Colorectal cancer is a leading cause of cancer-related mortality, particularly in populations consuming diets based on animal-derived products.[1] It accounts for 10% of cancer deaths in the United States. Although the disease is common and often lethal, the risk is significantly reduced with regular screenings and timely removal of precancerous lesions. Evidence also suggests that dietary habits may influence both cancer incidence and progression.

More than 95% of colon cancers are adenocarcinomas, which originate from glandular tissue. Presenting symptoms and complications depend on the location of the tumor. General symptoms include abdominal pain, a change in bowel habits, decreased caliber of stool, and constitutional symptoms, such as weight loss, weakness, and fatigue. Right-sided tumors may additionally present with melena or occult bleeding and/or a right-sided abdominal mass. Left-sided tumors may cause constipation, diarrhea, and, especially with distal left-sided and rectal tumors, hematochezia. Further, patients with left-sided tumors are at much higher risk of intestinal obstruction, which may present with nausea, vomiting, absence of bowel movements and flatus, and abdominal distention. Many patients have anemia.[2]

Local spread and distant metastases are common. Between 15-20% of patients initially present with metastases, most commonly to the regional lymph nodes, liver, lungs, and peritoneum.

Risk Factors

Age: Incidence increases with age. While most cases occur in people age 50 and older, incidence is increasing in younger adults and decreasing in older adults.

Race: In the US, Blacks have higher rates of colorectal cancer and a 20% higher mortality, compared with whites.[3]

Family history: 25% of patients have a positive family history. There is a several-fold increased risk if one or more first-degree relatives have colon cancer.[4]

Environment: Incidence is highest in developed countries. Individuals migrating from areas of low incidence to areas of high incidence eventually assume a risk similar to that of their adopted country.

Diet: Numerous studies have detected associations between diet and the development of colon cancer, as described below in Nutritional Considerations.

Tobacco use: Smoking is a risk factor for both colon polyps and colorectal cancer. Smokers with colorectal cancer also have a higher mortality rate.[5]

Hereditary syndromes: There are several syndromes that increase the risk for colorectal cancer, such as familial polyposis and Lynch syndrome.

Acromegaly: The incidence of both colorectal cancer and adenomas is increased in patients with acromegaly.[6]

Diabetes and insulin resistance: Colon cancer risk is almost 40% higher in people with diabetes compared to those without diabetes.[7] This risk may be related to increased levels of insulin-like growth factor (IGF-1).

Inflammatory bowel disease: Both ulcerative colitis and Crohn’s disease predispose to colon cancer. There appears to be a higher risk with ulcerative colitis (as much as a 5-fold to 15-fold increased risk) than with Crohn’s disease.

Overweight: A number of studies, including the NIH-AARP Diet and Health Study involving more than 500,000 women and men, have found a linear relationship between excess weight and death from colon cancer.[8] Individuals with a BMI ≥ 40 have a roughly 45% greater risk for colorectal cancer, compared with those who are at a healthy weight (BMI 18.5-24.9). Individuals who are mildly or moderately obese appear to have a 10% and approximately 35% greater risk, respectively.[9]

Protective Factors

Exercise: Physical activity may decrease the risk for colorectal cancer. In a study of more than 120,000 female teaching professionals, among women who had never used hormone therapy, exercising for 4 or more hours per week was associated with roughly half the risk for colon cancer, compared with the risk for women who exercised 30 minutes per week or less.[10] Possible mechanisms include reduction in weight or in blood concentrations of insulin or IGF-1.[11]

Postmenopausal hormone therapy: Hormone replacement therapy may influence risk. Data from the Women’s Health Initiative suggest a reduced risk of colorectal cancer in postmenopausal women using hormone “replacement” therapy.[12],[13] This is not a reason for prescribing hormones, however, as they are associated with increased risk of other conditions, including certain cancers.

Aspirin and NSAIDs: Regular use of aspirin and other NSAIDs is associated with a 20- 40% reduction in the risk of colonic adenomas and colorectal cancer in individuals at average risk.[14]

Diet: Numerous dietary factors can lower the risk of colorectal cancer as described below in Nutritional Considerations.

Screening

Certain tests (discussed below) are approved for colorectal cancer screening and several groups have published screening guidelines.[15],[16],[17],[18],[19] No single screening test has unequivocally been shown to be superior. Most of the guidelines agree that some type of screening (see specific tests below) should begin at age 45-50 years for average-risk patients and should continue until the individual’s estimated life expectancy is less than 10 years.[20] Taking into consideration patients’ personal preferences may increase screening rates.

Patients at higher risk should have more frequent screening, depending on the nature of that risk.

Fecal Occult Blood Testing: Stool guaiac tests have a fairly low sensitivity and specificity but are non-invasive and inexpensive. Fecal immunochemical testing (FIT) may have a higher sensitivity and specificity but is more expensive. This method of screening is recommended annually by the US Preventive Services Task Force.

Stool DNA testing: Neoplasms in the colon shed DNA in the stool, which can be tested for mutations. Current tests combine stool DNA, patterns of DNA methylation, and testing for hemoglobin with an FIT. This method of screening is recommended every 1 to 3 years.

Endoscopy: Colonoscopy with biopsy identifies colonic growths and may allow for removal of early lesions. Colonoscopy is also indicated for further evaluation of other abnormal screening test. It requires bowel preparation and sedation and carries a small risk of perforation and bleeding. Colonoscopy is the most common test used to screen for and diagnose colorectal cancer and is typically recommended every 10 years.

Flexible sigmoidoscopies can only detect neoplasm on the left side of the colon, but can be performed with minimal bowel preparation and do not require sedation. This method of screening can be performed every 5 years. When paired with annual FIT testing, flexible sigmoidoscopies can be performed every 10 years.

Computed tomography colonography: “Virtual colonoscopy” uses thin-slice CT scanning to identify colonic neoplasms. Bowel preparation is required, but the test can be performed without sedation. Any abnormalities require colonoscopy for further evaluation. There is radiation exposure associated with the procedure.

[16]

Diagnosis

The diagnosis of colorectal cancer is made by tissue biopsy, typically obtained during a colonoscopy.

Tumor markers: Tumor markers (CEA, CA 125, CA 19-9, CA 50, CA 195) are not sufficiently specific for general screening, but they can be used to determine prognosis and to monitor for disease recurrence.

Metastatic workup: Once colon cancer is diagnosed, a metastatic evaluation should be performed, which includes liver function tests and CT scans of the thorax, abdomen, and pelvis. CT scan is also used for clinical staging. The TNM (Tumor, Node, Metastasis) classification is the preferred system for tumor staging:

• TNM stage I: Tumor is localized to the mucosa and submucosa.
• TNM stage II: Tumor has extended into the muscle layer but without lymph node involvement.
• TNM stage III: Regional lymph node involvement.
• TNM stage IV: Distant metastases.

Treatment

Surgical resection is the definitive treatment for colorectal cancer and is often curative for early cancers. A combination of surgical resection and adjuvant chemotherapy is indicated for advanced cancers. Radiation and chemotherapy are mainstays of treatment for rectal cancers, in addition to surgical resection.

Liver metastases are treated by resection, radiofrequency ablation, or chemoembolization. Some lesions may be treated with direct arterial infusion chemotherapy into the hepatic artery.

Nutritional Considerations

Diet is a significant contributor to colon cancer risk. The following factors are associated with reduced risk of colorectal cancer:

Maintaining a healthy weight. A meta-analysis of observational studies, including more than 16,000 cases, concluded that for every 5 kg of weight gained during adulthood, the risk for colorectal cancer increased by 4%. For a weight gain of roughly 30 pounds, the risk increased by 22%, compared with individuals who had maintained weight.[21] Compared with individuals who were healthy weight or slightly overweight, both obese and underweight patients had significantly weaker cancer-specific and overall mortality, while underweight patients also had significantly higher disease recurrence and lower disease-free survival.[22]

Consuming a healthful dietary pattern. In the Adventist Health Study, including nearly 100,000 women and men, those avoiding meat and fish consumption had significantly lower risk, compared with those following omnivorous diets. A systematic review and meta-analysis of primary prevention cohort studies found that greater adherence to a Mediterranean dietary pattern was associated with a roughly 10% lower risk for colorectal cancer, and a systematic review and meta-analysis of observational studies found a 17% lower risk.[23],[24] In the Women’s Health Initiative Observational Study, greater adherence to either the Dietary Approaches to Stop Hypertension (DASH) or the Healthy Eating Index (HEI-2010) diets was inversely associated with the risk for colorectal cancer.[25]

Avoidance of red and processed meats. Studies show roughly 20-30% higher risk for colorectal cancer when comparing high to low intakes of red meat.[26],[27],[28] In contrast, protein from plant sources is associated with reduced risk for colorectal cancer (see below).

According to the World Health Organization, colon cancer risk increases by 17% per 100 g of red meat consumed daily and by 18% for every 50 g of processed meat consumed daily.[29]

The association between meat and colon cancer risk has been explained by the presence of nitrosamines, polycyclic aromatic hydrocarbons (PAH), heterocyclic amines (carcinogens formed as a result of high-temperature cooking), and by the pro-oxidant effects of heme iron.[30],[31],[32] Foods high in saturated fat and cholesterol, higher serum cholesterol and triglycerides, and higher levels of oxidized LDL are also associated with greater colorectal cancer risk.[33],[34],[35]

High-fiber foods. Studies of both total fiber intake, as well as high-fiber foods individually (fruits and vegetables, whole grains, legumes, and nuts), have all revealed protection against colorectal cancers. A meta-analysis found a 12% lower risk for colorectal cancer in highest versus lowest consumers of total dietary fiber, and consumption of 3 servings per day of whole grains was also associated with a 17% lower risk.[36] In a meta-analysis of 19 prospective studies that included between 12,000 and 16,000 cases and approximately 1.7 million individuals, the risk for colorectal cancer was roughly 10% less for those who consumed the most versus the least fruits and vegetables.[37] Similarly, a meta-analysis of cohort studies, including nearly 2 million persons, concluded that the risk for individuals consuming the highest versus lowest amount of legumes was also roughly 10% less.[38] A systematic review and meta-analysis also found a roughly 25% reduction in risk for colorectal cancer in persons consuming the most nuts.[39] The Multiethnic Cohort Study of nearly 200,000 women and men found a nearly 40% lower risk for colorectal cancer in men who ate more than 35 g of fiber per day, compared with those who ate roughly 13 g per day.[40]

The best-established mechanism for the potential of fiber to reduce the risk of cancerous or precancerous lesions derives from the ability of insoluble fiber to reduce fecal bile acid concentrations.[31] Some have also suggested that the potential preventive effect of fiber-containing foods may be due to an association with micronutrients, including carotenoids, sulfur compounds in garlic, or glucosinolates found in brassica vegetables, which accelerate Phase II detoxification of potential carcinogens.[41],[42],[43],[44] Also, several flavonoid subclasses have shown a significant, inverse association with the risk of colorectal cancer.[45]

Many foods high in fiber are also high in magnesium, a nutrient that may reduce the risk for colorectal cancer through its role in promoting genomic stability and DNA repair.[46] A meta-analysis of prospective studies, including nearly 340,000 individuals and 8,000 cases, found a roughly 10% lower risk for colorectal cancer in highest versus lowest magnesium consumers.[47]

Avoidance of fat. Saturated fats modify bile acid metabolism and alter gut flora populations, encouraging a pro-oncogenic colon.

Foods high in B vitamins. Leafy green vegetables, beans, and whole grains are good sources of folate, an essential determinant of DNA methylation, which affects the maintenance of DNA integrity and stability.[48] Similarly, vitamin B6 is involved in DNA methylation and suppresses tumorigenesis by reducing cell proliferation, oxidative stress, angiogenesis, and other mechanisms.[49] Although a relationship between folate and other dietary factors may account for a lower risk for colorectal cancers, a systematic review and meta-analysis found that individuals eating the most folate had an 8% risk reduction for colorectal cancer in cohort studies and 15% reduction in case-control studies.[50] In the Women’s Health Initiative Observational Study, the highest dietary and total intake of vitamin B6, and highest total intake of riboflavin, were each associated with a 20% lower risk for colorectal cancer, compared to those in the lowest consumption categories.[51]

Calcium-containing foods and supplements and vitamin D status. Systematic reviews and meta-analyses have found significant protective effects of calcium supplements and vitamin D status for colorectal cancer risk. One of these found an inverse association between the use of both calcium and multivitamin supplements and the risk for colorectal cancer.[52] Another found a significant protective effect ( > 30% lower risk) for persons with the highest blood levels of vitamin D, compared to people with the lowest.[53] However, a US Preventive Services Task Force publication concluded that vitamin D supplements had not been found to reduce the risk for colorectal cancer significantly.[54] The purported ability of calcium and calcium-containing foods to reduce the risk for colorectal cancer may be due to calcium’s effect on proliferation, differentiation, apoptosis, and binding of bile acids that may act as mutagens in the colon.[55]

A systematic review and meta-analysis found protective effects associated with both total dairy products and milk, but not cheese.[56] Dairy products may be double-edged swords, however, reducing the risk of colon cancer but increasing risk of prostate cancer and possibly other conditions, such as Parkinson’s disease (see Prostate Cancer and Parkinson’s Disease chapters).

Selenium-containing foods. A meta-analysis of 12 observational and 2 clinical studies found an inverse association between selenium and the risk for colorectal cancer in men only.[57]

Coffee. In the NIH-AARP Diet and Health Study that included 489,706 men and women followed over 10.5 years, higher intakes of coffee ( > 4 c/day) were associated with a significantly lower risk for colon cancer when compared to nonconsumers.[58]

Limiting alcohol use. A 2015 review showed that consumption of ≥ 1 drink per day was significantly associated with increased risk for colorectal cancer.[59]

Nutrition and Colorectal Cancer Survival

There remains a dearth of information on the role of nutrition in the prognosis, recurrence, and survivability after the diagnosis of colorectal cancer. A limited number of studies of prospective observational design suggest that a Western dietary pattern is associated with reduced survival.[60] Presumed explanations include higher intakes of cured/processed meats and a higher intake of refined carbohydrates.[61],[62]

A study from the University of California San Francisco found that people with stage III colon cancer had more prolonged overall survival and disease-free survival rates when they avoided red and processed meat; consumed more fruits, vegetables, and whole grains; exercised; and had a healthy body weight, compared with patients who did not follow these parameters.[63]

The choice of beverage also seems to be essential. In a study of 953 patients with stage III colon cancer, individuals consuming 4 or more cups of coffee per day (regular or decaffeinated) had a 40-50% lower risk for cancer recurrence or mortality compared with nonconsumers.[64] In the same study, consuming 2 or more servings of a sugar-sweetened beverage each day increased the risk for disease recurrence or mortality by 67% when compared to those who consumed 2 or fewer servings per month.[65]

A systematic review and meta-analysis found a 45% lower risk for colorectal cancer-specific mortality in patients with the highest versus the lowest quartile of circulating 25(OH)D levels at or near the time of diagnosis. Vitamin D supplements have not shown the same benefit.[66]

Orders

• Regular physical activity
• Low-fat, high-fiber, plant-based diet
• Limit alcohol intake
• Routine screening, as appropriate

What to Tell the Family

The risk for colon cancer may be reduced through a plant-based diet and healthy lifestyle. Even after cancer diagnosis and treatment, diet and lifestyle changes may be helpful, reducing the risk of recurrence. Family members can help by supporting the patient in adopting healthful diet and lifestyle habits and by adopting such habits themselves.

References