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Treatment of Prostate Cancer with Gonadotropin-Releasing Hormone Agonists

Departments of Molecular Endocrinology, Medicine, Nuclear Medicine and Urology, Laval University Medical Center Quebec G1V 4G2, Canada
Hotel-Dieu Hospitals St-Jerome and Lévis, Canada

Correspondence: Address requests for reprints to: Dr. F. Labrie, Department of Molecular Endocrinology, Laval University Medical Center, 2705 Boulevard Laurier, Ste-Foy, Quebec G1V 4G2, Canada.

Abstract

IT IS now well established that chronic treatment with GnRH agonists offers an advantageous alternative to orchiectomy and estrogens for the treatment of prostate cancer. Castration levels of androgens can thus be easily achieved without side effects other than those related to castration levels of serum androgens. However, man is unique among species in having a high secretion rate of precursor adrenal steroids which are converted into active androgens in the normal prostate and prostatic cancer. All the enzymes required for the transformation of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and androst-5-ene-3β,17β-diol are present in prostatic tissue. Moreover, as shown in many systems, castration levels of serum testosterone (T) at 0.2–0.4 ng/ml exert significant androgenic activity in target tissues. In order to inhibit the action of androgens of both testicular and adrenal origin, GnRH agonists have been administered in association with the pure antiandrogen Flutamide in patients having clinical stage D2 (bone metastases) prostate cancer. A positive objective response assessed according to the criteria of the United States National Prostatic Cancer Project (USNPCP) has been observed in 84 of the 88 patients who had received no previous treatment (95.4%). After 2 yr of treatment, the probability of continuing response is 70% compared to 0–10% by previous approaches. In addition, the death rate at 2 yr is at 10.9% as compared to approximately 50% after standard hormonal therapy. When the same treatment was applied to patients who had received previous hormonal therapy (orchiectomy, estrogens or GnRH agonists alone) before showing a relapse, the response rate decreased to 62.9% and the death rate at 2 yr was 52%. The present data show that the combination therapy applied as first treatment decreases by more than 4-fold the death rate within the first 2 yr of treatment while preserving a good quality of life.

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