Chemoprevention for prostate cancer – the way forward?

Authors


Prostate cancer continues to be of considerable interest to urologists, despite being a subject of much controversy for several years. Screening, markers, diagnostic methods, therapeutic strategies, methods of selection for specific treatments, complications of treatment, advanced disease, and hormone-resistant disease still retain interest and still occupy much discussion time at conferences. The issue, which will increasingly be read about, is chemoprevention. What happened first in cardiology, i.e. a movement of research support to ‘prevention’, so that it became a major part of the science of cardiology, will also happen in urological cancer. If the public is offered scientific evidence that prevention works, they will be happy to perhaps alter their approach to their lifestyle.

In simplest terms, the public could adopt measures to prevent prostate cancer by altering their lifestyle in one of the followings ways: do something, stop doing something, or do nothing. From the experience of prevention in other cancers, it is unlikely that people will stop doing something (e.g. giving up cigarettes); in addition, if there is proof that prevention is possible by taking a pill, the public is very likely to take an active rather than an inactive approach (e.g. taking statins or salicylate to prevent the onset or effects of atherosclerosis). Indeed, people will even take a drug as potentially risky as warfarin in such a situation.

Where breast cancer leads, urologists often follow, and so it is helpful to learn lessons from these trials, which have been taking place to evaluate chemoprevention in that condition. In two recent articles the science of cancer prevention [1] and the main outcomes of breast cancer prevention trials [2] were described extensively. Tamoxifen definitely reduces the risk of developing breast cancer by ≈ 49%; it is the first drug to be shown to be able to do this in cancer. It has also been suggested that this is maximal in oestrogen-receptor positive breast cancer, that newer agents such as raloxifene and the aromatase inhibitors should be evaluated further, and that attention also needs to be directed at preventing oestrogen-receptor-negative disease and reducing the side-effects of tamoxifen.

However, several other issues relating to chemoprevention have been revealed by these large randomized controlled trials. Although tamoxifen has been found to have a definite chemopreventive role, it has yet to be accepted universally in this role. Some chemopreventive agents may have a neutral effect, e.g. zinc, retinol or niacin, and some may actually be harmful, e.g. beta-carotene (which is probably a co-carcinogen with cigarette smoke). In addition, some agents may actually inhibit and promote carcinogenesis in different organs.

Now prostate cancer is being studied in the same way and although no results are yet available, it is timely to anticipate these trials and assess the impact they might have. There are two main trials already underway in the USA; the Prostate Cancer Prevention Trial (PCPT) [3,4], and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The first of these can be expected to generate meaningful results by 2004, but the second [5], which has not been described in print, will still be enrolling for some time, with results appearing in 8–10 years time.

The PCPT is based on the use of finasteride as a chemopreventive agent and was recently discussed at a meeting in Europe (supported by a grant from Merck). The trial was proposed because of the finding that boys born with a defect in the 5α-reductase enzyme had a rudimentary prostate, undetectable PSA levels as adults, no evidence of prostatic epithelium, and that they did not develop BPH or prostate cancer as adults [6].

The PCPT opened for accrual in October 1993 and closed 3 years later after randomizing 18 881 men. This enables a 90% power to detect a 25% reduction in prostate cancer incidence;the outcome of the trial is keenly awaited. It is to be hoped that there will be a positive result from this study in the same way that a hormone-based trial showed a positive result in breast cancer. Finasteride has a side-effect profile which should probably yield a positive risk-benefit analysis unless new, unsuspected adverse events are unearthed by the trial.

There are questions to be anticipated; if a 25% reduction in prostate cancer incidence is statistically confirmed by this study, then a valuable adjunct in the overall management of prostate cancer will have been discovered. If it is not thus proven, the opposite will be the case. The grey area lies in the ‘almost’ result. What will be the view of the urological world if there is ‘almost’ a 25% reduction, but not quite, e.g. an 18% reduction? The question of statistical vs potential clinical significance will again be debated.

The PCPT is as significant as were the trials of chemoprevention in breast cancer. Perhaps chemoprevention, or indeed any form of prevention, might challenge screening as an area where resources should be channelled. It may indeed become the way forward in prostate cancer.

Ancillary