Clinical Outcomes among Patients with Radiorecurrent Gleason Grade Group 5 Prostate Cancer: Impact of Initial Treatment Strategy

Abstract

Treatment with external beam radiation therapy (EBRT) + brachytherapy (BT) and androgen deprivation therapy (ADT) has been associated with lower prostate cancer (PCa)-specific mortality (PCSM) and longer time to distant metastasis (DM) compared with EBRT + ADT alone in Gleason grade group 5 (GG 5) PCa. However, outcomes are heterogeneous, and the addition of BT may also add toxicity. An alternative approach given the high competing risk of distant failure would be to treat with EBRT alone and reserve BT for local salvage if needed. However, it is unknown whether omitting the BT boost upfront might compromise the chance of cure. The purpose of this study is to examine the downstream ramifications of initial treatment selection in patients who developed biochemical recurrence (BCR) after EBRT or EBRT+BT. We hypothesized that upfront treatment intensification would still be associated with a benefit when restricting analysis to patients with BCR. Out of 1170 patients with GG 5 PCa treated at 12 institutions between 2000-2013 with definitive radiotherapy, we extracted data for 361 patients who experienced BCR by Phoenix criteria (n=84/436 with EBRT+BT, 277/734 with EBRT). Covariate-adjusted cumulative incidence rates for DM and PCSM were generated with Kaplan-Meier methods with inverse probability of treatment weights adjusting for age, Gleason score, initial PSA, T stage, and use of systemic salvage. Cox proportional hazards models with propensity scores included a covariate were used to compare DM and PCSM outcomes between treatment groups. Median follow-up was 6.6 and 6.0 years from initial treatment and 2.4 and 2.7 years from BCR, for EBRT+BT and EBRT, respectively. Median respective time to BCR was 3.2 and 3.0 years. Median duration of ADT was 12 months with EBRT+BT and 21 months with EBRT. Local salvage and systemic salvage treatment rates were 4.8% and 28.6% after EBRT+BT, and 5.4% and 31.8% after EBRT. From time of BCR, 3-year DM and PCSM rates were 52% and 33% after EBRT+BT and 59% and 30% after EBRT. Treatment with EBRT+BT was associated with a significantly longer time to DM (HR 0.63, 95% confidence interval (CI) 0.41-0.97, p=0.03) but was not associated with a difference in PCSM (HR 1.33, 95% CI 0.86-2.07, p=0.20). When focusing on patients who experienced BCR after definitive radiotherapy for GG 5 PCa, initial treatment with EBRT+BT vs EBRT was associated with significantly improved rates of DM. PCSM did not significantly differ between groups. Importantly, outcomes remain poor, and salvage treatments, particularly local salvage, appear underutilized. While limited by the relatively small numbers and retrospective design, these results imply that in the absence of improved salvage utilization in patients initially receiving EBRT+ADT, upfront treatment intensification with BT may translate to a delay in time to DM.