Complete Androgen Blockade versus Chemical Castration in Advanced Prostatic Cancer: Analysis of an Italian Multicentre Study

Abstract

Objectives: In spite of a great amount of data, the hormonal treatment of advanced prostatic carcinoma (CaP) still remains controversial. As a relevant amount of dihydrotestosterone is present within the prostate tissue after castration, complete androgen blockade (CAB), with inhibition of the activity of both testicular and adrenal androgens, has been advocated as up-front treatment of advanced CaP. However, many controlled studies have failed to demonstrate a benefit for CAB in comparison with simple surgical or chemical castration. The present study was performed to bring additional data for a worldwide meta-analysis of all phase III trials comparing castration and CAB. Methods: This is a centrally controlled phase III study in which chemical castration with leuprorelin acetate depot was compared with leuprorelin plus flutamide in stage C and D CaP. Two hundred and forty-one eligible and evaluable patients with histologically proven CaP were recruited for the study (120 treated with castration and 121 with CAB). The diagnostic and staging workup consisted of blood chemistry, general condition assessment, prostate-specific antigen (PSA), abdominal sonography and computed tomography scan, and whole-body isotopic bone scan. End points of the study were survival, time to treatment failure, and time to progression. The patients were followed every 6 months with PSA and sonography. Results: At a cut-off analysis performed in December 1996, when the mean follow-up period was 43.7 ± (SD) 24.1 months, no statistical differences in terms of time to treatment failure, time to progression, and death rate could be detected. Also considering the common risk factors, such as basal PSA, haemoglobin, alkaline phosphatase, and Gleason score, the outcome did not show any clear advantage for CAB. Conclusions: This study appears to confirm that the advantages of first-line CAB in CaP are at best marginal. The final analysis will be performed when the follow-up period has reached 5 years, but it seems unlikely that the present results will change.

Maximum androgen-blockade with medical or surgical castration in advanced prostate cancer: A meta-analysis of nine published randomized controlled trials and 4128 patients using flutamide

“…3,15 Data that were available only in abstract form or in non-peer reviewed literature were excluded. 9,14 Letters were sent to the principle authors of each study requesting updated information. Data from each eligible new and updated study were extracted using forms developed previously.…”

Systematic review and meta‐analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma

“…Only 4 of the 12 trials that used an LHRH agonist for monotherapy also used an initial brief treatment with an antiandrogen to control the tumor flare reaction. [25][26][27][28] Therefore the other eight trials may be biased against the monotherapy arm because they did not use an antiandrogen to control flare. The flare reaction is not reported to occur when orchiectomy is used as monotherapy.…”

The discharge

“…Only 4 of the 12 trials that used an LHRH agonist for monotherapy also used an initial brief treatment with an antiandrogen to control the tumor flare reaction 25–28. Therefore the other eight trials may be biased against the monotherapy arm because they did not use an antiandrogen to control flare.…”

“… Meta‐analysis of survival at 5 years, monotherapy versus combined androgen blockade. Point estimates for hazard ratios (center marks) relative to orchiectomy and their 95% confidence intervals (ends of the horizontal bars) for 10 studies reporting 5‐year survival (Klosterhalfen and Becker,41 Iverson et al,31 Denis et al,32 Robinson et al,33 de Voogt et al,25 Crawford et al,30 Djikman et al,37 Tyrrell et al,46 Bono et al,28 Eisenberger et al,15 and all studies). …”