Colorectal cancer is the third most common type of cancer worldwide, with the highest incidences in Australia, New Zealand, Europe and North America, and the lowest in Africa and South-Central Asia. Rates are substantially higher in males than in females. Bowel cancer is the most preventable cancer type in Australia, with an estimated 44% preventability achievable through improvements in diet and physical activity. In 2005, the National Health and Medical Research Council published Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer. This chapter builds on the conclusions from these guidelines, drawing on the comprehensive review undertaken by the World Cancer Research Fund/American Institute for Cancer Research (Second Expert Report) published in 2007, and Continuous Update Project review published in 2011. The evidence is convincing that physical activity and foods containing dietary fibre protect from colon and colorectal cancer respectively, and that red and processed meat, ethanol from alcoholic drinks and body and abdominal fatness increase risk of colorectal cancer. Strategies to support these lifestyle and dietary changes in practice should be strongly recommended. The smoking of tobacco probably causes colorectal cancer and foods containing garlic, milk and calcium probably protect against colorectal cancer. The use of anti-inflammatory drugs as prophylaxis against further adenoma development in individuals with familial adenomatous polyposis should be considered, especially where surgery is inappropriate; low dose aspirin in those at high familial or personal risk is recommended. Based on the current evidence, the level of protection offered by physical activity and dietary fibre, and the level of risk resulting from the consumption of red and processed meat and high body and abdominal fatness, is stronger and more conclusive than the evidence documented in previous reviews.
The Second Expert Report (SER) (2007),1 by the World Cancer Research Fund and American Institute for Cancer Research recommended people be moderately physically active, equivalent to brisk walking for at least 30 minutes a day, with the objective of ≥60 minutes of moderate or ≥30 minutes of vigorous physical activity every day, and to limit sedentary habits to prevent colorectal cancer (CRC).
The Continuous Update Project (CUP) (2011),2 reviewed the outcomes of cohort studies published since 2007, and concluded that a lower risk of colon cancer was associated with higher overall levels of physical activity, with evidence of a dose-response effect within the range studied. The effect was strong for colon cancer, but there was no evidence of an effect for rectal cancer. The effect was strong and consistent for men, but less strong in women. The meta-analyses showed that recreational physical activity resulted in an 11% decrease in risk for colorectal and 12% decrease for colon cancer per 30 minutes of exercise per day. While these effects were independent of any effect of exercise on obesity, additional benefits of longer term, sustained, moderate physical activity may also be realised through reduced body fatness and may protect against colon cancer by decreasing inflammation, reducing insulin levels and reducing insulin resistance. More recently, physical activity and fewer sitting hours were found to significantly reduce colon cancer risk in both the distal and proximal colon, although results for rectal cancer were mixed.3-5
The CUP review concluded that new cohort studies published between 2007 and 2011, investigating body mass index, showed increased risk of CRC with increased body fatness. The meta-analyses showed increased risks of 2, 3 and 1% per kg/m2 for colorectal, colon and rectal cancers respectively. There tended to be a larger effect for men than women and the effect was stronger for the US and Asia than Europe. The CUP agreed with the SER finding that there was convincing evidence that greater body fatness is a cause of CRC. Similarly, the CUP found that all new cohort studies demonstrated that increasing waist circumference and/or waist to hip ratio measurements increased risk for CRC. The meta-analyses showed increased risks of 3, 5 and 3% (per inch for studies that did not adjust for body mass index) respectively for colorectal, colon and rectal cancers. In the UK, 13% of CRC has been attributed to overweight and obesity. In the large European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study, individuals who gained >20kg of weight since age 20, had a 38% higher risk of colon, but not rectal cancer, compared to those whose weight remained stable. This association only applied to those with high attained waist circumference, suggesting fat accumulation in the abdominal area is important in relation to CRC risk.6 A recent review involving seven studies, found obese patients were more likely to have distal tumours, show intact DNA mismatch repair, and have increased lymph node metastases compared with normal-weight patients.7 Other recent reviews made similar conclusions, with the risk of CRC from excess body fatness being stronger in men than women, rectal cancer being less affected by body fatness than colon cancer and with general and regional fatness both playing a role.8-12 Body and abdominal adiposity may increase risk through systemic effects, in which insulin and oestrogen levels encourage carcinogenesis and discourage apoptosis.4
Dietary fibre is a heterogeneous group of plant-derived structural components not digested by human digestive enzymes, consisting largely of non-starch polysaccharides and resistant starch. The suggested mechanisms for protection from CRC from high dietary fibre include fibre diluting or absorbing digesta carcinogens, reducing intestinal transit time, reducing secondary bile acid production, reducing colonic pH and increasing the production of short chain fatty acids.13 The short chain fatty acid butyrate may play an important role,14 as it enhances the deletion of genetically damaged cells by inducing cell cycle arrest, differentiation and apoptosis.15 The CUP concluded that 13 of 18 studies published since the SER (2007) review showed decreased risk of CRC with increased intake of total dietary fibre. The updated meta-analyses showed a 12% decreased risk for men and an 8% decreased risk for women (per 10g dietary fibre/d), with a 21% decreased risk per three servings of wholegrains for CRC and a 16% decreased risk for colon cancer. Based on consistent evidence, with clear dose-response relationships for both women and men the CUP concluded that the protective effect of dietary fibre had strengthened from ‘probable’ to ‘convincing’. The CUP agreed with the SER conclusion that evidence of protection from non-starchy fruits and vegetables was limited. The CUP review included a pooled analysis of 756,217 participants from 14 cohort studies, followed up for six to 20 years.16
Red and processed meat
Based on the findings of nine of 12 studies published between 2007-2011, the CUP agreed with the SER that there was convincing evidence that higher intakes of red and processed meat increase the risk of CRC. Meta-analysis showed a 17% increase in risk of CRC per 100g red meat consumed per day. This conclusion is further supported by more recent studies confirming red meat consumption is a risk factor for cancer of several sites, including colon and rectum, with no effect of cooking method.17 Others have found an association between cooking method and CRC and rectal adenoma risk.18,19 The risk of CRC and rectal cancer differ according to the subtype of red meat consumed.20 The mechanism underlying the increase in risk may be associated with the presence of heme in red meat, which undergoes endogenous nitrosation with the formation of potentially carcinogenic N-nitroso compounds,21 or due to the production of potentially carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons during the cooking of meat, or the presence of nitrites and nitrates.18 In 10 of 13 studies reviewed by the CUP, increased risk of CRC with higher intake of processed meat was observed. The meta-analysis showed an 18% increased risk for CRC and a 24% increased risk of colon cancer per 50g processed meat/day intake. There was an indication of increased risk of rectal cancer, but the effect was not significant. The CUP concluded there was a dose-response relationship apparent from cohort studies and agreed with the SER that processed meat was a convincing cause of CRC. More recent studies have confirmed a positive association between red processed meat and proximal colon cancer,18 and that in Europe the negative effect of processed meat was mainly driven by the consumption of sausages.22
The CUP and SER concluded milk probably protected from CRC with a 9% decreased risk for CRC per 200g milk consumed/day. This conclusion is supported by the EPIC study, which found dairy products protective irrespective of fat content of the products,23 but not non-dairy calcium products. However, the CUP and SER reviews found that in six of seven cohort studies, calcium supplements reduced the risk of CRC, and the CUP panel concluded that calcium probably protected against CRC. Other nutrients or foods for which there is limited or inconsistent evidence to support their role in CRC protection or development are listed in table 1.
The 15 new papers reviewed by the CUP showed an increased risk with increased intake of ethanol for CRC and colon cancers. The meta-analyses showed a 10% increased risk for CRC and rectal cancers, and an 8% increased risk for colon cancer per 10g ethanol consumed per day. The effect was stronger in men than women, with 11% increased risk in men compared to 7% in women. The CUP agreed with the SER conclusion that ethanol from alcoholic drinks as a cause of CRC in men was convincing, and was probably a cause of CRC in women. In the UK, 15.5% of CRC in men and 6.9% in women has been attributed to consumption of alcohol.24 Alcohol interacts with tobacco by interfering with the repair of specific DNA mutations caused by smoking, and may also enhance the penetration of other carcinogenic molecules into mucosal surfaces.
Significant associations were found between daily cigarette consumption, duration, pack years and age of initiation with CRC incidence, with an increase in risk of 38% for every 40 cigarettes smoked per day.25 Tobacco smoking is considered to be an established cause of CRC,26 with 8.1% of CRC in the UK attributed to tobacco use.24
Chemoprevention is the regular use of drugs to prevent or delay the development of cancers. As chemoprevention strategies require regular use of agents over many years by people who are disease free and may never develop cancers, chemopreventive agents need to be easily administered with a convenient dosing schedule, inexpensive and extremely low in side-effects. There is strong evidence supporting the chemopreventive activity of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) against CRC. However, data on the risk-benefit profile of these drugs is currently insufficient to allow definitive recommendations for their use at a population level for primary cancer prevention. Aspirin is the NSAID most likely to be used, largely because its cancer-preventive actions augment its already established cardiovascular benefits and its safety and efficacy profile is well understood.27 Indeed, with the recent publication of data from the CAPP2 study, there is consensus among familial cancer clinics that daily aspirin use at a dose of at least 100mg per day be recommended for patients with Lynch Syndrome,28 subject to consideration of their history of indigestion, peptic ulcer, Helicobacter pylori infection, renal impairment, allergy to aspirin and uncontrolled hypertension. In some circumstances, patients with familial adenomatous polyposis are currently treated with traditional NSAIDs (e.g. sulindac) to reduce their risk of developing CRC, even though these drugs provide no cardio-protection.29
The commonly prescribed cholesterol-lowering statin drugs also have chemopreventive properties. They are very well tolerated and serious adverse effects of these drugs are rare. While currently less compelling than for aspirin, accumulating clinical evidence suggests a significant association of certain statins with lowered gastrointestinal (particularly colorectal) tumour occurrence, or increased patient survival when the drugs are taken for >3 years or >5 years in modest doses (e.g. 40 mg simvastatin; reviewed in.27 These benefits are likely to be more marked in populations with a higher lifetime risk of cancer e.g. the hereditary colorectal cancer syndromes.
Patients with diabetes mellitus have an increased risk of CRC.30 Metformin is an anti-hyperglycaemic drug, widely prescribed for the treatment of type-2 diabetes with few side-effects. Metformin lowers intestinal glucose absorption, hepatic glucose production and improves insulin sensitivity in the peripheral tissues, leading to lower levels of circulating insulin.31 Elevated insulin levels have been associated with an increased risk of CRC. Two meta-analyses of cancer incidence in patients with type-2 diabetes have both shown an inverse association between metformin use and CRC.32,33 Given the increased risk of CRC associated with type-2 diabetes, metformin’s potent anti-hyperglycaemic activity and its protective activity against CRC make it an attractive drug for the management of diabetes patients.
Bisphosphonates are used in treatment of osteoporosis, multiple myeloma, for the treatment of bone overgrowth in malignancy and for the prevention or treatment of solid tumour metastases to the bone.34 Their anti-cancer activity is likely mediated through inhibition of angiogenesis and cell proliferation, induction of cell-cycle arrest, and apoptosis in cancer cells, and immune cell activation.34 Three studies in women found quite substantial reduction in the risk of CRC,35-37 while analyses of data from the Women’s Health Initiative and the Nurse’s Health Study found no such reduction.38,39 More research is needed to confirm the utility of bisphosphonates in the prevention of CRC and to quantify the benefits of bisphosphonates against the rare but serious adverse events.