Endocrine treatment in prostate cancer

Over its natural course, prostate cancer is a heterogeneous tumour with a g enerally slow but constant rate of growth. The androgen dependence of the p rostate gland was demonstrated more than half a century ago by the landmark studies of Professor C. Huggins and colleagues. They established that andr ogens are implicated not only in growth regulation of the normal gland but also in the pathogenesis of prostate cancer, and that this malignant tissue retains some degree of androgen dependence. This concept was supported by studies of symptomatic clinical cancer, with androgen ablative therapy brin ging relief to the patient in more than 80% of the cases. The classical tre atment consisted of either bilateral orchiectomy, or administration of diet hylstilbestrol (DES). Other forms of therapy followed, involving successive waves of new compounds that either withdrew androgen support from the canc er or blocked the androgens from their receptors in the prostate cancer cel ls. Chronologically, the progestagens can be well recognised, with one in p articular: The successful derivative, cyproterone acetate (CPA). There also have been a number of oral vs. parenteral estrogens, the development of th e luteinizing hormone-releasing hormone agonists (LH-RHA), the introduction of the non-steroidal anti-androgens characterised by flutamide and casodex , and more recently, the introduction of the LH-RHA. Moreover, there have b een multiple possible forms of combination treatment to obtain maximal andr ogen blockade (MAB). However, no major differences in treatment outcome hav e been reported during the last 5 decades and most treatment choices have b een based on tradition, associated side effects, the preferences of a parti cular doctor and patient, together with economic considerations. Furthermor e, endocrine treatment has never been shown to curl clinical prostate cance r, which consequently has led to initiatives to defer endocrine treatment o r to use it intermittently or use it as a form of neo-adjuvant or adjuvant treatment with surgery or radiotherapy. The history of endocrine therapy is replete with clinical trials that do not represent the patient population in general, and these trials share the clinical fact that they ignore the 2 0% to 30% of all patients who lack an initial response to a given endocrine treatment. Thus, it is no wonder that prognostic factors determine the out come more than the treatment itself. Important to current endocrine treatme nt, however, is the shift to earlier stages of prostate cancer at initial d iagnosis. Integration of endocrine treatment at this earlier phase in the p athogenesis of prostate cancer will substantially alter the treatment strat egy in relation to long-term benefit with regard to survival, associated si de effects, and costs. This complex adjustment is enhanced by recent discov eries in the molecular biology of the prostate which show, on the one hand, that the dihydrotestosterone-androgen receptor (DHT-AR) complex is importa nt in the regulation of gene expression, but also that a number of intrinsi c factors (e.g., peptide growth regulatory factors) can, through various pa racrine, autocrine or intracrine interactions, exercise a major influence o n cellular homeostasis and the regulation of prostatic growth. (C) 2000 Wil ey-Liss, Inc.