Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

Purpose/objective: Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose-volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG Oncology/RTOG 0415 low-risk prostate cancer trial (N = 521). Material/methods: Treatment in the studied HRT arm was delivered as 70 Gy at 2.5 Gy/fraction with 3D-CRT/IMRT (N = 108/413). At a median follow-up of 5.9 years, the crude late >= Grade 2 GI and GU toxicities were 19% and 29%, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70% and 30%; preserved toxicity rates). Within training, dose-response modeling was based on dose-volume cut-points (EQD2Gy; bladder/rectum: alpha/beta = 6 Gy/3Gy), age, acute >= Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p <= 0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUC(validation)) was within AUC(training) +/- SD with p <= 0.05, and with an Hosmer-Lemeshow p-value (p(HL)) > 0.05. Results: Three candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5% rectal volume (D5%[Gy]), the absolute rectal volume < 35 Gy, and acute GI toxicity (AUC = 0.59-0.63; p = 0.02-0.04). The two generalizable MVA models, i.e., D5%[Gy] with or without acute GI toxicity (AUC(validation) = 0.64, 0.65; p = 0.01, 0.03; p(HL) = 0.45-0.56), suggest that reducing late GI toxicity from 20% to 10% would require reducing D5%[Gy] from <= 65 Gy to <= 62 Gy (logistic function argument: 17 +(0.24D5%[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUC(training) (=) 0.57; p = 0.07). Conclusion: Late GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose 'hotspots' in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity. (C) 2019 Elsevier B.V. All rights reserved.