colon cancer

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

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

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

Colorectal cancer
Classification and external resources
Diagram of the stomach, colon, and rectum
ICD-10	C18.-C20.
ICD-9	153.0-154.1
ICD-O:	M8140/3 (95% of cases)
OMIM	114500
DiseasesDB	2975
MedlinePlus	000262
eMedicine	med/413 med/1994 ped/3037

Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. With 655,000 deaths worldwide per year, it is the third most common form of cancer and the third leading cause of cancer-related death in the Western world.^[1] Many colorectal cancers are thought to arise from adenomatous polyps in the colon. These mushroom-shaped growths are usually benign, but some may develop into cancer over time. The majority of the time, the diagnosis of localized colon cancer is through colonoscopy. Therapy is usually through surgery, which in many cases is followed by chemotherapy.

Contents 1 Signs and symptoms 1.1 Local 1.2 Constitutional 1.3 Metastatic 2 Causes 2.1 Alcohol 3 Pathogenesis 4 Diagnosis 4.1 Other screening methods 4.2 Monitoring Colorectal Cancer 4.3 Pathology 4.4 Staging 5 Prevention 5.1 Surveillance 5.2 Lifestyle and nutrition 5.3 Chemoprevention 5.3.1 Aspirin chemoprophylaxis 5.3.2 Calcium 5.4 Vitamin D 6 Management 6.1 Surgery 6.2 Chemotherapy 6.3 Radiation therapy 6.4 Immunotherapy 6.5 Vaccine 6.6 Treatment of liver metastases 6.7 Aspirin 6.8 Support therapies 7 Prognosis 7.1 Follow-up 8 Epidemiology 9 Society and culture 9.1 Notable people diagnosed with colorectal cancer 10 Research 10.1 Mathematical modeling 11 See also 12 References 13 External links

Signs and symptoms

The symptoms of colorectal cancer depend on the location of tumor in bowel and whether it has spread to elsewhere in the body (metastasis). Most of the symptoms may occur in other diseases as well, and hence none of the symptoms mentioned here is diagnostic of colorectal cancer. Symptoms and signs are divided into local, constitutional (affecting the whole body) and metastatic (caused by spread to other organs).

Local

Local symptoms are more likely if the tumor is located closer to the anus. There may be a change in bowel habit (new-onset constipation or diarrhea in the absence of another cause), and a feeling of incomplete defecation (tenesmus) and reduction in diameter of stool; tenesmus and change in stool shape are both characteristic of rectal cancer. Lower gastrointestinal bleeding, including the passage of bright red blood in the stool, may indicate colorectal cancer, as may the increased presence of mucus. Melena, black stool with a tarry appearance, normally occurs in upper gastrointestinal bleeding (such as from a duodenal ulcer) but is sometimes encountered in colorectal cancer when the disease is located in the beginning of the large bowel.

A tumor that is large enough to fill the entire lumen of the bowel may cause bowel obstruction. This situation is characterized by constipation, abdominal pain, abdominal distension and vomiting. This occasionally leads to the obstructed and distended bowel perforating and causing peritonitis.

Certain local effects of colorectal cancer occur when the disease has become more advanced. A large tumor is more likely to be noticed on feeling the abdomen, and it may be noticed by a doctor on physical examination. The disease may invade other organs, and may cause blood or air in the urine (invasion of the bladder) or vaginal discharge (invasion of the female reproductive tract).

Constitutional

If a tumor has caused chronic occult bleeding, iron deficiency anemia may occur; this may be experienced as fatigue, palpitations and noticed as pallor (pale appearance of the skin). Colorectal cancer may also lead to weight loss, generally due to a decreased appetite.

More unusual constitutational symptoms are an unexplained fever and one of several paraneoplastic syndrome. The most common paraneoplastic syndrome is thrombosis, usually deep vein thrombosis.

Metastatic

Colorectal cancer most commonly spreads to the liver. This may go unnoticed, but large deposits in the liver may cause jaundice and abdominal pain (due to stretching of the capsule). If the tumor deposit obstructs the bile duct, the jaundice may be accompanied by other features of biliary obstruction, such as pale stools.

Causes

Micrograph of a tubular adenoma (left of image), a type of colonic polyp and a precursor of colorectal cancer. Normal colorectal mucosa is seen on the right. H&E stain.

The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person's risk of developing the disease.^[2] These include:

• Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.^[3]
• Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.
• History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.
• Heredity:
  • Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives.^[4]
  • Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated
  • Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
• Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that "Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked."^[5][6]
• Diet. Studies show that a diet high in red meat^[7] and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish showed a decreased risk.^[8] However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding.^[9] The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.
• Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.
• Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.
• Primary sclerosing cholangitis offers a risk independent to ulcerative colitis
• Low levels of selenium.^[10][11]
• Inflammatory bowel disease.^[12][13] About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.^[14]
• Environmental factors.^[12] Industrialized countries are at a relatively increased risk compared to less developed countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers.
• Exogenous hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens.^[15] There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast, there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.^[16]
• Alcohol. Drinking, especially heavily, may be a risk factor.^[17]

Alcohol

The WCRF panel report Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective finds the evidence "convincing" that alcoholic drinks increase the risk of colorectal cancer in men.^[18]

The NIAAA reports that: "Epidemiologic studies have found a small but consistent dose-dependent association between alcohol consumption and colorectal cancer^[19][20] even when controlling for fiber and other dietary factors.^[21][22] Despite the large number of studies, however, causality cannot be determined from the available data."^[17]

"Heavy alcohol use may also increase the risk of colorectal cancer" (NCI). One study found that "People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer."^[23][24] Another found that "The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer."^[25][26][27]

One study found that "While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.".^[28]

Other research suggests that "to minimize your risk of developing colorectal cancer, it's best to drink in moderation."^[17]

On its colorectal cancer page, the National Cancer Institute does not list alcohol as a risk factor:^[29] however, on another page it states, "Heavy alcohol use may also increase the risk of colorectal cancer"^[30]

Drinking may be a cause of earlier onset of colorectal cancer.^[31]

Pathogenesis

Colorectal cancer is a disease originating from the epithelial cells lining the gastrointestinal tract. Hereditary or somatic mutations in specific DNA sequences, among which are included DNA replication or DNA repair genes,^[32] and also the APC, K-Ras, NOD2 and p53^[33] genes, lead to unrestricted cell division. The exact reason why (and whether) a diet high in fiber might prevent colorectal cancer remains uncertain. Chronic inflammation, as in inflammatory bowel disease, may predispose patients to malignancy.

Diagnosis

Endoscopic image of colon cancer identified in sigmoid colon on screening colonoscopy in the setting of Crohn's disease.

Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the chances of a cure. The National Cancer Policy Board of the Institute of Medicine estimated in 2003 that even modest efforts to implement colorectal cancer screening methods would result in a 29 percent drop in cancer deaths in 20 years. Despite this, colorectal cancer screening rates remain low.^[34] Therefore, screening for the disease is recommended in individuals who are at increased risk. There are several different tests available for this purpose.

• Digital rectal exam (DRE): The doctor inserts a lubricated, gloved finger into the rectum to feel for abnormal areas. It only detects tumors large enough to be felt in the distal part of the rectum but is useful as an initial screening test.
• Fecal occult blood test (FOBT): a test for blood in the stool. Two types of tests can be used for detecting occult blood in stools i.e. guaiac based (chemical test) and immunochemical. The sensitivity of immunochemical testing is superior to that of chemical testing without an unacceptable reduction in specifity.^[35]
• Endoscopy:
  • Sigmoidoscopy: A lighted probe (sigmoidoscope) is inserted into the rectum and lower colon to check for polyps and other abnormalities.
  • Colonoscopy: A lighted probe called a colonoscope is inserted into the rectum and the entire colon to look for polyps and other abnormalities that may be caused by cancer. A colonoscopy has the advantage that if polyps are found during the procedure they can be immediately removed. Tissue can also be taken for biopsy.

In the United States, colonoscopy or FOBT plus sigmoidoscopy are the preferred screening options.

Other screening methods

• Double contrast barium enema (DCBE): First, an overnight preparation is taken to cleanse the colon. An enema containing barium sulfate is administered, then air is insufflated into the colon, distending it. The result is a thin layer of barium over the inner lining of the colon which is visible on X-ray films. A cancer or a precancerous polyp can be detected this way. This technique can miss the (less common) flat polyp.
• Virtual colonoscopy replaces X-ray films in the double contrast barium enema (above) with a special computed tomography scan and requires special workstation software in order for the radiologist to interpret. This technique is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.
• Standard computed axial tomography is an x-ray method that can be used to determine the degree of spread of cancer, but is not sensitive enough to use for screening. Some cancers are found in CAT scans performed for other reasons.
• Blood tests: Measurement of the patient's blood for elevated levels of certain proteins can give an indication of tumor load. In particular, high levels of carcinoembryonic antigen (CEA) in the blood can indicate metastasis of adenocarcinoma. These tests are frequently false positive or false negative, and are not recommended for screening, it can be useful to assess disease recurrence.
• Genetic counseling and genetic testing for families who may have a hereditary form of colon cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP).
• Positron emission tomography (PET) is a 3-dimensional scanning technology where a radioactive sugar is injected into the patient, the sugar collects in tissues with high metabolic activity, and an image is formed by measuring the emission of radiation from the sugar. Because cancer cells often have very high metabolic rate, this can be used to differentiate benign and malignant tumors. PET is not used for screening and does not (yet) have a place in routine workup of colorectal cancer cases.
• Whole-Body PET imaging is the most accurate diagnostic test for detection of recurrent colorectal cancer, and is a cost-effective way to differentiate resectable from non-resectable disease. A PET scan is indicated whenever a major management decision depends upon accurate evaluation of tumour presence and extent.
• Stool DNA testing is an emerging technology in screening for colorectal cancer. Pre-malignant adenomas and cancers shed DNA markers from their cells which are not degraded during the digestive process and remain stable in the stool. Capture, followed by PCR amplifies the DNA to detectable levels for assay. Clinical studies have shown a cancer detection sensitivity of 71%-91%.^[36]

Monitoring Colorectal Cancer

Carcinoembryonic antigen (CEA) is a protein found on virtually all colorectal tumors. CEA may be used to monitor and assess response to treatment in patients with metastatic disease. CEA can also be used to monitor recurrence in patients post-operatively.^{[citation needed]}

Pathology

Gross appearance of a colectomy specimen containing two adenomatous polyps (the brownish oval tumors above the labels, attached to the normal beige lining by a stalk) and one invasive colorectal carcinoma (the crater-like, reddish, irregularly-shaped tumor located above the label).

Gross appearance of a colectomy specimen containing one invasive colorectal carcinoma (the crater-like, reddish, irregularly-shaped tumor).

Micrograph of an invasive adenocarcinoma (the most common type of colorectal cancer). The cancerous cells are seen in the center and at the bottom right of the image (blue). Near normal colon-lining cells are seen at the top right of the image.

Histopathologic image of colonic carcinoid stained by hematoxylin and eosin.

The pathology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.

Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.

Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.^[37]

Most colorectal cancer tumors are thought to be cyclooxygenase-2 (COX-2) positive. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.

Staging

Colon cancer staging is an estimate of the amount of penetration of a particular cancer. It is performed for diagnostic and research purposes, and to determine the best method of treatment. The systems for staging colorectal cancers depend on the extent of local invasion, the degree of lymph node involvement and whether there is distant metastasis.

Definitive staging can only be done after surgery has been performed and pathology reports reviewed. An exception to this principle would be after a colonoscopic polypectomy of a malignant pedunculated polyp with minimal invasion. Preoperative staging of rectal cancers may be done with endoscopic ultrasound. Adjunct staging of metastasis include Abdominal Ultrasound, CT, PET Scanning, and other imaging studies.

The most common staging system is the TNM (for tumors/nodes/metastases) system, from the American Joint Committee on Cancer (AJCC). The TNM system assigns a number based on three categories. "T" denotes the degree of invasion of the intestinal wall, "N" the degree of lymphatic node involvement, and "M" the degree of metastasis. The broader stage of a cancer is usually quoted as a number I, II, III, IV derived from the TNM value grouped by prognosis; a higher number indicates a more advanced cancer and likely a worse outcome. Details of this system are in the graph below:

AJCC stage	TNM stage	TNM stage criteria for colorectal cancer[38]
Stage 0	Tis N0 M0	Tis: Tumor confined to mucosa; cancer-in-situ
Stage I	T1 N0 M0	T1: Tumor invades submucosa
Stage I	T2 N0 M0	T2: Tumor invades muscularis propria
Stage II-A	T3 N0 M0	T3: Tumor invades subserosa or beyond (without other organs involved)
Stage II-B	T4 N0 M0	T4: Tumor invades adjacent organs or perforates the visceral peritoneum
Stage III-A	T1-2 N1 M0	N1: Metastasis to 1 to 3 regional lymph nodes. T1 or T2.
Stage III-B	T3-4 N1 M0	N1: Metastasis to 1 to 3 regional lymph nodes. T3 or T4.
Stage III-C	any T, N2 M0	N2: Metastasis to 4 or more regional lymph nodes. Any T.
Stage IV	any T, any N, M1	M1: Distant metastases present. Any T, any N.

Dukes system

Micrograph of a colorectal adenocarcinoma metastasis to a lymph node. The cancerous cells are at the top center-left of the image, in glands (circular/ovoid structures) and eosinophilic (bright pink). H&E stain.

Dukes classification is an older and less complicated staging system, that predates the TMN system, and was first proposed by Dr. Cuthbert Dukes in 1932; it identifies the stages as:^[39]

• A - Tumour confined to the intestinal wall
• B - Tumour invading through the intestinal wall
• C - With lymph node(s) involvement (this is further subdivided into C1 lymph node involvement where the apical node is not involved and C2 where the apical lymph node is involved)
• D - With distant metastasis

A few cancer centers still use this staging system.

Prevention

Most colorectal cancers should be preventable, through increased surveillance, improved lifestyle, and, probably, the use of dietary chemopreventative agents.

Surveillance

Most colorectal cancer arise from adenomatous polyps. These lesions can be detected and removed during colonoscopy. Studies show this procedure would decrease by > 80% the risk of cancer death, provided it is started by the age of 50, and repeated every 5 or 10 years.^[40]

As per current guidelines under National Comprehensive Cancer Network, in average risk individuals with negative family history of colon cancer and personal history negative for adenomas or Inflammatory Bowel diseases, flexible sigmoidoscopy every 5 years with fecal occult blood testing annually or double contrast barium enema are other options acceptable for screening rather than colonoscopy every 10 years (which is currently the Gold-Standard of care).

Lifestyle and nutrition

The comparison of colorectal cancer incidence in various countries strongly suggests that sedentarity, overeating (i.e., high caloric intake), and perhaps a diet high in meat (red or processed) could increase the risk of colorectal cancer. In contrast, a healthy body weight, physical fitness, and good nutrition decreases cancer risk in general. Accordingly, lifestyle changes could decrease the risk of colorectal cancer as much as 60-80%.^[41]

A high intake of dietary fiber (from eating fruits, vegetables, cereals, and other high fiber food products) has, until recently, been thought to reduce the risk of colorectal cancer and adenoma. In the largest study ever to examine this theory (88,757 subjects tracked over 16 years), it has been found that a fiber rich diet does not reduce the risk of colon cancer.^[42] A 2005 meta-analysis study further supports these findings.^[43]

The Harvard School of Public Health states: "Health Effects of Eating Fiber: Long heralded as part of a healthy diet, fiber appears to reduce the risk of developing various conditions, including heart disease, diabetes, diverticular disease, and constipation. Despite what many people may think, however, fiber probably has little, if any effect on colon cancer risk."^[44]

Chemoprevention

More than 200 agents, including the above cited phytochemicals, and other food components like calcium or folic acid (a B vitamin), and NSAIDs like aspirin, are able to decrease carcinogenesis in pre-clinical development models: Some studies show full inhibition of carcinogen-induced tumours in the colon of rats. Other studies show strong inhibition of spontaneous intestinal polyps in mutated mice (Min mice). Chemoprevention clinical trials in human volunteers have shown smaller prevention, but few intervention studies have been completed today. The "chemoprevention database" shows the results of all published scientific studies of chemopreventive agents, in people and in animals.^[45]

Aspirin chemoprophylaxis

Aspirin should not be taken routinely to prevent colorectal cancer, even in people with a family history of the disease, because the risk of bleeding and kidney failure from high dose aspirin (300 mg or more) outweigh the possible benefits.^[46]

A clinical practice guideline of the U.S. Preventive Services Task Force (USPSTF) recommended against taking aspirin (grade D recommendation).^[47] The Task Force acknowledged that aspirin may reduce the incidence of colorectal cancer, but "concluded that harms outweigh the benefits of aspirin and NSAID use for the prevention of colorectal cancer". A subsequent meta-analysis concluded "300 mg or more of aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years".^[48] However, long-term doses over 81 mg per day may increase bleeding events.^[49]

Calcium

The meta-analysis by the Cochrane Collaboration of randomized controlled trials published through 2002 concluded "Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.".^[50] Subsequently, one randomized controlled trial by the Women's Health Initiative (WHI) reported negative results.^[51] A second randomized controlled trial reported reduction in all cancers, but had insufficient colorectal cancers for analysis.^[52]

Vitamin D

A scientific review undertaken by the National Cancer Institute found that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels of 80 nmol/L or higher associated with a 72% risk reduction compared with lower than 50 nmol/L.^[53]

Management

The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However, when it is detected at later stages (when distant metastases are present) it is less likely to be curable.

Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient's staging and other medical factors.

Because colon cancer primarily affects the elderly, it can be a challenge to determine how aggressively to treat a particular patient, especially after surgery. Clinical trials suggest that "otherwise fit" elderly patients fare well if they have adjuvant chemotherapy after surgery, so chronological age alone should not be a contraindication to aggressive management.^[54]

Surgery

Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.

Curative Surgical treatment can be offered if the tumor is localized.

• Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.
• In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.
• Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.

In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.

If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.

The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures would do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to "open and close" procedures are now diagnosed in advance and surgery avoided.

Laparoscopic-assisted colectomy is a minimally-invasive technique that can reduce the size of the incision and may reduce post-operative pain.

As with any surgical procedure, colorectal surgery may result in complications including

• wound infection, Dehiscence (bursting of wound) or hernia
• anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis
• bleeding with or without hematoma formation
• adhesions resulting in bowel obstruction. A 5-year study of patients who had surgery in 1997 found the risk of hospital readmission to be 15% after panproctocolectomy, 9% after total colectomy, and 11% after ileostomy^[55]
• adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder
• Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc

Chemotherapy

Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration. In colon cancer, chemotherapy after surgery is usually only given if the cancer has spread to the lymph nodes (Stage III). At the 2008 annual meeting of the American Society of Clinical Oncology, researchers announced that colorectal cancer patients that have a mutation in the KRAS gene do not respond to certain therapies, those that inhibit the epidermal growth factor receptor (EGFR)--namely Erbitux (cetuximab) and Vectibix (panitumumab).^[56] Following recommendations by ASCO, patients should now be tested for the KRAS gene mutation before being offered these EGFR-inhibiting drugs.^[57] In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.^[58]

However, having the normal KRAS version does not guarantee that these drugs will benefit the patient.^[56]

“The trouble with the KRAS mutation is that it’s downstream of EGFR,” says Richard Goldberg, MD, director of oncology at the Lineberger Comprehensive Cancer Center at the University of North Carolina. “It doesn’t matter if you plug the socket if there’s a short downstream of the plug. The mutation turns [EGFR] into a switch that’s always on.” But this doesn’t mean that having normal, or wild-type, KRAS is a fail-safe. “It isn’t foolproof,” cautions Goldberg. “If you have wild-type KRAS, you’re more likely to respond, but it’s not a guarantee.” Tumors shrink in response to these drugs in up to 40 percent of patients with wild-type KRAS, and progression-free and overall survival is increased.

The cost benefit of testing patients for the KRAS gene could potentially save about $740 million a year by not providing EGFR-inhibiting drugs to patients who would not benefit from the drugs. "With the assumption that patients with mutated Kras (35.6% of all patients) would not receive cetuximab (other studies have found Kras mutation in up to 46% of patients), theoretical drug cost savings would be $753 million; considering the cost of Kras testing, net savings would be $740 million."^[59]

• Adjuvant (after surgery) chemotherapy. One regimen involves the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)
  • 5-fluorouracil (5-FU) or Capecitabine (Xeloda)
  • Leucovorin (LV, Folinic Acid)
  • Oxaliplatin (Eloxatin)

• Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab or the same chemotherapy drug combinations with cetuximab in KRAS wild type tumors
  • 5-fluorouracil (5-FU) or Capecitabine
  • UFT or Tegafur-uracil
  • Leucovorin (LV, Folinic Acid)
  • Irinotecan (Camptosar)
  • Oxaliplatin (Eloxatin)
  • Bevacizumab (Avastin)
  • Cetuximab (Erbitux)
  • Panitumumab (Vectibix)

• In clinical trials for treated/untreated metastatic disease.^[60]
  • Bortezomib (Velcade)
  • Oblimersen (Genasense, G3139)
  • Gefitinib and Erlotinib (Tarceva)
  • Topotecan (Hycamtin)

Radiation therapy

Radiotherapy is not used routinely in colon cancer, as it could lead to radiation enteritis, and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:

• Colon cancer
  • pain relief and palliation - targeted at metastatic tumor deposits if they compress vital structures and/or cause pain
• Rectal cancer
  • neoadjuvant - given before surgery in patients with tumors that extend outside the rectum or have spread to regional lymph nodes, in order to decrease the risk of recurrence following surgery or to allow for less invasive surgical approaches (such as a low anterior resection instead of an abdomino-perineal resection)
  • adjuvant - where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke's B or C tumors)
  • palliative - to decrease the tumor burden in order to relieve or prevent symptoms

Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.

Immunotherapy

Bacillus Calmette-Guérin (BCG) is being investigated as an adjuvant mixed with autologous tumor cells in immunotherapy for colorectal cancer.^[61]

Vaccine

In November 2006, it was announced that a vaccine had been developed and tested with very promising results.^[62] The new vaccine, called TroVax, works in a totally different way to existing treatments by harnessing the patient's own immune system to fight the disease. Experts say this suggests that gene therapy vaccines could prove an effective treatment for a whole range of cancers. Oxford BioMedica is a British spin-out from Oxford University specialising in the development of gene-based treatments. Phase III trials are underway for renal cancers and planned for colon cancers.^[63]

Treatment of liver metastases

According to the American Cancer Society statistics in 2006,^[64] over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.^[65]

Resectability of a liver metastasis is determined using preoperative imaging studies (CT or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic "segments", while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic "wedge" resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimens. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.

Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.

Aspirin

A study published in 2009 found that Aspirin reduces risk of colorectal neoplasia in randomized trials and inhibits tumor growth and metastases in animal models. The influence of aspirin on survival after diagnosis of colorectal cancer is unknown ^[66]. Several reports including a prospective cohort of 1,279 people diagnosed with stages I-III (non-metastatic) colorectal cancer^[67] have suggested a significant improvement in cancer-specific survival in a subset of patients using aspirin^[68].

Support therapies

Cancer diagnosis very often results in an enormous change in the patient's psychological wellbeing. Various support resources are available from hospitals and other agencies which provide counseling, social service support, cancer support groups, and other services. These services help to mitigate some of the difficulties of integrating a patient's medical complications into other parts of their life.

Prognosis

Survival is directly related to detection and the type of cancer involved. Survival rates for early stage detection is about 5 times that of late stage cancers. CEA level is also directly related to the prognosis of disease, since its level correlates with the bulk of tumor tissue.

Follow-up

Micrograph of a colorectal villous adenoma. These lesions are considered pre-cancerous. H&E stain.

The aims of follow-up are to diagnose in the earliest possible stage any metastasis or tumors that develop later but did not originate from the original cancer (metachronous lesions).

The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer.^[69][70] A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.

Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended.^[69][70] These guidelines are based on recent meta-analyses showing that intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.^[71][72][73]

Epidemiology

Age-standardized death from colorectal cancer per 100,000 inhabitants in 2004.^[74]

     no data      less than 2.5      2.5-5      5-7.5      7.5-10      10-12.5      12.5-15      15-17.5      17.5-20      20-22.5      22.5-25      25-27.5      more than 27.5

Society and culture

Notable people diagnosed with colorectal cancer

Main article: List of people diagnosed with colorectal cancer

• Corazon Aquino, former president of the Philippines^[75]
• Pope John Paul II^[76]
• Ronald Reagan^[77]
• Harold Wilson, former Prime Minister of the United Kingdom^[78]
• Rod Roddy, second announcer on The Price is Right who became a spokesperson for early detection of cancer in his last years.^[79]

Research

Mathematical modeling

Colorectal cancer has been the subject of mathematical modeling for many years.^[80][81]

See also

• Hereditary nonpolyposis colorectal cancer
• Diet and cancer
• Bowel & Cancer Research
• Mouse models of colorectal and intestinal cancer

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External links

• American Cancer Society's Detailed Guide: Colon and Rectum Cancer
• Colorectal cancer at the Open Directory Project
• ColonCancerCheck including fact sheets in 24 languages at Ontario Ministry of Health and Long-Term Care
• List of clinical labs performing KRAS mutation analysis

v • d • e Digestive system · Digestive disease · Gastroenterology (primarily K20–K93, 530–579) Upper GI tract Esophagus Esophagitis (Candidal) · rupture (Boerhaave syndrome, Mallory-Weiss syndrome) · UES (Zenker's diverticulum) · LES (Barrett's esophagus) · Esophageal motility disorder (Nutcracker esophagus, Achalasia, Diffuse esophageal spasm, GERD) · Esophageal stricture · Megaesophagus Stomach Gastritis (Atrophic, Ménétrier's disease, Gastroenteritis) · Peptic (gastric) ulcer (Cushing ulcer, Dieulafoy's lesion) · Dyspepsia · Pyloric stenosis · Achlorhydria · Gastroparesis · Gastroptosis · Portal hypertensive gastropathy · Gastric antral vascular ectasia · Gastric dumping syndrome · Gastric volvulus Lower GI tract: Intestinal/ enteropathy Small intestine/ (duodenum/jejunum/ileum) Enteritis (Duodenitis, Jejunitis, Ileitis) — Peptic (duodenal) ulcer (Curling's ulcer) — Malabsorption: Coeliac · Tropical sprue · Blind loop syndrome · Whipple's · Short bowel syndrome · Steatorrhea · Milroy disease Large intestine (appendix/colon) Appendicitis · Colitis (Pseudomembranous, Ulcerative, Ischemic, Microscopic, Collagenous, Lymphocytic) · Functional colonic disease (IBS, Intestinal pseudoobstruction/Ogilvie syndrome) — Megacolon/Toxic megacolon · Diverticulitis/Diverticulosis Large and/or small Enterocolitis (Necrotizing) · IBD (Crohn's disease) — vascular: Abdominal angina · Mesenteric ischemia · Angiodysplasia — Bowel obstruction: Ileus · Intussusception · Volvulus · Fecal impaction — Constipation · Diarrhea (Infectious) Rectum Proctitis (Radiation proctitis) · Proctalgia fugax · Rectal prolapse Anus Anal fissure/Anal fistula · Anal abscess  · Anal dysplasia  · Pruritus ani GI bleeding/BIS Upper (Hematemesis, Melena) · Lower (Hematochezia) Accessory Liver Hepatitis (Viral hepatitis, Autoimmune hepatitis, Alcoholic hepatitis) · Cirrhosis (PBC) · Fatty liver (NASH) · vascular (Hepatic veno-occlusive disease, Portal hypertension, Nutmeg liver) · Alcoholic liver disease · Liver failure (Hepatic encephalopathy, Acute liver failure) · Liver abscess (Pyogenic, Amoebic) · Hepatorenal syndrome · Peliosis hepatis Gallbladder Cholecystitis · Gallstones/Cholecystolithiasis · Cholesterolosis · Rokitansky-Aschoff sinuses · Postcholecystectomy syndrome · Porcelain gallbladder Bile duct/ other biliary tree Cholangitis (PSC, Secondary sclerosing cholangitis, Ascending) · Cholestasis/Mirizzi's syndrome · Biliary fistula · Haemobilia · Gallstones/Cholelithiasis common bile duct (Choledocholithiasis, Biliary dyskinesia) · Sphincter of Oddi dysfunction Pancreatic Pancreatitis (Acute, Chronic, Hereditary) · Pancreatic pseudocyst · Exocrine pancreatic insufficiency · Pancreatic fistula Abdominopelvic Hernia Diaphragmatic: Congenital diaphragmatic · Hiatus — Abdominal hernia: Inguinal (Indirect, Direct) · Umbilical · Incisional · Femoral — Obturator hernia · Spigelian hernia · Internal hernia Peritoneal Peritonitis (Spontaneous bacterial peritonitis) · Hemoperitoneum · Pneumoperitoneum digestive system navs: anat of tract,glands,perit,diaphragm/physio/dev, noncongen/congen/congen of d+w/neoplasia, symptoms+signs/eponymous, proc

v • d • e Tumors: digestive system neoplasia (C15-C26/D12-D13, 150-159/211) GI tract Upper GI tract Esophagus Squamous cell carcinoma · Adenocarcinoma Stomach Gastric carcinoma · Signet ring cell carcinoma · Gastric lymphoma (MALT lymphoma) · Linitis plastica Lower GI tract Small intestine Duodenal cancer (Adenocarcinoma) Appendix Carcinoid · Pseudomyxoma peritonei Colon/rectum colorectal polyp: Peutz-Jeghers syndrome · Juvenile polyposis syndrome · Familial adenomatous polyposis/Gardner's syndrome · Cronkhite–Canada disease neoplasm: Adenocarcinoma · Familial adenomatous polyposis · Hereditary nonpolyposis colorectal cancer Anus Squamous cell carcinoma Upper and/or lower Gastrointestinal stromal tumor · Krukenberg tumor (metastatic) Accessory Liver malignant: Hepatocellular carcinoma (Fibrolamellar) · Hepatoblastoma benign: Hepatocellular adenoma · Cavernous hemangioma hyperplasia: Focal nodular hyperplasia · Nodular regenerative hyperplasia Biliary tract bile duct: Cholangiocarcinoma · Klatskin tumor gallbladder: Gallbladder cancer Pancreas exocrine pancreas: Adenocarcinoma · Pancreatic ductal carcinoma Pancreatoblastoma Peritoneum Primary peritoneal cancer digestive system navs: anat of tract,glands,perit,diaphragm/physio/dev, noncongen/congen/congen of d+w/neoplasia, symptoms+signs/eponymous, proc

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