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DSI Newsletters, Issue 57:
Colon Cancer

Colon and Rectal Cancers
WHAT ARE COLON AND RECTAL CANCERS?
 Cancers of the colon and rectum, often referred to collectively as colorectal cancer, are life-threatening tumors that develop in the large intestine.
 More than 80% of colorectal tumors evolve from adenomatous polyps. These are gland-like growths that develop on the mucous membrane that lines the large intestine. They are usually one of the following types:
  • Tubular polyps, which protrude mushroom-like.
  • Villous adenomas, which are flat and spreading and are more apt to become malignant (cancerous).
 It should be noted that these polyps are very common and almost always benign. Their numbers increase with age. Polyps are found in about 25% of people by age 50 and half of people by age 75. Fewer than one percent of polyps under one centimeter (slightly less than half an inch) become cancerous (malignant). About 10% of larger polyps become malignant within 10 years and about 25% of these larger polyps become cancerous after 20 years. Certain inherited polyps can become malignant more rapidly.
The Gastrointestinal Tract
 Digestion takes place in the gastrointestinal (GI) tract, essentially a long tube that extends from the mouth to the anus. It is a complex organ system that first carries food from the mouth down the esophagus to the stomach. Food then travels through the small and large intestines before being excreted through the rectum and out the anus.
Esophagus
 The esophagus is a narrow muscular tube, about nine and a half inches long that begins below the tongue and ends at the stomach.
Stomach
In the stomach, acids and stomach motion break food down into particles small enough so that nutrients can be absorbed by the small intestine.
Small Intestine
 The small intestine, despite its name, is the longest part of the gastrointestinal tract, extending for about 20 feet. Food passes from the stomach through its three parts: first the duodenum, then the jejunum, and finally the ileum. Most of the digestive process occurs in the small intestine.
Large Intestine
 Undigested material, such as plant fiber, is passed next to the large intestine, mostly in liquid form. The large intestine is wider than the small intestine but only about six feet long. It is the final portion of the digestive tract and includes the cecum, the appendix, the colon, and the rectum, which extends to the anus.
 Cecum and Appendix. The cecum and the appendix are located in the lower-right quadrant of the abdomen.
 Colon. The colon absorbs excess water and salts into the blood. The remaining waste matter is converted to feces through bacterial action. The colon is divided into four major sections.
  • The first section, the ascending colon, extends upward from the cecum on the right side of the abdomen.
  • The second section, the transverse colon, crosses the upper abdomen to the left side.
  • The third section extends downward on the left side of the abdomen toward the pelvis and is called the descending colon.
  • The final section is the sigmoid colon.
    •  Rectum and Anus. Feces are stored in the descending and sigmoid colon until they are passed through the rectum and anus. The rectum extends through the pelvis from the end of the sigmoid colon to the anus.
    WHAT CAUSES COLON AND RECTAL CANCERS?
     In most cases of colon or rectal cancers the cause or causes are unknown. Defects in genes that normally protect against cancer play the major role in causing polyp cells to proliferate unceasingly and become cancerous. Some of these cases are caused by inherited genetic defects, and such patients usually have family histories of colorectal cancer. Most of genetic mutations involved in colon cancers, however, appear to arise spontaneously (no strong family history) rather than being inherited. In such cases, environmental or other factors trigger genetic changes in the intestine that lead to cancer.
    Inherited Genetic Factors
     About 6% of cases of colon cancer are due to inherited facts.
     APC Gene and Familial Adenomatous Polyposis (FAP). When the adenomatous polyposis coli (APC) gene is normal, it helps suppress tumor growth. In its defective form, it permits high levels of the protein beta-catenin to accumulate, which accelerates cell growth leading to polyps. Various genetic mutations that affect the APC gene directly or indirectly have been identified:
    • Familial adenomatous polyposis (FAP) is a rare and serious disorder in which the patient inherits an APC mutation from either parent. It occurs in about 1 in 8,000 people. During early adulthood, hundreds to thousands of polyps grow in the colon. FAP causes less than 1% of all cases of colorectal cancer, but if untreated, virtually everyone who inherits this condition develops cancer before the age of 40. Many of the deaths attributed to FAP can be prevented with early and aggressive surgical treatment.
    • Non-inherited mutations of the APC gene have been detected in nearly all patients with spontaneous colon cancers. Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, probably accounts for at least half of colorectal cancers that run in families (but only 3% or less of all colorectal cancers are due to this problem). From 50% to 80% of people who inherit the abnormal gene will develop colon cancer. HNPCC appears to be less aggressive and survival rates are longer than for colon cancer that developed without known risk factors. These cancers tend to develop in the right side of the colon, often in young individuals. (Left sided cancers can still occur as well.) People who inherit HNPCC and other defects are prone to other cancers, including uterine and ovarian cancers, as well as cancers of the small intestine and kidney system (very rare). HNPCC is highly associated with genes containing an abnormality called MSI (microsatellite instability), which is a sign of defective DNA repair. Testing tumors for MSI in people with newly diagnosed colon cancer who also have a family history of the disease may prove to be an effective method for identifying patients with HNPCC. Tests are being developed that can detect the actual HNPCC genetic abnormality (mutation) that was inherited from a father or mother. The two most commonly affected genes are MSH-2 and MLH-1.
    Biochemical Factors Involved in Colon and Rectal Cancers
     Cyclooxygenases and Prostaglandins. Cyclooxygenase 1 and 2 (COX-1 and COX-2) are enzymes involved in the production of prostaglandins, substances produced by the body that cause inflammation, widen and narrow blood vessels, control muscle contractions, and inhibit hormones that regulate fat metabolism. COX-2, but not COX-1, appears to play a role in the development and spread of colorectal tumors. COX-2 increases the levels of prostaglandin E2 (PGE2), which, in turn, stimulates factors that inhibit apoptosis, the natural process whereby all cells, including cancerous ones, self-destruct. It also activates interleukin-6 (IL-6), a factor in the immune system that is associated with cancer cell invasion.
     Bile Acid Salts. Deoxycholic acid, which is found in the fat-digesting bile salts released by the gallbladder, appears to have carcinogenic properties. Its effects are now believed to play a role in some cases of colon cancer. Levels of the acid can rise as a result of high-fat diets or certain diseases.
     Growth Factors. Chronically higher circulating levels of growth factors, including insulin-like growth factor (IGF), have been associated with colorectal cancer.
    Inflammatory Bowel Disease
     Inflammatory bowel diseases (IBDs) include Crohn's disease and ulcerative colitis. These chronic disorders cause persistent injuries in the intestinal tract that can, in some cases, produce cancerous changes. [For IBD patients at higher risk for colorectal cancers, see Who Gets Colon and Rectal Cancers?]
    WHAT ARE THE SYMPTOMS OF COLON AND RECTAL CANCERS?
     It is possible to have colon or rectal cancer without symptoms. Many patients are free of symptoms until their tumors are quite advanced.
    Weight Loss and Changes in Bowel Movements
     Weight loss and changes in bowel movements are general symptoms for colon cancer, but also occur in many other diseases.
    Rectal Bleeding
     Blood in the stools is a common sign of many intestinal cancers. It may appear red if it is fresh or black if it is old. It should be reported to a physician immediately, even though it is often caused by conditions other than cancer, including the following:
    • Hemorrhoids.
    • Minor tears around the rectal or anal areas.
    • Diverticulosis.
    • Stools can turn red after eating certain red foods, such as beets or red licorice.
    • Iron supplements and medications that have bismuth subsalicylate, most commonly Pepto-Bismol, can cause stools to turn black.
     Nevertheless, blood in the stools is an abnormal finding that should never be ignored. Always report it to your doctor for further advice.
    Symptoms of Cancers in Specific Areas of the Colon
     Symptoms of colorectal cancer vary widely depending on the location of the cancer within the large intestine.
     Tumors in the Cecum and Ascending Colon (Right Colon). The waste matter in the first portion of the colon is in liquid or semi-liquid form. Tumors that develop here do not change bowel habits or stool formation, but they may cause intermittent or chronic bleeding. Although the stools look normal, patients may develop symptoms of anemia from iron deficiency. Such symptoms include weakness, fatigue, heart palpitations, shortness of breath, and exercise intolerance.
     Tumors in the Transverse Colon. As waste material passes across the upper quadrants of the abdomen (the transverse colon), the intestine absorbs water and the waste matter becomes more solid. In addition to bleeding, tumors here may cause cramps, gas, partial or complete obstruction, and even perforation of the bowel. Anemia as described above can also occur.
     Tumors in the Descending Colon and Rectum (Left Colon).When tumors partially block the lower intestine, thin, pencil-shaped stools may form. Bowel habits can change. Tumors in the rectum and lowest part of the intestine can cause pain and a feeling of fullness. Defecation may be painful or patients may feel the urge to defecate, but nothing happens. Bleeding from these locations may be brisk and bright red or maroon, but cancer is often detected before symptoms of chronic anemia develop.
    WHO GETS COLON AND RECTAL CANCERS?
     Colorectal cancer is the fourth most common cancer in the US, with Americans facing a lifetime risk of 6% for this cancer. An estimated 147,500 people in the US are expected to be diagnosed with colon or rectal cancer in 2003.
    Sex
     The risks overall are equal in men and women, but men have a higher risk for rectal cancers and women for colon cancers.
    Age
     The most important risk factor for colon cancer is getting older. More than 90% of these cancers occur in people over 50. The rate of colorectal cancer in patients under 20 years is less than 1 in 100,000 per year. At age 50 about one in 2,000 people per year will develop colorectal cancer, and after age 65, this rate increases to almost 3 in 1,000.
    Ethnicity
     Compared to Caucasians, African Americans are at higher risk of colon (but not rectal) cancer. The highest risks are in men of African descent, particularly in the sub-Saharan region. Ashkenazi Jews, of Eastern Europe descent, also have a higher incidence of colorectal cancer.
    Family History
     About 25% of patients under 45 years old and 15% of everyone who develops colorectal cancer have a genetic risk. The average lifetime risk of developing colorectal cancer is approximately 2%. People who have a sibling or parent (first degree relative) who developed colorectal cancer have three times (6%) the lifetime risk of developing colorectal cancer. People who have a first degree relative who developed colorectal cancer before age 45 have an even higher, 10%, lifetime risk of developing colorectal cancer.
    Lifestyle Factors
     The risks for colon cancer are far higher in industrialized nations than less developed countries. A Western lifestyle, being sedentary, smoking, and excess weight have all been associated with increased risk for colorectal cancer. (It should be noted, however, that about 75% of cases occur without a known predisposing factor.)
     Dietary Factors. Studies indicate that diets low in fruits and vegetables and high in meats pose a risk for colon cancer. Research also indicates that diets rich in fruits and vegetables are protective against many cancers. [See What Is the Role of Diet in Colon and Rectal Cancers below.]
     Alcohol and Smoking. Smoking may increase the risk for colon cancer, and drinking alcohol regularly appears to compound this risk. Nonsmokers who drink alcohol and have diets rich in vegetables and fruits do not seem to have an increased risk.
     Obesity. There is a demonstrated link between body mass and colon cancer risk for both men and women. The Centers for Disease Control and Prevention has reported that the risk of colon cancer rises as body mass index (BMI) increases. Obesity has been associated biologically with higher circulating levels of insulin and a hormone called insulin-like growth factor (IGF). Chronically high levels of these substances may increase colorectal cancer risk.
    Risk Factors for People with Inflammatory Bowel Disease
     Crohn's disease and ulcerative colitis are chronic afflictions of the large intestine known as inflammatory bowel diseases (IBDs). Both have been linked to increased risk for colorectal cancer. Family histories are helpful in determining risk associated with inflammatory bowel disease. Some studies suggest the following:
    • Patients with IBD who have a family history of colorectal cancer face up to a five-fold risk of colon cancer themselves.
    • Individuals without IBD who have relatives who suffered from both IBD and colorectal cancer may face a higher risk for developing colorectal cancer themselves.
    • Individuals without IBD but with a family history of IBD and no colon cancer most likely face no higher risk for cancer themselves.
    [For more information, see the Well-Connected Report Inflammatory Bowel Disease.]
    Other Risk Factors
     Ureterosigmoidostomy. People who have had ureterosigmoidostomy, a surgical procedure to correct a birth defect in the bladder or to treat some bladder cancers, may develop tumors near the site of the defect, which is chronically exposed to urine and feces. Such patients have a 5% to 10% chance of developing colon cancer 15 to 30 years after the operation.
    WHAT IS THE ROLE OF DIET IN COLON AND RECTAL CANCERS?
     Previous research suggested that diets low in fruits and vegetables and high in meats pose a risk for colon cancer, and that those rich in fruits and vegetables are protective against many cancers.
    Fruits, Vegetables, and Whole Grains
     There has been a prevailing belief from a number of studies that high intake of fruits and vegetables can lower the risk for colorectal cancer. Studies have been mixed, however, on their benefits. A 2002 study, for example, reported that these foods do not prevent polyps from forming but may help prevent them from becoming cancerous.
     It should be noted that it is nearly impossible to do controlled studies on dietary factors, since people's eating habits can rarely be made consistent. Dietary studies also use a variety of different approaches to obtain results that make comparisons very difficult. To help determine their specific effects researchers are studying the phytochemicals (plant chemicals) in fruits and vegetables and also fiber (which is also found in whole grains.)
     Phytochemicals. Many studies have demonstrated the cancer-fighting effects of plant chemicals called phytochemicals. Fruits and vegetables that contain phytochemicals can often be identified by colors:
    • Dark green (broccoli, spinach, kale, collard greens, mustard greens). These specific vegetables contain chemicals called isothiocyanates, which have been associated with a lower risk for cancer in general.
    • Red (red pepper, tomatoes, watermelon, raspberries, pink grapefruit). Lycopene is a chemical found in these foods that may have strong cancer-protective properties. Cooking tomatoes appears to increase their benefits.
    • Yellow-orange (carrots, pumpkin, sweet potatoes, oranges, tangerines). The colors in these foods are due to carotenoids, which have been associated with health protection, although may not have much effect on colon cancer itself.
    • Blue-black (many berries). Dark berries appear to have potent chemicals that may be protective against cancer. In one animal study, extracts from black raspberries reduced colon cancer tumors in rats.
        •  Organosulfurs are important food chemicals that are part of the allium family and there have been studies reporting health benefits from foods containing them. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots. A review of 300 studies concluded that people who eat raw or cooked garlic regularly experience about two-thirds the risk of colorectal cancer as people who eat little or none. Another analysis, however, found the available evidence about garlic to be inconclusive. Garlic supplements, in any case, do not appear to be protective.
         Fiber. Studies have been mixed on whether fiber (found in fruits, vegetables, and whole grains) protects the colon from cancer. For example, three major studies in 2002 and 2003 reported no difference in the development of colorectal polyps or cancer recurrence with high intake of fiber. On the other hand, other studies have been positive. In fact, 2003 results of the European Prospective Investigation into Cancer and Nutrition (EPIC)--the largest study ever conducted on the role of diet in the development of cancer--suggested that fiber is protective regardless of its source. However, in the study, the greatest benefits were observed for the left side of the colon and the least for the rectum. In any case, fiber, which is only found in plant products, may be beneficial for the heart and have other health advantages.
        Fats and Oils
         The role of fats in inflammatory bowel disease is complex and not fully known. Any benefits or risks appear to depend on the type of compounds that make up fats (the fatty acids) or other nutrients or substances with fatty acids.
         Saturated Fats and Trans-fatty Oils. Some studies had found an association between colon cancer and consumption of saturated fats (found primarily in animal fats). The association is not altogether clear, however, and more recent evidence has not supported a strong link. Some experts suggest that the real hazard is iron from red meat, which is often high in saturated fats and may have confused study results [see below].
         Of further interest, however, is a 2001 study that reported a possible link between colon cancer and trans fatty acids, which are partially hydrogenated oils found in stick margarine, fried foods and commercial baked goods. The association is supported by known chemical effects of these manufactured fats, and more research is warranted.
         Monounsaturated Fats. Monounsaturated fats are mostly present in olive, canola, and peanut oils and in most nuts. Olive oil, for example, may protect the colon. Some evidence suggests that it reduces levels of deoxycholic acid, an acid found in bile that has tumor-promoting properties.
         Polyunsaturated Fats. Polyunsaturated fats are found in both plant and fish oils, and are composed of essential fatty acids including omega-3 and omega-6 fatty acids. These fatty acids may play different roles in colon cancer.
        • Omega-3 fatty acids are found in oily fish and canola oil, soybeans, flaxseed, and certain nuts and seeds. They have been associated with protection against inflammation in the intestinal tract. It should be noted, however, that not all studies show protection. For example, omega-3 fatty acids in fish are composed of docosahexaenoic (DHA) and eicosapentaneoic (EPA) acids. Some evidence suggests that EPA — although not DHA — may be protective.
        • Omega-6 fatty acids, found in corn, safflower, soybean, and sunflower oil, constitute most of the oils consumed in the US. Some omega-6 fatty acids are important for health. However, a high intake has been associated with heart disease and certain cancers.
         Currently it is reasonable to reduce saturated fats and transfatty acids and to favor monounsaturated oils and polyunsaturated oils, particularly containing omega-3 fatty acids.
        Meat and High-Temperature Cooking
         Some evidence suggests that red meat raises the risk for colon cancer. Red meat contains dietary iron, which has been associated with a higher risk for colon cancer. In fact, early results in 2000 from the largest study on diet and cancer to date have supported previous studies linking red meat with intestinal tumors.
         High-temperature cooking (grilling, broiling, or pan-frying) has been specifically associated with increased risk for colon polyps and colon cancer. Over-cooking meat increases the amount of carcinogens called heterocyclic amines, which has been associated with cancerous changes.
         Some research has been focussing on acrylamide, a chemical found in high amounts in certain foods cooked at high temperatures, especially fried potatoes, and also bread products. Animal studies have suggested that acrylamide is a carcinogen. A surprising 2003 study, however, found no evidence of risk for colorectal or other cancers with high intake of foods that contain large amounts of this chemical.
        Dairy Products and Calcium
         Milk, Lactose, and Probiotics. In a Finish 2001 population study, adults who drank the most milk had the lowest risk for colon cancer. Milk not only contains calcium but also other compounds, such as lactose, that may help protect against colon cancer. Yogurt specifically has been associated with a lower risk for colon cancer if it contains live active bacterial cultures, such as Lactobacillus acidophilus, that are called probiotics. These "friendly bacteria" appear to protect the colon from cancerous changes. (Acidophilus and other probiotic capsules are also available in health food stores.) Results are mixed on other fermented milk products, such as buttermilk and cheese, which in one study were associated with a higher risk. The reasons for this were not clear.
         Calcium. Calcium, which is found in dairy products, is also associated with colon cancer protection. Most studies show a possible protective effect from either high-calcium diets or calcium supplements. The protective effect has been observed as early as one year after calcium supplementation began. A large 2002 study concluded that daily intake of about 700 mg, from food or supplements, reduces the risk of colon cancer, but intake beyond this level does not add any further protection. Calcium supplements may even offset certain effects of dietary iron, found in red meat and other foods, which may increase the risk for colon cancer. More work in this area is needed, however.
        Total Calories and Sugar
         Obesity has been associated with colon cancer. In some studies of people under 67 years old, the amounts of fat and protein were less important than the total number of calories consumed: the higher the energy intake, the greater the risk for developing colon cancer. In older adults, high calorie intake did not make any significant difference. Other studies have indicated that excessive sugar-intake may increase the risk for colon cancer.
        Coffee and Tea
         Studies conducted in a number of countries have found that drinking four or more cups of coffee a day is associated with a lower risk for colorectal cancer. Green tea may have beneficial properties, but more research is needed in both of these areas.
        Vitamin and Mineral Supplements
         Folate and B Vitamins. There is evidence that the B vitamin folate (called folic acid) is protective. Both folate and vitamin B12 convert the amino acid homocysteine to methionine, a chemical that protects certain genes that help prevent cells from becoming malignant. Folate is found in beans, citrus fruits, and green vegetables, but benefits seem higher when taking supplements. The protective effect appears to be greatest for people who are genetically predisposed to colorectal cancer.
         Antioxidant Supplements.Antioxidants are chemicals the help eliminate harmful particles called oxygen-free radicals that have been associated with cancerous changes. Some studies have associated supplements of the antioxidants selenium and vitamins A, C, D, and E with lower colon cancer risk, but most studies have found no protective effect.
        WHAT ARE NON-DIETARY MEASURES FOR PREVENTING COLON AND RECTAL CANCERS?
        Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
         Nonsteroidal anti-inflammatory drugs (NSAIDs) are very common agents available over-the-counter and by prescription that are used to relieve pain. They have specific actions against prostaglandins and the enzymes called cyclooxygenases (COX 1, COX 2, or both), which have with colon cancer risk [see Cyclooxygenases and Prostaglandins above].
        • Over-the-Counter NSAIDs. Over the counter NSAIDs include aspirin, ibuprofen (Motrin, Advil, Nuprin, Rufen), and naproxen (Aleve). A number of studies have reported that taking these agents at doses similar to those commonly taken to relieve arthritis pain is associated with a lower rate of colorectal cancer by up to 40% over the long term. For example, landmark studies in 2003 reported protection in high-risk patients with even low daily doses of aspirin (81 mg, one "baby" aspirin). Long-term use of any NSAID increases the risk for gastrointestinal bleeding and ulcers, however, and experts to not yet recommend NSAIDs for prevention of colon cancer. They are certainly no substitute for regular screening procedures to catch cancer at an early, and curable, stage [See How Are Colon and Rectal Cancers Diagnosed? below].
        • Prescription NSAIDs for Prevention of Hereditary Cancers. Some studies report that the potent prescription NSAIDs indomethacin and sulindac can cause regression of polyps and stave off colon cancer for several years in people with FAP. A 2002 study in children and young adults with FAP who were given sulindac for four years, however, did not show any reduction in new polyp formation. More research is needed to determine if NSAIDs have preventive value in high-risk individuals.
        • COX-2 Inhibitors. Selective COX-2 inhibitors, such as celecoxib (Celebrex) and rofecoxib (Vioxx), are newer enzymes that only block the enzyme cyclooxygenase-2 (COX-2), which has been specifically linked to colon cancer. Both are being investigated for possible protection against colon cancer. Early studies indicate that celecoxib may help prevent new growth and retard the growth of existing polyps. Experts hope, then, COX-2 inhibitors may prevent colon cancer without posing as high a danger of bleeding and ulcers as standard NSAIDs. Celecoxib has now been approved for patients with familial adenomatous polyposis (FAP). Studies report significant reduction in disease activity in the large and small intestines of these patients.
         In some studies, combining NSAIDs with the cholesterol-lowering drugs known as statins (for example, lovastatin, pravastatin, simvastatin) significantly lowered the rate of colon cancer compared to taking NSAIDs alone. Experts are hoping that such combinations may allow lower NSAIDs dosages, thereby reducing the risk for side effects, but further study is required.
         Complications. It is important to note that NSAIDs, even in low doses, can cause gastrointestinal bleeding and ulcers in some people. In fact, studies estimate NSAID-related deaths in the United States at 10,000 to 20,000 per year, and NSAID-related hospitalizations at 100,000 per year. COX-2 inhibitors may have fewer of these side effects, although long-term studies are still needed.
        Exercise
         Studies have indicated that regular, even moderate exercise (30-minute daily jog or 60-minute daily walk) reduces the risk of colon cancer. Regular activity may be the most important lifestyle component in decreasing colon cancer risk. In one 2002 study, women who performed strength training exercises twice a week reduced several markers for both breast and colon cancer. The ultimate impact of these changes on breast and colon caner remains to be determined.
        Estrogen in Women
         Estrogen has been associated with a lower risk for colon cancer, perhaps because of specific enzymes the prevent cell proliferation. Agents containing estrogen, then, may help high-risk women:
        • There is some evidence that hormone replacement therapy (HRT) reduces the risk of colon cancer in postmenopausal women. It carries other risks, however, including a higher risk for breast and uterine cancer and blood clots. Older women who are at higher risk for colon cancer might discuss risks and benefits of HRT with their physician.
        • Oral contraceptives may reduce younger women's risk of colon cancer. Duration of use does not seem to be associated with decreased risk, but protection appears stronger for women who have used oral contraceptives more recently.
        Ursodiol
         Ursodiol is a drug sometimes used to treat gallstones or a rare inflammation of the bile ducts associated with ulcerative colitis. It helps reduce deoxycholic acid levels, a bile acid that has tumor-promoting properties. Animal studies have indicated colon cancer protection with the drug, but a 2002 study found no protective benefits for humans.
        Melatonin
         Melatonin is a hormone found in the brain that is mostly associated with its role in sleep. Researchers have also observed that the gastrointestinal tract is rich in melatonin, and that the hormone may have properties that help prevent ulcers, reduce acid secretion, and improve blood flow. It is not known whether this would help prevent colon cancer, but it appears to warrant some research. It should be stressed that melatonin is currently classified as a dietary supplement and not as a drug, so its purity, safety, and effectiveness are uncontrolled in the US. Melatonin is a powerful hormone that can have major effects, many still unknown, on many parts of the body. The bottom line is that at this time, people who take melatonin are experimenting on themselves.
        HOW ARE COLON AND RECTAL CANCERS DIAGNOSED?
         Colon and rectal cancers are diagnosed using the screening tests discussed below. These tests can detect precancerous polyps and colorectal cancers at stages early enough for complete removal and cure.
         Unfortunately, only 30% to 40% of adults over 50 years old (mostly in the upper socioeconomic group) have regular screening tests that could detect a cancer early enough for curative treatment. A survey reported that many people are not screened because they are too embarrassed and revealed that they would rather lose months off their life than face these tests. Those who had already had the tests were willing to have them again if they saved one additional day of their lives. There is some debate about what is the best screening modality. However almost all experts agree that not enough people are screened and that if these tests were adopted with the same regularity as other screening tests, such as Pap smears, they would save many lives. It is especially important that anyone at increased risk or with symptoms, such as rectal bleeding, undergo testing.
        General Screening Guidelines
         Individuals should discuss with their physician the risks and benefits of all screening procedures. Some controversy exists over how often people without risk factors for cancer should be screened and which detection method should be used for them.
        Guidelines for Adults Age 50 and Over with Average Risk
         The following are the most recent expert screening guidelines for people at age 50 and over who have no symptoms and no family history of colon cancer (or possibly also no family history of benign polyps):
        • A fecal occult blood test (FOBT) every year and a flexible sigmoidoscopy every five years. A follow-up colonoscopy should be done if any questionable results are found in either test. (The FOBT should be conducted first, since sigmoidoscopy would be replaced by colonoscopy if findings were suspicious.)
        • Many medical experts are now recommending a colonoscopy every 10 years, replacing sigmoidoscopy at that interval. Another alternative for viewing the entire colon is a barium enema every five years, although it is less clear if this screening test offers any survival advantages.
         In spite of the importance of screening, a government survey reported that in 2001 less than half of adults over 50 had ever had either an FOBT or endoscopy (that is, either sigmoidoscopy or colonoscopy).
         Choosing between Colonoscopy and Sigmoidoscopy. The choice between the use of colonoscopy and sigmoidoscopy for routine screening for older adults with average risk is, in fact, an area of intense debate. The issues are as follows:
        • Sigmoidoscopy is less costly, less invasive, quicker, and safer than colonoscopy. Although it allows inspection only of the left side of the colon, any abnormal findings from sigmoidoscopy trigger a full colonoscopy. Therefore, experts estimate that the use of sigmoidoscopy results in detecting 80% of all significant problems.
        • Colonoscopy is more sensitive than any other current screening methods for detecting colon cancer. If the goal is to maximally reduce the number of cancer cases regardless of cost, colonoscopy would be the preferred approach. A landmark 1993 study reported an approximate 90% reduction in colorectal cancers in patients with precancerous polyps who were regularly screened with colonoscopy and who had all colonic polyps removed. And, no deaths were reported from cancers that were detected during screening. Colonoscopy, however, is more costly than sigmoidoscopy and carries a slightly higher risk for complications.
        Guidelines for Increased- and High-Risk Groups
        Screening, particularly with colonoscopy, in increased- and high-risk populations can save lives.
         Guidelines for Increased-Risk Groups. Anyone with first-degree relatives diagnosed with colon cancer younger than 60 or with two relatives who have been diagnosed with colon cancer at any age. Such individuals should consider beginning the standard screening regimen with a colonoscopy every five years beginning at age 40 or ten years before the youngest case in the family (whichever is earlier). Of note: a 2002 study suggested that people in this group who have a personal history of polyps should talk to their physician about having colonoscopy every three years.
         Men of African descent (particularly from sub-Saharan Africa) are also considered to be at increased risk for colon cancer and should discuss similar screening guidelines with their doctor.
         Guidelines for High-Risk Groups. The following guidelines may be specifically useful for specific high-risk groups.
        • People known to have the mutated hereditary nonpolyposis colorectal cancer (HNPCC) gene (e.g., MSH-2 or MLH-1). Frequent colonoscopy (for instance, every one to two years) beginning in early 20s. (Regular screening for other cancers, such as uterine cancer, is also reasonable.)
        • People known to have the mutated familial adenomatous polyposis (FAP) gene. Frequent screening with endoscopy (e.g., flexible sigmoidoscopy or colonoscopy) beginning in early puberty. Genetic testing is now recommended for family members of people with known FAP.
        • People with predisposing intestinal problems such as widespread and active ulcerative colitis or Crohn's disease. Annual screening with colonoscopy with biopsies of suspicious areas.
          • Guidelines for Follow-Up After Detection of Precancerous Polyps
           Patients who have had a previous examination in which polyps were detected (and removed) should have a repeat colonoscopy one to three years later, depending on the size, number, and type of polyps removed.
          Digital Rectal Examination (DRE)
           The digital rectal examination is used to detect tumors in the rectum, lower intestine, and prostate gland. The doctor inserts a lubricated-gloved finger into the patient's rectum and feels for lumps or other abnormalities. The exam is quick and painless but embarrassing for some. Fewer than 10% of colon cancers develop within the region that can be evaluated by a DRE, so it is not useful as a sole screening test.
          Fecal Occult Blood Test (FOBT)
           Blood in bowel movements is not always visible, in which case it is called occult blood. Fecal occult blood tests (FOBTs) are used to detect this hidden blood. The most common FOBT method is called the guaiac-based test. The patient is asked to supply up to six stool specimens in a specially prepared package. A small quantity of feces is smeared on specially treated paper, which reacts to hydrogen peroxide. If blood is present, the paper turns blue.
           Accuracy. FOBTs can miss more than 75% of advanced cancers. Nevertheless, large studies have indicated that this simple test, performed annually, saves lives and may reduce the risk of dying from colon cancer by 15% to 33%. The following may affect its accuracy:
          • The levels of iron in the blood can affects results. Patients should not take iron supplements or eat red meats several days before the test.
          • Certain raw fruits and vegetables, including cauliflower, horseradish, radishes, melons, and turnips, that contain the chemical peroxidase can cause a positive test reaction even if no blood is present.
          • Aspirin and other NSAIDs can cause minor bleeding and should not be taken for a week before the test.
          • Vitamin C and foods rich in this vitamin may cause a false negative reaction and should be avoided a few days before the test.
          • Bleeding from other causes, such as menstruation, hemorrhoids, gingivitis, or urinary infections, can produce blood in the stools and affect results.
           Even if none of these conditions is present, a test that shows hidden (occult) blood does not necessarily mean that cancer is present. About 20% to 30% of people with occult blood have noncancerous polyps or other conditions, such as gastritis, and only 5% to 10% actually have cancer. Any abnormal result, however, requires further testing, such as colonoscopy [see below].
           Lack of Compliance. Compliance is a major problem. Patients are asked to perform the tests at home and send the test cards to the laboratory; only 35% to 50% of patients actually follow through. Occult-blood tests that give results at home are available but are extremely inaccurate. In one large study, these tests failed to detect advanced cancer in about 62% of cases, although they may detect some early cancers.
          Visualizing the Colon: Colonoscopy, Sigmoidoscopy, and Barium Enema
           If a digital rectal exam (DRE) or fecal occult blood test (FOBT) shows signs of trouble, several methods to visualize the colon are available. They include colonoscopy, sigmoidoscopy, and double-contrast barium enema. They have the following similarities and differences:
          • Sigmoidoscopy can only view the rectum and the left side of the colon, while colonoscopy and barium enemas allow a view of the entire large intestine.
          • Both flexible sigmoidoscopy and colonoscopy involve snaking a fiber optic tube through regions of the rectum and colon to view the walls of the intestine. The tube contains a tiny camera that transmits the image to a video screen. The use of an ultrasound (sound wave) scanner is proving to enhance viewing quality. Barium enemas simply use x-rays.
          • During either sigmoidoscopy or colonoscopy, the physician is able to remove polyps or other abnormalities revealed by these procedures with surgical instruments inserted through the tube. It is not possible to remove polyps with a barium enema, which is not invasive.
            •  Sigmoidoscopy. Sigmoidoscopy examines the rectum and the lower two feet of the colon. It cannot, however, detect the roughly half of cancers that occur in the right colon. Right-sided cancers are more common in older people.
            • The procedure employs a flexible fiberoptic tube (it is thus referred to as flexible sigmoidoscopy) that contains a tiny camera and surgical instruments.
            • It lasts about 10 minutes and may be mildly uncomfortable, but it is not painful and is generally very safe. In one study, 70% of patients reported that the procedure was far less unpleasant than they had expected.
             This procedure has been found to reduce the risk of fatal cancers in the rectal and sigmoid area by 60%. If polyps are detected, a colonoscopy is then used.
             Colonoscopy. Colonoscopy is the most accurate testing method and can reduce cancer incidence by up to 90%. It is clearly indicated for anyone with an increased risk for colorectal cancer, including those with a personal or family history of the disease. As with sigmoidoscopy, a colonoscopy uses a flexible tube but it is snaked through the entire large intestine.
            • For about a day before the procedure the patient eats nothing and drinks a laxative solution that cleans out the colon. The taste of the solution is unpleasant, although it has improved in recent years.
            • The procedure typically uses a sedative that produces a "twilight" sleep and often makes the procedure more comfortable than sigmoidoscopy.
            • Air may be introduced into the intestine to widen it and allow the tube to navigate curves. A colonoscopy avoids the risk of radiation associated with a barium enema [see below], but it is important to note that even a colonoscopy does not detect all cancers.
             Complications are rare, but include the following:
            • Hyponatremia. Hyponatremia is a low concentration of sodium in the blood. The complication may be caused by the effects of bowel cleaning before the procedure that can result in water retention and reductions in sodium. When severe, it can cause temporary neurological symptoms, such as confusion, lethargy, unsteadiness, and slurred speech. Researchers suggest that sodium concentrations be measured in patients who develop such symptoms after colonoscopy.
            • Bowel perforation (very low risk, about two cases per 1,000 procedures).
             Barium Enema. The double-contrast barium enema, which uses an x-ray image, is the less expensive alternative for viewing the entire colon. It is not as accurate as colonoscopy [see above], and if any polyps or abnormalities are revealed on x-ray, a colonoscopy is then required to remove suspicious tissue, so it is now recommended much less often than in the past.
            Genetic Screening
             Screening for FAP. Genetic screening for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) is now available and may be recommended for high-risk patients. The test for FAP detects a mutation in the APC (adenomatous polyposis coli) in up to 90% of people who carry it. Testing for HNPCC mutation is somewhat more complex. Screening for ICF-2. A gene that regulates insulin-like growth factor (IGF-2) is functional during fetal development and then becomes inactive. Some evidence now suggests that people who have IGF-2 in adulthood have a higher risk for colon cancer. Blood tests for detecting IGF-2, then, may be helpful in identifying patient who should have more intensive screening. Currently, however, this is only used as a research tool.
             Stool DNA Testing. A promising technique for colorectal cancer screening is the detection of altered DNA in cancer cells that have shed from the colon and are excreted in the stool. Such tests may prove to detect both inherited and noninherited genetic mutations. This may become a widely used tool in the future; however, larger clinical studies are needed.
            Experimental Screening and Diagnostic Methods
             Virtual Colonoscopy.A promising experimental technique called virtual colonoscopy allows three-dimensional imaging of the colon without using invasive instruments. As with standard colonoscopy, the patient takes a laxative first to clear out the intestine. The procedure itself involves pumping air into the colon and scanning the intestine using computed tomography (CT). It is very safe and takes only about 10 minutes. The procedure is similar in accuracy to conventional colonoscopy for detection of larger polyps (6 mm or more in diameter) and is also potentially less expensive. Colonoscopy is required, however, if suspicious areas are found, which may occur frequently with the CT procedure, since it erroneously identifies a high number of nonexistent polyps.
             Magnetic Resonance Colonography (MRC). Magnetic resonance colonography (MRC) is another non-invasive technique for visualizing the colon. The patient receives an enema containing a contrast agent, and then magnetic resonance images are taken. MRC is fast, comfortable, and less invasive than colonoscopy. Currently, however, there is a poor detection rate for flat tumors and for polyp tumors less than 10 mm in diameter.
             Encapsulated Video Camera. Researchers have developed a video camera that is small enough to be swallowed. It works its way through the digestive tract, beaming data to a receiver worn on the patient's waist, and is excreted in eight to 72 hours. The camera was not designed to replace standard visualization procedures and is currently being used to assess problems in the hard-to-reach small intestine. More testing is needed to determine whether it has value in colon cancer screening as well.
            HOW IS A PROGNOSIS FOR COLON AND RECTAL CANCERS DETERMINED?
             A diagnosis of cancer will lead to staging and other tests to help determine the outlook and the appropriate treatments.
            Staging
             Unlike many other cancers, the size of the tumor is not a major factor in determining the outcome of colorectal cancer. Of greater importance is how far the cancer has spread. To determine this, physicians will assign a stage to the tumor. There are several methods for staging. The older system, known as Dukes', categorizes four basic stages: A, B, C, and D. A more recent system refers to these stages as I, II, III, and IV but divides the categories slightly differently. The term "five-year survival" means that patients have lived at least five years since diagnosis. Most patients who live five years without a recurrence are considered to be cured of their disease.
            Stage — Condition — Five-Year Survival
            A or I — Tumor superficially involves the inner lining of the intestine — More than 90%
            B or II — Tumor has penetrated through the muscle wall of the intestine but has not reached the lymph nodes — 70% to 85%
            C or III — Lymph nodes are involved — 65% or below
            D or IV — Tumor has spread to other organs (metastasized), usually the liver first. Disease is generally considered incurable — Rare
            Tumor Markers
             Researchers are continually seeking to identify tumor markers, substances (usually found in blood samples) that will assist in the diagnosis of cancer and in monitoring effects of treatment.
             Carcinoembryonic Antigen (CEA). High blood levels of a protein called carcinoembryonic antigen (CEA) sometimes indicate the presence of colon cancer. Unfortunately, it is also elevated in other cancers and in some noncancerous conditions. CEA is not effective as a screening tool for healthy people, but might eventually be helpful for cancer patients.
            • An advanced diagnostic technique called polymerase chain reaction (PCR) can detect genetic evidence of CEA. One study indicated that when these microscopic footprints of colon cancer are detected in the lymph nodes of Stage II patients (whose lymph nodes otherwise appear to be not involved with cancer), the outlook is similar to that of Stage III patients. Patients without this so-called micrometastasis have a very favorable prognosis. Further research is needed, however, before PCR can be used in widespread practice.
            • In patients with a history of or active colon cancer, follow-up measuring of blood CEA levels may be helpful in detecting recurrence of the cancer and effectiveness of treatments.
             Defective P53 Gene. The presence of a defective p53 gene is a marker for very poor prognosis in patients with advanced colon cancer. In its normal state, the gene is important for regulation of cell growth. Testing for this abnormality, however, is not widely done because it is not clear how to use this information.
             Other Tumor Markers. Other tumor markers under investigation include a protein called GLUT1, cancer antigen 19-9 (CA 19-9), matrix metalloproteinase-9 (MMP-9) RNA, HER-2/neu oncoprotein, transforming growth factor beta-1 (TGF-beta-1), and CD44. However, their role is unknown and they should not be used outside the setting of a clinical study.
            Sentinel Node Biopsy
             A technique known as a sentinel node biopsy is increasingly performed by experienced surgeons in selected patients. This procedure is used to determine if cancer has spread beyond the nodes help and so possibly reduce the need for complete axillary lymphadenectomies. It involves the following:
            • The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
            • The tracer or dye then flows via the lymphatic system into the so-called sentinel node. This is the first lymph node to which any cancer would spread.
            • The sentinel lymph node and possibly one or two others are then removed.
            • If they do not show any signs of cancer, it is highly likely that the remainder of the lymph nodes will be cancer free, and further surgery becomes unnecessary.
             It is still not known if the sentinel node biopsy has any survival advantages compared to the standard procedures with lymph nodes removal.
             Of note, however, a 2002 study indicated that careful and complete removal of potentially cancerous lymph nodes is still very important for improving survival in Stage II and III patients.
            HOW SERIOUS ARE COLON AND RECTAL CANCERS?
             Over 57,000 people are expected to die from colorectal cancer in 2003. Only lung cancer is responsible for more cancer deaths, despite the fact that colorectal cancer is almost always a preventable or curable disease when proper screening is used.
            Survival Rates
             Survival rates for colorectal cancer have been rising in recent years. The five-year survival rate for patients undergoing colon cancer surgery is as high as 90% for cancer that has not spread to the lymph nodes. When cancer has spread to lymph nodes, survival rates drop to 65% and below. Because many cancers are detected at later stages, the overall survival rate is currently about 60%. African-Americans and other minorities tend to have lower survival rates than Caucasians. Studies suggest, however, these higher mortality rates are largely due to less access to optimal health care, including appropriate surgical care and aggressive treatments.
            Factors in Treatment Success
             In most cases age is not a factor in treatment success; good survival rates are achieved in the elderly as well as in young people. Chances for survival are less in Stage II cancers if the intestine is obstructed or perforated. If cancer has spread to lymph nodes (Stage III), the outlook is better if three or fewer lymph nodes are involved. Treatment can prolong life even when cancer has spread.
            WHAT ARE THE SURGICAL TREATMENTS FOR COLON AND RECTAL CANCERS?
             Surgical removal of the tumor along with any affected surrounding tissue is the standard initial treatment for potentially curable colorectal cancers (cancers that have not spread beyond the colon or lymph nodes). Drug therapy, radiation, or both are often used for advanced cancers and are continuously being tested with surgery in different combinations and sequences. [See sections What Are the Drug Treatments for Colon and Rectal Cancers? and What Is Radiation Treatment for Rectal Cancer?]
             Although choosing a qualified surgeon is critical, choosing a hospital experienced in procedures is also important. The more often colon cancer surgery is performed at a given hospital, the lower the mortality rate at that hospital is likely to be. In one 2000 study, the 30-day postoperative mortality rate for patients treated at hospitals in the top quartile of procedure volume was 3.5%. For hospitals in the bottom quartile, mortality was 5.5%. However, the differences were small, and significantly less than seen for more complex cancer surgeries.
            Colectomy
             Unless cancer is very advanced, most tumors are removed by an operation known as colectomy:
            • Colectomy involves removing the cancerous part of the colon and nearby lymph nodes.
            • The surgeon then reconnects the intestine by a procedure known as anastomosis.
            • If the surgeon cannot reconnect the intestine, usually because of infection or obstruction, a colostomy is performed [see below]. The need for colostomies is higher after surgery for rectal cancer. In most cases of colon cancer, colostomies are not needed.
             The Surgical Approach. The standard surgical technique is an open approach. Laparoscopy is a less invasive technique that is currently recommended only as part of clinical trials:
            • The open approach uses a wide incision to open up the patient's abdomen. The surgeon then performs the procedures with standard surgical instruments. This is the usual method for performing colectomy.
            • Laparoscopy is less invasive and may be as effective as the open approach with fewer side effects in selected patients. It is still investigative, however. It is generally used for early colon cancer (for tumors less than 2 centimeters or for well-defined tumors less than 3 centimeters), but it also is being investigated for rectal and advanced colorectal cancers. Laparoscopy employs a few small incisions through which the surgeon passes a fiber optic tube (laparoscope) containing a small camera or tiny instruments.
             Other Investigative Measures. Some investigators are testing expandable metal tube-like devices called stents to keep the intestine open. It may used before a procedure to allow bowel cleansing or it may be used for long-term use to keep open colons that are inoperable.
            Colostomy
             A colostomy is performed in order to bypass or remove the lower colon and rectum. The procedure generally involves creating a passage, called a stoma, through the abdominal wall that is connected to the colon. The feces pass through this passage and are eliminated. Patients must learn how to care for the stoma and keep the area sanitary.
             A colostomy is usually by its location (for example in the sigmoid area) or by the have one opening (single-barreled), or there may be two loops opening through the skin (double-barreled).
             Usually the colostomy is temporary and can be reversed by a second operation after about three to six months. It the rectum and sphincter muscles in the rectum need to be removed, the colostomy is permanent. Permanent colostomies are more common when the cancerous regions are within two to three centimeters of the anus. Fortunately, surgical advances and knowledge of the extent of safe margins are reducing the need for permanent colostomies.
             Managing Permanent Colostomies. In cases where the colostomy is permanent, the patient must wear a colostomy pouch, which sticks to the skin using a special glue. Pouches are available as one- or two-piece systems. The one-piece system is simpler, but the two piece system allows replacement of the pouch without removing the tape.
             For best results, the pouch should be emptied when about one-third full. It should be replaced one or two times a week, depending on signs of leakage (itching or burning of the skin near the stoma). It is important to stress that the pouches are odor proof.
            Surgical Treatments for Rectal Cancer
             Surgical treatments for cancer in the rectum are complex since they involve muscles and tissue that are critical for urinary and sexual function.
             Local Excision or Polypectomy for Early Stages. In order to preserve the function of the anal sphincter and prevent the need for colostomy, Stage I and Stage II tumors may be removed by local excision, sometimes followed by chemotherapy and radiation. In this procedure, the tumor is cut out without removal of a major section of rectum. In some cases cancer recurs, but a second operation may be possible. Another treatment for early-stage rectal cancer called electrocoagulation, which destroys tumors using a high frequency electric current, is being tested but should only be used in the setting of clinical trials.
             Radical Resection. In about a third of cases of rectal cancer, the cancer occurs in the lower part of the rectum, where between 70% and 80% of cancers have spread beyond the rectal wall. In such cases, a radical resection is required, in which surrounding structures, including the sphincter muscles that control bowel movements, must often be removed.
             The use of chemotherapy and radiation prior to surgery may prevent the need for permanent colostomy in some patients. This is an active area of clinical research and current trials are under way to address this issue. An alternative technique called coloanal anastomosis reconstructs the area to avoid the need for colostomy, and may be appropriate in selected patients.
             Total Mesorectal Excision. Total mesorectal excision (TME) involves dissection and removal of the entire cancerous area of the rectum along with surrounding fatty regions where the lymph nodes are located (the mesorectum). When successful, TME preserves the sphincter muscle, reducing the need for a permanent colostomy. Increasing use of this procedure is resulting in lower recurrence rates, lower levels of impotence and incontinence, and better overall survival rates compared to other resection techniques. Some experts now recommend that it be the first choice for certain patients with locally advanced rectal cancer.
             Combining chemotherapy and radiation either before or after TME is yielding promising long-term results and a low risk for local recurrence. There are many questions, however, and it is not clear which approach is better for specific patients.
            Managing Side Effects and Psychological Repercussions
             Side effects of colon surgery include:
            • Sexual dysfunction. This is of particular concern. In general, colostomy does not usually affect sexual function. However, wide rectal surgery can cause short- or long-term sexual dysfunction. Sildenafil (Viagra) may help men who experience this after surgery.
            • Irregular bowel movements.
            • Gas and flatulence. Pouching filters are available to reduce gas. Certain foods produce more gas than others — usually within six to eight hours for colostomy patients. They include beans, oat bran, most fruit, and certain vegetables (cabbage, cauliflower, Brussels sprouts, broccoli, and asparagus). To prevent swallowing air, patients should avoid sipping through straws, chewing gum, and chewing with their mouths open.
            • Diarrhea.
            • Bladder complications.
            • Sense of urinary urgency.
            • Fecal incontinence. Patients with rectal surgery have a higher risk for bowel dysfunction than those who had a colostomy.
            • Complications in or around the stoma. These can occur early after surgery to many years after the procedure. They include skin infection or breakdown, hernias, narrowing of the stoma, bleeding, and collapse.
             There are no dietary restrictions, although many patients avoid foods that can produce gas. Everyone should drink plenty of fluids and sufficient fiber.
             The potential side effects of sexual and bowel dysfunction for colorectal surgical patients can be devastating, although many patients do very well and live normal productive lives. Positive emotions play a strong role in recovery. Patients who are depressed should discuss with a physician all aspects of treatment that affect the quality of life and possibly seek support groups.
            WHAT ARE THE DRUG TREATMENTS FOR COLON AND RECTAL CANCERS?
            Chemotherapy Guidelines
             Chemotherapy uses drugs that kill cancer cells throughout the body. There are two situations in which chemotherapy is used:
            • The adjuvant setting. Adjuvant refers to the use of chemotherapy after surgery in patients with stage III tumors and selected patients with high-risk stage II tumors (i.e., disease that is potentially curable). The goal of this therapy is to eliminate any cancer cells that surgery may have missed, thereby preventing recurrence and increasing the chance of cure. Patients of all ages, including the elderly, can benefit.
            • In metastatic disease. In patients with metastatic disease the goal of chemotherapy is to shrink tumors, improve symptoms and quality of life, and to lengthen life. [See What Are the Treatment Options for Metastasized Colorectal Cancer?]
             In the adjuvant setting, there are some differences in chemotherapy treatments between colon and rectal cancers:
            • Chemotherapy for Stage II patients is considered standard care for stage II rectal cancer but is under debate for colon cancer.
            • Chemotherapy is standard for stage III colon cancer patients. Chemotherapy is also standard for stage III rectal cancer patients but is used in combination with radiation.
              •  Chemotherapy for Stage II Patients with Colon Cancer.Adjuvant chemotherapy for Stage II colon cancer patients is controversial. Such patients tend to have a good outcome after surgery and the positive effects of chemotherapy have been difficult to demonstrate. To date, the survival advantage of adjuvant chemotherapy in this group has been reported to be only in the range of 2%. However, better trials are still needed to confirm or refute the benefits in specific patient groups.
               Although not yet known with certainty, some data suggest that certain Stage II patients may be at higher risk of recurrence and would theoretically benefit from adjuvant therapy. These include patients with the following conditions:
              • Cancers that have obstructed the bowel,
              • Cancers that have perforated the wall of the colon, or
              • Cancers that have adhered to structures outside the intestine.
               Advanced diagnostic techniques are under investigation for helping to select appropriate Stage II candidates for adjuvant therapy. None of these methods, however, are ready to be used routinely to help make treatment decisions. The decision whether to pursue chemotherapy for stage II disease should be made after careful discussion between the patient and his or her oncologist, especially after features, such as bowel perforation or obstruction, are taken into account. Chemotherapy for Stage III Patients with Colon Cancer. Since the early 1990s, adjuvant chemotherapy with 5-FU and leucovorin has been the standard of care for stage III colon cancer. Numerous trials have shown that adjuvant chemotherapy in this setting reduces the absolute risk of death from colon cancer by approximately one-third and improves survival by 10%. Current clinical trials are investigating whether the addition of new chemotherapy drugs, suchas irinotecan, oxaliplatin, capecitabine, and antibody therapies, will improve cure rates over 5-FU and leucovorin alone. However, most of these new agents should currently not be used for adjuvant treatment of colon cancer unless as part of a clinical trial. Chemotherapy for Advanced Colorectal Cancer. Chemotherapy and radiation are generally used to reduce symptoms and prolong life in advanced colorectal cancer. Some experts suggest that chemotherapy should be considered for the following patients:
              • Able to carry out all normal activity without restriction.
              • Restricted in physically strenuous activity, but able to walk about and carry out light work.
              • Able to walk about and capable of all self care, but unable to carry out any work. Out of bed or chair for more than 50% of waking hours.
               Chemotherapy in most studies offers a modest improvement in survival and often relieves symptoms. One 2003 study suggested that for these patients chemotherapy given intermittently has fewer toxic or serious adverse effects and may be as beneficial as continuous administration.
               The following patients are unlikely to benefit from chemotherapy:
              • Those capable only of limited self care. Confined to bed or chair for more than 50% of waking hours.
              • Severely disabled. Cannot carry out any self care. Totally confined to bed or chair.
               The standard chemotherapeutic drug, 5-fluorouracil (5-FU), is used alone or with other drugs, most commonly leucovorin. Patients should consider clinical trials with immunotherapies and combinations with other chemotherapy drugs, including irinotecan, and oxaliplatin.
              Specific Chemotherapy Agents
               5-Fluorouracil (5-FU) with Leucovorin. Adjuvant therapy using 5-fluorouracil along with leucovorin (5-FU/LV) is currently the standard treatment for patients with high-risk colon cancer (Stage III or selected patients with Stage II tumors). Leucovorin, also called folinic acid, is a form of the B vitamin folic acid. Patients are given a series of cycles that usually continue for at least six months. 5-FU is given intravenously at present, but oral preparations are currently being tested in clinical trials.
               There are many different ways of giving 5-FU, including intravenously over several hours once a week, intravenously daily for five consecutive days every month, or as continuous infusion with a portable pump.
               The side effects can be quite different depending on the way 5-FU is given, and women may be more susceptible than men. In one analysis, 53% of women and 40% of men experienced severe side effects, while response rates and survival were similar for both sexes. Many patients, however, tolerate 5-FU with leucovorin well, with manageable side effects.
               Irinotecan. Irinotecan (Camptosar) inhibits an enzyme essential for cell division and works in combination with 5-FU. When it was approved in the mid 1990s, it was the first new drug developed for colon cancer in over 30 years. Two studies in 2000 reported that a combination of irinotecan along with 5-fluorouracil and leucovorin (5-FU/LV) significantly delays the time at which tumors progress and improves survival in metastatic cancer compared to 5-FU/LV alone. While the survival advantage is small, the combination has become the standard of care for metastatic cancer for many oncologists. Of concern, however, were 2001 studies reporting an increased risk of death from toxic effects with the use of the three-drug combination. Such deaths appeared to be related to blood clotting complications. Experts recommend careful monitoring and use of lower drug doses.
               Capecitabine. Capecitabine (Xeloda) is the first oral agent approved for metastatic colorectal cancer. It allows fewer days of hospitalization, and side effects are manageable. In the body, it is taken up by tumor cells, then converted to 5-FU, which kills the cancer cells. Compared to standard therapy, capecitabine has demonstrated similar results, although combinations with 5-FU, irinotecan, and oxaliplatin [ see below] are being investigated. It is also showing promise when used with radiation therapy for rectal cancers. (Doxifluridine, an oral drug with similar properties, is under investigation.)
               Oxaliplatin. Oxaliplatin (Eloxatin) is a variant of cisplatin, a widely used platinum-based chemotherapy drug. It is now approved for use in combination with 5-FU and leucovorin for recurring cancer or cancer has progressed after initial therapy. In one study, the combination was more effective in achieving response and slowing progression than either treatment alone. It is still now known if survival rates improve. Oxaliplatin can cause a unique peripheral neuropathy (pain and tingling sensations in the hands and feet) that is exacerbated by exposure to cold.
               Raltitrexed. Raltitrexed (Tomudex) may be effective and may have additive or synergistic effects with 5-FU.
              Side Effects of Chemotherapy
               Side effects occur with all chemotherapeutic drugs; they are more severe with higher doses and increase over the course of treatment. Because cancer cells grow and divide rapidly, anticancer drugs work by killing fast-growing cells. This means that healthy cells that multiply quickly can also be affected. The fast-growing normal cells most likely to be affected are blood cells forming in the bone marrow, and cells in the digestive tract, reproductive system, and hair follicles.
               Side effects vary specifically with different drugs, but, in general, they include the following:
              • Nausea and vomiting. Drugs are available to significantly reduce these dreaded side effects. Serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
              • Diarrhea (very common with 5-FU).
              • Temporary hair loss (usually minimal with 5-FU).
              • Weight loss.
              • Mouth ulcers.
              • Pain and redness of the hands and feet.
              • Fatigue.
              • Anemia.
              • Depression.
               These side effects are nearly always temporary, and medications are available to help manage them. Most patients are able to continue with normal activities for all but perhaps one or two days a month.
               More serious complications can also occur and may vary depending on the specific agents used. They include the following:
              • Increased chance for infection (from suppression of the immune system).
              • Bleeding.
              Anti-Angiogenic Therapy
               Angiogenesis is the process of new blood vessel growth, including blood vessels that feed tumors. Researchers are studying a number of agents that block angiogenesis. The following are some examples.
              • Bevacizumab (Avastin) targets vascular endothelial growth factor (VEGF), which regulates angiogenesis. Early studies on the use of this agent in combination with standard chemotherapy are promising, including for metastatic color rectal cancer. There is some concern about severe bleeding and other serious adverse effects, such as bowel perforation, with this agent.
              • Marimastat inhibits matrix metalloproteinase, an enzyme important in angiogenesis. In one controlled study, it had no effect on survival for most patients with metastasized colorectal cancer that had spread to the liver.
               Tyrosine Kinase Inhibitors. Some angiogenesis inhibitors target receptors of endothelial growth factors, such as one called tyrosine kinase. Those under investigation include ZD 1839 or gefinitib (Iressa) and OSI-774 (Tarceva).
              Immunotherapy
               Immunotherapy uses the body's own disease fighters to attack the cancer. These agents hold promise for adjuvant therapy of colorectal cancer but are still under investigation. Some approaches enhance the body's defense systems; others use genetic engineering techniques to design molecules that target and attack tumor cells.
               Monoclonal Antibodies (MAb). Of particular interest are specially-developed immune factors called monoclonal antibodies, which attack specific proteins located in colon cancer cells. No monoclonal antibody is curative. The following are some MAbs showing promise:
              • Cetuximab (Erbitux) binds to a substance called epidermal growth factor receptor (EGFR), which colon cancer cells require in order to proliferate. A 2001 study reported that 48% of patients with metastatic colon cancer who had failed both 5-FU and irinotecan responded to a combination of Erbitux and irinotecan. Other studies are showing promise with these agents, not only for colon but also for other cancers.
              • Herceptin and 2C4 target an area specific to cancer cells called the HER-2/neu receptor, and may fight cancer growth when combined with the COX-2 inhibitor drug celecoxib. More research is necessary.
              • Edrecolomab (Panorex) targets a factor on cancer cells called Ep-CAM. It showed promise in early studies. A late phase trial in 2002, however, did not find any improvement in survival with its use.
               Adenovirus Therapy. Researchers report that a genetically modified cold virus called Onyx-015, which targets cancer cells containing a defective p53 gene, has the potential to boost chemotherapy's effects. In one study, it shrunk tumors that had spread to the liver.
               Vaccine. Researchers are also creating vaccines, such as one that uses genetically altered nerve cells (dendritic cells) harvested from the patient and tagged with a tumor protein. Another vaccine produces antibodies to beta-hCG, although the clinical benefit of this agent remains to be defined.
              WHAT IS RADIATION TREATMENT FOR RECTAL CANCER?
               Radiation therapy uses x-rays to kill cancer cells that might remain after an operation or to shrink large tumors before an operation so that they can be removed surgically. The object of radiation therapy is to damage the tumor as much as possible without harming surrounding tissues. Radiation may be administered in the following ways:
              • Externally by an x-ray machine (external beam radiation).
              • By passing radioactive pellets through thin plastic tubes inserted into the intestine.
              • By implanting tiny radiation seeds directly into the tumor (brachytherapy).
              • Computer imaging techniques providing 3-dimensional pictures of the cancerous area are allowing precise targeting of radiation to the tumor.
              Postoperative Radiation with Chemotherapy for Rectal Cancer
               Postoperative radiation treatment combined with chemotherapy is common practice for patients with rectal cancer in Stages II and III. Such patients are at risk of recurrence both at the site of their original tumor and elsewhere in the body. Although there can be significant long-term side effects, the combination of 5-FU and radiation is still considered standard after surgery.
              Preoperative Radiation
               The standard procedure in the US is to apply radiation after surgery (postoperative). Preoperative chemotherapy and radiation, however, are sometimes used to preserve sphincter-muscle function and reduce the chance that a patient will require a colostomy. Furthermore, some studies suggest that the use of radiation before surgery reduces the likelihood of recurrences and may slightly prolong survival in some patients with rectal cancer. (It has no additional advantages, however, if the subsequent surgery does not completely remove the cancerous regions.) Studies comparing preoperative and postoperative chemotherapy and radiation are currently under way.
              Intra-Operative Radiotherapy (IORT)
               Radiation therapy is also being used during surgery (a procedure called intra-operative radiotherapy.) It allows the surgeon to move healthy tissue out of the path of the radiation beam.
              Side Effects of Radiation Therapy
               Short-term side effects of radiation include:
              • Diarrhea.
              • Skin irritation around the anus.
              • Incontinence.
              • Fatigue.
              • Bowel movement problems.
               Longer-term complications may include the following:
              • Incontinence.
              • Soiling.
              • Hip and pelvic fractures.
              • Diarrhea.
              • Increased risk for bowel obstruction.
              HOW SHOULD THE PATIENT BE MONITORED AFTER TREATMENT?
               The American Society of Clinical Oncology (ASCO) sets guidelines for follow-up testing to detect recurring cancer after treatment has been completed. These ASCO guidelines may not apply to particular patients. Although they are based on the best available evidence, rigorous studies are still needed to determine which tests can best cost-effectively detect recurrence at its earliest stage.
              Physical Examination and Colonoscopy
               After surgery, patients should have a physical examination every three to six months for the first three years. Some guidelines recommend colonoscopy within six months of surgery, performed again at 18 months, and then less frequently (e.g., 18 to 24 months), depending on individual factors. There is some debate about whether there should be more frequent colonoscopies for the first few years after colon surgery. In one 2002 study, patients with Stage II and III cancers had a 1.5% chance of developing a new primary colon cancer within two years after surgery. Experts suggested that the frequency of colonoscopies may not need to be increased, but the examinations themselves should certainly be very meticulous.
              CEA Levels
               CEA levels [see Carcinoembryonic Antigen (CEA) above] should be measured every two to three months after surgery for two years in Stage II or III patients. An elevated CEA level, confirmed by retesting, warrants further evaluation for return of metastatic disease. It should be noted that almost a third of all recurring cancers do not produce abnormal CEA levels.
              Imaging Techniques
               An advanced imaging technique called a fluorodeoxyglucose positron emission tomography (FDG-PET) scan may be used to detect recurrent or metastasized colorectal cancer in the setting of an elevated CEA. This test is proving to be very sensitive in detecting diseased areas.
              Other Tests
               There appears to be no additional benefit for anyone from routine follow-up liver function tests, fecal occult blood tests (FOBT), or computed tomography (CT) scans. There is some debate about whether chest x-rays should be administered annually; they appear to detect recurring cancers but not early enough to be very helpful for the great majority of patients.
              WHAT ARE THE TREATMENT OPTIONS FOR COLORECTAL CANCER THAT HAS SPREAD TO THE LIVER?
               The liver is the most frequent site for metastasized colorectal cancers. Here, treatments may slow the spread of cancer and even prolong survival. Cure is very rare.
              Surgery
               When cancer has spread, surgery to remove or bypass obstructions in the intestine may be performed. In these circumstances, surgery is considered palliative in that it may improve symptoms but will not lead to cure. In rare cases, metastatic colon cancer may be cured with surgical removal of tumors in areas to which the cancer has spread, such as the liver, ovaries, and lung. The liver is the most common site of spread. Only selected patients may be eligible for such surgery, but in such patients five-year survival has been 25% and may be higher.
              Chemotherapy
               Chemotherapy may be used to improve symptoms and possibly a prolong survival in metastasized colorectal cancers. A number of investigative agents are being tested. Physicians are testing chemotherapy administered directly into the liver — a treatment called intrahepatic arterial chemotherapy. It is possible to shrink swollen, painful livers this way, but to date studies are not reporting any survival advantages with this approach compared to chemotherapy delivered intravenously.
              Other Techniques
               Other investigative techniques used to destroy liver tumors include:
              • Cryosurgery. This approach freezes the tumor or surrounding tissue.
              • Embolization. Embolization employs a catheter to deliver agents into the liver that block blood vessels and therefore starve the tumor. Chemotherapy is often delivered with these agents.
              • Radiation.
               For end-stage cancer, hospice care is a compassionate option.
              WHERE ELSE CAN HELP BE FOUND FOR COLON AND RECTAL CANCERS?
              American Cancer Society Call (800-ACS-2345).
              National Cancer Institute Call (800-422-6237).
              United Ostomy Association Call (800-826-0826).
              American Institute for Cancer Research Call (800-843-8114).
              The National Colorectal Cancer Research Alliance Call (800-872-3000).
              American Society of Clinical Oncology Call (703-299-0150) or access its journal
              An excellent site for colon cancer is Foundation for Digestive Health and Nutrition Call (866-337-3346).
              National Comprehensive Cancer Network Call (888-909-6226). For information on clinical trials or www.DrugStudyInstitute.com
              Special Instructions:
               Try to eat a high fiber low fat diet. Take Metamucil with each meal. Begin with one cap three times a day and slowly increase to six caps before meals three times a day as side effects (diarrhea, crampy abdominal pain, gas) allow. Any questions or concerns call Dr. Saponaro at Drug Study Institute at: 866-575-1212 or Pi@DrugStudy.MD

              Sincerely:

              Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
              Expert Medical Witness, ExpertMD
              PI (Principal Investigator), DSI (Drug Study Institute)
              Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
              DABIM (Diplomat American Board of Internal Medicine)
              FACP (Fellow American College of Physicians)
              CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
              CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
              CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
              CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
              CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
              Member, SIMPD (Society for Innovative Medical Practice Design)
              Member, ACPM (American College Preventive Medicine)
              Ethics Committee Member, Jupiter Medical Center
              IRB Member, Jupiter Medical Center
              Founder, CertifiedResearchers.com