2 nausea. The addition of ENI to SBRT was associated with decreased locoregional progression but not improved survival. Further studies are warranted to determine whether ENI offers meaningful benefit., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The corpus callosum (CC) and intrahemispheric white matter tracts (IHWM) subserve critical aspects of attention and processing speed. We analyzed imaging biomarkers of microstructural injury within these regions and association with attention and processing speed performance before and after radiation therapy in primary brain tumor patients., Methods and Materials: In a prospective clinical trial, 44 primary brain tumor patients underwent cognitive testing and magnetic resonance imaging/diffusion-weighted imaging at baseline (pre-radiation therapy) and 3-, 6-, and 12-months post-radiation therapy. CC (subregions, total) and IHWM tracts (left/right without CC, total) were autosegmented; tumor, tumor bed, and edema were censored. Biomarkers included volume changes (cm 3 ), mean diffusivity ([MD]; higher values indicate white matter injury), fractional anisotropy ([FA]; lower values indicate white matter injury). Reliable-change indices measured changes in attention (Weschler Adult Intelligence Scale [WAIS-IV] digits-forward; Delis-Kaplan Executive Function System Trail Making [D-KEFS-TM] visual-scanning), and processing speed (WAIS-IV coding; D-KEFS-TM number-sequencing, letter-sequencing), accounting for practice effects. Linear mixed-effects models evaluated associations between mean radiation dose and biomarkers (volume, MD, FA) and imaging biomarkers and neurocognitive performance. Statistics were corrected for multiple comparisons., Results: Processing speed declined at 6 months following radiation therapy (number sequencing, letter sequencing; P < .04). Seizures and antiepileptic drug therapy were associated with lower visual-scanning attention reliable-change indices at 6 months (P = .039). Higher radiation dose correlated with smaller midanterior CC volume (P = .023); lower FA in posterior CC, anterior CC, and total CC (all P < .03); and higher MD in anterior CC (P = .012). Smaller midanterior CC and left IHWM volume correlated with worse processing speed (coding, letter-sequencing, number-sequencing; all P < .03). Higher FA in right, left, and total IHWM correlated with better coding scores (all P < .01). Lower FA in total IHWM (P = .009) was associated with worse visual-scanning attention scores. Higher FA in midposterior CC (P = .029) correlated with better digits-forward attention scores., Conclusions: The CC demonstrated radiation dose-dependent atrophy and WM injury. Microstructural injury within the CC and IHWM was associated with attention and processing speed decline after radiation therapy. These areas represent possible avoidance regions for preservation of attention and processing speed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Older patients undergoing radiation therapy (RT) for pelvic malignancies are at increased risk for pelvic fracture, which is associated with significant morbidity and mortality. RT techniques such as brachytherapy or intensity modulated RT (IMRT) allow for more conformal dose distributions, but it is not known whether the risk for pelvic fracture varies by RT modality., Methods and Materials: This observational cohort study involved 28,354 patients ≥65 years old, treated with RT for pelvic malignancies. We evaluated the relative risk of pelvic fracture by type of RT when accounting for baseline factors. To test for nonspecific effects, we also evaluated risk of nonpelvic fractures in the same population., Results: The 5-year incidence of pelvic fractures was 12.7% (95% confidence interval [CI], 11.6%-13.8%), 11.8% (10.8%-12.8%), and 3.7% (3.4%-4.0%) for patients with gastrointestinal, gynecologic, and prostate cancer, respectively. On multivariable analysis, being treated with IMRT (hazard ratio, 0.85; 95% CI, 0.73-0.99) or brachytherapy therapy alone (hazard ratio, 0.43; 95% CI, 0.34-0.54) was associated with a reduced hazard for pelvic fractures compared with 3D conformal radiation therapy in female patients. In contrast, there was no association with RT modality and the hazard for nonpelvic fractures among females. There was no significant association between pelvic fractures and IMRT or brachytherapy for male patients. White race, advanced age, and higher comorbidity were associated with an increased hazard for pelvic fracture., Conclusions: IMRT and brachytherapy were associated with a reduced risk of pelvic fractures in older women undergoing RT for pelvic malignancies. Pelvic insufficiency fracture risk should be considered when treating with pelvic RT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Previous studies have found that patients with head and neck cancer (HNC) with a higher relative hazard for recurrence versus competing mortality (ω + ratio) are more likely to benefit from intensive therapy. Nomograms to predict this ratio (ω scores) can be useful to guide clinical management; however, comorbidity and other risk factors are frequently lacking from trial samples., Methods and Materials: In this study of 7117 US veterans, we evaluated the ability of a ω score nomogram developed from clinical trial data to stratify patients with HNC treated with radiation therapy by their relative risk of cancer progression versus competing mortality. We then fit generalized competing event models to determine the effect of comorbidity and other covariates on the ω + ratio., Results: The ω score was effective in stratifying patients with HNC according to their risk for cancer recurrence relative to competing mortality, especially among patients aged >70 years. Patients with ω score ≥0.80 were more likely to receive intensive therapy compared with patients with a ω score <0.80 (66 vs. 54%; P < .001). On multivariable generalized competing event regression, T2-4 category (relative hazard ratio [RHR], 1.08; 95% confidence interval [CI], 1.01-1.16), N2-3 category (RHR, 1.07; 95% CI, 1.01-1.15), and being employed (RHR, 1.11; 95% CI, 1.03-1.20) were associated with increased ω + ratio, and increasing age (RHR, 0.83; 95% CI, 0.78-0.89), Charlson comorbidity index ≥2 (RHR, 0.85; 95% CI, 0.79-0.91), being a current smoker (RHR, 0.90; 95% CI, 0.84-0.96), and lower body mass index (RHR, 0.89; 95% CI, 0.84-0.95) were associated with a decreased ω + ratio., Conclusions: The ω scores are effective in stratifying patients with HNC and are correlated with the intensity of treatment given. The ω scores incorporating comorbidity and other risk factors could help identify patients with HNC most likely to benefit from intensive therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)