Patterns of Clinical Progression in Radiorecurrent High Risk Prostate Cancer and Impact of Initial Treatment Selection

Abstract

The natural history of radiorecurrent of high-risk prostate cancer (HRPCa) is poorly understood, despite the proportionally higher rates of BCR in this risk group. Treatment HRPCa with external beam radiotherapy (EBRT) plus brachytherapy (BT) boost (EBRT+BT) has been associated with lower rates of BCR, distant metastasis (DM), and PCa-specific mortality (PCSM) compared to EBRT alone. However, it is unclear whether patients who develop BCR following either approach have similar downstream oncologic outcomes. To understand the clinical course of HRPCa patients who develop BCR after initial RT, and to evaluate how initial upfront treatment intensification with EBRT+BT may affect clinical outcomes after BCR compared to initial treatment with EBRT. We identified 706 out of 3820 men with HRPCa treated at 13 institutions from 1998-2015 with EBRT (n=468/2134) or EBRT+BT (n=238/1686) who developed BCR. We compared rates of DM, PCSM, and all-cause mortality (ACM) after BCR between treatment groups using Fine-Gray competing risk regression. Models were adjusted for age, Gleason grade group, initial PSA (iPSA), clinical T stage, time-dependent use of systemic salvage, and interval to BCR using inverse probability of treatment weighting. Two-tailed chi-square testing was used to evaluate the relationship between early BCR (≤3 years from RT) and DM. Median follow-up was 9.9 years from RT and 4.8 years from BCR. Groups were similar in age, iPSA, presence of ≥2 HR features, and median interval to BCR (3.3 years). Most men received neoadjuvant/concurrent androgen deprivation therapy (ADT), 92.5% and 91.0% for EBRT and EBRT+BT, respectively, though for a longer duration with EBRT (median 14.7 vs. 9.0 months, p=0.0012). Early BCR occurred in 44.3% of men and was associated with a higher risk of DM compared to BCR at >3 years (62.0% vs. 36.1%, p < 0.0001). Among all DM events, 60.4% occurred within 1 year of BCR (median 29 days) and 39.6% occurred after 1 year (median 968 days). Local and systemic salvage rates were 2.4% and 37.2% after EBRT, and 3.4% and 42.9% after EBRT+BT, respectively. Initial EBRT+BT was associated with significantly lower rates of DM after BCR (HR 0.48, 95% CI 0.36-0.64, p < 0.001). Rates of PCSM and ACM did not significantly differ (HR 0.93, 95% CI 0.67-1.30, p=0.93, and HR 0.8, 95% CI 0.6-1.1, p=0.11, respectively). In this large retrospective series of radiorecurrent HRPCa, initial treatment with EBRT+BT was associated with significantly lower rates of DM after BCR compared with EBRT, despite shorter ADT use and a similar median interval to BCR. Local salvage was rarely utilized in both groups. Early BCR was associated with increased DM, and though over half of DMs occurred early, there was a sizeable wave of late DMs. In the absence of salvage for local failure after EBRT, upfront treatment intensification with BT may reduce DM, though not PCSM or ACM, even after development of BCR.