Second most common internal cancer in humans; accounts for 10% of cancer-related deaths in the United States; incidence increases dramatically above age 50, nearly equal in men and women. In 2019, 145,600 new cases, 51,020 deaths.
ETIOLOGY AND RISK FACTORS
Most colon cancers arise from adenomatous polyps. Genetic steps from polyp to dysplasia to carcinoma in situ to invasive cancer have been defined, including point mutation in K-ras proto-oncogene, hypomethylation of DNA leading to enhanced gene expression, allelic loss at the APC gene (a tumor suppressor), allelic loss at the DCC (deleted in colon cancer) gene on chromosome 18, and loss and mutation of p53 on chromosome 17. Hereditary nonpolyposis colon cancer arises from mutations in the DNA mismatch repair genes, hMSH2 gene on chromosome 2 and hMLH1 gene on chromosome 3. Mutations lead to colon and other cancers. Diagnosis requires three or more relatives with colon cancer, one of whom is a first-degree relative; one or more cases diagnosed before age 50; and involvement of at least two generations. Environmental factors also play a role including exposure to therapeutic radiation; smoking; increased prevalence in developed countries, urban areas, advantaged socioeconomic groups; increased risk in pts with hypercholesterolemia, coronary artery disease; correlation of risk with low-fiber, high-animal-fat diets, although direct effect of diet remains unproven; decreased risk with long-term dietary calcium supplementation and, possibly, daily aspirin ingestion. Risk increased in first-degree relatives of pts; families with increased prevalence of cancer; and pts with history of breast or gynecologic cancer, familial polyposis syndromes, >10-year history of ulcerative colitis or Crohn’s colitis, >15-year history of ureterosigmoidostomy. Tumors in pts with strong family history of malignancy are frequently located in right colon and commonly present before age 50; high prevalence in pts with Streptococcus bovis bacteremia.
Nearly always adenocarcinoma; 75% located distal to the splenic flexure (except in association with polyposis or hereditary cancer syndromes); may be polypoid, sessile, fungating, or constricting; subtype and degree of differentiation do not correlate with course. Degree of invasiveness at surgery (Dukes’ classification) is single best predictor of prognosis (Fig. 72-1). Rectosigmoid tumors may spread to lungs early because of systemic paravertebral venous drainage of this area. Other predictors of poor prognosis: preoperative serum carcinoembryonic antigen (CEA) >5 ng/mL (>5 µg/L), poorly differentiated histology, bowel perforation, venous invasion, adherence to adjacent organs, aneuploidy, specific deletions in chromosomes 5, 17, 18, and mutation of ras proto-oncogene. Fifteen percent have defects in DNA repair.
Left-sided colon cancers present most commonly with rectal bleeding, altered bowel habits (narrowing, constipation, intermittent diarrhea, tenesmus), and abdominal or back pain; cecal and ascending colon cancers more frequently present with symptoms of anemia, occult blood in stool, or weight loss; other complications: perforation, fistula, volvulus, inguinal hernia; laboratory findings: anemia in 50% of right-sided lesions.
Early diagnosis aided by screening asymptomatic persons with fecal occult blood testing (see next); >50% of all colon cancers are within reach of a 60-cm flexible sigmoidoscope; air-contrast barium enema will diagnose ∼85% of colon cancers not within reach of sigmoidoscope; colonoscopy most sensitive and specific, permits tumor biopsy and removal of synchronous polyps (thus preventing neoplastic conversion), but is more expensive. Radiographic or virtual colonoscopy has not been shown to be a better diagnostic method than colonoscopy.
Treatment: Colorectal Cancer
Local disease: Surgical resection of colonic segment containing tumor; preoperative evaluation to assess prognosis and surgical approach includes full colonoscopy, chest films, biochemical liver tests, plasma CEA level, and possible abdominal CT. Resection of isolated hepatic metastases possible in selected cases. Adjuvant radiation therapy to pelvis with concomitant 5FU chemotherapy decreases local recurrence rate of rectal carcinoma (no apparent effect on survival); radiation therapy without benefit on colon tumors; preoperative radiation therapy may improve resectability and local control in pts with rectal cancer. Total mesorectal excision is more effective than conventional anteroposterior resection in rectal cancer. Adjuvant chemotherapy (5FU/leucovorin plus oxaliplatin, or FOLFOX plus bevacizumab, or 5FU/leucovorin plus irinotecan, or FOLFIRI) decreases recurrence rate and improves survival of stage C (III); survival benefit from adjuvant therapy is not so clear in stage B (II) tumors; periodic determination of serum CEA level useful to follow therapy and assess recurrence. Follow-up after curative resection: Yearly liver tests, complete blood count, follow-up radiologic or colonoscopic evaluation at 1 year—if normal, repeat every 3 years, with routine screening interim (see below); if polyps detected, repeat 1 year after resection. Advanced tumor (locally unresectable or metastatic): Systemic chemotherapy (5FU/leucovorin plus oxaliplatin plus bevacizumab), irinotecan usually used in second treatment; antibodies to the epidermal growth factor (EGF) receptor (cetuximab, panitumumab) appear to enhance the effect of chemotherapy but are ineffective in tumors with ras mutations; intraarterial chemotherapy (floxuridine [FUDR]) and/or radiation therapy may palliate symptoms from hepatic metastases. Solitary hepatic metastases may be resected by partial hepatectomy with 25% 5-year survival. The subset of pts with mismatch repair deficiency appear more sensitive to chemotherapy and to immune checkpoint inhibitors.
Early detection of colon carcinoma may be facilitated by routine screening of stool for occult blood (Hemoccult II, ColonCare, Hemosure); however, sensitivity only ∼50% for carcinoma; specificity for tumor or polyp ∼25–40%. Newer tests (e.g., Cologard) incorporating detection of blood and mutated genes are more sensitive and specific. False positives for occult blood: ingestion of red meat, iron, aspirin; upper GI bleeding. False negatives: vitamin C ingestion, intermittent bleeding. Genetic testing is unaffected by these factors. Annual digital rectal examination and fecal occult blood testing recommended for pts over age 40, screening by flexible sigmoidoscopy every 3 years after age 50, earlier in pts at increased risk (see above); careful evaluation of all pts with positive fecal occult blood tests (flexible sigmoidoscopy and air-contrast barium enema or colonoscopy alone) reveals polyps in 20–40% and carcinoma in ∼5%; screening of asymptomatic persons allows earlier detection of colon cancer (i.e., earlier Dukes’ stage) and achieves greater resectability rate; decreased overall mortality from colon carcinoma seen only after 13 years of follow-up. More intensive evaluation of first-degree relatives of pts with colon carcinoma frequently includes screening air-contrast barium enema or colonoscopy after age 40. NSAIDs and cyclooxygenase 2 inhibitors appear to prevent polyp development and induce regression in high-risk groups, but have not been recommended for average-risk pts at this time.