WHAT ARE COLON AND RECTAL CANCERS?

* Please note that most treatment modalities listed below are based on conventional medicine. PreventDisease.com does advocate the use of any pharmaceutical drug treatments. Long-term drug therapy is detrimental to human health. All drug information is for your reference only and readers are strongly encouraged to research healthier alternatives to any drug therapies listed.

Colon and rectal cancers (often referred to collectively as colorectal cancer) are malignancies (life-threatening tumors) that develop in the large intestine. [ See Box The Gastrointestinal Tract.] Most tumors evolve from adenomatous polyp s (small benign gland-like growths) that develop on the mucous membrane, which lines the large intestine. They are usually one of the following types:

• Tubular polyps, which protrude mushroom-like, or
  
  
• Villous adenomas, which are flat and spreading and are more apt to become malignant.

Larger polyps (over an inch) are more dangerous than smaller ones. Progression to cancer takes about five to ten years in most cases, except for certain inherited forms, which develop more rapidly.

THE GASTROINTESTINAL TRACT The gastrointestinal (GI) tract (the digestive system) is a 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 and then through the small and large intestine to be excreted out through the rectum and anus. Esophagus The esophagus, commonly called the food pipe, 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 and is about 20 feet long. Food that passes from the stomach into the small intestine first passes through three parts: First it enters 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 to the large intestine , mostly in liquid form. The large intestine is approximately six feet long and is the final portion of the digestive tract. It follows the small intestine 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. F eces 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?

Genetic Factors

Genetic defects in genes that normally protect against cancer play the major role in causing polyp cells to proliferate unceasingly and become cancerous. Most of these defects however are acquired in an individual patient, and are not inherited. In some cases of hereditary colon cancer, the responsible genetic abnormalities have not yet been identified.

APC Gene. 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. A non-inherited mutation of the APC gene occurs in nearly all patients with sporadic colon cancer. (Sporadic in such cases refers to the development of cancer without a strong family history.) Various genetic mutations that affect the APC gene directly or indirectly have been identified, including the following:

• Familial Adenomatous Polyposis (FAP). In the rare disorder familial adenomatous polyposis (FAP), the patient inherits a mutated APC gene from his mother or father. In this severe genetic disorder, thousands of polyps grow in the colon during early adulthood. FAP causes less than 1% of all cases of colorectal cancer, but if untreated, almost everyone with this condition develops cancer before the age of 40. Many of the deaths attributed to FAP could be prevented with early and aggressive monitoring.
  
  
• AXIN2 Gene. The AXIN2 gene interacts with the APC gene and with beta-catenin. Researchers have shown that mutations in this gene may cause a small percentage of colorectal cancer and are trying to determine its role in cancer development.
  
  
• Alpha-1 Antitrypsin Gene. A mutation in a gene that causes a deficiency in alpha-1 antitrypsin may increase the risk for a certain subtype of colorectal cancer called MSI (microsatellite instability) colorectal cancer. Alpha-1 antitrypsin is a substance that neutralizes protein-destroying enzymes, and deficiencies may encourage cancer by allowing chronic damage to cells. A genetic deficiency is a well-known risk factor for emphysema and liver disease. The genetic mutation has also been linked to liver and bladder cancer. And research now suggests that it triples the risk for the MSI subtype, which occurs in 15% to 30% of colorectal cases. The risk in smokers with alpha-1 antitrypsin deficiency is up to 20 times the normal rate.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, accounts for 5% of all colorectal cancers. This abnormality occurs in genes that error-check DNA. People who inherit the abnormal gene have an extremely high risk of developing 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. People who inherit HNPCC are prone to other cancers, including uterine and ovarian cancer.

Cyclooxygenases and Prostaglandins

Cyclooxygenase 1 and 2 (COX-1 and COX-2) are enzymes involved in the production of prostaglandins, substances that regulate blood vessel narrowing and opening and muscle contraction and inhibit hormones that regulate fat metabolism. COX-2, but not COX-1, appears to be a major suspect 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 induces interleukin-6 (IL-6), a factor in the immune system that is associated with cancer cell invasion.

Lifestyle Factors, Circulating Insulin, and Insulin-Like Growth Factor (IGF)

A Western lifestyle, being sedentary, and excess weight have all been associated with increased risk for colorectal cancer. 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.

Bile Acid Salts

Deoxycholic acid, which is found in bile, appears to have carcinogenic properties. Its effects are now believed to play a role in some cases of colon cancer. Increased levels of the acid can develop with high-fat diets or in certain diseases.

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 found in the stools is a common sign of many intestinal cancers. Blood in the stool may appear red if it is fresh or black if it is old. Although it should be reported to a physician immediately, 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 stool is an abnormal finding that should never be ignored. This always should be reported 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, which 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?

Over 135,000 people in the US are expected to be diagnosed with colon or rectal cancer in 2001. The risks over all are equal in men and women, but men have a slightly higher risk for rectal cancers and women for colon cancers.

Age

Non-inherited colorectal cancers usually 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 1 in 2000 people per year will develop colorectal cancer, and after age 65, this rate increases to almost 3 in 1000.

Ethnicity and Life Style

African Americans are at higher risk of colon cancer. The highest risks are in men of African descent, particularly in the sub-Sahara region. The risk appears to be higher for colon but not rectal cancer compared to Caucasians. ⁷

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. Although a number of specific risk factors have been identified, about 75% of cases occur without a known predisposing factor.

Diet. 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 reported in 1999 that the risk of colon cancer rises as body mass index (BMI) increases.

Other Intestinal Conditions

Crohn's Disease and Ulcerative Colitis. 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 Report Inflammatory Bowel Disease. ]

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 implant, 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.

Plant Chemicals (Phytochemicals) Found in Fruits and Vegetables

A 2000 study by Harvard researchers concluded that eating fruits and vegetables had little or no effect on colorectal cancer rates. These findings contradicted prevailing belief in the medical community and previous studies that found an association between a high intake of these foods and a lower risk for colorectal cancer. For example, early results in 2000 of the European Prospective Investigation into Cancer and Nutrition (EPIC) have suggested that a diet high in fruits and vegetables can help prevent colorectal cancer. This is the largest study ever conducted on the role of diet in the development of cancer.

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).
  
  
• Red (red pepper, tomatoes, watermelon, raspberries, pink grapefruit).
  
  
• Yellow-orange (carrots, pumpkin, sweet potatoes, oranges, tangerines).
  
  
• Blue (blueberries).

Carotenoids. Carotenoids are red, yellow, and orange pigments found in some animal tissues and in many fruits and vegetables. Carotenoids being investigated include the following:

• Lutein (found in spinach, broccoli, lettuce, tomatoes, oranges and orange juice, carrots, celery, and greens) may protect against colon cancer among the general population, although the benefits may not be significant for individuals with a family history of the disease.
  
  
• Lycopene (found in tomatoes and other red fruits and vegetables) may have strong cancer-protective properties. Cooking tomatoes appear to increase their benefits.
  
  
• High intakes of other carotenoids (including alpha-carotene, beta-carotene, lycopene, zeaxantin, and beta-cryptoxanthin) did not appreciably affect colon cancer risk in another study.

Isothiocyanates and Indoles. Isothiocyanates and related substances, indoles, are also known as mustard oils and are responsible for the sharp taste in cruciferous vegetables (broccoli, cabbage, Brussels sprouts, cauliflower, collards, kale, kohlrabi, mustard greens, rutabaga, turnips, bok choy). When digested, indoles yield 3,3'-diindolylmethane (DIM). DIM appears to fight cancer in laboratory tests by stopping malignant cells from dividing and multiplying, and by affecting levels of proteins that affect tumor cells. Whether this has implications in humans is unclear.

Lectin. Lectin, which is found in broad beans and mushrooms, may also be protective.

Organosulfur Compounds. Organosulfurs are part of the allium family of phytochemicals. They may have benefits on the immune system, assist the liver in rendering carcinogens harmless, and reduce production of cholesterol in the liver. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots. Two recent studies drew conflicting conclusions about the preventive effects of garlic. 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 found the available evidence about garlic to be inconclusive, however. Garlic supplements, in any case, do not appear to be protective.

Fiber

A number of studies have shown that fiber protects against colon cancer, but recent research contradicts this long-held belief. Two studies reported no difference in the development of colorectal polyps with high or low intake of fiber. These studies did not report on overall effects on cancer itself, though one would expect there to be no difference. Different fiber forms may also have different effects on tumor growth, which the studies did not address. One study, in fact, suggested that fiber supplements containing the ispaghula husk may actually increase the risk for tumors. This substance is similar to psyllium, another common fiber supplement. In any case, fiber, which is only found in plant products, may be beneficial for the heart and have other health advantages.

Fats and Meat

Fats. A number of studies have found an association between saturated fats (found primarily in animal fats) and colon cancer. Olive oil, however, may be protective according to a study of 28 countries. Some evidence suggests that it reduces levels of deoxycholic acid, an acid found in bile that has tumor-promoting properties. Researchers in the study suggested, in fact, that the protective role in fruits and vegetables observed in various studies may simply be due to a high intake in olive oil in the same people who consumed large amounts of produce.

Meat. Some evidence suggests that it is only the particular type of fatty acid found in red meat, not all animal fat, that raises the risk for colon cancer. Red meat may increase levels of deoxycholic acid, a bile acid associated with 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 or pan frying) has been specifically associated with increased risk for colon polyps. Over-cooking meat increases the amount of carcinogens called heterocyclic amines, although whether they or any other chemical released with grilling pose any significant risk for cancer is as yet unproven.

Dairy Products and Calcium

One major analysis suggested that milk, particularly fermented milk (buttermilk, yogurt), may have compounds or bacterial culture that help protect against colon cancer. Calcium, which is found in dairy products, is also associated with colon cancer protection.

Lactic Acid Bacteria Cultures. There is some evidence that consumption of lactic acid bacteria cultures called lactobacilli may suppress cancer. Such bacteria must be probiotic. That is, they must be able to reproduce in the intestinal tract. Many brands of yogurt and other fermented dairy products contain probiotic bacteria, such as acidophilus. People should look for labels that identify active cultures. Acidophilus capsules are available in health food stores.

Calcium. Most studies show a protective effect from high-calcium diets or calcium supplements, but the association is statistically significant in only a few studies. The protective effect has been observed as early as one year after calcium supplementation began.

Soy Protein

Preliminary research suggests that soy protein may help prevent colon cancer. A small 1999 study suggests that soy protein reduces the incidence of colon cancer in people who have a history of the disease or who have had pre-cancerous polyps removed.

Sugar and Total Calories

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.

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.

The role of vitamins in colon cancer is unclear. Some studies have associated supplements of vitamins A, C, D, and E with lower colon cancer risk, but other studies have found no protective effect.

Selenium

Selenium is a trace element in meats, whole grains, egg yolks, fish, and some other foods, such as Brazil nuts. In one study, people who took a daily selenium supplement of 200 micrograms for more than four years had half the rate of lung, colon, rectal, and prostate cancer as those who did not. The study had limitations, however, and high amounts can be toxic, causing hypothyroidism and hair and nail loss. The overall health benefits of selenium are still unknown

WHAT ARE NON-DIETARY MEASURES FOR PREVENTING COLON AND RECTAL CANCERS?

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the frequency of colorectal cancer. A number of studies have suggested that taking NSAIDs at doses similar to those taken by arthritic patients for pain protection confers protection against colon cancer.

Protective NSAIDs. There are many NSAIDs available, including aspirin, ibuprofen (Motrin, Advil, Nuprin, Rufen), and naproxen (Aleve). Taking any NSAIDs for short periods of time is not protective. However, long-term use of NSAIDs to prevent colorectal cancer is not yet recommended. The following are some NSAIDs and NSAID combinations of particular interest:

• COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx) block the enzyme cyclooxygenase-2 (COX-2), which has been particularly associated with cancer risk [ see Cyclooxygenases and Prostaglandins above]. Early studies indicate that celecoxib may help prevent new growth and retard the growth of existing polyps. Celecoxib has now been approved for patients with familial adenomatous polyposis (FAP).
  
  
• Studies report that the potent NSAIDs indomethacin and sulindac caused regression of rectal polyps in people with FAP. The polyps most likely resume progression when the drugs are stopped.
  
  
• Combining NSAIDs with the cholesterol-lowering drugs known as statins (lovastatin, pravastatin, simvastatin) in some studies, has 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 gastrointestinal side effects. This combination, however, requires further study.

Complications. It should be noted 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. Strenuous activity adds only slight or no additional benefit.

Estrogen in Women

Hormone Replacement Therapy. Studies continue to show that hormone replacement therapy, with or without progesterone, protects against colon cancer. Risk reduction for colon cancer is also associated, however, with a healthy lifestyle, and it is still not yet known whether estrogen protects against colon cancer or if, rather, women who take HRT tend to be healthier. HRT carries certain risks and other benefits that women should discuss with their physician.

Oral Contraceptives. Use of oral contraceptives may reduce 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, an acid that has tumor-promoting properties. Studies now suggest it may prevent colon cancer in persons at high risk. More research is needed.

HOW ARE COLON AND RECTAL CANCERS DIAGNOSED?

Colon and rectal cancers are diagnosed using the screening tests discussed below. These tests can detect premalignant polyps and colorectal cancers at stages early enough for complete removal and cure. Unfortunately, only a minority 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. [ See Box General Screening Guidelines.]

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 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) should have the following: An annual digital rectal exam (DRE) and fecal occult blood test (FOBT). A follow-up colonoscopy follows any questionable results. A flexible sigmoidoscopy every five years is the standard recommendation. A follow-up colonoscopy is conducted if sigmoidoscopy reveals multiple polyps, polyps that show precancerous signs, or polyps larger than 6 millimeters. A colonoscopy or double barium enema might be considered instead of sigmoidoscopy every five to ten years. (When using a barium enema, a colonoscopy should follow any questionable results.) 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 and invasive than colonoscopy, but it allows inspection only of the left side of the colon. (African American men, for example are more likely to have left-sided colon cancers.) A 2000 study reported a decline in left-sided colon cancer with increased use of sigmoidoscopy screening, but also indicated that further declines would occur if widespread colonoscopy were used. Two studies in 2000 suggested that sigmoidoscopy is likely to miss growths in as many as 20% to 30% of those who have them. A landmark 1993 study reported an approximate 90% reduction in colorectal cancers in patients with pre-cancerous 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. While it is clear that colonoscopy is more sensitive than other methods for detecting colon cancer, it has a higher rate of complications and cost. Most polyps found during an examination are not cancerous. It is not cost efficient to use colonoscopy as standard screening for everyone over 50, but some experts now recommend that it be routine for any high-risk and older patients. Guidelines for Increased-Risk Groups Groups at increased risk include the following: Men of African descent (particularly from sub-Sahara Africa). Men with first-degree relatives diagnosed with colon cancer younger than 60. 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). Guidelines for High-Risk Groups The following guidelines may be specifically useful for high-risk groups. People with a family history of FAP. DRE and colonoscopy beginning at age 10. Consider genetic testing. People with a family history of HNPCC. The same tests as those with FAP performed beginning at age 21 (some recommend adolescence). (It should be noted that colonoscopy should always be used in this group. About 72% of hereditary nonpolyposis colorectal cancers are out of the view of a sigmoidoscope.) 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. One 2000 study indicated that screening, particularly with colonoscopy, in this population can significantly save lives. For example, a 2000 study concluded that colonoscopy can reduce risk of colorectal cancer and death in individuals at risk for HNPCC by up to 65%. 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)

he 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 and will only detect a minority of cancers.

Fecal Occult Blood Tests (FOBT)

Blood in bowel movements is not always visible, in which case it is called occult blood. Fecal occult blood tests (FOBT) 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. Some experts argue that FOBTs miss too many cancers and should not be relied on. Controversy has been on-going as to whether this test is too inaccurate to be very beneficial, both in missing cancers and in showing false positive results that lead to invasive and expensive tests, most of which turn out to be unnecessary. Large studies, however, have indicated that this simple test does indeed save lives and may reduce the risk of dying from colon cancer by 15% to 33%.

The following may affect results:

• 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) show 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 fiberoptic tube through regions of the rectum and colon to view the walls of the intestine. 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. This is not possible using a barium enema.

Sigmoidoscopy. Sigmoidoscopy examines the rectum and the lower two feet of the colon. It cannot detect right-colon cancers.

• The procedure employs a flexible fiberoptic tube that contains a tiny camera and surgical instruments.
  
  
• It lasts about 10 minutes and may be mildly uncomfortable, but it is not painful. 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. A colonoscopy, as with sigmoidoscopy, 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 solution that essentially cleans out the colon. Patients often complain about the taste of the solution.
  
  
• 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 should be noted 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).

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.

Experimental Screening and Diagnostic Methods

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. This may become a widely used tool in the future, however larger clinical studies are needed.

Virtual Colonoscopy. Another promising experimental technique called virtual colonoscopy allows three-dimensional imaging of the colon without using invasive instruments. The procedure involves pumping air into the colon and scanning it using computed tomography (CT). The procedure is very safe and takes only 10 minutes. This 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, 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.

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 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 (elevated substances usually found in blood samples) that will assist in 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 this technique 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 are a protein called GLUT1, cancer antigen 19-9 (CA 19-9), matrix metalloproteinase-9 (MMP-9) RNA, HER-2/neu oncoprotein, and CD44, however their role is unknown and they should not be used outside the setting of a clinical study.

HOW SERIOUS ARE COLON AND RECTAL CANCERS?

About 57,000 people are expected to die from colorectal cancers in 2001. Only lung cancer is responsible for more cancer deaths. This occurs despite the fact that colorectal cancer is almost always a preventable or curable disease when proper screening is used.

Survival Rates

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%.

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. It is important to note that 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. According to a 2000 study, the more often colon cancer surgery is performed at a given hospital, the lower the mortality rate at that hospital is likely to be. 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

For larger Stage I lesions, or for cancers that have gone beyond the mucous membrane and have penetrated into or through the intestinal wall, an operation known as colectomy is the standard treatment. Colectomy involves removing the cancerous part of the colon and nearby lymph nodes and then reconnecting 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 open procedure involves an abdominal incision and is the standard method for performing colectomy. Laparoscopy is a more recent and investigative approach. It employs a few small incisions through which the surgeon passes a fiber optic tube containing a small camera or tiny instruments. When performed by an experienced surgeon, laparoscopy for selected patients may be equal to open surgery in effectiveness. One study suggested that patients in early stages with any tumors less than 2 centimeters or with well-defined tumors less the 3 centimeters might be candidates for laparoscopic colon surgery. This procedure is still under investigation, however, and should only be performed in clinical trials or in special circumstances by experienced surgeons.

Colostomy

A colostomy connects the colon to a hole through the abdominal wall, called a stoma, through which the feces are eliminated. A colostomy may 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. Patients must learn how to care for the stoma and keep the area sanitary.

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. Men tend to have more emotional difficulties dealing with permanent colostomies than women do. In one study, the four major concerns after treatment were the following:

(1) Fear of being unable to take care of themselves.

(2) Leakage from the pouch, odor, and gas.

(3) Other health problems.

(4) Recurrence of cancer.

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. Another treatment for early-stage rectal cancer, electrocoagulation (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 underway 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. Studies have also suggested 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 pre-operative chemotherapy and radiation with TME is yielding promising long-term results and a low risk for local recurrence.

Side Effects and Psychological Repercussions

Side effects of colon surgery include:

• sexual dysfunction,
  
  
• irregular bowel movements,
  
  
• diarrhea,
  
  
• bladder complications,
  
  
• sense of urinary urgency, and
  
  
• fecal incontinence.

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. Colon cancer patients without a colostomy are at lower risk for these problems than patients with rectal cancer whose sphincter muscles are affected, but no one is immune to the psychological repercussions of cancer and its consequences. 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 II and stage III tumors (patients who are 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.
  
  
• 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 alone 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 uses for stage IV colon and rectal cancer are essentially the same and are discussed together.

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. A 1999 combined analysis of four studies showed a 30% reduction in death rate from the use of adjuvant chemotherapy in these cancer patients. A more recent 2001 survey, however, found no significant survival differences. In the study, 5-year survival was 74% with chemotherapy and 72% without it. The researchers believe that patients not treated with chemotherapy should have the same level of confidence as those given these agents. The decision whether to pursue chemotherapy for stage II disease should be made after careful discussion between the patient and his or her oncologist.

Although not yet known with certainty, some data suggest that specific Stage II patients may be at higher risk of recurrence and would theoretically benefit from adjuvant therapy. These include the 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. Among them are the following:

• A test that can detect genetic evidence of cancer cells in the lymph nodes of Stage II patients. Their presence would suggest the need for treatment.
  
  
• A test called the liver Doppler perfusion index (DPI), which measures blood flow to the liver. A high DPI score suggests liver involvement and therefore might indicate a need for more aggressive treatment.
  
  
• There are also many genetic markers that are being developed which may help identify patients at higher risk.

None of these methods, however, are ready to be used routinely to help make treatment decisions.

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. Current clinical trials are investigating whether the addition of new chemotherapy drugs (irinotecan, oxaliplatin, and antibody therapies) will improve cure rates over 5-FU and leucovorin along. However, 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. Chemotherapy in most studies offers a modest improvement in survival and often relieves symptoms. 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.

The following patients are unlikely to benefit from chemotherapy:

• 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 seek clinical trials with immunotherapies and other new chemotherapy drugs.

Specific Chemotherapy Agents

5-Fluorouracil (5-FU) with Leucovorin. Adjuvant therapy using 5-fluorouracil (5-FU) with leucovorin 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 serious 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. Research in Spain indicates that home chemotherapy programs can increase compliance and patient satisfaction. 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. Most patients tolerate 5-FU with leucovorin well, with manageable side effects.

Irinotecan. Irinotecan (Camptosar). Irinotecan 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 reported in 2000 have shown 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 this 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. Experts recommend careful monitoring and alternative methods for administrating the drugs.

Capecitabine. Capecitabine (Xeloda) is the first oral agent approved for metastatic colorectal cancer. It allows fewer days of hospitalization and side effects are manageable. Compared to standard therapy, capecitabine has demonstrated similar results, although combinations with 5-FU are being investigated.

Oxaliplatin. Oxaliplatin is variant of cisplatin, a widely used platinum-based chemotherapy drug. The drug appears to be active in some patients with metastatic colorectal cancer who have failed treatment with 5-FU and irinotecan. Oxaliplatin can cause a unique peripheral neuropathy (abnormal sensations in the hands and feet) that is exacerbated by exposure to cold. The drug has been widely used in Europe but was rejected for approval by the FDA in 2000. Many investigators objected to this decision, and current trials using oxaliplatin in stage II, III, and IV colon cancer are underway.

Raltitrexed. Raltitrexed (Tomudex) may be as effective and less toxic than the 5-FU and leucovorin combination. Preclinical studies indicate that raltitrexed and 5-FU may have additive or synergistic effects.

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.
  
  
• Diarrhea (very common with 5-FU).
  
  
• Temporary hair loss (usually minimal with 5-FU).