The first anti-androgen was the female sex hormone, oestrogen. Giving oestrogen to a man with prostate cancer shuts down the production of testosterone, the main male sex hormone, by the testes. As most prostate cancer cells depend on testosterone to grow and multiply, this arrests the progress of the cancer, and leaves the cells open to ‘apoptosis’, the process in which cells ‘commit suicide’. Oestrogen treatment did ease the symptoms of prostate cancer, but at the expense of feminizing the man, so that he grew feminine breasts, lost all sexual desire, and became impotent. It was a high price to pay for a treatment that in the end was not a cure.
Castration, by removing the testes at operation, was introduced in the 1940s. It had far fewer side effects. The prostate gland no longer has the stimulus of testosterone, and without the extra oestrogen the man does not turn into a pseudo-female. Castration is highly successful: it checks the growth of cancer, reducing the volume of the growth by more than 60 per cent, and often by 80 per cent in almost even case. For locally advanced cancers inside the pelvis, this means there is much less pressure on the bladder, urethra and rectum.
Men who had the operation felt much better within hours of the operation. Their bladder outflow problems, their pelvic and abdominal tenderness, difficulties with bowel movements, and feelings of general ill health, are almost instantaneously relieved. The operation itself is a relatively minor one, usually performed under a local or spinal anaesthetic, and causes much less discomfort than radiation. A few men are bruised afterwards, and even fewer have minor infections at the site of the operation (these can be readily dealt with).
Naturally, castration has its major drawbacks, not least the understandable reluctance that any man would feel at losing his testes. After castration, most men lose their sexual feelings and become impotent: in men with a good sex life its loss can seem worse than death itself. And castration is irreversible.
Happily there are now excellent medical, reversible, alternatives to castration that do exactly the same thing – remove the ability of the testes to produce testosterone. These are drugs that fall into two classes: pure anti-androgens, and “LHRH agonists’. The most commonly used anti-androgen drugs for locally advanced cancers are bicalutamide (Casodex), flutamide (Drogenil), leuprorelin acetate (Prostap), goserelin (Zoladex), and buserehn (Suprefact).
Win should they be used intermittently? Some researchers believe that giving anti-androgens constantly to men with locally advanced cancer may increase the risk that the cancer cells may become able to multiply in the absence of androgens. In medical terms they become ‘androgen-independent’, and therefore much more difficult to control. Androgen-independent cancers no longer respond to anti-androgen treatment, and need different types of chemotherapy. It would be far better to avoid this development. One way to do this, according to the new view, is to deprive the cancer of androgen enough to drive the PSA level below 4 ng/ml. and to keep it there for 32 weeks. The man should then be considered for stopping his anti-androgen treatment at the thirty-sixth week.
Over the next 8 to 14 weeks his testes will start to work again, and his testosterone level, and his PSA level, will gradually climb until they are back to their pre-treatment figures. The general rule is that if the man’s PSA level is under 20 ng/ml at first diagnosis, then the next course of anti-androgen drugs is started when the PSA has returned to that first measurement. If the initial PSA was above 20 ng/ml (and it can be in the thousands), then the next course of anti-androgens is started when the PSA (having fallen to near zero after the first course of treatment) has returned to 20 ng/ml.
This second course of treatment continues until the PSA has fallen again to near zero, and carries on for another 32 weeks before the treatment is again stopped. The next cycle of treatment is again started only after the PSA has risen as after the first cycle. Many patients go through five or more of these treatment cycles with no evidence of any advance in the tumor, and most show real shrinkage of their cancers.
These repeated courses of anti-androgen therapy interspersed with periods of no treatment have several advantages. They may prevent cancers from becoming androgen-independent and therefore resistant to treatment. Just as important, they improve the man’s quality of life. Stopping the drugs causes any side effects to disappear. The men recover their sexual feelings (that are almost always lost on anti-androgen), they feel generally better, and they are protected to some extent from one common complication of deprivation of androgen : the ‘brittle bone disease’ called osteoporosis. It is difficult to know for sure that intermittent anti-androgen therapy is better than constant anti-androgen therapy. The only evidence so far is a small trial in which the long-term results were similar to those of continuous androgen deprivation. Trials now under way (in 2001) in many more men with localized spread of their prostate cancers will settle the question.