Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer

Abstract

Background: Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown.

Methods: In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival.

Results: The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001).

Conclusions: The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874 .).

Figure 1. Enrollment, Randomization, and Follow-up of the Patients

PSA denotes prostate-specific antigen.

Figure 2. Kaplan–Meier Estimates of Overall Survival and Cumulative Incidence Estimates of Rates of Death from Prostate Cancer and of Metastatic Prostate Cancer

All patients underwent radiation therapy in addition to receiving either antiandrogen therapy with bicalutamide or placebo. The overall survival analysis among patients with a PSA level of more than 1.5 ng per milliliter at trial entry was a post hoc analysis. Death from prostate cancer included all deaths from prostate cancer or treatment complications as well as death from an unknown process in patients with active prostate cancer on the basis of central review.

Figure 3. Effect of Antiandrogen Therapy with Bicalutamide on 12-Year Overall Survival

All patients underwent radiation therapy in addition to receiving either antiandrogen therapy with bicalutamide or placebo. The scale for the Gleason score ranges from 2 to 10, with higher scores indicating a worse prognosis. Data on the Gleason score were missing for one patient in each group. P values were calculated with the use of the log-rank test.