Primary Prevention of Colorectal Carcinoma

Submitted by Dr. Andreas Lambrianides
General Surgeon, Brisbane, Australia

With an estimated 150 000 new cases per year and about 58 000 deaths, colorectal carcinoma accounts for nearly 15% of all cancer related deaths in the United States. Colorectal carcinoma has a world wide incidence with higher rates in the United States, Canada, Australia, Sweden and other affluent countries. The incidence is significantly lower in Japan, South America and South Africa.

Environmental factors, particularly dietary practices are implicated in these contrasts. Migrants from Japan or Africa who have turned their dietary habits to those of their adoptive country (United States) have acquired over the course of twenty years the rates prevailing in their new environment.

Factors receiving the most attention as predisposing to a higher incidence of colorectal cancer are:

Energy

Dietary Factors

Nutritional Supplements

Other Agents: Aspirin, Non steroidal, anti-inflammatory agents

Physical activity

Smoking

Studies in the prevention of colorectal malignancy include a number of different disciplines such as, cell biology, human nutrition, epidemiology, molecular genetics and animal models.

The proportion of colorectal malignancy attributed to nutritional factors has been estimated to be about 50%. A recent review of diet and cancer estimates that 66 - 75% of malignancy of the colon and rectum can be prevented by diet and physical activity.

 

Energy Intake

 

There is a consistent positive association with energy intake and the risk of colorectal cancer. The evidence is sufficient enough to recommend reducing energy intake, both to prevent colorectal cancer and also for other reasons.

Recommendation

Restricting the energy intake in most males to less than 2500 kilocalories (10, 480kj) per day and in most females to less than 2000 kilocalories (8360kj) per day helps to prevent carcinoma or adenoma (a benign tumor arising from the glandular epithelium in the colon.) Most colon cancers arise in pre existing adenoma formation.

 

Dietary Fat

The incidence of colorectal cancer and adenoma formation is high with a high fat intake (more than 40% of the total calorie intake). Increase dietary fat has shown to increase the hepatic synthesis of cholesterol and bile acids, and their increase presence in the colon and faeces. Bacteria flora can convert these sterols into cholesterol metabolites and oxidized bile acids, which have a tumor promoting activity in animal models. The Toronto polyp study showed no benefit, though the results were not differentiated by adenoma size. The Australian polyp study demonstrated a marginally statistically significant result for low fat diets (less than 25% of the calories as fat) after two and four years of intervention on the occurrence of adenomas of 1cm in size. Results show that since there has been no change in the weight of participants the carcinogenic potential is due to dietary fat rather than associated energy. A notable exception in the relationship of fat to colorectal carcinoma is omega-3 fatty acids (fish and fish oils), which reduce epithelial cell proliferation. Further trials are in progress on the effects of fat and development of malignancy.

Recommendation

Dietary fat should be less than 25% of the calorie intake

 

Meat

Whilst the majority of studies on the effect of meat showed a positive association between red meat and colorectal carcinoma, this association however is weak and in only two studies was the trend towards increasing the risk statistically significant. The American institute of Cancer research attributed increases in risk, more to red meat than to fat. In the Australian Polyp study fat reduction was achieved by design without reduction in red meat. It was concluded that inhibition of polyp growth was due to fat reduction rather than red meat consumption. High temperature cooking (barbecuing) of red meat causes the formation of heterocyclic amines, which are subsequently metabolized to form carcinogens. The evidence however is inconsistent that increased intake of heavily browned meat or high values of heterocyclic amines produced as a result of cooking meat, increases the risk of colorectal cancer.

Fiber

Cellulose or fiber is a major component of plant cell walls. On a global scale, it is estimated that plants produce one hundred billion tones of cellulose per year. Cellulose is a polymer of glucose. Each glucose molecule in cellulose is in the beta configuration, making every other glucose molecule up side down with respect to the others. Cellulose macromolecules are straight and are never branched. Humans do not produce the enzymes necessary to digest cellulose. The fibers pass through the digestive tract and are eliminated with the feces. Some bacteria can digest cellulose, breaking it down to glucose monomers. Parallel cellulose molecules are held together by hydrogen bonds. About eighty molecules of cellulose associate together to form a microfibril the main architectural unit. In 8 of 10 controlled studies the risk of polyp formation was decreased with higher consumption of plant food. The mechanism of action is not clear but it may act by decreasing the concentration of carcinogens or by reducing the transit time and thus the exposure time to the carcinogens. Carcinogens are thought to induce carcinoma in two stages, initiation and promotion. Initiation results from exposure of the mucosa cells to an appropriate dose of the carcinogen causing permanent DNA damage, and is therefore irreversible and has "memory". Promoters can induce cancer in initiated cells, but they are not tumorigenic by themselves. Tumors do not result when the promoting agent is applied before the initiating agent. Another possible mechanism is through the formation of bacterial fermentation products - short chain fatty acids. There appears to be a better protection from vegetables than cereals. Vegetable intake seems to be particularly important especially from vegetables such as brussel sprouts, broccoli, cabbage, cauliflower, mustard greens and turnips. The active components of these vegetables have not as yet been identified however scientific pursuit is at full flower.

 Recommendation

Eat 5 or more portions a day of a variety of vegetables and fruit.

Cereal fiber varies in its solubility. Poorly soluble fiber such as wheat bran, continue to be fermented in the intestines, producing short chain fatty acids, which decrease the luminal pH, inhibiting bacterial enzymes capable of carcinogen production. A number of studies have shown greater protection from insoluble than soluble cereal fiber.

Recommendation

Select poorly soluble cereal fibers (Wheat bran)

In contrast to the data for vegetable fiber, evidence for a protective affect by fruits is more limited and inconsistent both for colorectal carcinomas and adenomas.

Micronutrients

Recent studies show no significant effect of calcium and vitamin D on the development of colorectal cancer and no general recommendation can be made at present regarding carcinoma prevention. In contrast to calcium and vitamin D, folate studies suggest a beneficial effect. Low folate diets are a risk for adenoma and carcinoma especially in habitual alcohol consumers. Low folate diets enhance the development of chemically induced cancers in rodents.

Recommendations

Vegetable diet high in folate (wheat bran, bakers yeast, spinach)

 

Phytonutrients

Nutrients in plants (vegetables, fruits and cereals) have anti cancer properties independent of their fiber content. Vegetables of importance include cabbage, cauliflower, broccoli, brussel sprouts, garlic, onion, chives, tomatoes as well as fruits containing vitamin C, E and carotenoids. The evidence at present is only epidemiological, however it underlines the need for a high vegetable and fruit intake.

Alcohol

Total alcohol intake rather than specific types of alcohol is more consistently associated with increase risk of colorectal cancer.

Mechanisms that could be involved include enzyme induction of procarcinogens, inhibition of DNA repair and concurrent nutritional deficiency. The effect of alcohol appears to be stronger in men then women. Australian studies have found the association to be particularly prominent in beer drinking men. Wine is less implicated and rectal carcinoma does not seem to be related to wine drinking.

Nutritional Supplements

A good general principle is to encourage eating whole foods rather than promoting nutritional supplements, as it is more likely that whole foods will contain more anticancer agents than those identified so far. Calcium and folate supplements are unlikely to be useful on the current evidence available. It has been shown that in animals calcium binds to fatty acids and therefore protects the colonic epithelium from their toxic effects. Randomized double blind, placebo control studies in humans did not show any significant effect on the proliferation of rectal mucosa. As for folate, although supplementation has a protective effect in rats,

no human studies have been performed so far. The story with selenium however is more promising. This is an essential trace element in humans. The main effect is to reduce oxidative damage to the DNA. Deficiency may occur in diets lacking whole grain and vegetables, and from foods derived from soils with low selenium concentration. Populations deficient in selenium have an increased incidence of, and mortality from colorectal carcinoma. Studies provide evidence that supplementation with selenium has a protective effect against colorectal cancer. Despite the current evidence further information with appropriately designed trials is necessary before recommendations regarding selenium supplementation should be made.

Antioxidants such as vitamin A and C are not advised at the present to protect against colorectal carcinoma. Randomized controlled studies of vitamin A, C, E and beta-carotene have been negative. A Canadian trial of vitamin A and E, an Australian study of beta-carotene and a further study with vitamin C and E showed no significant benefits.

Other Chemoprevention agents

Other candidates for chemoprevention of colorectal carcinoma include aspirin and non-steroidal anti-inflammatory agents. The Melbourne colorectal study showed that regular aspirin use was associated with a 40% lower risk of colorectal cancer. Further case controlled studies have shown significant reduction of the relative risk for those taking non-steroidal anti-inflammatory agents on a regular basis. It has been suggested that the effect was achieved because the drugs lead to bleeding which thus lead to earlier diagnosis. This suggestion was settled in a case control studied in the United States where those taking aspirin for medical reasons were compared with those taking other anticoagulants. Although all had and increase risk of bleeding only the aspirin group had a decrease risk of colon cancer. Studies in Sweden and Finland showed that patients with Rheumatoid arthritis show a reduced incidence of colorectal cancer. The likelihood of developing colorectal cancer is 30% - 40 % lower in these patients as compared to the general population. In the Nurse’s health study, five hundred and fifty one thousand female nurses taking aspirin were followed for eight years. Those who were regular users of aspirin over a ten to twenty year period showed a reduction in the relative risk to .56. The most significant prospective study of aspirin use and cancer was preformed by the American cancer society. Aspirin intake of more than 662 000 adults in the United States was documented and then followed for seven years; the death rate from colorectal cancer was noted. A dose - response relationship was noted. For those who took 16 or more aspirins per month for at least ten years, the relative risk of fatal colon carcinoma was .36. For those taking aspirin 16 or more times a month for at least a year, the relative risk was .60 for males and .58 for females. The current pool provides evidence of reduction in the risk of colorectal cancer from regular use of aspirin or NSAID but, the results are not consistent and there is lack of information regarding dosage, duration, age of recommended onset and options regarding different NSAID. The balance between toxicity and benefit has to be clearly evaluated. Of additional interest was the finding that other gastrointestinal cancers were also reduced.

Recommendation

Aspirin and NSAID chemoprevention is consistently protective in case control studies but is not recommended until dosage and balance between risk and benefit is evaluated in randomized controlled trials.

Physical Activity

The evidence that physical activity protects against colon cancer as distinct from rectal cancer is strong and convincing. The data for rectal cancer is not consistent. The majority of studies show protection. The exact mechanism is not clear although stimulation of transit times, and immune or hormone mechanisms have been postulated. The data for carcinoma of the rectum is not consistent.

Recommendation

Be physically active to protect against colon cancer.

Smoking

The majority of studies show an increase in the risk from smoking of at least 50%. A number of results are statistically significant. The evidence is stronger for rectal rather colonic carcinoma. The risk is also higher in those patients that have been smoking for longer periods of time. The results are even more consistent with adenomas.

Recommendation

Avoid Smoking

Appropriate dietary measures; together with physical activity and maintaining a healthy weight and avoiding smoking and alcohol could in time substantially reduce the incidence of colorectal cancer.

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