Controversial Topics In Prostatic Cancer
Artykuł opublikowany w Urologii Polskiej 1994/47/1-2.

The incidence and death rate from prostatic cancer in Western Society is increasing for reasons that are still unknown. Presumably initiating and promoting agents are activating an increasing number of the latent cancers which are known to be present in 30 — 50% of men over the age of 60 (1).

In recent years there has been increasing interest in radical prostatectomy following the work of Walsh, who demonstrated the nerve sparing techniąue for this operation (2), a debatę on the role of screening for this condition (3) and a recognition that hormonal therapy, whilst palliative, probably has less effect upon survival than do the yarious Prognostic factors, including grade of tumour, clinical stage and the presence or absence of pain at diagnosis (4).

SCREENING AND RADICAL PROSTATECTOMY Screening for any disease involves additional expense, produces anxiety in the patient when the condition is found and is justifiable only if an effective treatment is available. The basis of screening in prostatic cancer is that those patients in whom the diagnosis is made early may be treated by radical prostatectomy in the hope of cure.

In screening any population for prostatic cancer, the problem is compounded by the fact that, bacause of competing couses of death, 85- 90% of patients with latent prostatic cancer will die of other conditions. Inevitably, if a man is screened by PSA, digital rectal examination and perhaps trans-rectal ultrasound, lesions of doubtful significance will be diagnosed at a time when the person will be leading a perfectly normal life.

If the diagnosis is to be followed by radical prostatectomy, the patient must accept at least a 40% chance of impotence with a 5% chance of being incontinent after two years to the extent that he will be reąuesting a second operative procedure.

In addition the operation is major and utilises resources which could otherwise be deployed elsewhere.

The procedure will be justifiable if the condition is cured. However, the results of Smith (5) and Zincke (6) following radical operation and the work of Adolfsson 97), Johannson (8) and Whitmore (9) who have managed whole populations, (or a selfselec- ted group of patients) by deferred therapy with hormonal or other treatment upon progression of the disease and at a time reąuested by the patient, suggest there is no clear advantages for radical prostatectomy. It seems that this operation is not yet capable of providing a cure in all patients since the death rates from prostatic cancer at 10 years are approximately 20% whether a policy of radical surgery or deferred therapy at the time of diagnosis is chosen (Table 1).

There is equally no evidence from the results of the Veterans Administration

Cooperative Urological Research Group (VACURG) (10), the radiotherapy literature or the recent study of the Medical Research Council (MRC) Urological Group\\\'s study of radiotherapy in patients with localised disease (11) that hormonal therapy or radiotherapy offer a hope of cure. Table 2 shows the death rate form prostatic cancer in patients receiving prostatectomy with or without hormonal therapy in the YACURG study. Prostatectomy was associated with a 10% incidence of death from

Progression and Survival Rates at 10 Years in Patients with T2/3, No-1, Mo Prostatic Cancer

Receiving Deferred Treatment, Radical Radiation Therapy, and Radical Operation with or

Without Additinal Hormonal treatment prostatic cancer at 10 years whilst patients receiving hormone therapy also still died of prostatic cancer. The majority of the deaths in each group were, however, due to coincidental disease.

In the MRC study in which patients were randomised to receive orchidectomy, radiotherapy or the Combination of both, the use of radiotherapy did nothing in

Comparison with orchidectomy to control local disease, delay metastases or improve survival.

From these data one must conclude that the case for radiotherapy or radical prostatectomy as an effective cure, thus justifying screening, has yet to be made.

THE PATIENT WITH METASTATIC DISEASE

Over 50 years the mainstay of treatment has been the use of Diethylstilboestrol, initially at 1 mg daily at 5 mgs daily in the 1960\\\'s and at 1 mg three times a day in the 1970\\\'s and 1980\\\'s. This agent has always produced results in which the control of the disease was marginally superior to orchidectomy and to the other agents tried but has become very unpopular because of its recognised cardiovascular hazards and the suggestion that alternative treatments are preferable and superior.

Since the results of the VACURG trial which showed a three year median survival for DES 1 mg daily in patients with metastatic disease, the EORTC

Urological Group and other groups have undertaken a number of studies involving oestrogens, antiandrogens, LHRH analogues and the concept of total androgen ablation advanced by Labrie in which an anti-gonadotrophic agent is gigen combined with an anti-androgen.

In one trial, Stilboestrol was compared with Estracyt. The differences in survival were minimal and far less than the differences in survival in relation to grade of tumour and the presence or absence of pain on diagnosis (12). From the determination of Prognostic factors of importance in patients with metastatic disease, including T category, grade and the presence of pain in diagnosis, it is clear that patient selection is important in relation to outcome and that only comparisons of stratified equally representative groups in randomised clinical trials can be used to determine the important issues that are currently under debate. As an example of this, it is of interest to note that in successive EORTC studies Comparing a variety of agents the median survival has gradually increased. This is almost certainly due to patient selection rather than to the results of therapy.

The LHRH analogues (provided the initial flare phenomenon is covered by an anti-androgen or by Stilboestrol) are at least as effective as orchidectomy or

Stilboestrol. The evidence in favour of the Superiority of Combination therapy is, however, less clear. A meta-analysis was organised recently between representatives of groups undertaking studies in the United States and Europę. This showed no convincing evidence of the Superiority of the Combination treatment at one or two years after start of therapy in an analysis of 21 studies involving over 5,000 patients, all of which had reached the median survival. The median survival for monotherapy was 26 months compared with 27 months for the Combination treatment. All the new treatments whether given alone or in Combination are very much more expensive than Stilboestrol or orchidectomy and there seems little justification for their routine use, especially when one considers that anti-androgens can be added when progression occurs and that the cardiovascular side-effects of oestrogen therapy could almost certainly be reduced by the addition of one aspirin daily which is recognised to have an effect on both arterial thrombosis and venous thromboembolic disease.

A trial Comparing oral oestrogens plus aspirin against any other treatment of the investigators choice is long overdue and it is also, in my view, important to undertake further work on the use of intermittent oestrogen treatment which, in some patients at least, provides control of the disease with the possibility of continuing sexual function, at least on an intermittent basis.

CONCLUSION Despite an enormous amount of work over the last 50 years which has resulted in much greater knowledge of the pathology and behaviour of prostatic cancer, we have still to admit that we cannot distinguish between the latent and the Clinically important tumours, that there appears to be no justification for a screening programme since radical surgery has yet to be shown to cure the condition, and that the use of any agent more expensive than Stilboestrol plus aspirin has yet to be proved to be of value.

These simple statements must distress Urologists with a particulat interest in this condition and must act as a stimulus to further research.

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