Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma.
Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy.
                Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually.
                After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome.
                Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer. The results of a large randomized prospective clinical trial conducted by the Veterans Administration Co-operative Urological Research Group (VACURG) in 1968 are updated and reevaluated. In this study, placebo, diethylstilbestrol (DES, 5 mg/day), orchiectomy plus placebo, and orchiectomy plus DES were compared in patients whose conditions were initially diagnosed as stage III and IV carcinoma of the prostate. Results showed that orchiectomy alone or in combination with estrogen did not improve overall survival rates in stage III and IV carcinoma of the prostate. In the two treatment groups receiving estrogen, however, there were fewer deaths due to cancer of the prostate, but this effect tended to be offset by an increased number of deaths due to cardiovascular causes. Deaths from other causes showed no particular pattern with respect to treatment. These studies showed that estrogen is more effective than orchiectomy in preventing deaths from cancer and that the addition of orchiectomy to estrogen does not offer any clear-cut advantage over estrogen therapy alone. If cancer symptoms necessitate treatment, initial therapy with estrogen is preferred. Orchiectomy should be reserved for those circumstances in which a patient is not reliable, cannot tolerate estrogens, or has severe cardiovascular disease.
The evidence from randomized controlled trials is limited by the variability in study design, stage of cancer and subjects enrolled, interventions utilized, definitions and reporting of outcomes and the lack of PSA testing for diagnostic and monitoring purposes. However, the available information suggests that early androgen suppression for treatment of advanced prostate cancer reduces disease progression and complications due to progression. Early androgen suppression may provide a small but statistically significant improvement in overall survival at 10 years. There was no statistically significant difference in prostate cancer specific survival but a clinically important difference could not be excluded. These outcomes need to be evaluated with the evidence suggesting higher costs and more frequent treatment related adverse effects with early therapy. Additional studies are required to evaluate more definitively the efficacy and adverse effects of early versus delayed androgen suppression in men with prostate cancer. In particular trials should evaluate patients with advanced prostate cancer diagnosed by PSA testing and men with persistent or rising PSA levels following treatment options (e.g. radical prostatectomy, radiation therapy or observation) for clinically localized disease.