Endocrine treatment in prostate cancer (2000)

Over its natural course, prostate cancer is a heterogeneous tumour with a generally slow but constant rate of growth. The androgen dependence of the prostate gland was demonstrated more than half a century ago by the landmark studies of Professor C. Huggins and colleagues. They established that androgens 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 bringing relief to the patient in more than 80% of the cases. The classical treatment consisted of either bilateral orchiectomy, or administration of diethylstilbestrol (DES). Other forms of therapy followed, involving successive waves of new compounds that either withdrew androgen support from the cancer or blocked the androgens from their receptors in the prostate cancer cells. Chronologically, the progestagens can be well recognised, with one in particular: The successful derivative, cyproterone acetate (CPA). There also have been a number of oral vs. parenteral estrogens, the development of the 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 been multiple possible forms of combination treatment to obtain maximal androgen blockade (MAB). However, no major differences in treatment outcome have been reported during the last 5 decades and most treatment choices have been based on tradition, associated side effects, the preferences of a particular doctor and patient, together with economic considerations. Furthermore, endocrine treatment has never been shown to cure clinical prostate cancer, which consequently has led to initiatives to defer endocrine treatment or 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 20% 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 outcome more than the treatment itself. Important to current endocrine treatment, however, is the shift to earlier stages of prostate cancer at initial diagnosis. Integration of endocrine treatment at this earlier phase in the pathogenesis of prostate cancer will substantially alter the treatment strategy in relation to long-term benefit with regard to survival, associated side effects, and costs. This complex adjustment is enhanced by recent discoveries in the molecular biology of the prostate which show, on the one hand, that the dihydrotestosterone-androgen receptor (DHT-AR) complex is important in the regulation of gene expression, but also that a number of intrinsic factors (e.g., peptide growth regulatory factors) can, through various paracrine, autocrine or intracrine interactions, exercise a major influence on cellular homeostasis and the regulation of prostatic growth.