Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: A randomized, multicenter study of orchiectomy alone versus orchiectomy plus estramustine phosphate

Objectives. Based on the theory that hormone-resistant cells are present in all metastatic patients, early administration of chemotherapy appears to be logical and its use is supported by experimental studies. Therefore, trials with combined hormonal and cytotoxic treatment as primary therapy should be conducted. In the present trial, the efficacy and tolerance of estramustine phosphate (EMP) as a chemotherapeutic agent in addition to hormonal treatment (orchiectomy) was studied in patients with metastatic and nonmetastatic prostate cancer not previously treated. EMP was chosen because it produces few serious adverse reactions and no cumulative toxicity. Methods. Four hundred nineteen patients were included in a 1.5-year period starting in January 1989. Patients with locally advanced prostate cancer or with bone metastases were randomized to orchiectomy (O) or orchiectomy followed by EMP (O + E), given until progression. Results. Analysis of the total group showed no significant difference in time to progression between the treatment groups. Because the course of the disease is different in patients with either T4 tumor only or with lymph node metastases only (MO) as compared with patients with bone metastases (M1) and because the number of progressions in the MO patients was low, corresponding analyses were performed for these subgroups as well. In the Mi patients, there was a tendency for a longer time to progression in the O + E group than in the O group, but there was no indication of a difference between the groups with regard to survival. In the MO patients, there was no indication of any difference in results between the treatments. Multivariate analysis of prognostic factors showed pain, alkaline phosphatase, metastasis status, and tumor stage to be significant factors. There was a relation between age and drug treatment in that a significant beneficial effect of EMP in terms of prolonged progression-free interval as well as survival was evident in younger patients (aged less than 73 years) with metastatic disease. Tumor stage was also of importance for the drug effect; T0 to T3 patients who received EMP survived longer than those who were treated with orchiectomy only. The most common adverse reaction was nausea in the O + E group, which led to discontinuation of the drug in 7 patients. Cardiovascular problems are not uncommon in this age group, and there was a higher incidence of cardiovascular events, predominantly cardiac failure, in the O + E group, leading to treatment interruption in 16 patients. Conclusions. Our results indicate that future studies of hormono/chemotherapy should focus on younger patients with bone metastases. (C) 1997, Elsevier Science Inc.