Outcomes Based on Risk Factors in Intermediate Risk Prostate Cancer: a Secondary Analysis of a Randomized Phase III Trial

Abstract

Intermediate risk prostate cancer (IRPC) patients (pts) are stratified in favorable and unfavorable subgroups. To identify pts benefiting from therapeutic de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiotherapy (DERT), we measured biochemical failure (BF) and overall survival (OS) rates in IRPC pts according to risk classification subgroups. From 12/2000 to 9/2010, 600 pts with IRPC were randomized to ADT+ RT 70 Gy vs. ADT+DERT76 vs. DERT76 alone. First, we analyzed outcomes based on 3 prognostic risk factors (RF) using T stage (T1-T2a vs.T2b-T2c), PSA level (<10 vs. ³10) and Gleason (6 vs. 7). We then compared BF and OS between arms for the presence of 1, 2, or 3 RF. Using the same 600 pts, we further refined the group of pts with only 1 RF to a favorable intermediate risk (FIR) by excluding pts with a more aggressive biologic profile: Gleason pattern 4+3 or ≥50% of positive biopsy cores. The remaining pts represented an unfavorable intermediate risk (UIR) group. We compared BF and OS outcomes for FIR vs. UIR. BF was analyzed with competing risks methods and OS with Kaplan Meier method and the log rank test. Overall 122 pts (20%) developed BF. The rate of BF increased with number of RF from 14% for 1 to 41% for 3 RF, p<0.001. In the presence of 1 RF only, the incidence of BF increased significantly in DERT76 compared to ADT+RT70 or ADT+DERT76, p=0.02 and p=0.04, respectively, with no difference between ADT+RT70 and ADT+DERT76, p=0.5. There was no difference in OS between groups in the presence of 1 RF only. In the presence of 2 or 3 RF, BF was significantly higher in DERT76 alone compared to ADT+RT70, p=0.047 or ADT+DERT76, p<0.001. There was a trend in favor of ADT+DERT76 for better BF control compared to ADT+RT70 [HR=1.86 (CI, 0.98-3.54), p=0.06]. There was no difference in OS between the 3 arms in the presence of 2 or 3 RF. When comparing outcomes from the FIR group, there was no significant difference in BF or OS between the 3 arms. In the UIR group, BF was significantly higher for DERT76 alone compared to ADT+RT70 or ADT+DERT76, p=0.005 and p<0.001, respectively. No significant difference seen between ADT+RT70 and ADT+RT76 for BF and no difference in OS between arms. Late gastro-intestinal (GI) toxicity was significantly higher in patients receiving 76 Gy. In IRPC, when using prognostic RF and stratifying pts by subgroups, therapeutic de-escalation is possible for the end-point of BF. To avoid ADT side effects, DERT76 alone can be used in pts with only 1 RF and without Gleason 4+3 or ≥50% positive biopsies (FIR). ADT+RT70 can be safely used for the remaining pts with only one RF and including Gleason 4+3 or ≥50% positive biopsies, with dose de-escalation leading to a lower rate of late GI toxicity. For those pts with 2 or 3 RF, ADT seems to be an important component for BF control. Further studies are needed in these heterogeneous IRPC pts.