Prostate Cancer

Gordon Muir

Consultant Urologist

King’s College Hospital London SE5 9RS

This year, prostate cancer is likely to affect some 85,000 American men and kill nearly 10,000 in the UK In both countries it is now the second most common cause of male cancer death and the incidence appears to be increasing. This increase may be due in part to the confounding factors of an increasing longevity amongst the relevant male population and increased detection rates, but the underlying incidence of the disease also seems to show a true rise. Naturally, the disease tends to present at an advanced and incurable stage, although screening programmes (both official and unofficial) are diagnosing earlier stage tumours in a number of western countries.

While widely perceived as an indolent disease affecting elderly men, the number of cases being diagnosed in all age groups is increasing. The incidence is highest in the United States, although this may represent in part increased rates of diagnosis in that country, and lowest among Asiatic nations. In Europe, Scandinavian men are at the highest risk.

Interestingly, in those communities that have been displaced geographically the incidence of prostatic carcinoma increases in line with the local population's; Japanese men living in the USA have a considerably increased risk compared to their counterparts in Japan. Parallels between black men in the western world and in Africa are difficult to draw due to the differing life expectancy between the continents. In the USA black men have the highest risk of prostate cancer of all major racial groups. Our research at King's College Hospital suggests a greater than 50% increased risk for British black men developing this disease.

Despite several studies which have suggested that environmental factors may be more important in general than genetic predisposition, no conclusive evidence has proven the link between the disease and diet, sexual behaviour, occupation, pre-existing benign prostatic disease, industrial exposure, vasectomy or pollution.

Environmental factors are nevertheless highly likely to be implicated in view of the migrant studies referred to above with a "Western lifestyle" being an apparent risk factor.

Screening for prostate cancer

While there is no official screening programme for prostate cancer in this country it is true that many thousands of men are nonetheless being screened for early prostate cancer.

The Department of Health recommends that men who are interested in prostate cancer screening, should be counselled in primary care, but data is conflicting as to the potential benefits of screening for the disease. A number of studies are now suggesting a cancer specific survival benefit from early treatment and screening, but it will be some years before we can tell if this equates to an overall survivial improvement for screened populations.from the USA and Canada suggest there may well be a significant survival benefit for screened populations. Public knowledge of prostate cancer seems low in the UK.

There are two screening methods that may be used in the screening of prostate cancer: digital rectal examination (DRE) and prostate specific antigen (PSA). In general those studies which have looked at the place of DRE in screening have found a high sensitivity (for prostatic abnormality) but rather low specificity (i.e. large numbers of benign disease picked up). PSA is a compound involved in the liquefaction of semen and which is specific to the prostate. In prostate cancer, PSA is liberated to the serum in larger amounts than usual and is elevated in nearly all cases of advanced prostate cancer. Again however there is a low specificity when looking at the screened population target groups: many of these men will have benign prostatic hypertrophy, which can itself cause small increases in the PSA. The grey zone of PSA between 4ug/l to 10 ug/l is of great difficulty for the urologist. Of these men around 20 - 30 % will have prostate cancer, but to prove this means carrying out biopsies in many normal men. The clinical place of PSA isoforms such as free to total or complex PSA is not yet clear: these refinements of PSA testing should be interpreted with specialist input.

More and more men are asking for PSA testing now and informed consent is most important since there may be significant implications of an abnormal test. Table 1 shows our local recommendations for PSA testing

Table 1: recommendations for PSA testing

Ø Fit men of any age with symptoms of bladder outflow obstruction

Ø -the presence or absence of a tumour may influence treatment decisions

Ø Fit men with a life expectancy of ten years or more who request screening

Ø -a small cancer would indicate discussion of radical treatment: counselling about the uncertainties involved should be available

Ø Fit men with a family history of prostate cancer or breast cancer

Ø -a small cancer would indicate discussion of radical treatment: counselling about the uncertainties involved should be available

Ø All men with an abnormal digital rectal examination of the prostate

Ø -Very high PSA accurately diagnoses metastatic prostate cancer :such patients should at least be observed and usually treated by hormones

Ø Men over 40 with haematuria

Ø the presence or absence of a tumour may influence treatment decisions

Prostatic Biopsy

The diagnosis of prostate cancer can only be reliably made on biopsy. A prostate nodule may be cancer, prostatitis or BPH. As mentioned above, PSA is fallible in the diagnosis of early cancer. Similarly, while many cancers are hypoechoic on ultrasound scanning, 30% are iso- or hyperechoic and not every hypoechoic lesion is a cancer.

In most units biopsy will be done transrectally under ultrasound control using automated fine bore biopsy devices. A number of studies in the last few years have shown the benefit of local anaesthesia at the time of biopsy..

Occasionally in very unfit patients with a grossly elevated PSA, anti-cancer treatment might be started empirically, but since a biopsy will give extra prognostic information for little risk it is standard practice to carry one out.

Perhaps a photo of a prostate biopsy being done (TRUS)

How dangerous is early prostate cancer?

There is no absolute proof that patients treated (or screened) for early prostate cancer have an increased life expectancy.

Among those studies suggesting an equivalent effect of radical versus expectant treatment there is often a problem with the inclusion of poor performance status men who would not be expected to survive long enough to gain a benefit from radical treatment of what is often a slow growing cancer. Equally, in the many studies showing excellent long term results and cure rates from surgery or radiotherapy, patient selection may make comparison with population studies unreliable.

Nevertheless there is now good evidence from Denmark on the fact that for a man with prostate cancer in a given age group, a definable number of years of life will be lost with “watchful waiting.” This varies from 14 years for the under fifties to two years for those over seventy-five. Data fromscreening studies in Quebec and Austria would tend to add support to this estimate. A large recent study from Sweden showed that radical therapy reduced prostate cancer deaths and complications by half over a seven year period compared to active monitoring, although overall survival was not significantly different over this timescale.

Regardless of the pronouncement of some critics of treatment, more men are dying of prostate cancer every year. It is also evident that all lethal cancers must at some time have been early, organ confined and potentially curable. Perhaps more persuasively, the number of men presenting with advanced disease in the USA has one down in recent years despite the overall increase in cases diagnosed. This may be the first sign that aggressive early treatment is having an effect on the number of men developing advanced disease.

What we are unable to say today is which prostate cancers will progress to kill the patient and which will be safe to observe. As with many cancers, it may be that a number of potentially lethal tumours will never be amenable to a physical curative therapy. At present no adjuvant or chemical treatment has been shown to be of benefit.

There is similarly no agreement as to whether, if radical treatment is beneficial, radiotherapy or surgery is more effective.

How effective is radical treatment?

Many authorities in the UK and Scandinavia have been sceptical of radical treatment for early prostate cancer but in the rest of the world it is the accepted treatment (this does not of course mean it is necessarily right!)

Recent advances in surgical techniques mean that both treatments can be carried out with a minimal risk of mortality. Both techniques carry a risk of impotence (20-85% depending on the surgeon and the patient) and incontinence (3-10%): these are both slightly higher after surgery although this is operator dependent. Radiotherapy carries a small risk of long-term bowel toxicity, which is not seen with surgery. Whereas surgery involves a single operation with several weeks of catheterisation at home, radiotherapy involves a five to six week course of daily treatments. For younger patients there is reasonable evidence that surgery is able to give a slightly higher long term cure rate.

Our current position is to offer curative treatment to those patients with clinically organ-confined disease we feel are likely to be at high risk of progression. In practice this usually means healthy men in their fifties and sixties who have moderate to poorly differentiated tumours, but each patient is treated as an individual.

Radical Radiotherapy has also been improved in recent years, with the introduction of conformal radiotherapy and hormonal pre treatment reducing the irradiation of adjacent normal tissues while allowing a higher treatment does to the malignancy. Most radiotherapists will give this treatment over a six week period.

Prostate Brachytherapy, by implanting radioactive iodine seeds into the prostate under ultrasound control, shows promise, with five to seven year control data being similar to that seen with surgery and external beam radiotherapy for good risk tumours. Urinary symptoms and retention can be an issue. In view of the lack of long term follow up it is however difficult to recommend for younger patients.

Although debatable, surgery appears slightly more effective than radiotherapy in curing genuinely organ confined disease. Another possible benefit of surgery is that a full pathological examination can be carried out which gives better prognostic information. At present, pre-treatment staging is far from perfect, and identification of those patients who will be suitable for treatment forms a major part of our research work.

A hope is that in the next few years we will have some effective adjuvant therapy for minimal residual disease so that the men with locally advanced cancer can be offered a potential cure. Until then, the firm pronouncement of some specialists on the desirability of non-treatment is nihilistic, biased and above all unfair to patients who find the concept of prediction of cancer progression difficult and worrying.

Surgical Treatment of early prostate cancer

The operation of radical prostatectomy involves removal of the entire prostate with its capsule and the seminal vesicles. This leaves a gap between the bladder and the urethra, which must be repaired by carrying out a direct anastomosis between the transected bladder neck and the urethra. A number of variations on the technique exist, mainly related to preservation of continence and potency, but the two most important differences lie between the retropubic approach and the perineal approach.

In retropubic prostatectomy, an incision is made in the abdominal wall and the prostate is approached from the front. The perineal approach uses an incision between the scrotum and anus to come to the prostate from behind.

TURP remains a surgical option only for palliation or in rare cases diagnosis. It is not a curative procedure for prostate cancer.

Laparoscopic radical prostatectomy, which has been championed in France, appears to offer the possibility of minimal hospital stay and reduced blood loss with a better quality anastomosis. This is a difficult technique for urologists to learn, but given its advantages over the open route it is likely to become the standard therapy in years to come.

Treatment of metastatic disease

The effect of castration on the size of the prostate has been known about for centuries, but it was in the 1940’s that this became standard practice for men with prostate cancer. In essence, over 80% of men with metastatic disease will show a dramatic response to hormonal therapy. This may be in the form of surgical or medical castration, or the use of androgen blocking agents. Unfortunately the majority of men will progress, after a mean period of around 15 months.

There is no consensus as to whether hormonal treatment was best started at the diagnosis or when the patient presented with symptoms. It may be that early treatment of metastatic disease, while not increasing survival, reduces the risk of complications such as spinal cord compression and retention of urine, improving the patients’ quality of life.

Most urologists would therefore recommend early treatment when metastatic disease is diagnosed rather than awaiting symptoms.

Given the choice between surgical castration and medical treatment, most patients will opt for the latter and this is also of interest where operating lists are at a premium. The first choice for most UK urologists is the use of LHRH analogues such as Goserelin (Zoladex) or Leuprorelin (Prostap). Both these drugs work by blocking the stimulatory sites for luteinising hormone in the pituitary, resulting in an abolition of testicular stimulation and low levels of testosterone. Each is available in one or three month depot preparations.

Antiandrogen monotherapy appears equivalent to either LHRH analogue treatment or orchidectomy. Until recently the majority of clinicians and patients seemed happiest with a depot LHRH analogue injection, largely due to the ease of administration and good compliance that is assured. However the introduction of the drug Bicalutamide with a monotherapy licence has been a popular option and has some potential benefits. Because the serum testosterone is not reduced patients seem to feel more vigorous on the drug than with treatments which reduce the serum testosterone, and one might reasonably hope that the long term side effects of hormone suppression such as osteoporotic fractures would be less frequent. It appears that men treated with Casodex have less risk of progression and of prostate cancer related side effects than those on placebo.

Relapsed Disease

As mentioned above, all men with metastatic disease will suffer from hormone refractory prostate cancer if they survive long enough. This will usually manifest itself by either rising PSA (preclinical), bone pain, ureteric obstruction or anaemia. No treatment has been shown to affect survival for these patients although second line hormonal manipulation may give a subjective benefit in around one third.

Chemotherapy tends to have limited effect since most prostate cells appear to have a defect of cell death rather than cell growth. This means their life expectancy is increased, but due to the fact that turnover is not significantly higher than normal cells they are less susceptible to chemotherapy than some other solid tumours. Chemotherapy does however have a place in some younger and fitter patients, if only for general symptom relief. For management of bony problems, both bisphosphonates and bone seeking radioactive isotopes have an important place.

There is considerable interest in targeted second line therapies (such as cancer vaccines) since even relapsed prostate cancer continues to express the highly specific marker PSA, but these remain experimental.

Thus, palliation is the aim and for this a multidisciplinary approach involving urologist, GP, Palliative care team and radiotherapist is essential.

Figure outlines the therapeutic options available for the various stages of palliation. It is essential that patients realise that, even though their disease may not be curable, symptom control is usually very effective and that a good team will allow management of even the last stages of prostate cancer in a comfortable and dignified manner.

Normal production of testosterone stimulates the prostate gland and prostate cancer cells