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Colorectal Cancer
Stephen Scott, MD, MPH
image BASICS
  • Colorectal cancer (CRC) denotes a neoplasm that develops in the colon or rectum.
  • CRC is the second leading cause of cancer deaths and is the third most common cancer in men and women in the United States.
  • Screening for CRC reduces the incidence of and mortality from CRC.
93,090 new cases of colon cancer; 39,610 new cases of rectal cancer; and 49,700 deaths from colon and rectal cancer combined were estimated in the United States in 2015 (1).
  • The lifetime risk for developing CRC in the United States is about 1 in 21 (4.8%).
  • Incidence and death rates have been declining due to improved screening, prevention, and treatment.
  • Progression from the first abnormal cells to the appearance of CRC usually occurs over 10 to 15 years; a disease characteristic that contributes to the effectiveness of prevention.
  • High-risk polyp findings include multiple polyps, villous polyps, and larger polyps.
  • Hyperplastic polyps are less likely to evolve into CRC.
  • Multiple genetic and environmental factors have been linked to the development of CRC.
  • There does not seem to be a single genetic pathway to CRC.
  • <10% of CRC cases are linked to an inherited gene
    • APC, a tumor suppressor gene, is altered in familial adenomatous polyposis (FAP).
    • Genes encoding DNA mismatch repair (MMR) enzymes are implicated in hereditary nonpolyposis colon cancer (HNPCC): MLH1, MSH2, MSH6, PMS1, PMS2, and others.
    • STK11, a tumor suppressor gene, is altered in Peutz-Jeghers syndrome.
  • Sporadic cases of CRC have been linked to oncogenes: Kras, c-Myc, c-Src, HER-2/neu, and others.
  • Age: >90% of people diagnosed with CRC are >50 years of age.
  • Personal history of colorectal polyps
    • Risks increase with multiple polyps, villous polyps, and larger polyps.
  • Personal history of cancer
    • Rectal cancer has higher incidence of local recurrence than proximal cancers (20-30% vs. 2-4%).
  • History of inflammatory bowel disease
    • Prevalence of CRC in ulcerative colitis and Crohn disease is ˜3%, with a cumulative risk of CRC of 2% at 10 years, 8% at 20 years, and 18% at 30 years.
  • Family history of CRC
    • Having a single first-degree relative with a history of CRC increases risk 1.7-fold.
    • Risk is more than double for those who have a history of CRC or polyps in:
      • Any first-degree relative <60 years of age
      • ≥2 first-degree relatives, regardless of age
  • Inherited syndromes
    • HNPCC also called Lynch syndrome.
      • Often develops at younger age (Average age at diagnosis of CRC is 44 years.)
      • Lifetime risk of CRC is 52-69%.
      • Accounts for ˜2% of all CRCs
    • FAP
      • Affected individuals develop hundreds to thousands of polyps in colon and rectum.
      • CRC usually present by age 40 years.
      • Accounts for ˜1% of CRCs
    • Peutz-Jeghers syndrome
      • Individuals may have freckles (mouth, hands, feet) and large polyps in GI tract.
      • Greatly increased risk for CRC and cancers
  • Race and ethnicity
    • African Americans have the highest CRC incidence and mortality rates in the United States.
    • Several different gene mutations have been identified among Ashkenazi Jews.
  • Miscellaneous
    • Patients with obesity, diabetes, acromegaly, smoking, and alcohol use are at increased risk.
  • Diets high in fruits and vegetables have been linked with decreased risk; those high in red and processed meats may increase CRC risk.
  • Some studies suggest that vitamin D, calcium, folate, and fiber may lower CRC risk; more research is needed to understand how diet affects risks of CRC.
  • People who are physically inactive are at higher risk for CRC.
  • Long-term smokers are more likely than nonsmokers to develop and die from CRC.
  • CRC has been linked to heavy alcohol consumption; may be related to low folate intake or absorption
  • NSAIDs may reduce risk in some groups; experts do not recommend NSAID use as a cancer prevention strategy in people at average risk for CRC.
  • Colon cancer screening is one of the most powerful tools in preventing colon cancer.
  • American Cancer Society recommendations for screening include the following (2):
    • Fecal occult blood testing annually
    • Fecal immunochemical test (FIT) annually
    • Flexible sigmoidoscopy every 5 years
    • Colonoscopy every 10 years
    • CT colonography every 5 years (colonoscopy completed if positive)*
    • Double-contrast barium enema every 5 years*
    • Stool DNA test (sDNA) every 3 years*
    • *The USPSTF does not recommend barium enema as a screening test and concludes the evidence is insufficient to assess the benefits and harms of CT colonography and stool DNA testing as screening modalities for CRC.
  • Screening in high-risk groups
    • People with a personal history of polyps need more frequent colonoscopy screening, depending on risk (i.e., 1 or 2 <1-cm polyps with low-grade dysplasia is deemed low-risk and may warrant repeat colonoscopy in 5 to 10 years; decision is influenced by family history, age, quality of initial colonoscopy, and patient comorbidities).
    • People who have a family history of CRC or adenomatous polyps before age 60 years should begin colonoscopy at age 40 or 10 years younger than the age of relative at cancer diagnosis, whichever is earlier.
    • People with inflammatory bowel disease should have regular surveillance colonoscopy with biopsies to detect dysplasia; guidelines for timing and location vary by professional society but generally indicate starting surveillance by ˜8 years of onset of disease followed by surveillance every 1 to 2 years.
    • Genetic testing may be appropriate for individuals with a strong family history of CRC or polyps:
      • Family members of a person affected by HNPCC should start colonoscopy surveillance as early as age 20 years.
      • Individuals with suspected FAP should have yearly flexible sigmoidoscopy beginning at age 10 to 12 years; those who test positive for the gene linked to FAP may consider colectomy.
  • Weight loss
  • Signs of anemia (i.e., conjunctival pallor)
  • Palpable abdominal mass
  • >95% of CRCs are adenocarcinomas.
  • Other colonic tumors include carcinoid tumors, lymphomas, and Kaposi sarcoma in HIV.
  • Many conditions can mimic CRC, including other cancers, hemorrhoids, inflammatory bowel disease, infection, and extrinsic masses (i.e., cysts, abscesses).

Initial Tests (lab, imaging)
  • CBC (to evaluate anemia)
  • Liver function (CRC may spread to the liver)
  • Colonoscopy
  • CT colography if colonoscopy incomplete
Follow-Up Tests & Special Considerations
  • Carcinoembryonic antigen (CEA) should be obtained preoperatively to assist with follow-up screening.
  • CT to evaluate presence of metastatic disease
  • Chest x-ray to evaluate presence of chest metastases
  • Endoscopic ultrasound (EUS) may be used to evaluate the extent of rectal cancers; endorectal MRI may also provide further detail.
  • Intraoperative US may be used to evaluate solid organs (e.g., the liver) after tumor resection.
  • Positron emission tomography (PET) may be used in some cases to detect metastatic disease.
Diagnostic Procedures/Other
  • Biopsy is usually performed (most often during colonoscopy) if CRC is suspected.
  • CT needle-guided biopsy may be needed to evaluate a suspected tumor or metastasis.
Test Interpretation
The American Joint Committee on Cancer (AJCC) TNM staging is preferred
  • Stage 0: limited to the mucosa (carcinoma in situ or intramucosal carcinoma (Tis, N0, M0)
  • Stage I: invades mucosa (T1) or muscularis propria (T2); no invasion of lymph nodes or distant sites (T1, N0, M0 or T2, N0, M0)
  • Stage IIA: invades pericolorectal tissues; no lymph nodes or distant sites (T3, N0, M0)
  • Stage IIB: penetrates to surface of visceral peritoneum; no lymph nodes or distant sites (T4a, N0, M0)
  • Stage IIC: directly invades or adherent to other organs or structures (T4b, N0, M0)
  • Stage IIIA: invades submucosa or muscularis propria with spread to 1 to 3 lymph nodes; no distant sites (T1, N1, M0 or T2, N1, M0)
  • Stage IIIB: invades pericolorectal tissues or surface of visceral peritoneum + spread to 1 to 3 lymph nodes; no distant sites (T3, N1, M0, or T4a, N1, M0)
  • Stage IIIC: invades pericolorectal tissues or peritoneum or other organs and to ≥4 nearby lymph nodes; no distant sites (any T3 or T4, N2, M0)
  • Stage IVA: any level of invasion with spread to one organ or site (any T, any N, M1a)
  • Stage IVB: any level of invasion with spread to more than one organ or site or peritoneum (any T, any N, M1b)
Surgical resection is the primary treatment for CRC, as noted in the following texts. Adjuvant chemotherapy is most clearly beneficial for stage III (node-positive) disease, in which improvements of ˜30% may be achieved in both disease recurrence and overall survival, compared with nontreated controls. Chemotherapeutic regimens for metastatic disease may extend overall survival from 6 months to ˜2 years (3)[B].
First Line
Combination chemotherapy is common and may include oxaliplatin, irinotecan, fluorouracil, leucovorin, and capecitabine.
Geriatric Considerations
Elderly patients tend to tolerate CRC chemotherapy and should be considered for treatment.
Second Line
Targeted therapies may be used alongside first-line agents or alone if first-line agents are ineffective
  • Bevacizumab (Avastin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF); inhibits angiogenesis
  • Cetuximab (Erbitux) and panitumumab (Vectibix) are monoclonal antibodies that target epidermal growth factor receptor (EGFR).
  • Aflibercept and regorafenib are newer agents with actions on VEGF.
  • Surgery is the primary treatment for localized CRC
    • May involve segmental resection, hemicolectomy, or colectomy, as well as resection of nodes, depending on size and invasion
    • Laparoscopic-assisted colectomy is an emerging option for earlier stage tumors.
    • Surgery for rectal cancer may include local transanal, low anterior, or abdominoperineal resection or pelvic exenteration.
  • Radiation therapy is most often used for peritoneal or rectal cancers; it may also be used to relieve symptoms.
  • May serve as an adjunct to treatment for CRC
  • 70-75% of cancer survivors report using at least one type of complementary and alternative medicine (CAM), and almost all report that the alternative therapy improved well-being.
Patient Monitoring
  • People with a personal history of proximal cancer (nonrectal) should have follow-up colonoscopy in 1 year and, if normal, in 3 and 5 years subsequently.
  • CEA and/or CA 19-9 are used to detect recurrence in people treated for CRC. (Note: CEA levels may be elevated in ulcerative colitis, nonmalignant GI tumors, liver disease, lung disease, and in smokers.)
  • NIH: Colorectal cancer: http://www.nlm.nih.gov/medlineplus/colorectalcancer.html
  • NCI: Colorectal cancer: http://www.cancer.gov/types/colorectal
  • AAFP: Colorectal Cancer: http://www.aafp.org/afp/2015/0115/p93-s1.html
5-year relative survival rate is determined by stage (adjusted for patients dying of other diseases): stage I: 93%; stage II: 72-85%; stage III: 44-83%; stage IV: 8%.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1), 5-29.
2. American Cancer Society. Guidelines for the early detection of cancer. http://www.cancer.orghealthy/findcancerearly/cancerscreeningguidelinesamericancancer-society-guidelines-for-the-earlydetection-of-cancer. Accessed 2015.
3. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383(9927):1490-1502.
Additional Reading
  • Benson AB III, Venook AP, Bekaii-Saab T, et al. Colon cancer, version 3.2014. J Natl Compr Canc Netw. 2014;12(7):1028-1059.
  • National Institutes of Health, National Cancer Institute. Colorectal cancer—for patients. http://www.cancer.gov/types/colorectal/. Accessed 2015.
  • C19 Malignant neoplasm of rectosigmoid junction
  • C18.9 Malignant neoplasm of colon, unspecified
  • C20 Malignant neoplasm of rectum
Clinical Pearls
  • The USPSTF recommends screening beginning at age 50 years and notes that evidence supports fecal occult blood testing (yearly), sigmoidoscopy, or colonoscopy (every 10 years).
  • High-risk polyp findings include multiple polyps, villous polyps, and larger polyps; hyperplastic polyps are less likely to become cancerous.
  • 10% of cases of CRC occur in people <50 years of age. People who have a family history of CRC without other risks (i.e., polyposis syndrome) should begin colonoscopy at age 40 years or 10 years younger than the age of relative at cancer diagnosis, whichever is earlier.
  • Iron deficiency anemia in the elderly should prompt a search for CRC and should not be attributed to normal aging.