Cardiovascular Mortality Following Short-term Androgen Deprivation in Clinically Localized Prostate Cancer: An Analysis of RTOG 94-08

Abstract

Background Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa); however, controversy exists regarding ADT and cardiovascular mortality (CVM) with limited data for lower risk disease. Objective We conducted a hypothesis-generating retrospective analysis to evaluate the relationship between short-course ADT and CVM in patients with clinically localized PCa enrolled in a phase 3 trial. Design, setting, and participants A total of 1979 men with clinically localized (T1b–2b, prostate-specific antigen [PSA] <20 ng/ml) PCa enrolled in Radiation Therapy Oncology Group (RTOG) 94-08 from 1994 to 2001. Patients were randomized to radiation therapy (RT) with or without short-course ADT (4 mo of gonadotropin-releasing hormone (GnRH) agonist therapy and antiandrogen). Median follow-up was 9.1 yr for survivors. Outcome measurements and statistical analysis The Cox proportional hazards model assessed overall survival. The Fine-Gray proportional hazards model assessed disease-specific survival (DSS) and CVM. Covariates included age, race, weight, baseline cardiovascular disease, baseline diabetes, baseline hypertension, Gleason score, T stage, and PSA. Results and limitations Short-course ADT improved overall survival and DSS and was not associated with an increased risk of CVM. Overall, 191 cardiovascular-related deaths were observed. At 10 yr, 83 patients (cumulative incidence rate: 10%) receiving RT and ADT versus 95 patients (cumulative incidence rate: 11%) receiving RT alone experienced CVM. The treatment arm was not associated with increased CVM (unadjusted hazard ratio: 1.07; confidence interval, 0.81–1.42; p = 0.62). Increased CVM was not observed in patients at low risk of PCa death or at high risk of cardiac-related death. Conclusions Data from patients enrolled in RTOG 94-08 support the hypothesis that ADT does not increase CVM risk in all men with clinically localized PCa treated with short-course GnRH agonist therapy. These data support ADT use in settings with proven survival benefit. Patient summary We investigated the controversial relationship between hormone therapy and cardiovascular mortality in men with prostate cancer (PCa) treated with radiation in a large randomized trial. Our data suggest that hormone therapy does not increase the risk of cardiovascular death in patients with clinically localized PCa and support the use of such therapy in settings with proven survival benefit.

Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer

“…Cardiovascular mortality was similar in the two groups, as was seen in three previous RTOG phase 3 trials assessing the use or nonuse of androgen-deprivation therapy. 25–27 However, only data on cardiac events that were reported as adverse events were collected, which may have introduced an ascertainment bias.…”

Managing cardiovascular risk in high‐risk prostate cancer

“…1 The observational evidence linking ADT to increased CV risk is substantial (Table 1) Against this, there is evidence from RCTs, from secondary analyses and from a meta-analysis that have failed to identify any increased risk. Confusingly, Jespersen's nationwide cohort study of >30 000 men found an association between ADT and increased risk of MI and stroke.…”

Decisions Regarding Whether to Use Androgen Deprivation Therapy with Radiotherapy in Prostate Cancer: Is Cardiovascular Mortality the Most Relevant Outcome?

“…In this issue of European Urology, Voog and colleagues [4] update results from the RTOG 9408 trial with a specific focus on cardiovascular mortality. This is a highly clinically relevant study that directly informs the debate on ADT use and potential harms in patients with intermediaterisk disease.…”