Colon Cancer

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Definition

Cancer of the colon is the disease characterized by the development of malignant cells in the lining or epithelium of the first and longest portion of the large intestine. Malignant cells have lost normal control mechanisms governing growth. These cells may invade surrounding local tissue, or they may spread throughout the body and invade other organ systems.

Synonyms for the colon include the large bowel or the large intestine. The rectum is the continuation of the large intestine into the pelvis that terminates in the anus.

Description

The colon is a tubular organ beginning in the right lower aspect of the abdomen. Anatomically, it ascends on the right side of the abdomen, traverses from right to left in the upper abdomen, descends vertically down the left side, takes an S-shaped curve in the lower left abdomen, and then flows into the rectum as it leaves the abdomen for the pelvis. These portions of the colon are named separately though they are part of the same organ:

• cecum, the beginning of the colon
• ascending colon, the right vertical ascent of the colon
• transverse colon, the portion traversing from right to left
• descending colon, the left vertical descent of the colon
• sigmoid colon, the s-shaped segment of colon above the pelvis

These portions of the colon are recognized anatomically based on the arterial blood supply and venous and lymphatic drainage of these segments of the colon. Lymph, a protein-rich fluid that bathes the cells of the body, is transported in small channels known as lymphatics that run along side the veins of the colon. Lymph nodes are small filters through which the lymph travels on its way back to the blood stream. Cancer can spread elsewhere in the body by invading the lymph and vascular systems. Therefore, these anatomic considerations become very important in the treatment of colon cancer.

The small intestine is the continuation of the upper gastrointestinal tract that is responsible for the transport of ingested nutrients into the body. The waste left after the small intestine has completed absorption of nutrients amounts to a few liters (about the same as quart) of material per day and is directly delivered to the colon (at the cecum) for processing. Physiologically, the colon is responsible for the preservation of fluid and electrolytes as it propels the increasingly solid waste towards the rectum and anus for excretion.

When cells lining the colon become malignant, they first grow locally and may invade partially or totally through the wall of the bowel and even into adjacent structures and organs. In the process, the tumor can penetrate and invade the lymphatics or the capillaries locally and it gains access to the circulation. As the malignant cells work their way to other areas of the body, they again become locally invasive in the new area to which they have spread. These tumor deposits, originating in the colon primary tumor, are then known as metastases. If metastases are found in the regional lymph nodes from the primary, they are known as regional metastases or regional nodal metastases. If they are distant from the primary tumor, they are known as distant metastases. The patient with distant metastases has systemic disease. Thus the cancer originating in the colon begins locally and, given time, can become systemic in its extent.

By the time the primary is originally detected, it is usually larger than 0.4 in (1 cm) in size and has over a million cells. This amount of growth itself is estimated to take about three to seven years. Each time the cells double in number, the size of the tumor quadruples. Thus, like most cancers, the part that is identified clinically is later in the progression than would be desired and screening becomes a very important endeavor to aid in earlier detection of this disease.

There are about 94,000 cases of colon cancer diagnosed per year in the United States. Together, colon and rectal cancers account for 10% of cancers in men and 11% of cancers in women. It is the second most common site-specific cancer affecting both men and women. (Lung cancer is the first affecting both men and women, breast is the leader in women and prostate the leader in men.) Nearly 48,000 people died from colon cancer in the United States in 2000. In recent years the incidence of this disease is decreasing very slightly, as has the mortality rate. It is difficult to tell if the decrease in mortality reflects earlier diagnosis, less death related to the actual treatment of the disease, or a combination of both factors.

Cancer of the colon is thought to arise sporadically in about 80% of those who develop the disease. Twenty percent of cases are thought to have genetic predisposition that ranges from familial syndromes affecting 50% of the offspring of a mutation carrier, to a risk of 6% when there is just a family history of colon cancer occurring in a first degree relative. Development of colon cancer at an early age, or at multiple sites, or recurrent colon cancer suggests a genetically transmitted form of the disease as opposed to the sporadic form.

— Richard A. McCartney, MD

Key Terms: Adenocarcinoma, Adjuvant therapy, Anastomosis, Anemia, Carcinogens, Electolytes, Epithelium, Lymphatics, Lymph nodes, Malignant, Metastasis, Mutation, Occult blood, Polyps, Radical resection, Resect, Sacrum.

Definition

Cancer of the colon is the disease characterized by the development of malignant cells in the lining or epithelium of the first and longest portion of the large intestine. Malignant cells have lost normal control mechanisms governing growth. These cells may invade surrounding local tissue or they may spread throughout the body and invade other organ systems.

Synonyms for the colon include the large bowel or the large intestine. The rectum is the continuation of the large intestine into the pelvis that terminates in the anus.

Description

The colon is a tubular organ beginning in the right lower abdomen. It ascends on the right side of the abdomen, traverses from right to left in the upper abdomen, descends vertically down the left side, takes an S-shaped curve in the lower left abdomen, and then flows into the rectum as it leaves the abdomen for the pelvis. These portions of the colon are named separately though they are part of the same organ.

• cecum, the beginning of the colon
• ascending colon, the right vertical ascent of the colon
• transverse colon, the portion traversing from right to left
• descending colon, the left vertical descent of the colon
• sigmoid colon, the s-shaped segment of colon above the pelvis

These portions of the colon are recognized anatomically based on the arterial blood supply and venous and lymphatic drainage of these segments of the colon. Lymph, a protein-rich fluid that bathes the cells of the body, is transported in small channels known as lymphatics that run alongside the veins of the colon. Lymph nodes are small filters through which the lymph travels on its way back to the bloodstream. Cancer can spread elsewhere in the body by invading the lymph and vascular systems. Therefore, these anatomic considerations become very important in the treatment of colon cancer.

The small intestine is the continuation of the upper gastrointestinal tract responsible for carrying ingested nutrients into the body. The waste left after the small intestine has completed absorption of nutrients amounts to a few liters, (about the same as quart), of material per day and is directly delivered to the colon, (at the cecum), for processing. The colon is responsible for the preservation of fluid and electrolytes as it propels the increasingly solid waste toward the rectum and anus for excretion.

When cells lining the colon become malignant, they first grow locally and may invade partially or totally through the wall of the bowel and even into adjacent structures and organs. In the process, the tumor can penetrate and invade the lymphatics or the capillaries locally and gain access to the circulation. As the malignant cells work their way to other areas of the body, they again become locally invasive in the new area to which they have spread. These tumor deposits, originating from the colon primary tumor, are then known as metastases. If metastases are found in the regional lymph nodes from the primary, they are known as regional metastases, or regional nodal metastases. If they are distant from the primary tumor, they are known as distant metastases. The patient with distant metastases has systemic disease. Thus the cancer originating in the colon begins locally and, given time, can become systemic.

By the time the primary tumor is originally detected it is usually larger than one cm (about 3/8 in) in size and has over one million cells. This amount of growth itself is estimated to take about three–seven years. Each time the cells double in number, the size of the tumor quadruples. Thus like most cancers, the part that is identified clinically is later in the progression than would be desired and screening becomes a very important endeavor to aid in earlier detection of this disease.

Demographics

There are at least 100,000 cases of colon cancer diagnosed per year in the United States. Together, colon and rectal cancers account for 10% of cancers in men and 11% of cancers in women. It is the second most common site-specific cancer affecting both men and women. A 2003 study reported that for unknown reasons, women are more likely to have advanced colon cancer at diagnosis than men. Nearly 57,000 people died from colon and rectal cancer in the United States in 2003. In recent years the incidence of this disease has decreased slightly, as has the mortality rate. It is difficult to tell if the decrease in mortality reflects earlier diagnosis, less death related to the actual treatment of the disease, or a combination of both factors.

Cancer of the colon is thought to arise sporadically in about 80% of those who develop the disease. Twenty percent of people are thought to have genetic predisposition, meaning their genes carry a trigger for the disease. Development of colon cancer at an early age, or at multiple sites, or recurrent colon cancer, suggests a genetically transmitted form of the disease as opposed to the sporadic form.

Causes and Symptoms

Causes

Causes of colon cancer often are environmental in sporadic cases (80%) and sometimes genetic (20%). Since malignant cells have a changed genetic makeup, this means that in 80% of cases, the environment spontaneously induces change, whereas those born with a genetic predisposition are either destined to get the cancer or less environmental exposure can induce the cancer. Exposure to agents in the environment that may induce mutation is the process of carcinogenesis and is caused by agents known as carcinogens (cancer-causing agents). Specific carcinogens have been difficult to identify; however, dietary factors seem to be involved.

Colon cancer is more common in industrialized nations. Diets high in fat, red meat, total calories, and alcohol seem to predispose people to the disease. Diets high in fiber appear to decrease risk. High-fiber diets may help lessen exposure of the colon lining to carcinogens from the environment, as the transit time through the bowel is faster with a high-fiber diet than it is with a low fiber diet.

Age plays a definite role in the predisposition to colon cancer. Two-thirds of all cases occur after age 50 and the average age for those who develop the disease is 62.

There is also a slight increase risk for colon cancer in the individual who smokes.

Patients who suffer from inflammatory diseases of the colon known as ulcerative colitis and Crohn's colitis are also at increased risk.

Researchers know there is a genetic link to many cases of colon cancer, those called familial cases. This is the type of colon cancer that tends to run in families. In late 2003, a team of researchers identified the specific location on a human chromosome by analyzing blood samples from 53 families in which at least one member had a colon cancer or precancerous colon polyp. At least 200 genes exist on the location of chromosome 9, however, so the research will continue to identify the particular gene responsible for the cancer.

The development of polyps of the colon almost always precedes the development of colon cancer by five or more years. Polyps are benign growths of the colon lining. They can be unrelated to cancer, precancerous, or malignant. Polyps, when identified, are removed for diagnosis. If the polyps are benign, the patient should undergo careful surveillance for the development of more polyps or the development of colon cancer.

Symptoms

Colon cancer causes symptoms related to its local presence in the large bowel or by its effect on other organs if it has spread. These symptoms may occur alone or in combination:

• a change in bowel habit
• blood in the stool
• bloating, persistent abdominal distention
• constipation
• a feeling of fullness even after having a bowel movement
• narrowing of the stool—so-called ribbon stools
• persistent, chronic fatigue
• abdominal discomfort
• unexplained weight loss
• and, very rarely, nausea and vomiting

Most of these symptoms are caused by the physical presence of the tumor mass in the colon. Similar symptoms can be caused by other processes; these are not absolutely specific to colon cancer. The key is recognizing that the persistence of these types of symptoms without ready explanation should prompt the individual to seek medical evaluation.

If a tumor develops in the colon, it will begin to cause symptoms as it reaches a certain size. The symptoms are caused by the tumor blocking the opening in the colon. In addition, the tumor commonly oozes blood that is lost in the stool. (Often, this blood is not visible.) This results in anemia and chronic fatigue. Weight loss is a late symptom, often implying substantial obstruction or the presence of systemic disease.

Diagnosis

Screening

In all other cancers (breast and prostate, for example), screening tests look for small, malignant lesions. Screening for colorectal cancers, however, is the search for pre-malignant, benign polyps. This screening can be close to 100% effective in preventing cancer development, not just in detecting small cancers.

Screening involves physical exam, simple laboratory tests, and the visualization of the lining of the colon. To visualize the colon epithelium, clinicians use with x rays (indirect visualization) and endoscopy (direct visualization).

The physical examination involves the performance of a digital rectal exam (DRE). The DRE includes manual examination of the rectum, anus and the prostate. During this examination, the physician examines the anus and the surrounding skin for hemorrhoids, abscesses, and other irregularities. After lubricating the gloved finger and anus, the examiner gently slides the finger into the anus and follows the contours of the rectum. The examiner notes the tone of the anus and feels the walls and the edges for texture, tenderness and masses as far as the examining finger can reach. At the time of this exam, the physician checks the stool on the examining glove with a chemical to see if any occult (invisible), blood is present. At home, after having a bowel movement, the patient is asked to swipe a sample of stool obtained with a small stick on a card. After three such specimens are on the card, the card is then easily chemically tested for occult blood also. (The stool analysis mentioned here is known as a fecal occult blood test, or FOBT, and, while it can be helpful, it is not 100% accurate—only about 50% of cancers are FOBT-positive.) These exams are accomplished as an easy part of a routine yearly physical exam.

Proteins are sometimes produced by cancers and these may be elevated in the patient's blood. When this occurs, the protein produced is known as a tumor marker. There is a tumor marker for some cancers of the colon; it is known as carcinoembryonic antigen, or CEA. Unfortunately, this protein may be made by other adenocarcinomas as well, or it may not be produced by a particular colon cancer. Therefore, screening by chemical analysis for CEA has not been helpful. CEA has been helpful when used in a follow-up role for patients treated for colon cancer if their tumor makes the protein.

Indirect visualization of the colon may be accomplished by placing barium through the rectum and filling the colon with this compound. Barium produces a white contrast image of the lining of the colon on x ray and thus the contour of the lining of the colon may be seen. Detail can be increased if the barium utilized is thinned and air also introduced. These studies are known as the barium enema (BE), and the double contrast barium enema (DCBE).

Direct visualization of the colon lining is accomplished using a scope or endoscope. The physician introduces the instrument through the rectum. Older, shorter scopes were rigid. Today, utilizing fiberoptic technology, the scopes are flexible and can reach much farther. If the left colon only is visualized, it is called flexible sigmoidoscopy. When the entire colon is visualized, the procedure is known as colonoscopy.

A procedure called virtual colonoscopy has been developed but debate continues on whether or not it is effective as colonoscopy. Virtual colonoscopy refers to the use of imaging, usually with computed tomography (CT) scans or magnetic resonance imaging (MRI) to produce images of the colon. Studies in late 2003 showed that virtual colonoscopy was as effective as colonoscopy for screening purposes and it offered the advantage of being less invasive and less risky. However, many physicians were unwilling to accept it as a replacement for colonoscopy, particularly since some patients might still require the regular colonoscopy as a follow-up to the virtual procedure if a polyp or abnormality is found that requires biopsy.

Unlike the indirect visualizations of the colon (the BE and the DCBE), the endoscopic screenings allow the physician to remove polyps and biopsy suspicious tissue. (A biopsy is a removal of tissue for examination by a pathologist.) For this reason, many physicians prefer endoscopic screening. All of the visualizations, the BE, DCBE, and each type of endoscopy, require pre-procedure preparation (evacuation) of the colon.

The American Cancer Society has recommended the following screening protocol for those at normal risk over 50 years of age:

• yearly fecal occult blood test
• flexible sigmoidoscopy at age 50
• flexible sigmoidoscopy repeated every 5 years
• double contrast barium enema every five years
• colonoscopy every 10 years The American Gastroenterologial Association revised its screening guidelines in 2003 to recommend that people with two or more first-degree relatives with colorectal cancer or a first-degree relative with colon or rectal cancer before age 60 should have a screening colonoscopy beginning at age 40 or beginning 10 years prior to the age of the earlier colon cancer diagnosis in their family (whichever is earliest). Those with a first-degree relative diagnosed with colon cancer after age 60 or two second-degree relative with colon or rectal cancer should begin screening at age 40 with one of the methods listed above, such as annual sigmoidoscopy.

Evaluation of Patients With Symptoms

If patients have symptoms that could possibly be related to colon cancer, the entire colon will be examined. The combination of a flexible sigmoidoscopy and DCBE may be performed, but the preferred evaluation of the entire colon and rectum is a complete colonoscopy. Colonoscopy allows direct visualization, photography, and the opportunity to obtain a biopsy of any abnormality visualized. If, for technical reasons, the entire colon is not visualized endoscopically, a DCBE should complement the colonoscopy.

The diagnosis of colon cancer is actually made by the performance of a biopsy of any abnormal lesion in the colon. When a tumor growth is identified, it could be either a benign polyp (or lesion) or a cancer; the biopsy resolves the issue. The endoscopist may take many samples to exclude any sampling errors.

If the patient has advanced disease at the time of diagnosis, areas where the tumor has spread (such as the liver) may be amenable to biopsy. Such biopsies are usually obtained using a special needle under local anesthesia.

Once a diagnosis of colon cancer has been established by biopsy, in addition to the physical exam, studies will be performed to assess the extent of the disease. Blood studies include a complete blood count, liver function tests, and a CEA. Imaging studies will include a chest x ray and a CAT scan (computed tomography scan) of the abdomen. The chest x ray will determine if the cancer has spread to the lung, the CAT scan will evaluate potential spread to the liver as well as any local spread of the primary tumor. If the patient has any neurologic symptoms, a CAT scan of the brain will be performed, and if the patient is experiencing bone pain, a bone scan also will be performed.

Treatment Team

The surgeon and the medical oncologist each have a role in therapy that is dictated by the degree of progression of the disease. A radiation oncologist may also play a role on the team; however, radiation treatment is rare in colon cancer.

Clinical Staging, Treatments, and Prognosis

Clinical Staging

Once the diagnosis has been confirmed by biopsy, the clinical stage of the cancer is assigned. Using the characteristics of the primary tumor, its depth of penetration through the bowel, and the presence or absence of regional or distant metastases, stage is derived. Often, the depth of penetration through the bowel or the presence of regional lymph nodes can't be assigned before surgery.

Colon cancer is assigned stages I through IV, based on the following general criteria:

• Stage I: the tumor is confined to the epithelium or has not penetrated through the first layer of muscle in the bowel wall.
• Stage II: the tumor has penetrated through to the outer wall of the colon or has gone through it, possibly invading other local tissue.
• Stage III: Any depth or size of tumor associated with regional lymph node involvement.
• Stage IV: any of previous criteria associated with distant metastasis.

With many cancers other than colon cancer, staging plays an important pre-treatment role to best determine treatment options. Almost all colon cancers are treated with surgery first, regardless of stage. Colon cancers through Stage III, and even some Stage IV colon cancers, are treated with surgery first, before any other treatments are considered.

Treatments

Surgery

Surgical removal of the involved segment of colon (colectomy) along with its blood supply and regional lymph nodes is the primary therapy for colon cancer. Usually, the partial colectomies are separated into right, left, transverse, or sigmoid sections based on the blood supply. The removal of the blood supply at its origin along with the regional lymph nodes that accompany it ensures an adequate margin of normal colon on either side of the primary tumor. When the cancer lies in a position such that the blood supply and lymph drainage between two of the major vessels, both vessels are taken to assure complete radical resection or removal (extended radical right or left colectomy). If the primary tumor penetrates through the bowel wall, any tissue adjacent to the tumor extension is also taken if feasible.

Surgery is used as primary therapy for stages I through III colon cancer unless there are signs that local invasion will not permit complete removal of the tumor, as may occur in advanced stage III tumors. However, this circumstance is rare, occurring in less than 2% of all colon cancer cases.

After the resection is completed, the ends of the remaining colon are reconstructed; the hook-up is called an anastomosis. Once healing has occurred, there may be a slight increase in the frequency of bowel movements. This effect usually lasts only for several weeks. Most patients go on to develop completely normal bowel function.

Occasionally, the anastomosis is risky and cannot be performed. When the anastomosis cannot be performed, a colostomy is performed instead. A colostomy is performed by bringing the end of the colon through the abdominal wall and sewing it to the skin. The patient will have to wear an appliance (a bag) to manage the stool. The colostomy may be temporary and the patient may undergo a hook-up at a later, safer date, or the colostomy may be permanent. In most cases, emergent colostomies are not reversed and are permanent.

RADIATION Radiation therapy is used as an adjunct to surgery if there is concern about potential for local recurrence post-operatively and the area of concern will tolerate the radiation. For instance, if the tumor invaded muscle of the abdominal wall but was not completely removed, this area would be considered for radiation. Radiation has significant dose limits when residual bowel is exposed to it because the small and large intestine do not tolerate radiation well.

Radiation also is used in the treatment of patients with metastatic disease. It is particularly useful in shrinking metastatic colon cancer to the brain.

CHEMOTHERAPY Chemotherapy is useful for patients who have had all identifiable tumor removed and are at risk for recurrence (adjuvant chemotherapy). Chemotherapy may also be used when the cancer is stage IV and is beyond the scope of regional therapy, but this use is rare.

Adjuvant therapy is considered in stage II disease with deep penetration or in stage III patients. Standard therapy is treatment with fluorouracil, (5FU) combined with leucovorin for a period of 6 to 12 months. 5FU is an antimetabolite and leukovorin improves the response rate. (A response is a temporary regression of the cancer from chemotherapy.) Another agent, levamisole, (which seems to stimulate the immune system), may be substituted for leucovorin. These protocols reduce rate of recurrence by about 15% and reduce mortality by about 10%. The regimens do have some toxicity but usually are tolerated fairly well.

Similar chemotherapy may be administered for stage IV disease or if a patient progresses and develops metastases. Results show response rates of about 20%. Unfortunately, these patients eventually succumb to the disease, and this chemotherapy may not prolong survival or improve quality of life in Stage IV patients. Clinical trials have now shown that the results can be improved with the addition of another agent to this regimen. Irinotecan does not seem to increase toxicity but it improved response rates to 39%, added 2-3 months to disease-free survival, and prolonged overall survival by a little over two months. If the cancer is detected early, surgical removal of the tumor can lead to complete cure in 75%–90% of patients.

Prognosis

Prognosis is the long-term outlook or survival after therapy. Overall, about 50% of patients treated for colon cancer survive the disease. As expected, the survival rates are dependent upon the stage of the cancer at the time of diagnosis, making early detection crucial.

About 15% of patients present with stage I disease and 85-90% survive. Stage II represents 20-30% of cases and 65-75% survive. 30-40% comprise the stage III presentation of which 55% survive. The remaining 20-25% present with stage IV disease and are rarely cured.

Alternative and Complementary Therapies

Alternative therapies have not been studied in a large-scale, scientific way. Large doses of vitamins, fiber, and green tea are among therapies tried. Avoiding cigarettes and alcohol may be helpful. Before initiating any alternative therapies, the patient is wise to consult his or her physician to be sure that these therapies do not complicate or interfere with the established therapy.

Coping With Cancer Treatment

For those with familial syndromes causing colon cancer, genetic counseling may be appropriate. Psychological counseling may be appropriate for anyone having trouble coping with a potentially fatal disease. Local cancer support groups may be helpful and are often identified by contacting local hospitals or the American Cancer Society.

The Colon Cancer Alliance offers internet online support at the following web page: .

Clinical Trials

Clinical trials are scientific studies in which new therapies are compared to current standards in an effort to identify therapies that give better results.

Agents being tested for efficacy in patients with advanced disease include oxaliplatin and CPT-11. Please see reference below for current information available from the National Cancer Institute regarding these clinical trials.

Prevention

There is not an absolute method for preventing colon cancer. Still, there are steps an individual can take to dramatically lessen the risk or to identify the precursors of colon cancer so that it does not manifest itself. The patient with a familial history can enter screening and surveillance programs earlier than the general population. High-fiber diets and vitamins, avoiding obesity, and staying active lessen the risk. Avoiding cigarettes and alcohol may be helpful. By controlling these environmental factors, an individual can lessen risk and to this degree prevent the disease.

People who turn age 50, and all of those with a history of colon cancer in their families, should speak with their physicians about the most recent screening recommendations from physician and cancer organizations. They should watch for symptoms and attend all recommended screenings to increase the likelihood of catching colon cancer early.

Special Concerns

Polyps are growths of the epithelium of the colon. They may be completely benign, premalignant or cancerous. The association of colon cancers in patients with certain types of polyps is such that it is thought that many polyps begin as a benign growth and later acquire malignant characteristics. There are two types of polyps, pedunculated and sessile. This terminology comes from their appearance; those that are pedunculated are on a stalk like a mushroom, and the sessile polyps are broad based and have no stalk. Unless a pedunculated polyp gets large, malignant potential is very small. This type may also be easily removed at colonoscopy, by a snaring technique. (A snare is like a lasso introduced through the endoscope to encircle the polyp at its base and amputate it.) The sessile polyp is also known as a villous adenoma and as many as 1/3 of these harbor a malignancy. Therefore, the villous adenoma is considered premalignant. Sessile polyps may or may not be able to be managed with the colonoscope and may need surgical removal because of their pre-malignant nature.

Polyps commonly present with occult blood in the stool. Since they are associated with the development of cancer, patients who have developed polyps need to enter a program of careful surveillance.

There is an occasional patient who develops a pattern of metastatic disease that is isolated to either the liver or the lung and the deposit appears to be solitary. When patients have this type of pattern of metastatic disease, especially if there has been a long interval between the primary management and the development of metastasis, they may be considered for surgical resection of the isolated metastasis to effect a cure. In carefully selected patients, long-term survival approaching 20% has been achieved.

When a patient has developed metastatic cancer in the liver alone, a technique of administering chemotherapy directly to the liver is sometimes considered. This is called hepatic arterial infusion and requires the placement of a special device into the artery supplying the liver. This method of utilizing chemotherapy has been helpful in carefully selected patients only, and currently is not used as a cure.

Resources

Books

Abelhoff, Martin, MD, James O. Armitage MD, Allen S. Lichter MD, and John E. Niederhuber MD. Clinical Oncology Library. Philadelphia: Churchill Livingstone, 1999.

Jorde, Lynn B., PhD, John C. Carey MD, Michael J. Bamshad MD, and Raymond L. White, PhD. Medical Genetics. 2nd ed. St. Louis: Mosby, 1999.

Periodicals

"Colon Cancer; Facts to Know." NWHRC Health Center December 15, 2003.

Golden, William E., and Robert H. Hopkins. "Colon Cancer Screening 2003." Internal Medicine News 36 (December 1, 2003): 46.

Greenlee, Robert T., MPH, Mary Beth Hill-Harmon, Taylor Murray, and Michael Thun. "Cancer Statistics 2001." CA: A Cancer Journal for Clinicians 51, no. 1 (January-February 2001).

"Professional Organization Recommends Standard Colonoscopy Over Virtual." Biotech Week December 31, 2003: 422.

"Researchers Discover New Genetic Link to Common Colon Cancer." Genomics & Genetics Weekly November 7, 2003: 29.

Saltz, Leonard, et al. "Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer." The New England Journal of Medicine 343, no. 13 (September 28, 2000).

"Study Shows Virtual Colonoscopy as Effective as Traditional Colonoscopy." Biotech Week December 31, 2003.

Wachter, Kerri. "Reasons Unclear for Later Colon Cancer Diagnosis in Women: Regional or Distant Disease More Likely." Internal Medicine News 36 (December 1, 2003).

Organizations

American Cancer Society. (800) ACS-2345. .

Cancer Information Service of the NCI. (1-800-4-CANCER). .

Colon Cancer Alliance. .

National Cancer Institute Cancer Trials. . .

—Richard A. McCartney, M.D.; Teresa G. Odle

Definition

Colorectal cancer is a malignancy of the colon (bowel) and/or rectum. It is the second most common cause of cancer-related death in the United States, and is diagnosed in more than 130,000 new patients annually.

Description

Colorectal cancer occurs in either the last 6 ft (1.8 m) of intestine, known as the large bowel or colon, and/or in the rectum, where the colon terminates and waste (feces) leaves the body. The majority of malignancies that occur in colorectal cancers are called adenocarcinomas. When an individual develops colorectal adenocarcinomas, malignant cancer cells grow inside the colon and/or the rectum. Large clusters of these cells form structures known as tumors.

Causes & Symptoms

Causes & Risk Factors

The exact cause of colorectal cancer is unknown. However, there are a number of known risk factors that increase the odds for developing the disease. They include:

• Family history. Individuals who have one or more close relatives that were diagnosed with colorectal cancer may be at increased risk for the disease. In 2003, research showed that about 5% of colorectal cancer patients had inherited syndromes.
• History of bowel disease and/or colon polyps. Certain types of colon polyps, which are tumor-like, benign outgrowths of tissue within the colon, may act as an early warning sign of or a precursor to colorectal cancer. They may develop into malignancies later in life. Colon diseases that cause inflammation and irritation of the bowel, such as Crohn's disease and inflammatory bowel disease, also can increase an individual's risk of developing a colorectal malignancy.
• Obesity. Overweight individuals, especially those with an apple-shaped body type (where fat is concentrated around the waist) as opposed to a pear-shaped body (where fat is stored in the hips and thighs), are at an increased risk for colorectal cancer. A high fat diet also increases an individual's chance of developing colorectal cancer.
• Age. Individuals over age 50 are at an increased risk for colorectal cancer.
• Sedentary lifestyle. A moderate exercise program is thought to have a preventive effect against cancer.
• Night work. A 2003 study showed that working the night shift actually may increase risk of colorectal cancer in women. Exposure to light at night suppresses the body's natural production of melatonin, a hormone that helps keep certain intestinal cancers from proliferating.

Symptoms

Symptoms of colorectal cancer include:

• blood on the rectum or in the stool
• feelings of fecal urgency (feeling as if one has to have a bowel movement all the time)
• stomach and/or abdominal pain
• changes in bowel habits, including constipation, diarrhea, and/or pencil-thin stools
• extreme fatigue
• decreased appetite

Diagnosis

The simplest screening tests for colorectal cancer include a digital rectal exam and a fecal occult blood test (FOBT). In the digital rectal exam, a physician inserts a gloved finger into the rectum and feels for any irregularities. In the FOBT, stool samples are tested for traces of blood. The test can be done at home and sent to a lab for analysis. FOBT can reduce the death rate by about 33%. Unfortunately, in the United States, over the past six years less than 35% of the population had received a FOBT.

A flexible sigmoidoscopy and/or a colonoscopy may be performed to view the interior of the colon. The former examines the rectum and lower colon for cancer, and the latter examines the full length of the colon. During these procedures, a doctor passes a flexible tube with a tiny, fiber-optic camera device (an endoscope) through the rectum and into the colon. The doctor can carefully examine the lining of the intestine for signs of cancer. A tissue sample (a biopsy) of the colon also can be taken through the endoscope to examine under a microscope for evidence of malignancy. Both tests can cause discomfort, and may be done under a local anesthetic if desired.

A lower GI (gastrointestinal) x-ray series can be helpful in determining how much of the intestine is involved in the disease. A chalky solution called barium, which acts as a contrast agent to illuminate the gastrointestinal tract on x-ray film, is administered in enema form to the patient. In some cases, air also is pumped into the rectum to provide a clearer view of the large intestine. This is called a double-contrast barium enema. The pressure in the patient's abdomen from the air and barium contrast likely will cause some discomfort.

After colorectal cancer is diagnosed, further testing is required to determine how far the cancer has spread. This procedure is known as staging. There are five different stages of colorectal cancer:

• Stage 0 (carcinoma in situ). This is the earliest stage of colorectal cancer, and indicates that cancerous cells have not spread beyond the colon lining.
• Stage I. The cancer has spread to the second and third layers of the inside wall of the colon, but is still contained within the colon.
• Stage II. The cancer has spread beyond the colon, but has not spread to the lymph nodes.
• Stage III. The cancer has spread to a nearby lymph node, but has not spread throughout the body.
• Stage IV. The cancer has spread throughout the body.

There is a sixth subtype of cancer, called recurrent, which is used to classify colorectal cancer that was treated, seemed to resolve, and has now recurred either in the colon or in another part of the body.

Treatment

The best chance for successful treatment is to detect colorectal cancer early. Colorectal cancer is a life-threatening disease, and a correct diagnosis and appropriate treatment with surgery, chemotherapy, and/or radiation is critical to controlling the illness.

Acupuncture and guided imagery may be useful tools in treating pain symptoms and improving immune function associated with colorectal cancer. Acupuncture involves the placement of a series of thin needles into the skin at targeted locations on the body, known as acupoints, in order to harmonize the energy flow within the human body.

Guided imagery involves creating a visual mental image of pain as a means of relaxation. Once the pain can be visualized, the patient can adjust the image to make it more pleasing, and thus more manageable, to them.

Movement therapies, such as yoga, t'ai chi, and qigong can aid the recovering patient. They may lessen pain symptoms, and help the person to relax and reduce stress.

A number of herbal remedies also are available to lessen pain symptoms and promote relaxation and healing. However, cancer patients should consult with their healthcare professional before taking them. Depending on the preparation and the type of herb, these remedies may interact with or enhance the effects of other prescribed medications. Herbs that promote healing of the digestive tract include slippery elm bark (Ulmus rubra), marsh mallow root (Althaea officinalis), and goldenseal (Hydrastis canadensis).

Allopathic Treatment

Treatment options include surgery, chemotherapy, and radiation. Colorectal cancer is treated in two ways, locally to eliminate tumor cells from the colon by surgery and radiation, and to systemically destroy cancer cells that have traveled to other parts of the body. Systemic therapy includes the use of chemotherapy drugs.

Surgery

The extent of surgery depends on the type of colorectal cancer, whether the disease has spread, and the patient's age and health. A surgical procedure known as a bowel resection is performed for colon cancers, where the length of colon containing the cancerous cells is removed, along with nearby tissues and lymph nodes. The two ends of the remaining colon are then sewn back together.

For cancer affecting the rectum, several other surgical methods may be employed, including local excision of the cancer (where cancerous cells and nearby tissues are cut out of the rectum) and transanal resection, where invasive cancerous tissue is removed along with normal anal tissue.

Depending on the stage of the cancer and the degree of surgery required, some patients may need to get a colostomy. A colostomy involves surgically attaching the bowel to an opening in the abdominal wall where waste is eliminated into an attached bag.

The presence of cancer cells in the lymph nodes may require more extensive surgery. If the cancer has spread to the nodes, the patient will need either radiation, chemotherapy, hormone therapy, or a combination of all three after surgery. This is called "adjuvant therapy."

Radiation

Once the cancer has been removed, the doctor may recommend radiation treatment to destroy any remaining cancer cells. In cases where the cancer is located in hard to reach areas, radiation may be used to shrink the cancer growth or tumor. Radiation stops the cancer cells from dividing. It works especially well on fast-growing tumors. Unfortunately, it also stops some types of healthy cells from dividing. Healthy cells that divide quickly, like those of the skin and hair, are affected the most. This is why radiation can cause fatigue, skin problems, and hair loss.

Radiation therapy can be internal, where particles of radioactive materials are implanted into a tumor, or external, where energy rays (radiation) are directed at the cancer from outside the body. External radiation, the most common type of treatment for colorectal cancer, is usually administered five days a week for several weeks. Recent studies indicate that radiation therapy decreases the likelihood of local recurrence of colorectal cancer by a significant margin. Some clinicians argue that the therapy is most effective when given before surgery rather than after. No definitive clinical trials proved the most effective timing as of late 2001.

Chemotherapy

Colorectal cancer surgery may be followed by chemotherapy in even the earliest stages. Chemotherapy is administered either orally or by injection into a blood vessel. It is usually given in cycles, followed by a period of time for recovery, followed by another course of drugs. Treatment time may range between four and nine months. In the fall of 2001, the Food and Drug Administration (FDA) approved trials for a new vaccine to help treat colorectal cancer. Investigators planned to give the vaccine in conjunction with chemotherapy to help prevent recurrentce of the disease. In 2003, the FDA approved a new chemotherapy drug called Avastin to help fight metastatic spread of colorectal cancer.

Some types of chemotherapy produce significant side effects, including nausea and vomiting, temporary hair loss, mouth sores, skin rashes, fatigue, a weakened immune system, and infertility. However, most side effects are temporary and disappear once treatment has ended.

Expected Results

According to the American Cancer Society, colorectal cancers cause more than 56,000 deaths each year in the United States. However, the death rate for the disease has declined steadily over the past several decades, and since 1985, annual deaths due to colorectal cancer have declined at an average rate of 1.6% per year. Early detection is key to improved survival; patients with colorectal cancers detected early (at stage I) have a 96% survival rate. In comparison, patients who are diagnosed with stage IV colorectal cancer only have a 5% survival rate.

Prevention

Proper diet and exercise have been shown to help prevent many types of cancers, including colorectal cancer. Research published in 2003 confirmed the benefits of physical activity in reducing risk of colon and rectal cancers. A well-balanced diet consisting of a minimum of five servings of fruits and vegetables and six servings of food from other plant sources (i.e., cereals, grains, pastas) is recommended by the American Cancer Society. Additionally, patients may opt for a diet of whole foods. A number of fruits and vegetables have been shown to have antioxidant properties, and may be useful in preventing cancer. These include carotenoids, which are found in fruit pigments; flavenoids found in vegetable pigments; and particularly, lycopene, which is found in tomato juice.

Recent clinical studies also have indicated that regular use of green tea (produced from the Camellia sinensis plant) may reduce the risk of certain types of cancer, including colorectal cancers. Green tea contains polyphenols, an antioxidant substance that also may inhibit the growth of existing cancer cells. In some animal studies, injections of tea extracts reduced the size of cancerous tumors. The antioxidant effects of green tea need to be studied further to more clearly define the role of the herb in cancer treatment and prevention.

Because early detection is so critical to recovery from colorectal cancer, patients considered "at risk" for the disease due to genetic, lifestyle, or environmental factors should undergo regular screening after age 50 (and possibly before, depending on the individual's personal and medical history). The American Cancer Society recommends the following screening tests:

• an annual FOBT plus a flexible sigmoidoscopy every five years
• a colonoscopy every 10 years
• a double contrast barium enema every five to 10 years

A digital rectal exam also is recommended during each screening session.

Resources

Books

Fauci, Anthony S., et al., eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998.

Holmes, Nancy H., ed. Illustrated Guide to Diagnostic Tests. 2nd ed. Springhouse, PA: Springhouse Corporation, 1997.

Periodicals

"Approximately 5% of Colorectal Cancer Patients Have Inherited Syndromes." Cancer Weekly (July 8, 2003): 83.

"Avastin Receives FDA Fast-track Designation for Metastatic Colorectal Cancer." Cancer Weekly (July 22, 2003): 50.

"Colorectal Cancer Patients Participate in Clinical Trial." Gene Therapy Weekly (November 14, 2001): 14.

"Fecal Occult Blood Testing for Colorectal Cancer Screening: Use the Finger." Internal Medicine Alert 23, no. 24 (Dec 29, 2001): 187.

Minsky Bruce D. "Adjuvant Radiation Therapy for Rectal Cancer: Is There Finally an Answer?" The Lancet 358, no. 9290 (October 20, 2001): 1285.

Mukhtar, H., and N. Ahmad. "Green Tea in Chemoprevention of Cancer." Toxicological Sciences 52, no. 2 (December 1999): 111–7.

"Night-shift Work May Increase Risk of Colorectal Cancer in Women." Women's Health Weekly (August 14, 2003): 24.

"Physical Activity Lowers Risk of Colorectal Cancer." Obesity, Fitness & Wellness Week (September 27, 2003): 3.

Organizations

National Cancer Institute. Cancer Information Service. 31 Center Drive, MSC 2580, Bethesda, MD 20892-2582. (800) 4-CANCER. TTY: (800) 332-8615. .

American Cancer Society. (800) ACS-2345. .

[Article by: Paula Ford-Martin; Teresa G. Odle]

Colorectal cancer is a malignant neoplasm that affects the larger, lower portion of the intestinal tract. About two-thirds of such cancers occur in the colon, mainly in the sigmoid portion, and one-third occur in the rectum or at the recto-sigmoid junction. The third-leading cause of cancer morbidity and the second leading cause of cancer mortality, colorectal cancer has recently declined among white persons in the United States but is almost 50 percent higher, and rising, among African Americans. Hispanics have only half the mortality rate of non-Hispanic white persons. An estimated 135,400 new cases and 56,700 deaths are anticipated during 2001 in the United States. Risk factors for the disease include being older and male; having had polyps, inflammatory bowel disease, or previous other cancers; being physically inactive and obese; consuming excessive alcohol; and a low fiber diet. Five-year survival has recently been 62 percent among white persons and 53 percent among African Americans.

Worldwide, colorectal cancer amounts to about one-tenth of all cancers—almost 600,000 of the6.35 million cases of cancer that occur. Migrants to the United States tend to develop colorectal cancer rates that are similar to those among long-term residents of their adoptive country—even during the first generation or within twenty years of living in the United States. This relatively rapid change suggests the importance of lifestyle in the causation of the disease. This inference is further supported by the fact that colorectal cancer rates throughout the world tend to be substantially higher in urban areas than in rural areas in various countries.

Polyps in the colon, particularly multiple polyps and those exceeding 1.0 cm in diameter frequently precede the occurrence of malignant neoplasm; they therefore constitute a major risk factor.

Control measures include diet, screening, and treatment. It appears that a low fat diet that includes large amounts of vegetables and fruit reduces the risk of colorectal cancer, although the evidence is equivocal, especially as to the extent of reduction. Efforts to control the disease (e.g., the National Colorectal Cancer Awareness Month, supported by the Centers for Disease Control and Prevention of the United States Public Health Services), have recently been emphasizing screening by digital rectal examination (DRE), which is used to detect malignancies that can be reached by that means: the fecal occult blood test (FOBT); and sigmoidoscopy. Barium enemas and proctoscopy have also been used for screening, as well as diagnostically. In 1999 only two-fifths of the American people over fifty years of age had ever received the FOBT or sigmoidoscopy, the latter term including a colonoscopy, which reaches farther into the colon, and a proctoscopy, which extends only into the rectum. The FOBT is recommended annually after age fifty and sigmoidoscopy every five years. Sigmoidoscopy is particularly intended to disclose polyps which may evolve into cancer as well as malignancies that are already present. Both tests are somewhat awkward for patients, but are now recognized as important tools for controlling colorectal cancer. In several trials, biennial screening with FOBT among persons forty-five to eighty years of age reduced mortality from colorectal cancer by 15 to 21 percent; among persons over forty-five years of age, sigmoidoscopy reduced mortality in the distal colon by 59 to 79 percent.

The Office of Public Health and Science of the United States Department of Health and Human Services has set, as a goal for 2010, reduction of the colorectal mortality rate (age-adjusted) from 12.8 per 100,000 (in 1995) to 8.8 per 100,000.

(SEE ALSO: Cancer; Foods and Diet; Lifestyle; Screening)

Bibliography

Massachusetts Medical Society (2000). Morbidity & Mortality Weekly Report 50.

Schottenfold, D., and Fraumeni, J. E., Jr., eds. (1996). Cancer Epidemiology and Prevention, 2nd edition. New York: Oxford University Press.

United States Department of Health and Human Services (2000). Healthy People 2010. Washington, DC: USDHHS Office of Public Health and Science.

— LESTER BRESLOW

Colon cancer is the second leading cause of cancer death in the United States, occurring in approximately 5 percent of the population and resulting in roughly 55,000 deaths annually. New cases of colorectal cancer are diagnosed in approximately 90 per 100,000 people annually. The majority of cases occur in individuals older than age fifty. Of those who suffer from colorectal malignancy, an estimated 40 percent will die from the disease.

Colon cancer-related health-care costs, consisting of outpatient visits, hospitalizations, hospice and home health care, medications, and physician services, exceed $5 billion per year. This figure does not include the indirect costs of wages lost and reduced productivity.

Developing Cancer

The colon, also known as the large intestine, is the final portion of the digestive tract and consists of a tube (called the lumen) lined by specialized cells called colonic epithelial cells. These cells are constantly reproducing in a regulated manner, but when the growth and division of colonic epithelial cells becomes unregulated, colon cancer may result.

Cancer is a form of unregulated cell growth in which growing cells invade surrounding tissue. Such a growth is said to be malignant. Colon cancer results when there are certain changes in the genes that control normal cell replication. In most cases, when cell growth becomes abnormal, a visible growth (lesion) protrudes into the colon's lumen and is termed an adenomatous polyp (or adenoma). The polyp is not yet cancerous but may become so, at which point it is called carcinoma. This process, in which normal tissue becomes cancerous, is known as the adenoma-carcinoma sequence and may take between ten and fifteen years.

Major Genes Involved

The genes altered in the adenoma-carcinoma sequence normally play a role in regulating the cell cycle, controlling the division and turnover of epithelial cells. DNA mutations result in a loss of function of the gene and subsequent unregulated cell growth. While many genes have been studied, the ones most commonly associated with the majority of colon cancers are APC, p53 and K-ras.

Colorectal cancer may develop in an individual who has a strong inherited risk. This occurs, for example, in patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC). These patients will usually have a specific genetic alteration.

Apc

The Adenomatous Polyposis Coli (APC) gene is found on chromosome 5 and is a tumor suppressor gene. Both alleles of the gene must be inactivated for tumor growth to occur. In the normal cell, the APC gene plays a role in regulating the cycle of cellular division and replication, as well as in cell-to-cell communication, thereby suppressing tumor development. Mutations of APC result in a loss of gene function, thus allowing unregulated cellular proliferation. APC mutations are found in the majority of common colon polyps and cancers and in patients with FAP, and they may be one of the earliest genetic alterations in the adenoma-carcinoma sequence.

K-Ras

The K-ras gene plays an active role in cellular signaling and promoting cell growth. The normal gene exists in both an active and inactive form. However, in the abnormal state, the active form predominates and results in a continually growth-stimulated state.

P53

The normal p53 gene is responsible for regulating cells with damaged DNA by directing abnormal cells either to halt the cycle of cell division or to die as the result of a process called apoptosis. Like APC, the p53 gene is a tumor suppressor. With the p53 mutation, the gene no longer functions, and this permits the uninhibited proliferation of cells that may have damaged DNA. p53 mutations are seen in more than half of colorectal cancers.

Familial Adenomatous Polyposis (FAP)

FAP is characterized by the presence of hundreds or thousands of colonic polyps, and it accounts for less than 1 percent of colon cancers. Affected individuals are at increased risk of colorectal polyps and malignancy, and they usually develop polyps by age thirty-five and cancer by age forty. Because endoscopic removal of all the polyps is impossible, patients are usually advised to consider colectomy at a relatively young age. In addition to occurring in the colon, polyps occur in the upper digestive tract, and a variety of tumors may develop outside the gastrointestinal tract. Because mutations in the APC gene can be identified in most cases, genetic testing is now available for affected families.

FAP is inherited as an autosomal dominant disorder with 95 percent penetrance, meaning 95 percent of those who inherit one mutated APC gene will develop FAP. At the cellular level, the APC mutation is actually recessive: As long as there is one copy that is not mutated, the cell cycle will remain controlled.

The apparent paradox of a recessive gene causing a dominant disorder is resolved when we consider how a gene defect predisposes a person to cancer. Of the many millions of cells lining the colon, it is highly likely that some will undergo spontaneous mutation in one of the two copies of the APC gene.

For a person not affected by the APC gene, a spontaneous mutation of one allele will not lead to cancer, because the other gene copy remains intact. However, for a person affected who inherits one mutated copy of the APC gene, each of the cells lining the colon begins with one bad gene copy. Any mutation to the remaining good copy will cause the cell to lose control of its cell cycle and begin the process of polyp development. Given the number of cells involved, it is almost inevitable that this will occur in some of them. Hence FAP is a dominant condition.

Hereditary Nonpolyposis Colon Cancer

HNPCC is an autosomal dominant disorder that may be responsible for up to 5 percent of colon cancers. The genetic mutation leading to the abnormality is the mutation of DNA mismatch repair genes. Individuals with this mutation have up to an 80 percent chance of developing colon cancer. At least five genes are involved in this syndrome.

Malignancy in patients with HNPCC occurs at a younger age than in the general population, is more often located in the proximal colon (the portion nearest the small intestine), and may be associated with multiple tumors. HNPCC also carries an increased risk of tumors of the endometrium, ovaries, stomach, small intestine, bile ducts, bladder, renal pelvis, and ureters. Genetic testing is useful for HNPCC families.

Genetic Testing

Genetic testing may benefit patients and families affected by an inherited colon cancer syndrome. The genetic mutations in FAP and HNPCC can often be characterized. If a family member with colon cancer has an identified genetic abnormality, other family members can be tested to see if they have the same abnormality.

If the mutated gene is not found, the abnormal gene was not inherited and the family member is not at increased risk of developing cancer. Because screening (i.e., colon examination) is more frequently performed for those with FAP and HNPCC than others, genetic testing can be useful for determining who would benefit from intense surveillance.

Other Risk Factors

In addition to the well-described genetic syndromes of FAP and HNPCC, other factors that place an individual at increased risk include a personal or family history of colon cancer and the presence of inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease). Population studies support an association between the development of colon cancer and a high-fat, low-fiber diet, although a cause-and-effect relationship has not been proved.

Prevention

Inhibiting the development of polyps and cancers, finding and removing premalignant polyps, and testing individuals at high risk may reduce colon cancer-related morbidity and mortality. Colon cancer occurs less commonly in individuals whose diets are high in calcium and folate, who take multivitamins, and who maintain high-fiber and low-fat diets.

Non-steroidal anti-inflammatory medications like aspirin may reduce the numbers of polyps, particularly in families with FAP. Colonoscopy can identify polyps that may be premalignant and can facilitate polyp removal. It is recommended that all individuals have a colonoscopy at age fifty. Highrisk patients, such as those with inflammatory bowel disease, FAP, or HNPCC, should have screening initiated at an earlier age and repeat exams at shorter time intervals.

Bibliography

Giardiello, Francis M., Jill D. Brensinger, and Gloria M. Petersen. "AGA Technical Review on Hereditary Colorectal Cancer and Genetic Testing." Gastroenterology 121 (2001): 198-213.

Yamada, Tadataka, et al., eds. Textbook of Gastroenterology, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1999.

Internet Resource

"The Burden of Gastrointestinal Diseases." American Gastrointestinal Association. May 2001. http://www.gastro.org/pdf/burden-report.pdf.

—David E. Loren and Michael L. Kochman

For more information on colorectal cancer, visit Britannica.com.