Impact of Adjuvant Hormonal Therapy Duration and Timing of Salvage Hormonal Therapy in Prostate Cancer Patients With Unfavorable Prognosis Treated by Radiotherapy. A Secondary Analysis of RTOG 8531

Abstract

RTOG 85-31 was a randomized trial comparing radiotherapy (RT) alone versus RT plus lifelong adjuvant androgen suppression in unfavorable prognosis carcinoma of the prostate. Since not all patients remained on the protocol mandated long-term hormonal therapy, we examined the effect of hormonal duration in outcome. We also examined the impact of early initiation of salvage hormonal therapy (HT) in relapsing patients randomized to RT alone. The protocol mandated either pelvic RT (60–70 Gy) followed by goserelin 3.6 mg monthly given indefinitely or until disease progression (arm 1) or pelvic RT alone followed by observation and HT at relapse (arm 2). PSA determination was not mandatory at the initiation of the study. There were 477 cases in arm 1 and 468 in arm 2. To avoid potential bias due to early progression in the analysis of arm 1, only patients who were alive with no evidence of disease at the time of voluntary cessation of HT were included, leaving 377 analyzable patients. For the purpose of this analysis, arm 1 patients were divided in groups based on the hormonal therapy duration (HTD), as follows: ≤1 year (27.3%), 1< and ≤2 years (11.4%), 2< and ≤4 years (13.3%), 4< and ≤6 years (10.6%) and >6 years (37.4%). Arm 2 patients were divided in early and late salvage hormonal therapy. The early salvage was defined as receiving HT with a PSA <10 ng/ml prior to HT and late salvage was defined as receiving HT with a PSA ≥10 ng/ml prior to HT. End-points were overall survival, disease-free survival, disease-free survival with PSA <1.5 ng/ml, disease-specific survival and distant failure. Cox-proportional hazards regression model was used to test the outcomes among all groups. The median follow-up time for surviving patients is over 11 years. The median duration of adjuvant HT was 3.59 years. Adjusted for age and stratification variables, the HTD >6 year group remains the only group significantly associated with having fewer failure events in all measured outcomes. The 5- and 11-year overall survival rates for patients with HTD >6 years was 100 and 77% compared to 67 and 39%, 46 and 17%, 53 and 25%, 89 and 32% for those patients with HTD of ≤1 year, 1< and ≤2 years, 2< and ≤4 years, 4< and ≤6 years, respectively. Of the patients failing RT in arm 2, 132 (51%) initiated early HT and 125 (49%) late HT. The median follow-up of early vs later salvage HT patients was comparable. Pretreatment characteristics show that the early salvage group had significantly fewer nodal disease, post-prostatectomy patients, distant metastases and higher Gleason score. The 5-and 11-year overall survival rates were 86 and 47% for early HT and 65 and 22% for late HT, respectively (p < 0.0001). Early initiation of HT was also associated with a significantly improved disease-free survival, disease-free survival with PSA <1.5 ng/ml, local failure, distant failure and cause-specific survival. Despite the limitations of the retrospective nature of these data, the results from these analyses suggest that the use of HTD for more than 6 years appears to be significantly associated with improvements in all end-points studied and that early salvage HT post-RT failure may result in improved outcomes in patients with unfavorable prostate cancer treated by pelvic RT alone.