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Reference - RTOG 9601 trial (N Engl J Med 2017 Feb 2;376(5):417) (level 2 [mid-level] evidence)
- After radical prostatectomy, recurrence or persistence of prostate cancer detected by prostate specific antigen may be managed by watchful waiting, or salvage radiation therapy with or without androgen deprivation therapy in men without metastases.
- The RTOG 9601 trial compared survival at 12 years in 760 men with biochemical evidence of prostate cancer after radical prostatectomy with lymphadenectomy and without metastases randomized to the androgen receptor blocker, bicalutamide, plus salvage radiation therapy vs. salvage radiation therapy alone.
- Addition of bicalutamide to salvage radiation therapy improved overall- and disease-specific survival, and decreased occurrence of metastatic prostate cancer at 12 years.
After radical prostatectomy for prostate cancer, a failure of prostate specific antigen (PSA) to decrease to undetectable levels or a previously undetectable PSA level that increases on ≥ 2 measurements are considered evidence of recurrence without distant metastases. Treatment options recommended by the National Comprehensive Cancer Network Guidelines include watchful waiting or salvage radiation therapy with or without androgen deprivation therapy. In order to evaluate the effect of adding an androgen receptor blocker to salvage radiation on survival, 840 men with PSA levels 0.2-4 ng/mL for ≥ 8 weeks after radical prostatectomy with lymphadenectomy and who were to receive salvage radiation therapy were randomized to bicalutamide 150 mg orally once daily vs. placebo for 24 months. All men had either tumor stage T2 or T3 without nodal involvement at time of surgery. The median interval between surgery and detection of PSA was 1.4 years and between surgery and trial entry was 2.1 years. After randomization, 79 men were deemed ineligible, and 1 withdrew consent; the remaining 760 men who started treatment were evaluated.
The withdrawal rate before trial completion was 26.6% in the bicalutamide group and 12.8% in the placebo group; however analyses were conducted in all 760 men. Comparing bicalutamide plus salvage radiation therapy to salvage radiation therapy alone, the actuarial rate of overall survival at 12 years was 76.3% vs. 71.3% (p = 0.04, NNT 20). The 12-year incidence of prostate cancer-related death was 5.8% vs. 13.4% (p < 0.001, NNT 13) and metastatic prostate cancer occurred in 14.5% vs. 23% (p = 0.005, NNT 12). Gynecomastia was more common in the bicalutamide group, occurring in 69.7% vs. 10.9% (p < 0.001, NNH 1). Post hoc subgroup analysis indicated that bicalutamide significantly improved overall survival in 118 men with PSA level at trial entry > 1.5 ng/mL (73.5% vs. 48.9%, p = 0.007, NNT 4) with lesser, but significant benefits, seen in men with PSA level 0.7-1.5 mg/mL.
This trial indicates that addition of bicalutamide to salvage radiation therapy may increase overall survival and disease-specific survival and may decrease occurrence of metastases in men with biochemical evidence of prostate cancer after radical prostatectomy with lymphadenectomy. A potential source of bias in this study stems from the high rate of withdrawal that was greater in the intervention group than in the control group. The findings might be biased in favor of intervention if those who withdrew from the intervention group were at a disadvantage for survival compared to those who remained in the study. Gynecomastia was commonly observed, but it should be noted that measures to prevent its occurrence were not undertaken during the study in order to maintain blinding. Overall these results suggest that 24 months of bicalutamide 150 mg once daily, during and after salvage radiation therapy, may be preferred over salvage radiation therapy alone to improve survival in selected men with biochemical evidence of prostate cancer after prostatectomy with lymphadenectomy.
For more information, see the Management of biochemical relapse of localized prostate cancer topic in DynaMed Plus. DynaMed users click here.