Background. Radiation therapy combined with androgen suppression therapy has been shown to prolong survival in patients with locally advanced prostate cancer or unfavorable localized prostate cancer. However, androgen suppression therapy is associated with an increased risk of fatal and nonfatal cardiovascular events in older patients. D’Amico and colleagues report on the continuation of an earlier trial comparing radiation therapy with combined radiation and androgen suppression therapy (the latter was given for a duration of six months). Particular attention was given to the effect of the type and degree of comorbidities on overall survival.

The Study: Over a period of five years, 206 men with a median age of 72.5 years were randomized to receive radiation therapy alone or with androgen suppression therapy. The men had T1b to T2bN0M0 prostate cancer and one or more unfavorable prognostic findings (prostate-specific antigen [PSA] failure, PSA level greater than 10 ng per mL; Gleason score of 7 to 10; extracapsular extension; or seminal invasion). Inclusion criteria were life expectancy greater than 10 years, based on comorbidities other than prostate cancer, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Comorbidities were assessed using a validated scale. Patients were initially followed every three months, then every six months, and then annually. The 30 patients undergoing radiation therapy who had PSA failure at the follow-ups were advised to start concomitant androgen suppression therapy. The original study end point was time to PSA recurrence (PSA level greater than 1.0 ng per mL and increasing over two consecutive follow-up visits). Follow-up was extended after three years to evaluate overall survival and prostate cancer–specific mortality.

Results: After a median follow-up of 7.6 years, 74 of the 206 participants had died. Deaths attributed to prostate cancer occurred in 14 men in the radiation therapy group and four in the combination group. Thus, the combination group had an estimated eight-year survival of 74 percent (95% confidence interval [CI], 64 to 82) compared with 61 percent in the radiation therapy group (95% CI, 49 to 71). Comorbidity scores were similar in both groups at baseline. Of the 157 men with no to minimal comorbidity, 42 (27 percent) died; and of the 49 patients with moderate to severe comorbidity, 32 (64 percent) died. In the lower comorbidity group, 17 deaths (40 percent) were from prostate cancer compared with one death (3 percent) in the higher morbidity group. In the lower comorbidity group, those receiving combination therapy had a significantly higher survival rate than those receiving radiation therapy alone (hazard ratio = 4.2 [95% CI, 2.1 to 8.5; P < .001]). For those with moderate to severe comorbidities, survival was similar between groups.

Conclusion: In patients with locally advanced prostate cancer and unfavorable prognostic factors, there is an overall survival benefit with combined radiation and androgen suppression therapy compared with radiation therapy alone. Combination therapy leads to a 13 percent absolute improvement in eight-year survival in all men and a 26 percent improvement in men with low comorbidity, compared with radiation therapy alone. However, this survival benefit did not extend to men with higher comorbidities. An explanation for this finding is that androgen suppression therapy worsens existing comorbidities, specifically cardiovascular comorbidities, counteracting the prostate cancer–specific survival advantage.