Clinical Aspects

Prostate cancer has a slow natural history. This has a number of consequences, and is responsible for one of the unique therapeutic features of the disease - that some patients can be left untreated because the disease does not progress during their lifetime (3). Many years ago, autopsy data showed that the true incidence of prostate cancer, as defined on histological grounds, greatly exceeded the observed incidence of clinically significant disease (4). The prevailing concept resulting from this was that a form of prostate cancer existed, which inherently lacked the biological potential to spread locally and to metastasize - so-called "latent" prostate cancer. This, in turn, implies that in lesions which microscopically look like small cancers in the prostate gland, a specific event or series of events is required for a tumour to attain metastatic potential (and therefore clinical significance). In support of this hypothesis is the observation that, although the incidence of prostate cancer differs greatly worldwide, the incidence of "latent" prostate cancer (defined from autopsy studies) is the same. For example, Japan has a very low incidence of prostate cancer, but a similar (30-40%) incidence of incidentally discovered prostate cancer at autopsy (5;6). However, attempts to discover the biological basis for progression from a latent to potentially metastatic form have largely been unsuccessful. It seems plausible that the condition labeled "latent" prostate cancer includes a spectrum of disease, in which some tumours have higher metastatic potential than others - either by virtue of their size, or possibly due to differences at the genetic level (7). An alternative hypothesis might be that, although the disease is fundamentally the same in latent and metastatic forms (from the standpoint of molecular carcinogenesis), the speed at which it progresses is different in so-called latent and significant cases. The various environmental, genetic and other factors responsible for the differing incidence of clinical disease, may merely act by influencing the growth rate of an already metastasis-competent tumour. An added dilemma for the clinician is that the true effectiveness of radical therapy is fundamentally unproven. There is a tendency for clinicians to harbor particular allegiance to their own therapeutic modality. Surgeons with expertise in the operation of total prostatectomy often strongly defend it as a powerful means of effecting cure, as do radiotherapists with similar professional interests in radical radiotherapy (8). There is, however, a conspicuous lack of randomised trials, which is a serious drawback in a disease where the latent form will colour the results of treatment so strongly. The American Urologist Whitmore (9) summed up the dilemma thus:

"Is cure necessary in those in whom it may be possible? Is curepossible in those in whom it may be necessary?"

In assessing whether or not to treat a patient with prostate cancer, the clinician will take account of several factors: 1. The biological potential of the tumour, as judged by its histological grade (10). This is usually documented using the Gleason grading system, which is based on the premise that most prostate cancers exhibit a major and a minor pattern histologically. The pathologist assigns a score (1-5) to the major and minor patterns, and thence a sum score which will lie between 2 and 10. Tumours with a sum score of 2-4 are, generally, well differentiated, those with a score of 5-7 are moderately differentiated, and those with a score of 8-10 are poorly differentiated.

2. The biological potential of the tumour, as judged by the serum level of Prostate Specific Antigen (PSA) (10). This glycoprotein, produced by both normal prostatic epithelium, and by prostatic adenocarcinoma, is uniformly found to be a prognostic indicator. The risk of harboring bone metastases (occult or otherwise) increases as serum PSA increases; conversely, it is uncommon to find bone metastases in patients with a PSA of less than 20 ng/1 (11).

3. The patients age (both chronological age, and biological age). Many clinicians will not treat patients with slowly growing tumours (as defined by low histological grade and/or low PSA levels) in patients with a life expectancy of less than 10 years(12).

4. Clinical evidence that the disease is confined to the prostate. This is based on imaging (Computerised tomography, or magnetic resonance imaging of the prostate and pelvis, plus isotope bone scanning). Subsequently, in some patients, pelvic lymph nodes are sampled, and examined histologically, radical treatment being restricted to those patients who have no evidence of metastatic disease on these criteria. Alternatively, use may be made of retrospective data from radical prostatectomy series, which allow a prediction to be made of the likelihood of organ-confined disease and pelvic lymph node involvement based on the clinical extent of the primary tumour, the serum PSA level, and the histological grade of the tumour. (13).

The recent retrospective report from the US SEER programme has been invaluable in providing the largest published database on the outcome of patients with early prostate cancer treated by surgery, radiotherapy, or watchful waiting (14). While in no way does it replace a randomised trial, it does provide strong circumstantial evidence that, at least in patients with poorly differentiated tumours, radical treatment might lead to improved survival at ten years, compared with patients managed by surveillance. This would imply that, in at least some cases, prostate cancers are truly confined to the prostate gland at the time of diagnosis, and that treatment can eradicate some tumours. Rightly or wrongly, many clinicians - the present author included — are reluctant to withhold radical therapy from a younger, fitter patient, particularly if he has high-grade disease.

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