Radiotherapy Alone versus Radiotherapy plus Short-Term ADT in Prostate Cancer

Treatment regimens for clinically localized prostate cancer have, since the 1990s, included radiotherapy plus long-term treatment with luteinizing-hormone–releasing analogues and oral antiandrogen agents to induce apoptotic regression in androgen-responsive cancers. This regimen has been shown to improve the prospects of local control and the duration of survival free of metastatic disease. Long-term treatment (≥2 years) with this regimen improved overall survival but was associated with increased toxic effects, including erectile dysfunction and myocardial infarction. Short-term use of androgen-deprivation therapy (ADT) may mitigate the toxic effects, according to researchers. With the introduction of prostate-specific antigen (PSA) testing, more patients are being diagnosed with early-stage disease. In 1994, noting that less was known about the role of short-term ADT in men receiving radiotherapy for early-stage prostate cancer, a Radiation Therapy Oncology Group (RTOG) opened a large, randomized trial (RTOG 94-08) to evaluate the efficacy of adding short-term ADT to radiotherapy. The researchers sought to determine whether adding short-term ADT to radiotherapy would improve survival among men with nonbulky localized prostate adenocarcinomas and an initial PSA level of ≤20 ng/mL. Results of the trial were reported in the New England Journal of Medicine [2011;365(2):107-118]. The primary end point of the trial was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. The median follow-up period was 9.1 years. A total of 1979 eligible patients from 212 centers in the United States and Canada were randomly assigned to a combined-therapy group (radiotherapy plus short-term ADT; n=987) or radiotherapy alone (n=992). The groups were well balanced at baseline, with no significant differences in demographic or tumor-related characteristics. The 10-year overall survival rate in the combined-therapy group was 62%, compared with 57% among patients in the radiotherapy-alone group; the hazard ratio (HR) for death with radiotherapy alone was 1.17 (95% confidence interval [CI], 1.01-1.35; P=.03). The 10-year disease-specific mortality was 8% in the radiotherapy-alone group compared with 4% in the combined-therapy group (HR, 1.87; 95% CI, 1.27-2.74; P=.001). The addition of short-term ADT to radiotherapy significantly improved biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years. In the radiotherapy-alone group, the 10-year biochemical failure was 41% compared with 26% in the combined-therapy group (HR, 1.74; 95% CI, 1.48-2.04; P<.001); the 10-year cumulative incidence of distant metastases was 8% in the radiotherapy-alone group and 6% in the combined-therapy group (HR, 1.45; 95% CI, 1.03-2.06; P=.04). At 10 years, the cumulative incidence of death from causes other than prostate cancer was higher in the radiotherapy-alone group compared with the combined-therapy group, although the difference was not significant (37% vs 35%; P=.56). The groups had similar acute and late radiation-induced toxic effects. At pretreatment, 48% of patients in the combined-therapy group responding to a questionnaire reported that they were “always or almost always able to have an erection” compared with 54% of those in the radiotherapy-alone group, a nonsignificant difference (P=.15). At 1 year, the rates were 21% and 33%, respectively (P=.004). Compared with pretreatment scores, scores at 1 year were improved in 9% of patients, remained the same in 33%, and were worse in 58%; there were no significant differences between the groups. In summary, the researchers said, “among patients with stage T1b, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng/mL or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men.”