Health: Countdown on the cancer clock: Giving drugs at different times of the day or in certain months can make treatment more effective. Rob Stepney reports on chronotherapy

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Indy Lifestyle Online
Surgeons have recently suggested that the timing of breast cancer treatment within a woman's menstrual cycle can make the difference between life and death.

Researchers in Israel have found that girls who develop acute leukaemia during summer are much more likely to survive than those who do so during winter.

Doctors in New Zealand observed that breast cancer is more frequently diagnosed in December than June. They speculate that cancer growth is related to sex hormones, which vary seasonally.

The idea that natural body rhythms may be important to health and significant in disease has not been popular among mainstream medical scientists. This may be about to change.

Evidence to be presented today at a cancer specialists' meeting in Dallas, Texas, will suggest that giving cancer drugs at times dictated by the body's daily rhythms improves their effectiveness and reduces the risk of side-effects.

Dr Francis Levi, director of the Laboratory of Biological Rhythms and Chronotherapy, outside Paris and one of France's leading researchers, offers two explanations for this remarkable effect. One is that the body's healthy cells vary through the day in their ability to tolerate anti-cancer drugs. This means that precision in timing enables a higher dose of drug to be given without severe side-effects. The other is that tumour cells also have their own daily cycles of sensitivity and resistance.

The specialists will hear the results of a French study of almost 200 patients with advanced bowel cancer which had also spread, a condition that is notoriously hard to treat. One group was given continuous infusion of drugs for five days. The other received the drugs only at carefully chosen times of the day and night.

The researchers found that the tumour shrank to less than half its original size in 50 per cent of patients who had drug therapy adjusted to biological rhythms. But the cancer responded in only 30 per cent of the patients given the drugs at a constant rate.

Dr Levi says that comparable studies have failed to achieve a response rate greater than 32 per cent. The idea that drug treatment can be adjusted to fit in with the rhythms of our internal biological clock is not new, but the French study is the best evidence yet that the idea can work.

The trial involved two highly toxic cancer drugs, 5-FU and a platinum compound, and was based on experiments conducted 10 years ago on mice and rats, which showed that 5-FU caused least damage to healthy animals when given in the middle of the day, while platinum toxicity was at its lowest when the drug was delivered at 4am.

Since rodents have a sleep and waking cycle that is the reverse of ours, Dr Levi reversed the timings for his human patients. The 5-FU was given in the middle of the night and platinum in the middle of the day.

'We arranged that the delivery of 5-FU would gradually increase over six hours, reaching a maximum at 4am, followed by a gradual reduction. The reverse pattern was followed with platinum,' Dr Levi says.

He says that it is too early to say how long the new treatment will keep patients free of disease symptoms, but there is a trend towards longer disease-free survival.

Karol Sikora, professor of clinical oncology at London's Hammersmith Hospital, is also impressed. 'It's important to note that no one is talking about cure here, but the observation that the cancer is more likely to respond to treatment if drugs are given at particular times of day is an interesting one,' he says.

'The benefit probably occurs because you can give higher doses. The problem with chemotherapy is that, in trying to kill cancer cells without harming healthy ones, you are working close to the body's limits of tolerance. So anything that means you can give more drug with fewer side-effects is likely to help.'

Dr Levi says that one reason for the greater effect of treatment is that patients were able to take the anti-cancer drugs as planned, without the need for doses to be reduced or delayed. Far fewer of his patients on chronotherapy suffered serious mouth ulcers or loss of sensation in the fingers and feet, the two side-effects that normally limit the amount of drugs that can be given.

'But that may not be the only reason,' he says. 'Another possibility is that tumour cells also have a daily cycle of activity that makes them more sensitive to drugs given at certain times, particularly during the night, because that is when they are most likely to divide.'

Such cycles have not yet been indentified in bowel cancer cells. But they have been seen in cancers of the ovary, lymphatic system and head and neck.

Dr Bill Hrushesky, a senior cancer specialist at the Stratton Veterans' Administration Centre in Albany, New York, is another key figure in chronotherapy. In the Eighties, he studied the effect of giving drugs at specific times of the day to women with ovarian cancer. The evidence was that the precise timing of treatment could affect survival.

In the trial, half the patients were given one drug at 6am and another at 6pm. In the other group, the regime was reversed. In the first group, 44 per cent of women were alive after five years, while in the second group only 11 per cent remained.

'Our trial was small and conducted in a single hospital. Dr Levi's study is the first large trial, involving many hospitals, to demonstrate significant clinical advantage by giving drugs at a particular time of day,' Dr Hrushesky says.

He explains some mechanisms for the effect. Cells go through a cycle: they divide, rest, reproduce their genetic material and then divide again. In healthy cells, these phases tend to occur at particular times of day, and there is evidence that many cancer cells follow this rhythm. Anti-cancer drugs attack cells at the stage in their cycle when they are preparing to divide. Making treatment coincide with this phase should kill a greater number of cancer cells. There is also likely to be variation through the day in the ability of cancer cells to counter drug treatment. 'One of the purposes of daily cycles is to allow the same cellular machinery to accomplish different tasks at different times,' Dr Hrushesky says. 'So it may be that the mechanisms responsible for drug resistance are busy doing other things at the time when you give the drug.'

He also draws attention to the daily rhythms in the release of many of our hormones, such as cortisol and melatonin. The particular level of one or more of these hormones may influence the anti- cancer effect of drugs.

Finally, there is a daily cycle in the state of activation of the immune system. 'At certain times it may be easier to stimulate it into attacking cancer cells that have been damaged but not yet killed by anti-cancer drugs,' he argues. 'Each of these four factors is already known to be relevant to the response of cancer to treatment.'

At Dr Hrushesky's hospital, drug regimes varied according to time of day are now in routine use for cancer patients. And he believes that the importance of chronotherapy can only increase.

At the moment, the synthetic chemicals used in treatment are relatively non-specific in their effects. But as cancer therapy switches towards amplifying elements of the body's own immune response, more specific in their effects, the importance of adjusting their use to natural rhythms will become greater.

Daily variations are clearly important. He emphasises that there are monthly and seasonal cycles that should be taken into account as well as daily changes.

'In early breast cancer, the timing of surgery within the menstrual cycle seems to affect survival. We have been studying the effects of timing drug therapy to different stages in the menstrual cycle, and there are major differences,' he says.

'There is probably also an influence of season. We have been able to demonstrate seasonal effects on toxicity in two drugs. In the summer, whether the drugs are given during the day or night makes a large difference to their side-effects, but this is far less so in winter,' he says.

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