Sun, surf and a deradly melanoma

March 10, 2000

Australia could be turning the corner on its skin cancer epidemic. Julia Hinde explores the research frontier

Up to two out of every three Australians will develop skin cancer during their lifetime. Each year 0,000 new skin cancers are diagnosed Down Under, of which 1,000 are likely to be fatal. Compared with breast cancer, which affects one in 12 Australian women, and prostate cancer, which affects one in ten Australian men, skin cancer in Australia has reached "epidemic" proportions.

But, say experts, there is hope. After years of publicity to promote safe behaviour in the sun, the message finally seems to be getting through to younger Australians.

With better sun protection and changes in behaviour, the Australian skin cancer epidemic, said John Kelly, director of the Victoria Melanoma Service and associate professor at Monash University Medical School, is finally beginning to turn around, "just as the United Kingdom is experiencing an upturn".

"While the UK rates are less than one-tenth of ours, they are increasing quite rapidly," he warned.

There is no doubt that sun exposure is to blame for Australia's high incidence of skin cancer. Bruce Armstrong, director of research at the Cancer Council of New South Wales, estimates that worldwide, the proportion of melanomas caused by sun exposure is about 60 per cent.

Here in Australia, he puts that figure at nearer 90 per cent. He suggests that as Europeans increasingly earn the wealth to enable them to spend more time tanning overseas, they too can expect the incidence of skin cancer to increase.

Australia, with so many skin cancers, has become a world laboratory when it comes to clinical trials and researching the disease.

Whereas surgery is still the mainstay for the removal of skin cancers and melanomas, scientists such as Richard Kefford, director of the Westmead Institute for Cancer Research at the University of Sydney, have confidence that new approaches to treating melanomas - from gene therapy and immunobiology to anti-angiogenic agents - should soon supersede much current surgery.

"We have reached the new millennium and yet are still using medieval approaches," said Professor Kefford.

"Skin cancer is not inevitable," said Robin Marks, professor of dermatology at Melbourne University. "You have to push and scream and drag your body into getting it. The body has all these mechanisms to prevent cancer from developing. First your skin cells go into acute shut-down and stop dividing in the presence of UV radiation. Radiation can damage DNA, so they don't want to divide when radiation is around because they might include a bad gene. There are also cells in the skin that are prepared to sacrifice themselves if they have not been repaired adequately, while the body can also mount an immunological response to try to knock out bad cells."

The three types of skin cancer (see box) develop when mutations occur in certain genes in cells in the skin. Such mutations are the result of radiation. These mutations - if they are not stamped out by the body's own defences - may result in cells dividing as rapidly as the gene that regulates their division is impaired.

Scientists have already managed to clone two genes that they say are crucial to regulating the cell cycle and which they believe are impaired in patients with melanomas.

They have traced these genes by working with families where melanomas appear hereditary. According to Professor Kefford, between 5 and 10 per cent of patients with a melanoma are born with mutations in genes that will probably result in skin cancer.

Scientists suspect the genes affected in hereditary melanoma may be the same as those that lead to melanomas developing in the remainder of the affected population.

"We can account for one-third of melanoma families from the existing two genes. We have mapped another highly suggestive region of the genome," Professor Kefford said. "Understanding the genes affected will give us an understanding of the biochemical defects in melanoma. These could prove to be targets for arresting and preventing the disease."

As well as the small number of people who inherit a direct genetic mutation, it appears that some people are more at risk from skin cancers than others. The rate of skin cancer among Australia's Aborigines is negligible, and not all fair-skin populations appear to be at equal risk.

"There appears to be something about Celts that puts them at particular risk," said Professor Marks. "Scandinavians are fair-skinned, but here in Australia they are not at such risk as the Celts. We don't yet understand why."

Scientists are employing other cutting-edge science to beat skin cancer. There is interest in the ability of anti-angiogenic agents to prevent tumour growth. Tumours, and especially melanomas, need a constant and increasing blood supply as they take hold.

Scientists have now identified hormones responsible for making new blood vessels and have in turn produced counter drugs, anti-angiogenics, to stop new blood vessels forming.

"A number of agents are under clinical investigation," said Professor Kefford. "In lab animals, some have been shown to work brilliantly. We await the results with bated breath, but in humans there has been some unexpected toxicity."

Other interest has focused on the body's own immunological response and the possibilities of creating vaccines against melanomas. For the past 20 years, scientists have been stunned by some people's potent natural response to melanoma. In some cases, active lymphocytes, a subset of white blood cells, have attacked melanomas, destroying them. Doctors have tried to induce these effects in patients, injecting antigens, for example, into a patient's lymph nodes, to create a vaccine-style response.

But despite repeated efforts and clinical trials, no single approach to skin cancer has proved reliable. Now the interest is in dendritic cells, cells in the skin that process antigens. These cells transform the antigens into a form that the lymphocytes can recognise and hence attack. There is considerable interest in giving boosts of dendritic cells in a bid to produce more immunological response from the body.

Other research efforts have concentrated on refining surgery. Scientists at the University of Sydney are in the last stages of a clinical trial that should reduce the impact of surgery for some skin cancer patients. Once melanomas spread into the skin, they travel through the lymph channels to the lymph nodes and to other areas of the body.

Until now it has been hard for scientists to tell whether an established melanoma has yet moved to the lymph nodes. For years debate has raged over whether all lymph nodes in the vicinity should be removed just in case spread has occurred. In the groin, for example, there may be as many as 25 lymph nodes, whose removal is a major operation, and may leave permanent swelling of the leg. With so many nodes to test, laboratories are rarely able conclusively to give the all-clear for tiny quantities of melanoma.

The development of lymphatic mapping has revolutionised the research. Scientists are now able to locate the individual lymph node closest to the site of melanoma by injecting a tracer with a radioactive marker. This node can be removed separately and sliced very thinly in the search for evidence of melanoma spread.

If no spread is found, the patient can, in theory, be fairly certain the melanoma has not spread. Any sign of melanoma spread and the remaining lymph nodes can be removed.

The clinical trial has now been running for almost five years, with 1,400 participants worldwide, of which 800 have been seen in Sydney. Preliminary results suggest the method does not make a significant difference in terms of survival rates, but it has helped identify the people most at risk, that is those where the cancer has already reached the lymph nodes and may have spread further.

A SURFACE LOOK AT SKIN CANCER

There are three types of skin cancer. Basal cell carcinoma is the most common, accounting for about three-quarters of skin cancers in Australia. It virtually never spreads much below the skin surface and hence is rarely dangerous.

Squamous cell carcinoma makes up most of the other cancers. One in 100 of these carcinomas is likely to spread and affect a patient's life expectancy.

Melanomas are considerably rarer and far more invasive. Melanomas can invade the dermis and escape via the lymph system into the rest of the body.

It is only then, when tumours start appearing in vital organs, that a melanoma can become fatal.

Incidence of basal cell carcinoma and melanomas is finally beginning to fall among Australian under-50s, though this pattern is not being followed in squamous cell carcinoma.

This has led scientists to suggest that the role of sunlight and genetic predisposition may differ between the different cancers.

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