Chemopreventives for Colorectal Cancer
October 1, 2000 3 minutes read
Clinical Abstracts
With Comments from John La Puma, MD, FACP
Chemopreventives for Colorectal Cancer
October 2000; Volume 3; 120
Source: Janne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med 2000;342:1960-1968.
"Colorectal cancer is the second leading cause of cancer-related deaths in the United States. It is estimated that this cancer will develop in 130,000 people in the United States in 2000 and that 56,000 will die from the disease. Surgical resection remains the only curative treatment, and the likelihood of cure is greater when the disease is detected at an earlier pathological stage. Early detection is the goal of screening programs that use periodic examination of stool for occult blood, with or without intermittent endoscopic examination of the bowel. Three randomized studies have shown a reduction in mortality of 15-33% in those who undergo routine screening. Flexible sigmoidoscopy has been shown in case-control studies to decrease the incidence of and mortality associated with colorectal cancer. Nevertheless, the optimal method for early detection remains uncertain, and despite widely published recommendations for such screening programs, compliance remains poor.
"An alternative approach to reducing mortality from colorectal cancer involves the long-term use of a variety of oral agents that can prevent neoplasms from developing in the large bowel. Such pharmacologic prevention, known as chemoprevention, is directed at preventing the development of adenomatous polyps and their subsequent progression to colorectal cancers.
"...Recent observations suggest that aspirin and other NSAIDs [nonsteroidal anti-inflammatory drugs], supplemental folate and calcium, and postmenopausal hormone-replacement therapy (estrogen) have a chemopreventive benefit. Since the value of such prophylactic strategies has not yet been confirmed in double-blind, placebo-controlled, randomized studies, chemoprevention cannot yet be accepted as standard medical practice. Chemoprevention should not replace periodic fecal occult-blood tests and endoscopic screening, as well as modification in known risk factors for colorectal cancer, such as reduction in the intake of red meat, appropriate exercise, smoking cessation, and weight control."
COMMENT
How and when do chemopreventives work?
Aspirin and NSAIDs inhibit COX-1 and COX-2, which catalyze prostaglandin synthesis; high levels of prostaglandins and COX-2 are found in colon carcinomas. Aspirin and NSAIDs also have other independent effects. How long they take to work (years, and perhaps decades), and how much is required (probably more than an aspirin every other day) should keep researchers busy for years.
Folate (vitamin B9) has both epidemiologic and prospective evidence for prevention at the 400+ µg/d level. Part of DNA synthesis, folate takes 15 years to have a statistically significant effect, but it does.
Calcium binds bile acids and fatty acids in the colon, or it may simply inhibit the proliferation of colonic epithelium. In a well-done large prospective study, its effect was seen after just one year of supplementation.
No one knows whether estrogens act by reducing the bile acid production, by decreasing the production of insulin-like growth factor I, or directly on the colon and rectum. But prospective studies indicate reduced adenoma formation. These benefits are limited to five years after taking hormone replacement therapy (HRT). Estrogen probably acts at the later stages of colorectal carcinogenesis.
Unhappily, supplementation of low levels of beta-carotene and vitamins A, C, D, and E have not been shown to prevent colon cancer. Though meta-analyses of observational epidemiologic and case-control studies have found a protective effect of dietary fiber, increasing with intake, prospective studies have not confirmed these observations. Criticisms of these studies also include the relatively low level of supplementation of fiber, fruits, and vegetables.
On the other hand, red meat and high animal fat foods increase the production of secondary bile acids, which may cause hyperproliferation of the colorectal epithelium and which promote tumor formation in studies in animals.
Recommendation
Based on the highest level of evidence, essential lifestyle modifications for those who wish to avoid colon cancer include daily NSAIDs, aspirin, folate, and calcium supplements; possibly HRT for women; avoidance of red meat and animal foods; and weight control. This adds up to a plant-based diet with fish, and regular aerobic and strength-building exercise. This set of recommendations should form the foundation for any others, as new data become available.
October 2000; Volume 3; 120
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