Conventional vs. Hypofractionated, Radiotherapy for High-Risk Prostate Cancer: 7-Year Outcomes of the Randomized, Non-Inferiority, Phase 3 PCS5 Trial

Purpose/Objective(s) The low α\β ratio of prostate cancer (PCa), 1.5-2, suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (HFRT). Most available data of moderate HFRT have focused on low, intermediate and/or mixed risk groups. We therefore conducted the first randomized trial of moderately HFRT in high-risk PCa patients only, and present the pre-planned analysis of efficacy at seven years (Prostate Cancer Study number 5: PCS5) Materials/Methods PCS5 is a Canadian multi-centric, non-inferiority phase III trial of intensity-modulated conventionally fractionated radiation therapy (CFRT) vs. HFRT in men with high-risk PCa as per NCCN definition. From Feb. 2012 to Mar. 2015, 329 patients were randomized in a 1:1 ratio to receive either CFRT or HFRT. All patients received neo-adjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. CFRT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. HFRT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy, in 1.8Gy per fraction to the pelvic lymph nodes. Participants were analyzed as per intention-to-treat. Results Of the 329 patients, 164 were randomized to HFRT and 165 to CFRT. Of these, 159 men in the hypofractionation arm and 160 in the standard arm were included in survival analyses. At 7 years of follow up there were no significant differences in survival between HFRT and CFRT for overall mortality (81.7% vs. 82%; HR 0.92 [0.56-1.53]; CI:95%; p=0.76), prostate cancer specific mortality (94.9% vs. 96.4%; HR 1.31 [0.46-3.78]; CI:95%; p=0.61), biochemical recurrence (87.4% vs. 85.1%; HR 0.89 [0.49-1.60]; CI:95%; p=0.69), distant metastatic recurrence (91.5% vs. 91.8%; HR 0.89 [0.41-1.90]; CI:95%; p=0.76), or disease free survival, respectively (either biochemical or distant recurrence) (86.5% vs. 83.4%; HR 0.82 [0.47-1.46]; CI:95%; p=0.50). The Relative Risks were close to 1.00 for all outcomes at 3-, 5-, and 7-years after treatment, with very tight bootstrapped confidence intervals, suggesting equivalent risks for all outcomes in both study arms. There were no significant differences in grade 3 or higher acute and delayed genitourinary (GU) and gastrointestinal (GI) toxicities at 2 years and no new toxicities emerged thereafter. There were no grade 4 toxicities in either arm. Conclusion This is the first hypofractionated radiotherapy study in high-risk PCa patients treated with contemporary radiation and androgen suppression. Hypofractionated radiotherapy using 68 Gy in 25 fractions is non-inferior to conventional fractionation using 76Gy in 38 fractions and can be considered as a new standard of care for external-beam radiotherapy of high-risk prostate cancer.