Overview and Risk Factors
Colon cancer is the third most common malignancy worldwide and the second leading cause of cancer-related mortality. It accounts for 10% of cancer deaths in the United States. Although the disease is common and often lethal, risk is reduced with regular screenings and timely removal of precancerous lesions, and possibly through dietary modifications. Some evidence also suggests that diet may influence the likelihood that precancerous lesions will become cancerous.
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 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 distension.
Local spread and distant metastases are common. Between 15% and 20% of patients diagnosed with colon cancer initially present with metastases, most commonly of the regional lymph nodes, liver, lungs, and peritoneum.
The following factors are associated with increased risk for colorectal cancer:
Age. About 90% of cases occur in patients over 50 years of age, and incidence increases with age.
Family history. Approximately 25% of patients have a positive family history. Risk increases several-fold if one or more first-degree relatives have colon cancer.
Environment. Incidence is highest in developed countries. Those who migrate from regions of low incidence to regions of high incidence eventually assume a risk similar to that of their adopted countries. These associations may be attributable to diet (see Nutritional Considerations ).
Alcohol use (see Nutritional Considerations for more information).
Hereditary syndromes. These include Lynch syndrome and familial polyposis syndromes.
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.
Excess weight. Overweight is associated with colon cancer risk.1 Mildly and moderately obese individuals appear to have about 10% to 35% greater risk, respectively, compared with those who are at a healthy weight (BMI 18.5-24.9). Severely obese persons (BMI >40) have a 45% greater risk for colorectal cancer.2
In contrast to the above factors, increased physical activity is associated with reduced colon cancer risk. The presumed mechanisms are reduction in weight or in blood concentrations of insulin or insulin-like growth factor.
Diagnosis and Treatment
Presenting symptoms and complications are listed above.
- Guiac-positive stools should prompt evaluation with a colonoscopy.
- A colonoscopy with biopsy can diagnose colon cancer and allow for removal of early lesions during the same procedure.
- A barium enema is not as sensitive as colonoscopy (for diagnosis), and also does not permit polyp removal.
- A "virtual colonoscopy" via CT or MRI is under investigation, but reliability is not yet established.
- Complete blood count may reveal microcytic anemia from chronic blood loss.
- Tumor markers (CEA, CA 125, CA 19-9, CA 50, CA 195) are not sufficiently specific to screen for colon cancer, but can aid in determining prognosis and disease recurrence.
- Liver function tests and CT scans of the thorax, abdomen, and pelvis.
The TNM (Tumor, Node, Metastasis) classification is the preferred system for tumor staging. The CT scan helps determine the clinical stage.
- 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.
Surgical resection is the definitive treatment and is often curative for early cancers.
Surgical resection and adjuvant chemotherapy (eg, 5-fluorouracil, leucovorin, oxiliplatin) are 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, chemoembolization, or direct-infusion chemotherapy into the hepatic artery.
Avastin, an angiogenesis inhibitor, has been approved by the FDA as a first-line treatment for metastatic colon cancer.
Diet appears to be a major contributor to colon cancer risk. Several lines of evidence implicate meat (especially processed red meat) in colon cancer risk. The association is presumed due to macronutrients (such as saturated fat) found in meat products, as well as to carcinogens found in or formed by cooking or processing of meats. Plant-based and vegetarian diets are associated with a much lower incidence of colon cancer,4 probably due to the absence of meat and the inclusion of protective plant constituents.
Dietary Factors Associated with Increased Risk
Meat products. Higher intake of processed red meat, in particular, appears to increase the risk for distal colon (rectal) cancer, presumably due, at least in part, to its nitrosamine content5 or to the presence of polycyclic aromatic hydrocarbons (PAH), known mutagens and suspected carcinogens that are formed as a result of charbroiling.6 Heme iron found in meat is also associated with proximal colon cancer7. This association has been explained by the formation of cytotoxic compounds in the intestinal lumen.8 In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, individuals eating > 160 g/day of red or processed meat had a 70% greater risk for colorectal cancer than persons eating < 10 g/day.9 The Cancer Prevention Study II (CPS II) Nutrition Cohort considered long-term consumption of meat in determining colorectal cancer risk and determined that individuals eating the highest amount of red meat and processed meat were at 50% greater risk for colon cancer, compared with those eating the lowest amount. Eating the highest amount of red meat also appeared to increase the risk for rectal cancer by 70% when compared with the lowest level of consumption.10
Although white meat may carry a lower risk than red meat, Adventist men who ate white meat >1 time per week had a risk roughly 3.3 times that of those who abstained from eating white meat.11 This may be due to the presence of mutagenic heterocyclic amines (HCAs), which are found in chicken as well as other meats.12
A high cholesterol intake,13 higher serum cholesterol,14 and higher levels of oxidized LDL15 are also associated with greater colorectal cancer risk. High-cholesterol foods such as eggs may also increase risk of proximal colon cancer.16
Dietary Factors Associated with Decreased Risk
Fiber. Studies on dietary fiber and colorectal cancer risk have yielded conflicting findings. The best evidence for the role of fiber relates to its apparent ability to reduce the risk of adenomatous polyps, a precancerous lesion.18â€“20 Some research also shows a reduced risk for polyp recurrence in women who follow a high-fiber, low-fat diet or a fiber-supplemented, vitamin-enriched diet.21,22 The largest study to date, however, found that the reduction in colorectal cancer risk associated with high dietary fiber intake was small (6%) and not statistically significant.23
The possible preventive effect of fiber-containing foods may come from an association with micronutrients, including carotenoids,24 sulfur compounds in garlic,16,25 or glucosinolates found in Brassica vegetables,26 which accelerate Phase II detoxification of potential carcinogens. Data show that men who eat the most fiber-depleted refined carbohydrates (eg sucrose, refined starches) have roughly twice the risk for developing colon cancer as men who eat the least amount.27,28 Results for women have not been established.29 This risk is attributed to the high glycemic load these foods carry30 and their tendency to increase blood concentrations of insulin-like growth factor,3 a known risk factor for many cancers.
Folic acid and vitamin B6. Leafy green vegetables, beans, and whole grains are good sources of folate, an important determinant of DNA methylation that affects maintenance of DNA integrity and stability.31 Although a relationship among folate and other dietary factors may account for benefits, evidence indicates that individuals eating the most folate have a 39% lower risk for colon cancer32 and a 25% lower risk for colorectal cancer than persons eating the least folate.33
Similarly, vitamin B6 is involved in DNA methylation, and it suppresses tumorigenesis by reducing cell proliferation, oxidative stress, angiogenesis, and other mechanisms.34 Individuals who consume the highest amounts of vitamin B6 or have the highest blood concentrations of pyridoxal phosphate have a 34% to 44% lower risk for colorectal cancer, compared with those who have the lowest intakes or blood levels.3,35
Vitamin E, vitamin D, and calcium. Some evidence suggests that eating one-fourth of an ounce of nuts each day may protect against colorectal cancer, particularly in women.36 The lower risk is attributable to food (not supplemental) sources of vitamin E, higher intakes of which appear to reduce risk by 63% to 84% in persons younger than 65 years.37
Calcium may be a double-edged sword, reducing risk of colon cancer but increasing risk of prostate cancer with high intakes.38 Research found a lower risk for colon cancer in persons whose calcium intake was 700 mg per day, compared with those who have lower intakes; beyond this amount, benefit was minimal.39 Higher intakes of both calcium and vitamin D are associated with lower risk for colorectal cancer,40 and supplemental forms of calcium and vitamin D may be inversely associated with recurrence of colorectal adenoma.41
Calcium can bind bile acids that may act as mutagens in the colon, and vitamin D may act as an anticarcinogen through regulation of growth factor and cytokine synthesis and signaling, modulation of the cell cycle, apoptosis, and differentiation.42
What to Tell the Family
Colon cancer risk may be reduced through healthful diet and lifestyle measures. These include avoiding overweight, following a plant-based diet, choosing micronutrient-rich foods, and limiting alcohol use.
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