Intermittent androgen suppression for rising PSA level after radiotherapy

Abstract

Background: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial.

Methods: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals.

Results: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24).

Conclusions: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

Figure 1. Overall Survival in the Intention-to-Treat Population

The per-protocol analysis yielded very similar results to the analysis presented here, with an estimated hazard ratio for death with intermittent androgen-deprivation therapy (IAD), as compared with continuous androgen-deprivation therapy (CAD), of 1.03 (95% CI, 0.86 to 1.23). The P value for noninferiority (hazard ratio, <1.25) was 0.01.

Figure 2. Numbers of Patients Completing Treatment Cycles and the Median Duration of Off-Treatment Periods in the Intermittent-Therapy Group

The maximum number of nontreatment intervals observed was nine, with 95% of patients entering the first nontreatment period, 58% the second, and 32% the third.