January 17, 2007

Rectal Cancer


Background: Approximately 135,000 new cases of colorectal cancer occur in the United States each year, resulting in approximately 55,000 deaths per year. Two thirds of these cases occur in the colon and one third in the rectum. The incidence and epidemiology, etiology, pathogenesis, and screening recommendations are common to both colon cancer and rectal cancer. These areas are addressed together.

Adenocarcinomas (98%) comprise most rectal cancers and are the focus of this discussion. Other rare rectal cancers, including carcinoid (0.1%), lymphoma (1.3%), and sarcoma (0.3%), are not discussed. Squamous cell carcinomas may develop in the transition area from rectum to anal verge and are considered anal carcinomas. Very rare cases of squamous cell carcinoma of the rectum have been reported.

Pathophysiology: Carcinomas are found in as many as 4% of neoplastic polyps. Cells must accumulate 4-5 molecular defects, including activation of oncogenes and inactivation of tumor suppressor genes, to undergo malignant transformation. In normal mucosa, the surface epithelium regenerates approximately every 6 days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation, maturation, and, ultimately, lose the ability to replicate.

In adenomas, several genetic mutations alter this process, starting with inactivation of the adenomatous polyposis coli (APC) gene, allowing unchecked cellular replication at the crypt surface. With the increase in cell division, further mutations occur, resulting in activation of the K-ras oncogene in the early stages and p53 mutations in later stages. These cumulative losses in tumor suppressor gene function prevent apoptosis and give the cell eternal life.



Sex: The incidence of colorectal malignancy is slightly higher in males than in females.

Age: Incidence peaks in the seventh decade; however, cases have been reported in young children.






Lab Studies:

Imaging Studies:

Other Tests:

  • Average-risk screening (see Table 1): People who are asymptomatic, younger than 50 years, and have no other risk factors are considered at average risk for developing colorectal cancer. Begin screening this population at age 50 years.
    • Fecal occult blood test: Perform yearly FOBT by testing 2 samples from each of 3 consecutive stools. If any of the 6 samples is positive, recommend that the patient have the entire colon studied via colonoscopy or flexible sigmoidoscopy with double-contrast barium enema. FOBT has significant false-positive and false-negative rates.
    • Flexible sigmoidoscopy: Perform this test every 5 years. Perform a biopsy of any lesions identified, and perform a full colonoscopy. Lesions present beyond the reach of the sigmoidoscope may be missed.
    • Combined FOBT and flexible sigmoidoscopy: Theoretically, the combination of these 2 tests may overcome the limitations of each test.
    • Double-contrast barium enema: This test is offered every 5-10 years, usually in combination with flexible sigmoidoscopy. Lesions detected by this method may still require colonoscopy for biopsy or excision.
    • Colonoscopy: This procedure is recommended every 5-10 years. Colonoscopy allows full visualization of the colon and excision and biopsy of any lesions. The likelihood is extremely low that a new lesion could develop and progress to malignancy between examinations.
  • Table 1. Average Risk Colon and Rectal Cancer Patients Who Should be Screened

    Risk Category Signs and Symptoms
    Average risk No symptoms and age older than 50 years
    Average risk No symptoms requesting screening
    Average risk Change in bowel habits
    Rectal and anal bleeding
    Unclear abdominal pain
    Unclear iron-deficiency anemia

  • High-risk screening (see Table 2): People at increased risk for colorectal cancer include those with affected first-degree relatives, those with a family history of FAP or HNPCC, and those with a personal history of adenomatous polyps, colorectal cancer, or IBD.
    • First-degree relative affected: Offer family members the same screening tests as the general population; however, begin the screening at age 40 years rather than age 50 years. These people often undergo colonoscopy as their initial screening test, particularly if the relative was diagnosed with cancer at a young age.
    • Family history of FAP (see Table 2)
      • Genetic counseling and genetic testing are recommended to determine whether the person is a gene carrier. Current tests are approximately 80% accurate. In the remaining 20%, the mutation cannot be identified.
      • Genetic testing is useful only if the test result is positive or if the test is a true negative (ie, mutation present in other family members is not identified in the patient being tested).
      • Offer flexible sigmoidoscopy to known gene carriers and persons with an indeterminate carrier status every year to look for the presence of polyps. When polyposis develops, consider colectomy.
    • Family history of HNPCC (see Table 2)
      • Offer genetic counseling and genetic testing to individuals whose family histories meet the Amsterdam criteria.
      • Patients with documented HNPCC should undergo colonoscopy every 1-2 years when aged 20-40 years and every year when older than 40 years.
      • Since these cancers tend to be located on the right side of the colon, flexible sigmoidoscopy is not recommended.
    • Personal history of adenomatous polyps: Patients who have adenomatous polyps removed colonoscopically should have a repeat examination at 3 years. If the findings of this examination are normal, follow up at 5 years.
    • Personal history of colorectal cancer: Patients who have colorectal cancer and undergo resection for cure should have a repeat colonoscopy after 1 year. If this examination reveals no abnormalities, follow up at 3 years. In the absence of disease, perform colonoscopy every 5 years thereafter.
    • Personal history of IBD: Surveillance colonoscopy is performed to look for dysplasia as a marker for colorectal cancer in patients with long-standing IBD. These patients should undergo colonoscopy every 1-2 years after 8 years of diffuse disease or after 15 years of localized disease. Random biopsies are performed at specific intervals throughout the colon and rectum. Colectomy is recommended when dysplasia is present.
    • Table 2. High Risk Colon and Rectal Cancer Patients Who Should be Included in Surveillance Programs

      Risk Category Signs and Symptoms
      High-risk patients due to family history Family history of colon and rectal cancer
      First-degree relative with adenoma aged younger than 60 years
      Genetic family syndromes
      High-risk patients due to personal history Personal history of inflammatory bowel disease
      Personal history of adenomas
      Personal history of colon and rectal cancer
      Personal history of genetic family syndromes

    • Primary tumor (T)
      • TX - Primary tumor cannot be assessed or depth of penetration not specified
      • T0 - No evidence of primary tumor
      • Tis - Carcinoma in situ (mucosal); intraepithelial or invasion of the lamina propria
      • T1 - Tumor invades submucosa
      • T2 - Tumor invades muscularis propria
      • T3 - Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissue
      • T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum.
    • Regional lymph nodes (N)
      • NX - Regional lymph nodes cannot be assessed
      • N0 - No regional lymph node metastasis
      • N1 - Metastasis in 1-3 pericolic or perirectal lymph nodes
      • N2 - Metastasis in 4 or more pericolic or perirectal lymph nodes
      • N3 - Metastasis in any lymph node along the course of a named vascular trunk
    • Distant metastasis (M)
      • MX - Presence of metastasis cannot be assessed
      • M0 - No distant metastasis
      • M1 - Distant metastasis


Medical Care:

Surgical Care:

  • Abdominal perineal resection
    • Abdominal perineal resection (APR) is performed in patients with lower-third rectal cancers who cannot undergo a sphincter-sparing procedure. This includes patients with complex involvement of the sphincters, preexisting significant sphincter dysfunction, or pelvic fixation, and sometimes is a matter of patient preference.
    • A 2-team approach is often used, with the patient in modified lithotomy position. One team mobilizes the colon and rectum, transects the colon proximally, and creates an end-sigmoid colostomy.
      • The perineal team begins by closing the anus with a purse-string suture and making a generous elliptical incision. The incision is carried through the fat using electrocautery. The inferior rectal vessels are ligated and the anococcygeal ligament is divided. The dissection plane continues posteriorly, anterior to the coccyx to the level of the levator ani muscles. Then, the surgeon breaks through the muscles and retrieves the specimen that has been placed in the pelvis. The specimen is brought out through the posterior opening, and the anterior dissection is continued carefully. Care must be taken to avoid the prostatic capsule in the male and the vagina in the female (unless posterior vaginectomy was planned). The specimen is removed through the perineum, and the wound is irrigated copiously. A closed-suction drain is left in place, and the perineal wound is closed in layers by using absorbable sutures.
      • During this time, the abdominal team closes the pelvic peritoneum (this is not mandatory), closes the abdomen, and matures the colostomy.
  • Treatment of colorectal cancer with liver metastasis: Chemotherapeutic regimens for liver metastasis including systemic and intrahepatic administration have only had limited benefit. Systemic chemotherapy had 18-28% response rates. It is well accepted that liver resections in selected patients are beneficial. Overall, 5-year survival rates following surgical resection of liver metastasis vary from 20- 40%.


The goals of pharmacotherapy are to down-stage a tumor, induce remission, reduce morbidity, and prevent complications.

Drug Category: Antineoplastic agents -- Chemotherapy has been studied extensively in rectal cancer. The combination of preoperative RT and chemotherapy with fluorouracil improves local control, distant spread, and survival rate. The basis of this improvement is believed to be the activity of fluorouracil as a radiosensitizer.

Other drugs in combination with fluorouracil have demonstrated activity in neoadjuvant studies. These include leucovorin and irinotecan.
Drug Name
Fluorouracil (5-FU, Fluorouracil, Adrucil) -- Blocks methylation of deoxyuridylic acid to thymidylic acid, thereby interfering with DNA synthesis. Dose is body-weight dependent and varies with specific protocol in which patient is involved.
Adult DoseNot to exceed 800 mg/d IV
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression; serious infection; topical administration; pregnancy
InteractionsAnticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents increase risk of bleeding; other immunosuppressive agents exacerbate bone marrow toxicity
Pregnancy D - Unsafe in pregnancy
PrecautionsNausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow suppression) may occur; adjust dosage in renal impairment
Drug Name
Vincristine (Vincasar PFS, Oncovin) -- Mechanism of action uncertain. May involve decrease in reticuloendothelial cell function or increase in platelet production. It is mitotic spindle inhibitor.
Adult DoseDose determined by oncologist involved; not routinely used to treat rectal cancer
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsMitomycin-C may cause acute pulmonary reaction
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution in patients with severe cardiopulmonary or hepatic impairment or preexisting neuromuscular disease
Drug Name
Leucovorin (Wellcovorin) -- Potentiates effects of fluorouracil. Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis.
Given just prior to fluorouracil.
Adult DoseDose determined by predetermined dosing regimen of fluorouracil
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; pernicious anemia; vitamin-deficient megaloblastic anemias
InteractionsNone reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsDo not administer intrathecally or intraventricularly
Drug Name
Irinotecan (Camptosar, Camptothecin-11, CPT-11) -- Inhibits topoisomerase I, inhibiting DNA replication and, consequently, cell proliferation.
Adult DoseDose depends on protocol in which patient is involved
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression; renal function impairment
InteractionsConcomitant administration with other antineoplastics may result in prolonged neutropenia, thrombocytopenia, and increased morbidity/mortality rates
Pregnancy D - Unsafe in pregnancy
PrecautionsAdverse effects include myelosuppression, dermatitis, nausea, and vomiting; monitor bone marrow function
Drug Name
Oxaliplatin (Eloxatin) -- A platinum-based antineoplastic agent used in combination with an infusion of 5-fluorouracil (5-FU) and leucovorin for the treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. It forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. The cytotoxicity is cell-cycle nonspecific.
Adult DoseDay 1: 85 mg/m2 IV over 2 h; administer simultaneously with leucovorin 200 mg/m2; followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV continuous infusion in 500 mL D5W over 22 h
Day 2: Leucovorin 200 mg/m2 IV over 2 h, followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV as a continuous infusion in 500 mL D5W over 22 h
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity to oxaliplatin or other platinum compounds
InteractionsMay increase 5-FU serum concentration by approximately 20%
Pregnancy D - Unsafe in pregnancy
PrecautionsAnaphylaxis may occur within minutes of administration; may cause neuropathy, pulmonary fibrosis, bone marrow suppression, GI tract symptoms (eg, nausea, vomiting, stomatitis), renal or hepatic toxicity (decrease dose), or thromboembolism; dilute IV only in dextrose-containing solution
Drug Name
Cetuximab (Erbitux) -- Recombinant human/mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor. Indicated for treating irinotecan-refractory, EGFR-expressed, metastatic colorectal carcinoma. Treatment is preferably combined with irinotecan. May be administered as monotherapy if irinotecan is not tolerated.
Adult DoseFirst dose: 400 mg/m2 IV infused over 2 h
Weekly maintenance doses: 250 mg/m2 IV infused over 1 h
Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min); must administer with low-protein–binding 0.22 mm in-line filter; premedication with an H1 antagonist (eg, diphenhydramine 50 mg IV) recommended
Pediatric DoseNot established
ContraindicationsNone reported
InteractionsLimited data exist; none reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCaution with documented hypersensitivity, including allergy to murine proteins; may cause infusion-related hypotension and airway distress (eg, bronchospasm, stridor, hoarseness), particularly with the first infusion (90%); premedicate with diphenhydramine 50 mg IV; decrease dose with mild or moderate (grade 1 or 2) infusion reaction and immediately and permanently discontinue with severe (grade 3 or 4) infusion reaction; common adverse effects include acnelike rash, dry skin, tiredness or weakness, fever, constipation, and abdominal pain; may rarely cause interstitial lung disease; do not shake or dilute solution; sunlight can exacerbate any skin reactions
Drug Name
Bevacizumab (Avastin) -- Indicated as a first-line treatment for metastatic colorectal cancer. Murine-derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in combination with standard chemotherapy.
Adult Dose5 mg/kg IV q2wk until disease progression detected
Pediatric DoseNot established
ContraindicationsNone reported
InteractionsCoadministration with 5-fluorouracil increases frequency (2-fold) of serious and fatal arterial thromboembolic events (ie, CVA, MI, TIAs, angina)
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsAngiogenesis is critical to fetal development, and use of bevacizumab during pregnancy likely results in adverse fetal effects; common adverse effects include hypertension, fatigue, thrombosis, diarrhea, leukopenia, proteinuria, headache, anorexia, and stomatitis; may cause serious or fatal (but rare) events, including gastrointestinal tract perforation, intra-abdominal infections, impaired wound healing, hemoptysis (particularly with lung cancers), and internal bleeding; increases risk of serious and fatal arterial thrombotic events with 5-fluorouracil; do not initiate treatment for at least 28 d after major surgery (the surgical incision should be fully healed); breastfeeding should be discontinued during and for at least 20 d after treatment with bevacizumab
Drug Name
Panitumumab (Vectibix) -- Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). Indicated to treat colorectal cancer that has metastasized following standard chemotherapy.
Adult Dose6 mg/kg IV infused over 60 min q2wk
Pediatric DoseNot established
ContraindicationsNone known
InteractionsData limited; none reported
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsCommon adverse effects include rash, fatigue, abdominal pain, nausea, and diarrhea; serious adverse effects include pulmonary fibrosis, severe rash complicated by infections, infusion reactions (for grade I or II reaction, reduce infusion rate by 50%; for grade III or IV reaction, immediately discontinue permanently), ocular toxicity, abdominal pain, vomiting, and constipation; administer using low-protein–binding filter



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