Intermittent androgen-deprivation therapy in prostate cancer: a critical review focused on phase 3 trials

Abstract

Context: Intermittent androgen deprivation (IAD) in prostate cancer (PCa) patients has been proposed to delay development of castration resistance and to reduce the side effects and costs of androgen deprivation therapy (ADT).

Objective: This review analyzes (1) the oncologic and quality of life (QoL) results from randomized phase 3 trials comparing IAD and continuous ADT and (2) the prognostic parameters for IAD.

Evidence acquisition: We searched the Medline and Cochrane Library databases (primary fields: prostate neoplasm and intermittent androgen deprivation; secondary fields: randomized trials, survival, quality of life, predictors) without language restriction.

Evidence synthesis: We found seven extensively described phase 3 trials randomizing 4675 patients to IAD versus continuous ADT. Other randomized trials investigating IAD have been performed, but available data are limited and have been published only in preliminary fashion. In all seven trials, patients spent most of their time on, rather than off, ADT. The induction periods ranged from 3 mo to 8 mo; in all but one trial, the PSA level designated for ADT discontinuation was <4 ng/ml. Mean follow-up ranged from 40-108 mo. Collectively, these trials support the concept that, mainly in metastatic cases, IAD can produce oncologic results similar to continuous ADT. In terms of overall survival, the hazard ratios for IAD and continuous ADT were very similar (range: 0.98-1.08). The QoL benefit of IAD appears to be modest at best. With IAD, QoL is likely influenced by the duration of the off-treatment periods and by the rate of testosterone recovery.

Conclusions: The evidence indicates that IAD is not inferior to continuous ADT. Data are insufficient to determine whether IAD is able to prevent the long-term complications of ADT. More comparative analysis focused on QoL is warranted.

Keywords: Androgen deprivation; Intermittent therapy; Prostate neoplasm.