Androgen priming and cytotoxic chemotherapy in advanced prostatic cancer

Hormone manipulation has been standard therapy for metastatic adenocarcinoma of the prostate for many years. Recently cytotoxic drugs have been studied, but their effectiveness has been limited, indicating the need for new therapeutic approaches. Based upon the hypothesis that cytotoxic drugs are most effective against actively proliferating cells, we have designed a clinical pilot study employing cyclical androgen priming to transiently stimulate tumor cells followed by cytotoxic chemotherapy with cyclophosphamide and methotrexate. There were nine responders (43%) out of 21 patients entered in the study, with a median duration of response that has not been reached at 9+ months. Survival was significantly better in responders than in non-responding patients. These results are similar to those of other studies in which chemotherapy was used alone. Chemotherapy toxicity with this schedule was mild. However, the androgen priming frequently resulted in increased bone pain, and there was one episode of spinal cord compression, suggesting that tumor stimulation was achieved. These results demonstrate the need for additional basic studies of the effects of testosterone on tumor cell kinetics before further clinical trials of this approach are initiated.