Randomized Evaluation of the PET-Adjusted IMRT for NSCLC Trial (REPAINT)

Background: Standard radiation therapy (RT) for locally advanced nonsmall cell lung cancer (LA-NSCLC) employs a uniform dose of approximately 60 Gy. Recent trials demonstrated that RT dose escalation may not improve outcomes and may cause added toxicity. We previously performed a single-arm trial testing a personalized, risk-adapted, and deintensified RT strategy. We now report findings from a randomized trial testing this novel approach. Methods and Materials: Patients with LA-NSCLC with Eastern Cooperative Oncology Group performance status 0-2 were eligible for this trial. Metabolic tumor volume for each pulmonary tumor and involved lymph node was calculated using fludeoxyglucose PET. Participants were randomly assigned 1:1 to receive standard RT (60 Gy in 30 fractions delivered to pulmonary tumors and involved lymph nodes) versus dose-painted RT (55 Gy delivered to tumors and lymph nodes with metabolic volume exceeding 20 cm³ and 44-48 Gy to other lesions, all in 20 fractions). Concurrent chemotherapy and standard adjuvant therapy were given in both arms. The primary objective was to characterize patient-reported outcomes using Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events. Secondary objectives included comparing outcomes between study arms. Results: Fifty patients were enrolled. The most common grade 3 patient-reported adverse events within 90 days of RT completion were dysphagia (38%), fatigue (38%), cough (32%), and wheezing (28%). The median progression-free survival duration is 18 months, and the median overall survival duration is 42 months. Progression-free survival and overall survival rates are similar across study arms (logrank P = .562 and .765, respectively). There have been 3 cases of in-field disease progression, with 1 in the control arm and 2 in the dose-painted arm. Grade 3-4 lymphopenia was reduced with dose-painted RT (48% vs 81%, chi-square P = .012). Conclusion: High-grade patient-reported toxicity in patients with LA-NSCLC who are treated with concurrent chemoradiotherapy is common. We found no evidence that risk-adapted RT de-escalation compromises clinical outcomes. Follow-up studies testing the ability of this approach to improve the safety profile of chemoradiotherapy are warranted.