Diagram of the stomach, colon, and rectum

Colorectal cancer includes cancerous growths in the colon, rectum and appendix. It is the third most common form of cancer and the second leading cause of death among cancers in the Western world. Many colorectal cancers are thought to arise from polyps in the colon. These mushroom-like growths are usually benign, but some may develop into cancer over time. Diagnosis is by colonoscopy. Therapy is usually through surgery, with many cases also requiring chemotherapy.

Symptoms

Symptoms of colorectal cancer include:

• Change in bowel habits.
• Blood in stools (melena, hematochezia).
• Bowel obstruction (rare) by the tumor

Often, the symptoms are much less specific:

• Unexplained weight loss.
• Anemia, with symptoms such as tiredness, malaise, pallor
• Hepatomegaly (enlargement of the liver) due to speading of the tumor

It is also possible that there will be no symptoms at all. This is one reason why some recommend periodical screening for the disease.

Risk factors

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. These include:

• Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60's and 70's, while cases before age 50 are uncommon unless a family history of early colon cancer is present.
• History of cancer. 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
  • 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
• Long-standing ulcerative colitis or Crohn's disease of the colon, approximately 30% after 25 years if the entire colon is involved
• Smoking. Smokers are more likely to die of colorectal cancer than non-smokers
• Diet. Some studies have shown that people who have diets high in fresh fruit, vegetables, poultry and fish and low in red meat are at reduced risk of colorectal cancer.
• Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.
• Virus. Exposure to some viruses (such as human papilloma virus) may be associated with colorectal cancer.

Diagnosis, screening and monitoring

Indentification of malignancy

Colorectal cancer can take many years to develop and early detection of colorectal cancer greatly improves the chances of a cure. 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 and is not really a screening test.
• Fecal occult blood test (FOBT): a test for blood in the stool.
• 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.
• Double contrast barium enema (DCBE): An enema containing barium sulfate, which helps the outline of the colon and rectum stand out on X-rays, is given to the patient. The doctor then takes a series of X-rays of the colon and rectum.
• Virtual colonoscopy can image the colon using x-rays and is approaching colonoscopy in sensitivity for polyps. However, any polyps found must still be removed by standard colonoscopy.
• 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.
• Genetic counseling and genetic testing for families who may have a heriditary 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.

Pathology

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 caecum) 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 present with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring.

Staging

TNM or Duke's

Colon cancer staging is an estimate of the condition of a particular cancer for diagnostic and research purposes. The systems for staging colorectal cancers largely depend on the extent of local invasion, the degree of lymph node involvement and whether there is distant metastasis.

The most common currently used system for staging is the TNM system, though many doctors still use the older Duke's system. The TNM system assigns a number:

• T - The degree of invasion of the intestinal wall
  • T0 - no evidence of tumor
  • Tis- cancer in situ (tumor present, but no invasion)
  • T1 - tumor present but minimal invasion
  • T2 - invasion into the submucosa
  • T3 - invasion into the muscularis propria
• N - the degree of lymphatic node involvement
  • N0 - no lymph nodes involved
  • N1 - one to three nodes involved
  • N2 - four or more nodes involved
• M - the degree of metastasis
  • M0 - no metastasis
  • M1 - metastasis present

AJCC stage groupings

The 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 a likely worse outcome.

• Stage 0
  • Tis, N0, M0
• Stage I
  • T1, N0, M0
  • T2, N0, M0
• Stage IIA
  • T3, N0, M0
• Stage IIB
  • T4, N0, M0
• Stage IIIA
  • T1, N1, M0
  • T2, N1, M0
• Stage IIIB
  • T3, N1, M0
  • T4, N1, M0
• Stage IIIC
  • Any T, N2, M0
• Stage IV
  • Any T, Any N, M1

Pathogenesis

Colorectal cancer is a disease originating from the in epithelial cells lining the gastrointestinal tract. Mutations in specific DNA (particularily the FAP, KRAS and p53 genes) lead to unrestricted cell division. Various causes for these mutations are inborn genetic aberrations, tobacco smoking, environmental, and possibly viral causes. The exact reason why a diet high in fiber prevents colorectal cancer remains uncertain. Chronic inflammation, as in inflammatory bowel disease, may predispose patients to malignancy.

Treatment

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.

Surgery

Surgical treatment is by far the most likely to result in a cure of colon cancer if the tumor is localized. Very early cancer that develops within a polyp can often be cured by removing the polyp at the time of colonoscopy. More advanced cancers typically require surgical removal of the section of colon containing the tumor leaving sufficient margins to reduce likelihood of re-growth. 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. While surgery is not usually offered if significant metastasis is present, surgical removal of isolated liver metastases is common. Improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.

Laparoscopic assist resection of the colon for tumour can reduce the size of painful incision and minimize the risk of infection.

As with any surgical procedure, colorectal surgery can in rare cases result in complications. These may include infection, abscess, fistula or bowel obstruction.

Radiation therapy

Radiation therapy is used to kill tumor tissue before or after surgery or when surgery is not indicated. Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.

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 if surgery is not indicated (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality and have been approved for use by the US Food and Drug Administration.

• Adjuvant(after surgery) chemotherapy
  • 5-fluorouracil (5FU)
  • Leucovorin (LV)
  • Oxaliplatin (Eloxatin®)

Palliative Chemotherapy - Standard first-line therapy

• 5-fluorouracil (5FU)
  • Leucovorin
• Alternate first line Chemotherapy
  • capecitabine (Xeloda®)
• Other first line agents
  • Irinotecan (Camptosar®, CPT-11) -
  • Oxaliplatin (Eloxatin®)
  • bevacizumab (Avastin®)

• Second Line Chemotherapy
  • cetuximab (Erbitux®)

Alternative therapies

The agents listed here are not proven in clinical trials but may be considered to have anti-colon cancer properties in in-vitro studies, the popular press, folk medicine or other sources.

• Ginger
• Curcumin (Turmeric anti-angiogenesis factor)
• Mistletoe extract (as solid tumor reducer)
• Acupuncture (symptom reduction)

Support therapies

Cancer diagnosis very often results in an enormous change in the patient's sociological 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.

Prevention

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

1. 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 (Winawer et al 1993).
2. Lifestyle: The comparison of colorectal cancer incidence in various countries strongly suggests that sedentarity, overeating (= high caloric intake), and perhaps a diet high in meat (red or processed) could increase the risk of colorectal cancer. In contrast, physical exercise, and eating plenty of fruits and vegetables would decrease cancer risk, probably because they contain protective phytochemicals. Eating whole apples, including the skin, offers some anticancer benefits (Liu et al). Accordingly, lifestyle changes could decrease the risk of colorectal cancer as much as 60-80% (Cummings and Bingham 1998).
3. Chemoprevention: More than 200 agents, including the above cited phytochemicals, and other food components like calcium or folic acid (a B vitamin), and NSAIDS drugs like aspirin, are able to decrease carcinogenesis in preclinical 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. Calcium and aspirin supplements, given for 3 to 5 years after the removal of a polyp, modestly decreased the recurrence of polyps in volunteers (by 15-20%). The "chemoprevention database"[1] (http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html) shows the results of all published scientific studies of chemopreventive agents, in people and in animals.

References

• Cummings JH, Bingham SA. Diet and the prevention of cancer. BMJ 1998;317:1636-40. Fulltext (http://bmj.bmjjournals.com/). PMID 9848907.
• Liu RH et al, Phytochemicals in apples are found to provide anticancer and anti-oxidant benefits. http://www.news.cornell.edu/releases/June00/AntiCancerApple.bpf.html
• Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, Waye JD, Schapiro M, Bond JH, Panish JF, Ackroyd F, Shike M, Kurtz RC, Hornsby-Lewis L, Gerdes H, Stewart ET, The National Polyp Study Workgroup. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1977-81. PMID 8247072.
• Chao A et alii, Meat Consumption and Risk of Colorectal Cancer. JAMA [2] (http://jama.ama-assn.org/cgi/content/short/293/2/172)

External links

• Cancer.gov (http://www.cancer.gov/cancerinfo/wyntk/colon-and-rectum) colorectal cancer
• Colorectal-cancer.net (http://www.colorectal-cancer.net/)
• Current clinical trials (http://clinicaltrials.gov/ct/search?term=colorectal+cancer)
• Complementary medical clinical trials (http://nccam.nih.gov/clinicaltrials/colorectalcancer.htm)
• Medicinenet.com (http://www.medicinenet.com/colon_cancer/index.htm)