New approach in the treatment of prostate cancer: Complete instead of partial withdrawal of androgens

Abstract

To completely eliminate androgens of both testicular and adrenal origin, 37 previously untreated patients with advanced (stages C or D) prostatic cancer received the combination therapy using an LHRH agonist (HOE-766) and a pure antiandrogen (RU-23908). The response criteria developed by the National Prostatic Cancer Project were used. A positive response (assessed by bone scan and/or serum prostatic acid phosphatase measured by radioimmunoassay was observed in 29 of the 30 cases who could be evaluated by these objective criteria (97%). The objective response was parallel to a rapid and marked improvement of the clinical signs and symptoms related to prostate cancer (prostatism, bone pain, and general well being). In marked contrast, the same combination therapy applied to patients previously treated with high doses of diethylstilbestrol (13 patients) showed a positive objective response in only 55% of cases. In 23 previously castrated patients showing relapse, an objective response was seen in only 25% of cases after neutralization of adrenal androgens by the antiandrogen. Previous treatment with chlorotrianisene (TACE) had no detectable effect on prostatic cancer and patients having previously received such treatment had a rate of positive response similar to previously untreated patients (five of five). In the previously untreated patients receiving the combination therapy, a 60% fall in serum prostatic acid phosphatase was observed as early as five days after starting treatment, at a time when the serum androgen concentration was 100% to 200% above control. Combined treatment with the pure antiandrogen completely prevents flare-up of the disease, a complication previously found in a significant proportion of patients treated with an LHRH agonist alone. The present data show that complete withdrawal of androgens by combined hormonal therapy with the LHRH agonist (or castration) and a pure antiandrogen leads to a positive objective response in more than 95% of cases as opposed to 60%-70% as reported by many groups using the previous partial hormonal therapy (castration or high doses of estrogens). Adrenal androgens are most likely responsible for this difference. The present study also shows that the proportion of androgen-sensitive cells decreases from more than 95% in untreated patients to 25% to 55% after previous partial hormonal therapy. Such data clearly indicate that the previous partial hormonal therapy exclusively aimed at neutralizing testicular androgens left 25% to 55% of cancer cells having a relatively low sensitivity to androgens in a hormonal milieu compatible with their continuous growth. No clinical or biochemical side effect could be detected except those related to reduced serum androgen levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Bilateral orchiectomy versus total androgen blockade in the management of metastatic cancer prostate

“…Therefore it appears logical to treat patients of prostate cancer by combined / Total androgen blocked-both testicular& adrenal androgen -a theory first propounded by labrie et al in 1983. 3 Contrary to this report, studies by Schroder and lverson have showed no significant difference between the two arms. 4,5 An overview analysis of 22 studies by Prostate cancer Trial list Collaborative Group revealed only 3% improved overall 5-years survival in favour of combined androgen blocked.…”

A comparison of androgen deprivation therapy versus surgical castration for patients with advanced prostatic carcinoma

“…The discovery of synthetic luteinizing hormone-releasing hormone agonists reduced the cardiac toxicity and the other side effects of androgen deprivation therapy. Then, in 1983 Labrie et al [9] conducted a new trial for the total elimination of androgen from both the testes and adrenal glands. They reported a small series of patients with advanced prostate carcinoma managed with an LHRH analogue combined with an oral antiandrogen.…”

“…From that point on, surgical castration was largely replaced by medical castration with an LHRH agonist to reduce the psychological impact of orchiectomy to the patients and to preserve reversibility [7,8] . Then, maximal androgen blockade (MAB) was proposed to address the androgens of adrenal origin [9] . Many trials followed comparing MAB and monotherapy [10][11][12] .…”

Advanced prostate cancer

“…15 Several studies have investigated CAB, but only two have shown a statistically signi®cant survival advantage over monotherapy. 16,17 CAB is most effective in patients with minimal disease and may have a subjective bene®t in those with symptomatic disease.…”

“…The drawback of this study is that there was no control arm. 15 The superiority of CAB was documented by two major randomized studies. 16,19 Dijkman 20 also reported on a large double blind trial done on 457 patients randomized to placebo or nilutamide following orchiectomy.…”