Survival in colorectal cancer: impact of body mass and exercise

Short abstract

Is there a relationship between exercise and body composition prior to a diagnosis of colorectal cancer and survival afterwards?

Obesity and lack of physical exercise are on the ascendant—not only in their own right¹ but as targets of health policy. Recent discussions at the G8 summit and the “Make Poverty History” campaign have highlighted the growing inequalities of affluence worldwide and have made us feel embarrassed by our glutton and sloth. The government is now trying to tackle the problem at its roots, focusing on “healthy” school meals and promoting exercise with the hope that fit and lean children will grow up to be healthier adults.² The decision to host the 2012 Olympics in London will be a further fillip for this policy.

There are now multiple studies which demonstrate an association between obesity, exercise, and colorectal cancer incidence and mortality.³,⁴,⁵,⁶ It has been estimated that overweight and obesity could account for 14% of male and 20% of female cancer deaths in the USA.³ But getting a clear message from these studies can be difficult. Some papers report different associations for men versus women or for colon versus rectal cancer or for different measurements of overweight/obesity. It is reasonable to suppose that these types of risk factors might affect both sexes and parts of the colorectum in similar ways, although perhaps not to the same degree. So, do conflicting results reflect a true lack of association or are we missing the point by measuring the wrong parameters? Although the end points, such as cancer incidence and mortality, are simple to record accurately, measuring obesity and physical activity can be very difficult. There are no surrogate markers that can be easily measured in a blood test, for example. Weight, height, body mass index (BMI), waist circumference, hip circumference, waist to hip ratio, per cent body fat, adipose mass, and non‐adipose mass are some of the more regularly measured indicators of obesity. But which is the most important or useful?

Simple obesity, such as that measured by BMI, may not be the most useful indicator of risk, but measurements of hip circumference (an indicator of general obesity) versus waist circumference and waist to hip ratio (indicators of central abdominal obesity) may be more useful. In the field of cardiovascular disease for example, blood pressure has been found to correlate closely with waist to hip ratio, independently of BMI,⁷ and in the Framingham study central obesity was a better predictor of coronary artery disease than general obesity.⁸ In another study, a high BMI in adolescence was found to increase the subsequent risk of mortality from cancer in general, but this association was not found for colorectal cancer⁹; as discussed below, concerning another study, this does not necessarily mean that obesity is not relevant—if measures of abdominal obesity had been obtained, it is possible that they might have shown a correlation. Even harder to quantify than obesity is physical activity—how much, how often, how strenuous, and how sustained over a period of life might all be relevant. Research into these and other epidemiological factors rely almost entirely on massive cohorts of persons volunteering information about their lifestyle over many years.

Weight and exercise are connected and it is likely that for both there will be some shared mechanisms underlying their effects despite some of the differences in findings of epidemiological studies. One unifying hypothesis relates to insulin and regulation of energy metabolism. Diabetes and HbA1c concentrations are associated with increased risk of colorectal cancer¹⁰,¹¹ and the role of insulin and its associated growth factors and binding proteins have been implicated in colorectal carcinogenesis.¹² Recent analysis of two large American cohorts of health sector workers where detailed dietary and physical activity assessments had been made revealed a correlation between high glycaemic load, and fructose and sucrose ingestion to colorectal cancer risk in men but not in women.¹³ Taking this one step further, Slattery et al investigated whether polymorphisms in genes known to be involved in insulin related functions affected risk.¹⁴ Although they did not find an association, it is inevitable that genetic differences between individuals will be found that can explain the interaction between diet, exercise, obesity, and cancer susceptibility.

The paper by Haydon and colleagues¹⁵ in this issue of Gut is based on a large cohort study in the Australian state of Victoria—the Melbourne Collaborative Cohort Study (MCCS)—which has followed nearly 42 000 people recruited in 1990–1994 (see page 62). A previous report from this group demonstrated an association between central adiposity (waist circumference and waist to hip ratio) and risk of colon cancer in men.¹⁶ Interestingly, after adjustment for fat free mass and waist to hip ratio, BMI was no longer found to be a risk factor. The current study takes a new slant on the topic and examines the relationship between exercise and body composition prior to the diagnosis of colorectal cancer and survival afterwards. The parameters measured were recorded at the subjects' entry into the study which was a median of 5.3 years prior to colorectal cancer diagnosis. As concerns obesity, BMI showed no correlation with survival; however there were significant relationships between both smaller waist circumference and lower per cent body fat with prolonged survival. Exercise, too, showed a positive effect, mainly confined to stage II and III tumours. The effects held true even after correcting for other confounding factors such as age, sex, tumour stage, or diagnosis soon after enrolment.

If confirmed by other studies, these results tell us something quite new, that one's state of health, even years before a serious diagnosis such as cancer, can alter its prognosis. What is remarkable is that a single baseline measurement can demonstrate such a significant effect. For physical activity, the authors classified “exercisers” as those who said that they took any exercise at least once a week over the preceding six months, even if it did not make them sweat or feel out of breath. Even this crude categorisation seems to be predictive of prognosis. No further information about exercise or body composition was collected at the time of diagnosis or afterwards, and one might imagine that a measurement closer to diagnosis would be even more strongly predictive. Interestingly, the benefits of leanness and activity seemed to impact mainly on the cancer related deaths in the affected individuals, as mortality from other causes was not reduced. This is surprising as one would expect a “healthier” individual to have lower mortality from other causes too, especially cardiovascular events.

The findings of this study are not completely clear cut. Exercise showed no correlation with survival in those with very early or metastatic disease, and the beneficial effects were seen mainly in proximal colon cancers. The effects of central adiposity were most significant for distal tumours and were independent of tumour stage. Epidemiologists involved in such studies are acutely aware of potential confounding factors that might lead to a false assumption that association of variables is causal. For example, could exercisers or lean individuals somehow be reporting their cancers at an earlier stage and so only appear to have a better prognosis? There is at least some evidence that this is probably not so.¹⁷

What are the implications of this study? Firstly, we must encourage more studies into the effects of body composition and exercise on cancer, and ensure that they examine not just BMI but measurements of central abdominal obesity, in particular waist circumference or waist to hip ratio. If proven, there should be an even greater impetus in favour of weight reduction and physical activity, which we already know are good for us. Secondly, we need to understand how and why body composition and exercise affect cancer risk. This will require more basic research into the genetics of obesity and metabolism, the cellular effects of exercise, and its effects on tumour initiation, progression, and metastasis. More difficult is the next step which is interventional research: can we prove that alteration in body composition and/or taking more exercise can really benefit individuals and change their risk status? Would a programme of weight reduction and exercise in those just diagnosed with colorectal cancer benefit them or is it already too late?¹⁸ There is some evidence, at least in women with colon cancer undergoing chemotherapy, that a high BMI worsens mortality (although interestingly possibly lowers the risk of chemotherapy toxicity) in patients with stage II and III cancer¹⁹ although this does not rule out the effect predating the surgery. In other words, loosing weight after surgery might be of benefit. There is also hope that exercise after diagnosis of colorectal cancer might improve survival and decrease recurrence.²⁰

In summary, physical activity and excess body mass seem to affect colorectal cancer (among many other benign and malignant conditions) in its different stages of development. Increasing adiposity and inactivity predispose to the development of cancer in the first place; they may adversely affect morbidity and mortality from surgery; and we now find from the study published in this issue of Gut that they predispose to a worse prognosis after diagnosis. There is a least some expectation that long term health and fitness programmes might reap benefits not only in terms of reducing colorectal cancer incidence but in prolonging survival even if bowel cancer does occur.