Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 22, 2001
Colorectal cancer is a major public health problem in western countries, with the highest incidence rates in North America, Western Europe, Australia and New Zealand. It is the third most common cancer in both men and women, and the third most common cause of cancer death in both sexes. Colon cancer is 2.5 times more common than rectal cancer, and both have different natural histories and thus separate treatment strategies. About 90-95% of all colorectal cancers are adenocarcinomas, with the remainder comprised of squamous cell, neuroendocrine or undifferentiated carcinomas.
Epidemiology and Etiology
- Incidence of 61 per 100,000 males and 45 per 100,000 females, regardless of racial group. However, recent incidence rates are higher amongst African-Americans than Caucasians. Mortality rate as high as 55,000/year, with age-adjusted mortality rate highest in African-American male population.
- Etiology remains unknown, but disease has been linked to germline or somatic genetic mutations in colonic epithelium, ultimately leading to neoplastic phenotype
- Hereditary autosomal dominant syndromes associated with increased risk include familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer () [1,2]
Comparison of Hereditary Syndromes in Colorectal Cancer
Feature FAP HNPCC Age of onset 20's 40's Number of adenomas > 100 < 10 Adenoma distribution Left or total Right Cancer distribution Random Right Other cancers Periampullary Endometrial, ovarian, ureteral Germline mutation APC gene at 5q22 hMSH2, hMLH1, hPMS1
- Additional risk factors include adenomatous polyps, which are widely believed to be precursors; inflammatory bowel disease, high-fat, low-fiber diets, deficiencies of vitamins D and E, calcium and selenium.
Screening Recommendations for Average-Risk Patients
- ACS recommends
- flexible sigmoidoscopy every 3-5 years after age 50, or alternatively, colonoscopy every 10 years
- fecal occult blood test yearly after age 50
- digital rectal exam yearly after age 40
- History: Variable, nonspecific presentation including rectal bleeding, change in bowel habits and stool caliber, abdominal pain, especially with left-sided tumors; rectal cancers often present with tenesmus and rectal bleeding; metastatic disease presents with systemic symptoms of weight loss, anorexia, jaundice if liver involved
- Physical exam: Hemoccult positive stool, hepatomegaly, abdominal mass
- Lab studies: CBC with differential, showing anemia in right-sided tumors due to chronic blood loss; chemistry panel including liver and renal functions
- Diagnostic studies: Colonoscopy with biopsies is best; proctosigmoidoscopy gives limited data due to shorter length of scope, and air contrast barium enema is useful but requires colonoscopy if lesions are seen
- Preoperative studies: CXR, serum CEA level; metastatic search if suspected; abdominal CT and radionuclide scanning are not considered cost-effective and thus have no role in majority of patients
Natural Course and Pathology
- Staging: Pathologic stage following tumor resection is single most important prognostic factor and is based on the depth of tumor invasion into and through the intestinal wall, the number of regional lymph nodes involved, and the presence or absence of distant metastasis  Modified Aster-Coller Dukes system is most widely used clinical and pathologic staging system
- NCI recommends using the TNM system for treatment decisions; the TNM scheme has been modified to correlate with the Dukes system, which dates back to 1930.
- Most common sites of metastases are liver, lung and bone, but peritoneal metastases may also occur, with local pelvic recurrence a common problem in rectal cancer
- Poor prognostic factors include elevated preoperative CEA level, which is the only consistently predictive clinical feature; mucinous and signet-ring patterns on histology; bowel wall/regional lymph node/perineural invasion; evidence of bowel obstruction or perforation
Associated but not fully established prognostic markers include low DNA ploidy, high S-phase fraction, DCC gene deletion, p53 and Ki-ras mutations 
Early stage disease of colon
- Surgery is initial therapy of choice for localized, potentially curable cases. Postoperative treatment and survival depends on pathologic stage of tumor.
- Radiation therapy preoperatively has not improved overall rates of survival, distant recurrence or cure in colon cancer ; however locoregional tumor control rates have improved with sufficiently high doses, especially in rectal cancer cases. Radiation is more commonly used postoperatively, although rates of survival, local control and extrapelvic recurrence have NOT shown consistent improvement. Currently, intraoperative and stereotactic radiation therapy are being evaluated as possible options .
- Adjuvant chemotherapy with 5-FU and levamisole for one year post-operatively shown to reduce risk of recurrence by 41% and reduce risk of death by 33%, compared with no adjuvant therapy.  In stage III patients, 6 months of 5-FU and leucovorin is acceptable adjuvant regimen.
- Immunotherapy with autologous tumor vaccines shows no significant benefit, but murine antibody 17-1A administration is shown to reduce recurrence risk by 27% and improve survival by 30%, as compared to surgery alone, in potentially curable cases 
- Perioperative infusion of chemotherapy into portal vein may play role in reducing risk of developing hepatic metastases, but data inconclusive at present.
Early stage disease of rectum
- Combined modality, post-operative adjuvant chemoradiation is considered the standard, as studies clearly demonstrate superior local control and overall survival compared to surgery alone or surgery and postoperative pelvic radiation therapy.  Chemoradiation also may potentially downstage the tumor and improve sphincter preservation.
- Most well-studied regimens consist of surgery and postoperative chemotherapy within 6 weeks, followed by pelvic XRT plus concurrent chemotherapy. Additional cycles of chemotherapy are then administered.
- Chemotherapy agent of choice is 5-FU. Infusional 5-FU and mitomycin with radiation has achieved 5-year survival rates of about 70% 
Metastatic colorectal cancer
- Surgical resection of metastases associated with long-term disease-free survival in 25-40% of patients able to undergo resection . All operative candidates require extensive pre-operative evaluation to determine appropriateness of surgery.
- Radiation for palliative treatment and control of symptoms (pain, bleeding)
- Systemic chemotherapy with various 5-FU based regimens. Regional therapy includes delivery of chemotherapy into the hepatic artery thorough implantable infusion pumps, with fluorodeoxyuridine (FUDR) being the most commonly used agent.
2. Lynch H, Smyrk T, McGinn T, et al: Attenuated familial adenomatous polyposis. Cancer 76:2427-2433, 1997
3. Meyers MA: Overview, colorectal carcinoma: imaging, staging and management. Neoplasms of the Digestive Tract. Philadelphia, 1998, pp 203-217
4. Burt R: Update on genetic advances in colorectal cancer. Prac Gastroenterol 21:9-15, 1997
5. Rostock RA, Zajac AJ, Gallagher MJ: Radiation therapy in the treatment of colorectal cancer. Gastrointestinal Oncology (ed 1). Philadelphia, 1992, pp. 359-381
6. Iwamoto RJ: Emerging strategies in radiation therapy for colorectal cancer: intraoperative and stereotactic radiation therapy. Colorectal Cancer. Meniscus Educational Institute, 1998, pp. 14-23
7. Peters M, Haller D. Therapy for early-stage colorectal cancer. Oncology 13:307-315, 1999
8. Ohno S, Tomoda M, Tomiaski S, et al: Improved surgical results after combining preoperative hyperthermia with chemotherapy and radiotherapy for patients with carcinoma of the rectum. Dis Colon Rectum 40:401-406, 1997
9. Pazdur RL, Coia L, Wagman L, et al: Colorectal and anal cancer. Cancer Management: A Multidisciplinary Approach. New York, 1999, pp. 149-175
10. Chang AE: Colorectal cancer. Surgery: Scientific Principles and Practice. Philadelphia, 1997, pp. 1139-1146