Chapter 64. Colon Cancer

A 72-year-old man reports rectal bleeding with bowel movements over the past several months and the stool seems narrower with occasional diarrhea. He has a history of hemorrhoids but at this time is not experiencing rectal irritation or itching, as with previous episodes. His medical history is significant for controlled hypertension and a remote history of smoking. On digital rectal examination, his stool sample tests positive for blood but anoscopy fails to identify the source of bleeding. On colonoscopy, a mass is seen at 30 cm (Figure 64-1). A biopsy was obtained and pathology confirmed adenocarcinoma.

Colon cancer is a malignant neoplasm of the colon, most commonly adenocarcinoma. With the establishment of screening programs and treatment improvements, there has been a slow decline in both the incidence and mortality from colon cancer, although it is still a leading cause of cancer death.1

• Colon cancer is the third most common cancer in both men and women in the United States, second only to lung cancer as a cause of death.1
• The incidence and mortality have been slowly but steadily declining in the United States for the past decade.2 The American Cancer Society estimated there were 142,570 new cases of colorectal cancer (102,900 colon cancer cases) and 51,370 deaths in 2010.3
• Onset is after age 50 years and peaks at around age 65 years.
• Proximal colon carcinoma rates in blacks are higher than in whites.4

• Colon cancer appears to be a multipathway disease with tumors usually arising from adenomatous polyps or serrated adenomas; mutational events occur within the polyp including activation of oncogenes and loss of tumor-suppressor genes.1,5
• The probability of a polyp undergoing malignant transformation increases for the following cases:1
  • The polyp is sessile, especially if villous histology or flat.
  • Larger size—Malignant transformation is rare if smaller than 1.5 cm, 2% to 10% if 1.5 to 2.5 cm, and 10% if larger than 2.5 cm.
• Important genes involved in colon carcinogenesis include adenomatous polyposis gene mutations, KRAS oncogene, chromosome 18 loss of heterozygosity leading to inactivation of SMAD4, and DCC tumor-suppression genes (deleted in colon cancer). Other mutations in genes, such as MSH2, MLH1, and PMS2, result in what is known as high-frequency microsatellite instability (H-MSI), which is found in cases of hereditary nonpolyposis colon cancer and in approximately 20% of sporadic colon cancers.4

See References 1 and 6.

• Ingestion of red and processed meat.
• Hereditary syndromes—Polyposis coli and nonpolyposis syndromes (40% lifetime risk).4
• Inflammatory bowel disease.
• Bacteremia with Streptococcus bovis—Increased incidence of occult tumors.
• Following ureterosigmoidostomy procedures (5% to 10% incidence over 30 years).
• Smoking.
• Alcohol consumption.
• Family history of colon cancer in a first-degree relative.
• Obesity.

The diagnosis of colon cancer is sometimes made following a positive screening test [i.e., digital rectal examination, fecal occult blood test (FOBT), sigmoidoscopy, colonoscopy, or barium enema]. For patients who have symptoms and signs suggestive of colon cancer, the confirmative diagnostic test most commonly performed is colonoscopy with biopsy. Colonoscopy allows direct visualization of the lesion, examination of the entire large bowel for synchronous and metachronous lesions, and an ability to obtain tissue for histologic diagnosis.

Clinical Features

Symptoms vary, primarily based on anatomic location, as follows:1

• Right-sided colon tumors more commonly ulcerate, occasionally causing anemia without change in stool or bowel habits.
• Tumors in the transverse and descending colon often impede stool passage causing abdominal cramping, occasional obstruction, and rarely perforation (Figure 64-5).
• Tumors in the rectosigmoid region are associated more often with hematochezia, tenesmus (i.e., urgency with a feeling of incomplete evacuation), narrow caliber stool, and uncommonly, anemia.

Physical signs often appear later in the course of the disease and can include:4

• Weight loss and cachexia.
• Abdominal distention, discomfort, or tenderness.
• Abdominal or rectal mass.
• Ascites.
• Rectal bleeding or occult blood on rectal examination.

Typical Distribution

Colon cancers are approximately equally distributed between the right and left colon.7

Imaging, Endoscopy, and Work-Up

• Colonoscopy of the entire colon is recommended to identify additional neoplasms or polyps (Figures 64-1 and 64-2).
• Evaluation for metastatic disease includes:8
  • Local metastasis: Abdominal/pelvic CT scans.
  • Lung metastasis: Chest x-ray or chest CT.
  • Liver metastasis: MRI (pelvis), CT (abdomen and pelvis) or positron emission tomography (PET) CT scan (whole body).
  • The American College of Radiology also recommends transrectal rectum ultrasound for pretreatment staging for patients with rectal cancer and the addition of MRI of the abdomen for patients with large rectal tumors.9
  • Preoperative carcinoembryonic antigen (CEA)—An elevated CEA level can be used to monitor for recurrence. Pretreatment CEA (C-stage) is an independent predictor of overall mortality (60% increased risk) in patients with colon cancer.10 CEA may be elevated for reasons other than colon cancer, such as pancreatic or hepatobiliary disease; elevation does not always reflect cancer or disease recurrence.
  • At surgery, surgeons perform an examination of the liver, pelvis, hemidiaphragm, and full length of the colon for evidence of tumor spread.1

Biopsy

Colonic adenocarcinomas may be microscopically well-differentiated or poorly differentiated glandular structures.4 The addition of cytology brushings to forceps biopsies may increase the diagnostic yield, especially in the setting of obstructing tumors that cannot be traversed.11

Other causes of abdominal pain in patients in this age group:

• Inflammatory bowel disease, which includes ulcerative colitis and Crohn disease (see Chapter 65, Ulcerative Colitis); symptoms include bloody diarrhea, tenesmus, passage of mucus, and cramping abdominal pain. Extraintestinal manifestations, more common in Crohn disease, include skin involvement (e.g., erythema nodosum), rheumatologic symptoms (e.g., peripheral arthritis, symmetric sacroiliitis), and ocular problems (e.g., uveitis, iritis). Diagnosis may be made on the basis of endoscopy.
• Diverticulitis—Patients present with fever, anorexia, lower left-sided abdominal pain, and diarrhea. Abdominal distention and peritonitis may be found on physical examination. Diagnosis is clinical or made on the basis of abdominal CT scan.
• Appendicitis—Initial symptoms include periumbilical or epigastric abdominal pain that over time becomes more severe and localized to the right lower quadrant. Additional symptoms include fever, nausea, vomiting, and anorexia.

Other causes of rectal bleeding:

• Infectious agents—Salmonella, Shigella, certain Campylobacter species, enteroinvasive Escherichia coli, Clostridium difficile, and Entamoeba histolytica can cause bloody, watery diarrhea, and are identified by culture test. Bacterial toxins may be identified with C. difficile. Additional symptoms include fever and abdominal pain and the disease is often self-limited.
• Hemorrhoids (see Chapter 66, Hemorrhoids) and fissures—Bleeding is usually bright red blood and seen in the toilet or with wiping after bowel movements. Hemorrhoids can sometimes be visible as a protruding mass often associated with pruritus, and fissures are identified as a cut or tear occurring in the anus. Hemorrhoidal pain is described as a dull ache but may be severe if thrombosed.
• Diverticula—Bleeding is usually abrupt in onset, painless, and may be massive, but often stops spontaneously. These may be seen in endoscopy or in radiographic study.
• Vascular colonic ectasias—Bleeding tends to be chronic resulting in anemia. Bleeding source may be identified during colonoscopy, but a radionuclide scan or angiography may be needed.
• Colon polyp (see Chapter 63, Colon Polyps)—Usually asymptomatic, although abdominal pain, diarrhea, or constipation can occur often with decreased stool caliber. Imaging studies often can distinguish and biopsy confirms absence of malignancy.

Other causes of intestinal obstruction include adhesions, peritonitis, inflammatory bowel disease, fecal impaction, strangulated bowels, and ileus.2

Medications

• Chemotherapy with fluorouracil (5-FU), irinotecan, with or without leucovorin is of marginal benefit with overall response in approximately 15% to 20% of patients.1 For patients with stage II (Duke B) tumors (invasion into or through muscularis propria), authors of a systematic review found similar mortality rates with and without adjuvant chemotherapy.12
• Six months of postoperative treatment with 5-FU and leucovorin decreased recurrence for stage III (Duke C) tumors (lymph node involvement) by 40% and increased survival1; the absolute survival benefit in one trial over leucovorin alone was approximately 12% (49% vs. 37%, respectively).13 A reduction in relapse rate and a modest increase in 3-year disease-free survival were also seen in patients with Duke B and C colon cancer by adding oxaliplatin to 5-FU-leucovorin; however, overall survival is only improved for a subgroup of patients.14
• For patients with metastatic disease (stage IV/Duke D), first-line multiagent chemotherapy can be considered. Three randomized controlled trials have demonstrated improved response rates, progression-free survival, and overall survival when a biologic agent (irinotecan or oxaliplatin) was combined with 5-FU- leucovorin.15

Surgery or Other Treatments

• Total resection of the tumor is completed for attempted cure or for symptoms; open surgery or laparoscopic techniques may be used.16
• For superficial lesions, local excision or polypectomy with clear margins is performed; for other localized disease, wide surgical resection and reanastomosis is used.
• For patients with metastatic disease (stage IV/Duke D), treatment options include surgical resection, resection of liver metastases, palliative radiation or chemotherapy, first-line multiagent chemotherapy (see above), or participation in clinical trials.
• Total colonic resection is performed for patients with familial polyposis and multiple colonic polyps.
• For rectal carcinoma, sharp dissection is recommended (versus blunt) for rectal tumors to reduce recurrence to approximately 10%.1 In addition, radiation therapy of the pelvis also decreases regional recurrence.1 Postoperative treatment with 5-FU and radiation decreases recurrence for stages B2 and C tumors.1
• Preoperative radiation therapy can be used to shrink large tumors prior to resection.

• Primary prevention—Increased dietary fiber (conflicting evidence) and possibly increased ingestion of fruit, vegetables, fish, and milk.6,17 High levels of physical activity also appear protective.6,17 Low-dose aspirin is also associated with a lower risk of colon cancer and death from colon cancer.18 Other medications possibly associated with a lower colon cancer risk include hormone therapy and oral contraceptives.
• Individuals who undergo at least one round of screening for colon cancer have a reduced risk of death from bowel cancer. In addition, early polyp removal by colonoscopy with polypectomy is associated with a reduced risk for colorectal cancer in the population setting.19 Of the screening tests, high-sensitivity fecal occult blood testing, flexible sigmoidoscopy (FSG) with fecal occult blood testing, and colonoscopy are recommended options.20 The U.S. Preventive Services Task Force (USPSTF) recommends screening for colorectal cancer in adults, beginning at age 50 years and continuing until age 75 years.20 SOR A
• FOBT—This test will be positive in 2% to 4% of asymptomatic patients; less than 10% will have colon cancer.1 There is good evidence that periodic fecal occult blood testing reduces mortality from colorectal cancer; annual screening is recommended.20
• FSG—There is good evidence that sigmoidoscopy in combination with fecal occult blood testing reduces mortality from colon cancer.11 The ideal interval for surveillance is unknown, but the USPSTF recommends a 5-year interval of surveillance by FSG combined with a high-sensitivity FOBT every 3 years.20
• Colonoscopy—There is emerging evidence that screening colonoscopy is effective in reducing colorectal cancer mortality. Population-based observational study shows a declining incidence of colon cancer and gains in life-years where colonoscopy screening programs are in place. Colonoscopy also allows inspection of the proximal colon and early removal of polyps.11,21 Examples of colonoscopy pictures are shown in Figures 64-1, 64-2, 64-3
• Double-contrast barium enema—This test offers an alternative means of whole-bowel examination, but is less sensitive than colonoscopy and there is no direct evidence that it is effective in reducing mortality rates. Figures 64-4 and 64-5 display classic “apple-core deformities” of the colon from colon cancers.
• Other tests—CT colonography and stool DNA tests have been available for colorectal cancer screening. However, more research is needed to study their potential benefits and harms before widespread clinical use of these tests can be recommended as screening tools.22
• Secondary prevention—Low-dose aspirin (81 mg) prevents adenomas in patients with previous colon cancer.23

See References 1 and 24

• Duke A (T1N0M0)—Cancer limited to mucosa and submucosa; 5-year survival: 90.1%.
• Duke B1 (T2N0M0)—Cancer extends into muscularis; 5-year survival: 85%.
• Duke B2 (T3N0M0)—Cancer extends into or through serosa; 5-year survival: 70% to 80%.
• Duke C (TxN1M0)—Cancer involves regional lymph nodes; 5-year survival: 35% to 69.2%.
• Duke D (TxNxM1)—Distant metastases (i.e., lung, liver); 5-year survival: 5% to 11.7%.
• In addition to node involvement and metastases, poor outcome is associated with:1
  • Number of regional lymph nodes involved.
  • Tumor penetration or perforation through the bowel wall.
  • Histology of poor differentiation.
  • Tumor adherence to adjacent organs.
  • Venous invasion.
  • Elevated preoperative CEA (i.e., >5 ng/mL).
  • Aneuploidy.
• Specific chromosomal deletion (e.g., allelic loss on chromosome 18q).

• Staging is based on tumor depth and spread and predicts survival as above.1
• Surveillance recommendations are as follows:25
  • Office visits and CEA evaluations should be performed at a minimum of 3 times per year for the first 2 years of follow-up. SOR A
  • There is insufficient data to recommend for or against chest x-ray (CXR) as a part of routine colorectal cancer follow-up. SOR C
  • Posttreatment colonoscopy should be performed at 3-year intervals. SOR A
  • Periodic anastomotic evaluation is recommended for patients who have undergone resection/anastomosis or local excision of rectal cancer. SOR B
  • Serum hemoglobin, hemoccult II (FOBT), and liver function tests (hepatic enzymes tests) should not be routine components of a follow-up program. SOR A
• For patients with progressive disease, options for further therapy must be discussed, including discontinuing therapy, intrahepatic chemotherapy (if appropriate), and experimental (i.e., phase I) therapy.

• Most recurrences occur within the first 3 to 4 years, so survival at 5 years is a good indication of cure.1
• Surveillance for recurrence should be conducted over the first 5 years following treatment as noted above. In addition to identifying recurrence, a second tumor is found in 3% to 5% and adenomatous polyps will be found in more than 15% of patients over that period.1

Patient Resources

• www.nlm.nih.gov/medlineplus/ency/article/000262.htm.
• http://www.cancer.gov/cancertopics/pdq/treatment/colon/patient.

Provider Resources

• http://www.cancer.gov/cancertopics/pdq/treatment/colon/HealthProfessional.
• http://emedicine.medscape.com/article/277496-overview.