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How often does prostate cancer hit the headlines? Answer: when prominent politicians, rock stars and celebrities are diagnosed as having the disease. Predictable as such publicity is, it belies the true scale of the medical problem. After lung cancer, adenocarcinoma of the prostate is the biggest cancer killer of men in the Western world. Last year in Britain the disease claimed 9396 lives, more than four times as many as cervical cancer. And because prostate cancer afflicts mainly men in their fifties and sixties, the toll is certain to rise as the populations of Western countries continue to age.

The question that has thus echoed through the world’s medical conference halls in recent years is, should governments endorse national screening programmes for prostate cancer similar to the ones that already exist for cancer and breast cancer? The British government has no plans to do so, even though adequate tests now exist.

Nor for that matter have most British funding bodies and researchers shown much interest in the disease. Last year the Imperial Cancer Research Fund (ICRF), Britain’s second largest backer of cancer research, spent about Pounds sterling 100 000 on prostate cancer research, trifling compared with Pounds sterling 4.7 million on research into breast cancer. The gap was scarcely any narrower for Britain’s third biggest cancer charity, the Cancer Research Campaign (CRC), which spent Pounds sterling 250 000 on prostate cancer research and Pounds sterling 3.6 million on breast cancer projects. A spokesperson for Britain’s Medical Research Council, meanwhile, said the council was unable to break down its overall expenditure on cancer research – amounting to Pounds sterling 13.6 million in 1992 – to give a figure for prostate cancer research. Not for nothing has the CRC called prostate cancer the ‘Cinderella of cancers’.

Things are different in the US, where screening for prostate cancer is now commonplace and the government has recently doubled its spending on research into the disease to $24 million. Partly this reflects scale: more than 100 000 new cases of the disease are diagnosed annually in the US, and about 33 000 American men die from it each year. But, as recent events in the US (of which more later) show, factors such as public awareness of the disease and the attitudes of health policy makers to its prevention are equally important.

As Britain bides its time, the question of how best to tackle prostate cancer – to screen, or not to screen – is fast coming to symbolise a more fundamental health issue. What priority should governments attach to illnesses that usually occur in old age, particularly when health resources are scarce and populations as a whole are aging?

While men may develop prostate tumours in their forties, symptoms develop much later (if at all), and the death rate remains low for men under the age of 70. Basing his calculations on UN population projections, Peter Boyle, director of the division of epidemiology and biostatistics at the European Institute of Oncology in Milan, predicts that the number of prostate cancer cases will double in Europe over the next 20 to 30 years, continuing the upward trend of recent decades. In 1986, the latest year for which figures are available, there were 10 800 new cases in England and Wales alone – almost double the number reported 30 years ago.

The main cause of this increased incidence is that the average age of male populations in the West has been climbing steadily for many years. But improved rates of detection have also fed the upward trend, and some epidemiologists argue that poorly understood environmental factors, such as diet, are at least partly responsible for the statistical increase in cases.

Helping sperm

Despite growing publicity about prostate cancer, confusion still surrounds even the basic biological function of the prostate gland. Belying its name, the prostate gland is actually a bundle of glands, shaped like a walnut and situated just below the bladder, where it fits like a collar round the urethra. During ejaculation these glands discharge a range of substances – prostaglandins, proteolytic enzymes, growth factors, acids, sugars and trace metals – into the urethra. These secretions are thought to nourish the ejaculating sperm and help in transporting them during and after sexual intercourse. By softening the cervical mucosa and encouraging the cervix to dilate, the substances make it easier for sperm to pass through the neck of the womb into the uterus.

Many key biological questions remain at best only partially answered. Why does the prostate nearly always enlarge in middle or old age? Why does this enlargement lead to tumour growth in some cases, but not others? When it does, why do only some of the tumours cause medical problems? What we do know is that prostate growth is caused by the action of the male hormone testosterone, which is secreted by the testes. Once inside the gland, testosterone is converted into the hormone dihydrotestosterone, which is absorbed by cell nuclei. Once there, this hormone is thought to activate certain genes required for cell growth. Two drugs for use against benign enlargement – one already on the market and one so far used only in clinical trials – work by blocking the enzyme, called 5-alpha-reductase, that makes dihydrotestosterone. Prostate tumours may develop when certain cells become cancerous, growing uncontrollably when their nuclei absorb dihydrotestosterone.

The epidemiology of prostate cancer paints an equally complex picture. There are no proven links with factors such as alcohol and smoking. But diet could play a part; the main evidence being that the incidence of the disease varies enormously from country to country and among ethnic groups. Black North Americans have the highest incidence (about 100 cases per 100 000 men) while the Far East has the lowest incidence – about 6 cases per 100 000. These variations follow the pattern of heart disease, suggesting that a Western-style diet may be one risk factor. The fact that people of oriental origins who live in the West have relatively high rates of prostate cancer suggests that the varied incidence of the disease reflects a complex interplay of environmental factors and genetic make up.

And there is a further complication. The uneven distribution of prostate cancers may correspond not so much to tumour incidence as to the rate at which tumours progress to the point of causing clinical disease. If this is so, different populations might have different levels of immunity to prostate tumours. More controversially, some researchers claim to have found that promiscuity and certain occupations, notably farming, increase the risk of developing prostate cancer. Studies have shown that the more partners a man has, the greater his risk of developing the disease. The link with farming remains a mystery.

What is clear, though, is the disease’s reputation for stealth. A man may have prostate carcinoma for decades without displaying any symptoms. Indeed, postmortems show that some elderly men take the cancer to their graves without ever having realised they had a tumour. These so-called latent cancers are found in more than 70 per cent of men over the age of 80, and are not the cause of death.

In Britain, prostate cancer is usually detected at a late stage, when a man visits his doctor complaining of difficulty in passing urine or of pain while urinating. The doctor will judge whether the tumour is benign or malignant on the basis of a rectal examination. If it is malignant, the prognosis is poor: about 75 per cent of prostate cancers detected in this way have already spread to the lymph nodes and bones, whereupon only palliative treatment is possible. Of the cases diagnosed in Britain every year, only just over a third are alive five years later.

Political power

In the US and Germany, by contrast, all men over the age of 45 are advised to have both an annual rectal examination and a blood test. This ‘prostate specific antigen’ test relies on the fact that men with prostate cancer have unusually high levels of PSA – a protein fragment which is found in benign and cancerous prostate tissue, and occurs in much higher levels in tumours. Because of this test, a much higher proportion of tumours are detected before symptoms have developed.

On the face of it, the case for screening appears overwhelming. Yet researchers – urologists, radiotherapists, surgeons and oncologists – remain divided. Ardent anti-screeners contend that the disease is predominantly one of old age and is often not the primary cause of death: two-fifths of men over 65 who die from unrelated causes have a prostate cancer. Launching a mass screening programme, they argue, would be enormously costly and offer little health gain. Crusading proscreeners retort that testing all middle-aged men would improve rates of detection of curable tumours, and would be a key step towards curbing the rises in deaths from the disease expected over the next few decades.

In the US, meanwhile, events have moved on. Aided by a handful of powerful politicians and judges who have recently contracted prostate cancer, the debate is now firmly in the public arena. The appearance of the first results of PSA-based screening in 1991 in the New England Journal of Medicine generated a wave of publicity. By combining the PSA test with rectal examination to screen some 18 000 men, researchers could detect 30 to 40 per cent more cancers.

‘When our results were publicised, patients rushed to their doctors and insisted on having the test, the use of which has now spread throughout the country,’ says William Catalona of Washington University School of Medicine, St Louis, who pioneered the screening study. ‘Prostate cancer came out of the closet,’ he adds, and men started to join self-help groups to talk openly about prostate problems and the issue of screening. Last year the American Urological Association, Inc., in Baltimore, and the US College of Radiotherapists officially recommended the PSA test and a rectal examination for men aged over 50, and there is now an application pending before the Food and Drug Administration to sanction the PSA test as a screening aid.

On top of this, Republican Senator Robert Dole, who was recently treated for prostate cancer, has made it his personal business to spread the good word that the PSA test had saved his life. Before beginning his speech at the last Republican national convention, he urged the men in the audience to go and get a PSA test. He has also encouraged the transfer of funds from the US army research budget into prostate cancer research.

‘Until last year the total research budget for prostate cancer was $10 million,’ says Catalona. ‘That’s the cost of only one wing of a jet fighter, yet the cancer is the second biggest cancer killer of men.’ Because of Dole, the budget has increased to $24 million this year. A sign of prostate cancer’s new-found status in the US came last November, when the disease and screening featured on the agenda of the President’s Cancer Panel, a health care committee that reports directly to the president.

Yet many British specialists, including pro-screeners, are wary of the US approach because clinical trials have yet to prove that screening saves lives. ‘I think the Americans are going over the top,’ says Roger Kirby, a urologist at St Bartholomew’s Hospital in London. ‘They are spending millions of dollars on PSA tests and whipping out the prostates of thousands of patients before results from large, randomised, controlled screening trials are available.

‘The British approach of dipping the toe in the water means that we can tackle the issue in a stepwise fashion and not allow emotional arguments to overtake scientific and ethical ones,’ he adds. But this is possible only if public opinion – currently based on a limited understanding of prostate cancer – remains unswayed. And while people in Britain know too little about the disease to demand screening now, this state of affairs may soon change.

Many pharmaceuticals companies have recently launched or are close to marketing new drugs in Britain to treat a common prostate condition, benign prostatic hyperplasia (BPH), which afflicts about 2.4 million men over the age of 50. These same companies are also pouring money into educational campaigns aimed at raising public awareness of prostate disease, the rationale being that the more men know about prostate problems, the more likely they are to seek drugs. On top of this, the CRC is planning a major campaign to raise public awareness of the disease later this year.

It is too early to say whether such initiatives will have the added effect of provoking public cries for screening. But the history of cervical cancer suggests they might. When the ‘pap’ test, used to screen for cervical cancer, was developed in the 1960s, gynaecologists and activists pressurised the government to introduce a national detection programme. So the opportunity to ascertain whether the test saves lives, by implementing regional case-controlled screening trials, was missed, although retrospective evidence suggests that it does reduce mortality.

The story is quite different for breast cancer screening. By the time it was introduced in the late 1980s there was already plenty of evidence that screening saved the lives of many women older than 50. At present, a large, randomised study to assess the the benefits of mammography in women under 50 is being funded by the Department of Health together with the MRC and the main cancer charities. Last year an American study reported in the Lancet found that mammography can detect cancer lesions in younger women earlier than physical examination. But that trial was small and not randomised, so health officials in Britain await the outcome of their own trials before any new policy decisions are taken.

Cautious approach

Rather than rushing headlong into screening, most prostate cancer specialists in Britain want to follow the cautious path taken by breast cancer specialists. In a review (as yet unpublished) of all the data on screening for prostate cancer, the Institute of Cancer Research in London has concluded that population screening should not begin until the results of large, randomised clinical trials are available. Epidemiologist Jane Melia, who conducted the review, says that ‘the current data are based on studies that are too small to have statistical significance, were unrandomised, or studied a selected group’.

Moves are afoot to change this. The American government has just awarded $10 million to the National Cancer Institute in Bethesda, Maryland, to conduct a study that will screen 70 000 men for a number of cancers, including prostate cancer. But the results of this trial will not be available for 16 years, and in Britain recent pleas for government funding have been rejected.

Last year members of the British Prostate Group, a 20-year-old group of clinicians and scientists, met health officials to request funds for a study. The request was rejected on the basis that prostate cancer was too low on the government’s list of health priorities. Now individuals from the group have embarked on their own small-scale studies organised within the National Health Service.

This year Brian Peeling, a urologist at the Royal Gwent Hospital in Newport, Wales, will begin a study that will screen about 10 000 men aged 55 to 70 for prostate cancer. His study – which is expected to detect about 90 cancers – will contribute to a pan-European screening trial if researchers in other countries get funding from their respective governments. Another pilot study in Britain has so far screened 300 men and detected six cancers that have spread beyond the prostate gland. ‘We are going to use our results to push again for government funding to do a bigger study that will be statistically significant,’ says Michael Kirby, a family doctor based in Letchworth, Hertfordshire.

With or without government funding, it could be a decade or more before researchers are able to answer the key questions. How accurate is the PSA test when used with rectal examination? And will its use on the male population as a whole save lives? Specialists are least confident about the second of these because there is still no consensus about how best to treat prostate tumours. Most specialists either offer radical prostatectomy (surgical removal of the prostate gland, capsule and seminal vesicles) or radiotherapy, if the carcinoma is detected relatively early. If, however, it goes undetected until a fairly advanced stage, the most common treatment is hormone therapy, which may slow down or temporarily reverse growth, but an alternative approach is simply to wait and see whether the cancer progresses further. In fact, one of Europe’s largest clinical trials to study the best treatment for prostate cancer, with nearly 900 patients participating so far, is now under way in Britain. Funded by the MRC, it aims to determine whether early hormone therapy is any more beneficial than treatment deferred until after symptoms of the disease appear. The study has been running for seven years and is unlikely to be completed for a further six – interim data are so far inconclusive.

Overall, then, the picture is this. Without more data to support the scientific case for screening, the British government is reluctant to invest in a national screening programme. For the most part, health officials view prostate cancer as a disease of old age and therefore a low funding priority. The fact that recent research by the ICRF shows that screening reduced deaths from cervical cancer by 15 per cent between 1985 and 1991 does not tip the scales in favour of screening, they argue, because cervical cancer is not exclusively a disease of old age. It often afflicts relatively young, working women. And that makes the economics different.

Maybe. But in the end, it is medical ethics, not economics, that introduces the biggest complication. Many men with prostate cancer not only remain oblivious of their tumours but go on to die of unrelated causes. Is it right to affect the quality of these men’s lives by telling them they have prostate cancer?

Rhonda Siddall is a freelance writer.

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The research that nobody wants to fund

The object of screening is to detect tumours when they are small and most treatable. Better still would be to prevent tumour cells from forming in the first place, by identifying men who are genetically predisposed to the disease and advising them on how best to reduce their risk of developing it. The problem here is the dearth of knowledge about the causes of prostate cancer, genetic or otherwise.

Compared to current knowledge of breast cancer, the science of prostate carcinomas is in the Dark Ages. ‘Prostate cancer research is just not in the same league as breast cancer research,’ says Fouad Habib, a cell biologist who specialises in prostate research at the University of Edinburgh. ‘The disease has been under-researched and underfunded. Perhaps this is because it is not an emotive subject like breast cancer.’

ÐÓ°ÉÔ­´´s have put together a few pieces in the genetic jigsaw. For example, Robert Bookstein and his colleagues at the University of California in San Diego, have recently done transplant experiments on mice which suggest that tumour suppressor gene – which seems to suppress the development of breast and bladder cancers – also works on prostate cancer. Cells known to develop prostate cancer in vitro had the suppressor gene spliced into them using recombinant DNA techniques. When these were transplanted into mice, no cancers developed. But basic understanding of the disease is still limited. While breast cancer researchers are close to finding some of the genes involved in initiation and development of that disease, prostate cancer researchers can only say that a variety of abnormalities on chromosomes 7, 8, 10, 13, 16 and 17 may be important.

At least some forms of prostate cancer run in families, and may therefore be hereditary. A study by urologists in St Louis, Missouri, for instance, showed that men with one affected first-degree relative – brother or father – were 2.8 times more likely to develop prostate cancer than men in the population as a whole.

Prostate cancer also seems to be more prevalent in families affected by breast cancer. According to Icelandic research published last year in the British Medical Journal, first-degree relatives of women with breast cancer are 1.5 times more likely to develop prostate cancer, while second-degree relatives are 1.3 times more likely to develop it. These findings suggest that some genes may be involved in both breast and prostate cancer, although nobody yet knows their identity.

Clues may come from a study which has just begun at the Institute of Cancer Research in London. ÐÓ°ÉÔ­´´s there are hoping to isolate tumour cells and genetic material from families with siblings affected by prostate cancer. By screening the cells for genetic mutations, they hope to pinpoint genes involved in the disease, some of which might provide the basis of a diagnostic test for assessing which men are genetically predisposed to developing prostate cancer. But it will take years, probably decades, to develop such gene markers.

In the past few years, researchers such as Habib have concentrated on looking for oncoproteins. ‘But much of this work is still very tenuous,’ he says. This is partly because the prostate is a very heterogeneous organ. The exact sequence of events in the development of the cancer is unknown, but recent studies do indicate that it initiates in the fibromuscular tissue – the fibroblast cells – which then prompts changes in the secretory tissue – the epithelial cells – which go on to become cancerous.

Meanwhile, researchers in the US are investigating the preventative properties of agents such as 5-alpha-reductase inhibitors. These inhibit the action of steroid 5-alpha-reductase, an enzyme that converts testosterone into dihydrotestosterone, a hormone believed to encourage prostate tumours to grow. The inhibitors were originally developed for treating benign prostatic hyperplasia, but future studies will investigate whether long-term use of the drugs could prevent prostate cancer.