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Why exercise benefits patients with advanced prostate cancer

The incidence of prostate cancer has risen along with the increase in obesity levels in Ireland in recent years, while there is epidemiological evidence that exercise benefits even those men with advanced metastatic prostate cancer.

Dr Stephen Finn, Consultant Pathologist at St James’s Hospital, Dublin, and Associate Professor in Histopathology at Trinity College Dublin is investigating how exercise increases the longevity and quality of life in patients with advanced prostate cancer and the biological mechanisms that underpin and drive this positive health effect.

Dr Finn said the general feeling among researchers is that exercise is beneficial in respect of many cancers, but the real question is whether it can affect the cancer directly, and if it does, how precisely it does that. Is the benefit achieved by changing the balance of hormones in the body? Or is it because the tumour cells are less cloaked by blood platelets and therefore more visible to the cells of the immune system and more likely to be killed? These are the central questions.

“Evidence continues to accumulate that exercise is a ‘medicine’ that has dramatic effects in relation to cancer prevention, as treatment, and preventing cancer from recurring,” said Dr Finn. The specific cancer he has chosen to test the effect of an exercise intervention for cancer patients is advanced prostate cancer. This is not surprising when one considers the figures. The number of prostate cancers diagnosed in Ireland more than doubled between 1995 and 2010, from 1,162 to 3,122. In 2008, Ireland was found to have the highest estimated incidence of prostate cancers in Europe and the third-highest in the world. The link between this rise, and that of obesity, appears clear.

“It is known that men who have prostate cancer are more likely to die of their disease if they are overweight or obese than if they are of a healthy weight,” said Dr Finn. “In men with advanced cancer, individual cancer cells spread beyond the prostate gland and can be found floating in the blood. These cancer cells are known as circulating tumour cells, or CTCs. Tiny blood particles [platelets] become stuck to these CTCs in a process called ‘platelet cloaking’ and may prevent the body’s immune system from hunting down and killing the cancer cells before they can spread around the body. There is a greater tendency for blood to clot, due to stickier platelets, in obesity. This suggests that there may be more platelet cloaking of CTCs in overweight men with prostate cancer, which in turn makes the cancer more aggressive,” outlined Dr Finn.

Trials

Men with advanced cancer are initially put on drugs that affect their hormones, such as anti-androgens, said Dr Finn. These agents, while beneficial in terms of treating the cancer, have significant side-effects. Exercise helps to prevent some of the side-effects associated with these drugs, he said. One goal of his work is to determine the precise benefit offered by exercise tailored for the individual.

The EXPECT trial, which finished in April 2017, was set up as an individualised exercise intervention in men with advanced cancer, said Dr Finn. The men who were recruited took part in supervised exercise classes and they had to attain a certain level in terms of their heart rate and other measures, he said. The aim of this trial was to try and better understand the biological mechanisms at play, giving positive health benefits, and also to compare the hormonal systems in men with prostate cancer before and after exercise. Another part of the study investigated the process that leads to platelet cloaking, he said.

Furthermore, Dr Finn said an important part of EXPECT was to investigate whether there were biomarkers that could be used to indicate the level of platelet cloaking, where tumour cells were being cloaked by platelets, enabling them to hide from the patient’s immune system. The trial was set up as a clinical trial under the auspices of Cancer Trials Ireland and it took place over two years at St James’s Hospital and a number of other Dublin hospitals. It was not possible to spread the trial across the whole country, said Dr Finn, because the intervention required supervised exercise classes, which had cost implications. However, the men on EXPECT can go on to exercise themselves on a tailored programme.

There was no age exclusion for the EXPECT trial, said Dr Finn, even though a lot of patients with advanced prostate cancer are older men. He said the GP is best placed to judge what level of exercise is appropriate for the individual, and also what is not possible. For example, some men might lift weights with both arms, while others will only be able to lift weights with one arm, if the other arm has metastatic sites that impede the exercise.

The Global Action Plan (GAP) 4 initiative is another clinical trial with which Dr Finn is involved. This multidisciplinary trial, which is just starting, aims to recruit 866 men from seven different countries for a trial lasting five-and-a-half years. The standard of fitness required to get access to GAP4 is higher than EXPECT, said Dr Finn, because the men have to pass cardiopulmonary exercise testing (CPET).

The men have to be fit enough to undergo a fairly intense exercise schedule for GAP4, said Dr Finn, which involves lifting weights three days per week, and pushing themselves to reach personal maximums over an extended period of time.

As with EXPECT, there is no age exclusion criteria with the GAP4 trial, said Dr Finn. However, while some 80-year-old men with advanced cancer will be able to take part, not many do, due to having other diseases such as cardiovascular disease and arthritis.

The patient population that has advanced prostate cancer will be seeing an oncologist regularly, said Dr Finn, and oncologists are aware of exercise intervention trials that may be going on. The role of the GP in this instance is to refer to an oncologist in order to get the specialist to put their patient on a trial, he outlined.

There is some preliminary data becoming available from the EXPECT trial on the biology of exercise benefits in relation to inflammatory markers, circulating tumour cells and the phenomenon of platelet cloaking, said Dr Finn. However, it will be March 2018 before the data has been analysed to the extent that anything definite can be said about the biological benefits of exercise.

Access

In the meantime, the lack of access to supervised exercise for cancer patients outside of Dublin remains an issue. There are other countries, such as Australia, where the health system directly funds exercise for people with cancer or other chronic illnesses, particularly in the early stages of disease, explained Dr Finn. 

In Ireland, GPs are well aware that their patients need to exercise more for their cardiovascular health and if they have chronic disease, said Dr Finn. However, it is a ‘hard sell’, because if a person hasn’t exercised when they were healthy, they have to change their habits to do it when they have cancer. Those patients with advanced cancer should, at the least, have access to an educational programme to help them do exercise best suited to their needs.

People with cancer — even advanced cancer — should not give up on exercise, said Dr Finn. “Having cancer is not a license to sit down and not do anything,” he said. “In fact, it [exercise] can really help you mentally, psychologically, physically and potentially help the disease by exercising regularly and routinely, perhaps joining a gym, ideally with someone overseeing you, your doctor giving you the okay to do it. But not to sit down and say ‘now that I have got cancer I am not going to do anything, I’m not going to cycle my bike, I’m not going to walk’.”

Ideally, there should be multiple centres located nationwide where people with cancer could go to do tailored, supervised exercise, which are supported by the state or by health insurers, said Dr Finn. He said if this is not possible, then people could be offered an educational programme and given the support to work through it, perhaps further assisted by a helpline. There is a public health message that needs to get out that exercise benefits cancer patients, whether they are young or old, or at an early or advanced disease stage, he said.

“Let’s even say a young man who gets localised disease and is potentially cured, or may have a low-grade persistent disease — exercise for those men is very beneficial as well,” added Dr Finn. “We have focused on the advanced stage of prostate cancer because it asks and answers questions of the biology and the mechanisms, but in early-stage disease it is equally beneficial to do exercise.”

Questions

The World Cancer Research Fund — a not-for-profit organisation that is a world-leading authority on the link between diet, weight, physical activity and cancer — funded Dr Finn in 2013 to investigate why obesity makes prostate cancer more aggressive and to see whether a simple exercise programme could improve quality of life and prolong survival for advanced prostate cancer patients. The study is being carried out in collaboration with the University of Orebro, Sweden, and King’s College London, but it is too early to answer any of its key questions.

The study involved men with advanced prostate cancer gathered from European centres, and in Dublin at St James’s, St Luke’s Radiation Oncology Network, Tallaght Hospital, the Mater Misericordiae University Hospital and Beaumont Hospital.

The men were measured for height and weight to determine whether they were obese, overweight or a healthy weight. Blood samples were taken at intervals and questionnaires filled out at each visit to the clinic about physical and emotional wellbeing. The questions that Dr Finn and his collaborators want to answer is whether there is more platelet cloaking in overweight men, whether regular exercise can reduce that cloaking effect, if cloaking varies relative to how easily blood clots form, and to see if there are specific genes which make the platelet cloaking worse. 

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