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Adding Antiandrogen Therapy to Radiation Therapy in Recurrent Prostate Cancer

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Key Points

  • The addition of bicalutamide to radiotherapy improved overall survival in men with recurrent prostate cancer.
  • The risk of prostate cancer–specific mortality, distant metastases, and second biochemical recurrence was also reduced.

As reported in The New England Journal of Medicine by Shipley et al in the NRG Oncology Radiation Therapy Oncology Group (RTOG), the final analysis of the phase III RTOG 9601 trial showed that the addition of antiandrogen therapy with bicalutamide to radiation therapy significantly improves overall and prostate cancer–specific survival in men with recurrent prostate cancer.Since the inception of the trial, bicalutamide has been replaced by the use of injectable gonadotropin-releasing hormone agonists in this setting.

Study Details

In the double-blind trial, 760 patients from NRG Oncology member sites, including community-based sites, were randomized between 1998 and 2003 to receive antiandrogen therapy consisting of 24 months of bicalutamide at 150 mg daily (n = 384) or placebo (n = 376) daily during and after radiation therapy. Patients had undergone prostatectomy with lymphadenectomy and had disease on pathologic testing consisting of tumor stage T2 (confined to the prostate but with a positive surgical margin) or T3 (histologic extension beyond the prostatic capsule), no nodal involvement, and prostate-specific antigen level of 0.2 to 4.0 ng/mL. Radiation therapy consisted of two- or three-dimensional planning systems, according to institutional choice, and a total dose of 64.8 Gy given in 36 daily fractions of 1.8 Gy in 5 sessions per week. The primary endpoint was overall survival.

Patients had a median age of 65 years, median prostate-specific antigen level at baseline of 0.6 ng/mL, median interval between surgery and first detectable prostate-specific antigen level of 1.4 years, and median interval between surgery and trial entry of 2.1 years.

Improved Outcomes in Antiandrogen Group

Median follow-up among surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group vs 71.3% in the placebo group (hazard ratio [HR] = 0.77, P = .04). The 12-year prostate cancer–specific mortality rate on central review was 5.8% vs 13.4% (HR = 0.49, P < .001).

The cumulative incidence of distant metastases at 12 years was 14.5% vs 23.0% (HR = 0.63, P = 0.005). The cumulative incidence of a second biochemical recurrence at 12 years was 44.0% vs 67.9% (HR = 0.48, P < .001). In a post hoc analysis, the bicalutamide group had a 55% improvement in overall survival at 12 years among patients with a prostate-specific antigen level > 1.5 at study entry (HR = 0.45, P = .007).

In subgroup analyses, hazard ratios for overall survival favored bicalutamide according to Gleason score (significant for score = 7; HR = 0.69, P = .04), prostate-specific antigen levels of 0.7 to 1.5 (HR = 0.61, P = .03) or > 1.5 ng/mL, and positive or negative surgical margin (significant for positive margin; HR = 0.73, P = .04). The hazard ratio nonsignificantly favored placebo among patients with a baseline prostate-specific antigen level < 0.7 ng/mL (HR = 1.13, P = .53).

On multivariate analysis, bicalutamide treatment group (HR = 0.75, P = .025), entry prostate-specific antigen level of 1.6 to 4.0 vs 0.2 to 1.5 ng/mL (HR = 1.59, P = .003), age ≥ 65 vs < 65 years (HR = 2.18, P <.001), and Gleason score of 8 to 10 vs 2 to 6 (HR = 1.89, P < .001) were significantly associated with overall survival.

Adverse Events

Grade 1, 2, and 3 hot flashes in the bicalutamide vs placebo groups occurred in 16.6% vs 14.1%, 4.5% vs 2.9%, and 0.8% vs 0% of patients, respectively. Gynecomastia occurred in 69.7% vs 10.9% of patients, including grade 1, 2, and 3 events in 42.4% vs 8.8%, 23.6% vs 2.1%, and 3.7% vs 0% (P < .01 for all), respectively. Among late toxicities, grade 3 genitourinary adverse events occurred in 7.0% vs 6.0%, and grade 4 events occurred in 0.3% and 0.8%; grade 2 liver toxicity occurred in 1.6% vs 0.8%, and grade 3 toxicity occurred in 0.8% vs 0.3%.

The investigators concluded: “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.”

The study was funded by the National Cancer Institute and AstraZeneca.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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