[New approach in the treatment of prostatic cancer: combined use of a LHRH agonist and an androgen antagonist]

Abstract

Following the studies of Huggins and colleagues in 1941, the hormonal treatment of prostatic cancer has been aimed at neutralizing the influence of testicular androgens through surgical castration or the administration of high doses of estrogens. These two approaches cause a temporary improvement in 60 to 70% of advanced prostatic cancer. However, castration is not always well accepted and high doses of estrogens are frequently accompanied by lethal cardiovascular side effects. Following our observation that treatment with LHRH agonists causes a blockage in the biosynthesis of testosterone by the testis accompanied by a marked reduction in prostatic weight in the rat, the possibility was opened for a new approach in the treatment of prostatic cancer. Fortunately, among all species studied, man is the most sensitive to the inhibitory effect of LHRH agonists on testicular androgen biosynthesis and near-medical castration can be easily achieved without secondary effects other than those related to low androgen levels. Following long-term studies in the rat which have shown that the inhibitory effect of LHRH agonists is markedly potentiated by simultaneous administration of a pure antiandrogen, a study using the LHRH agonist [D-Ser(TBU)6, des-Gly-NH2(10)] LHRH ethylamide (HOE-766) and the pure antiandrogen RU-23908 was performed in men with advanced prostatic cancer. The combined treatment with the LHRH agonist and the antiandrogen in 37 patients not previously treated caused a positive objective response in 97% of cases while, previously, partial hormonal treatment achieved through castration or high doses of estrogens caused a positive response in 60 to 70% of patients. The serum levels of prostatic acid phosphatase (PAP) were decreased to 40% of control as early as four days after starting combined hormonal therapy. By contrast, in patients previously treated with estrogens or castrated, complete neutralization of adrenal androgens by the antiandrogen led to a much lower rate of positive response ranging from 25 to 55%. In patients previously treated, there is thus a predominance of tumor cells insensitive to androgens. An additional important finding in this study is that the administration of the antiandrogen prevents the flare-up of the disease frequently observed when LHRH agonists are administered alone.(ABSTRACT TRUNCATED AT 400 WORDS)