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INTRODUCTION

The androgen dependence of prostatic adenocarcinoma was first established more than 60 years ago by Huggins and Hodges [1]. The authors described both the effect of castration and oestrogens on advanced carcinoma of the prostate and on serum levels of acid phosphatase. Oral oestrogens and surgical castration subsequently became the standard primary treatments for advanced prostate cancer. It later became apparent that oestrogens may be associated with an increase in cardiovascular morbidity and mortality [2, 3]. As a result bilateral orchidectomy became the ‘gold standard’ against which other therapies were judged. Surgical castration results in a rapid reduction in circulating testosterone to < 2 nmol/l within 12 h. This defines the necessary reduction in circulating androgens to achieve therapeutic castration. Thus, achieving castrate levels of testosterone became the prime and only therapeutic strategy for advanced prostate cancer for several decades (Figure 11.1).

Figure 11.1

Androgen receptor signalling in the prostate. 5α-R, 5α-reductase; DHT, dihydrotestosterone; AR, androgen receptor; hsp, heat shock protein; IL-6, interleukin 6; GFs, growth factors; PKA, protein kinase A; STAT 3, signal transducers and activators of transcription 3; ARE, androgen response element.

These early insights into the hormonal control of prostate cells, both benign and malignant, led to further developments in the understanding of the mechanisms by which endogenous androgens stimulate cellular metabolism. Circulating androgens, either testosterone or adrenal androgens, are converted to dihydrotestosterone (DHT) in the cytoplasm by the enzyme 5-alpha-reductase. DHT binds to the androgen receptor which, under the influence of a number of cytoplasmic and nuclear factors, results in protein production and cell proliferation. Prostatic growth, and therefore prostate cancer growth, is mediated by this process and can be slowed or reversed by blocking the pathway at one of several points. As a result, a number of strategies for the hormonal control of prostate cancer have been developed.

The aim of this chapter is to examine contemporary approaches to the hormonal manipulation of prostate cancer. Developments of primary hormonal therapies and the evidence for antiandrogen monotherapy, luteinizing hormone-releasing hormone agonists (LHRHa) and maximal androgen blockade (MAB) will be addressed. The chapter will examine the timing of therapy and its value used as an adjunct to local ‘curative’ treatments. The length of therapy and the evidence for continual versus intermittent treatment will be examined. When hormonal therapy appears to be failing, there may still be androgen dependence and therefore an argument for second- and third-line hormonal manoeuvres.

THE TIMING OF HORMONAL THERAPY

The perceived wisdom until a decade or so ago was that the timing of hormonal intervention was irrelevant in influencing survival. This led to hormonal manoeuvres often being delayed until the disease was either metastatic and/or symptomatic. Evidence emerged during the last decade in favour of the earlier use of hormonal therapy. This evidence was twofold; the Medical Research Council (MRC) study of immediate versus delayed hormonal therapy for advanced prostate cancer and a group of studies investigating the use of hormones as an adjunct to local radiation or surgery ...

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