The Urological Group of the European Organization for Research and Treatment of Cancer (EORTC

Endocrine-Related Cancer (1998) 5 353-356 © 1998 Society for Endocrinology Printed in Great Britain 1351-0088/98/005-353 $08.00/0 353 Prostate cancer in its natural course is a single, biological process with an unusually slow but constant growth. This growth can be temporarily arrested by endocrine treatment but there are proven data that the clinical stage and grade of the tumor, as well as a number of other prognostic factors, define the outcome of the disease independently of a given treatment (Denis 1993). It is a fine point to know that the landmark publication by Huggins and Hodges (1941) on the effect of estrogens, castration, and androgens on serum phosphatases in metastatic carcinoma of the prostate claimed no more than a decrease of these serum markers as well as a net relief of pain in patients with symptomatic, widespread clinical prostate cancer. However, this publication led to the widespread use and abuse of diethylstilbestrol (DES), bilateral orchiectomy, or both. The equivalent efficacy of 5 mg DES and surgical castration was demonstrated in a large, randomized trial (Nesbit & Baum 1995), but it took a number of trials, the famous VACURG studies, to demonstrate the lethal side-effects of estrogens (Blackard 1975). Now, more than half a century later, we know that prostate cancer growth is partly dependent on androgens, with the dihydrotestosterone-androgen receptor complex (DHT-AR) regulating the gene expression. We also know that androgens are essential, but not directly or solely responsible, for cellular proliferation of prostate cancer cells. The homeostasis of the organ is secured by a balance between the growth and inhibiting factors. We also know that all endocrine treatment is based on the withdrawal or blockade of androgen stimulation from the androgen receptors in the prostate cells, with a subsequent temporary arrest of the cancer growth in about 60% of all treated cases. The happy clinician only remembers that the subjective response in symptomatic cases can reach up to 80% of all treated cases, making endocrine treatment the first primary choice treatment in these men. The marker response on prostate specific antigen (PSA) drives the clinician to ecstasy, since endocrine treatment is able to lower the serum values of these markers in up to 90% of treated patients. Once again, history repeated itself and, instead of concentrating on why 20% to 40% of the patients did not show objective response to endocrine treatment, extensive clinical research followed the easy road and sustained a wide array of first-line endocrine treatments utilized in daily practice to palliate symptomatic prostate cancer, while at the same time hoping to prolong the time to progression or, even better, to decrease the mortality due to prostate cancer. The scheme of routinely used endocrine treatments is listed in Table 1. It is regrettable that clinical practice completely abandoned DES treatment and adequate randomized, prospective trials were never performed after the publication of the cardio-vascular complications associated with its use. The Urological Group of the European Organization for Research and Treatment of Cancer (EORTC GU Group) followed the same cautious path, even after demonstrating that the response rates for DES (3 mg/per day) were the highest compared with medroxyprogesterone acetate and cyproterone acetate in two randomized protocols (30761 and 30762) (PavoneMacaluso et al. 1986, Smith et al. 1986). Instead, they followed the reported results of Bracci (1979), who noted an improved response and outcome of patients with advanced prostatic cancer when cyproterone acetate (CPA) treatment was combined with bilateral orchiectomy. The Group decided to gamble on the combination treatment and in the EORTC study 30805 bilateral orchiectomy, the then ‘gold standard’, was compared with DES (1 mg/per day), and with bilateral orchiectomy and CPA (50 mg 3 times per day). No difference in time to progression and overall survival was noted between the three treatment arms. Once again, the final analysis demonstrated that the outcome of the disease was determined more by the initial prognostic factors than by the allocated treatment (Robinson et al. 1995). With the Maximal androgen blockade: facts and fallacies