Phase 3 Study of Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Adenocarcinoma of the Prostate

Abstract

The low α/β ratio of prostate cancer (1.5-2) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (RT). Most available data of moderate hypofractionated RT have focused on low, intermediate, and/or mixed risk groups. We therefore conducted the first randomized trial of moderately hypofractionated RT in high-risk prostate cancer patients, with the hypothesis that moderately hypofractionated RT is similar in safety to conventional high-dose intensity-modulated RT at 24 months. Here, we present the primary outcome of the study: safety analysis of toxicities at 6 and 24 months post-RT. We conducted a Canadian multi-centric phase III trial of conventional vs. hypofractionated intensity-modulated radiotherapy in men with high-risk prostate cancer as per the ASTRO definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either conventional or hypofractionated RT. All patients received neo-adjuvant, concurrent, and adjuvant androgen suppression, with a median duration of 24 months. Conventional RT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The primary endpoint is to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. This study is registered on clinicaltrials.gov (NCT01444820). Of the 329 patients, 164 were randomized to hypofractionated RT and 165 to conventional RT. The median follow-up was 36 months (19-55 months). At 24 months, 8 patients in the conventional RT arm and 9 patients in the hypofractionated RT arm had grade 2 or worse gastrointestinal (GI) related adverse events (HR = 0.76; 95% CI = 0.26-2.19; P = ns). Similarly, 7 patients in the conventional RT arm and 5 patients in hypofractionated RT arm had grade 2 or worse genitourinary (GU) toxicities (HR = 0.57; 95% CI = 0.17-1.95; P = ns). Three patients in the hypofractionated RT arm and no patient in the conventional RT arm had grade 3 GI related toxicities, while one patient in hypofractionated RT group and 3 patients in conventional RT group had grade 3 GU related toxicities. There were no grade 4 toxicities in any of the groups. This is the first hypofractionated dose escalated radiotherapy study in high-risk prostate cancer patients treated with contemporary radiation techniques and androgen suppression. The results confirm our original hypothesis and indicate that moderate hypofractionated RT is equally well tolerated as conventionally fractionated radiotherapy at 2 years in high-risk prostate cancer patients.