Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 3/25/2013
Definition 
Colorectal Cancer (CRC) is a neoplastic disease arising from the mucosal surface of the large intestine, and attributable multiple factors including age, colorectal polyps, genetics, lifestyle factors and many other risk factors.
Description
- When localized to the large intestine and treated in its early stages, colorectal cancer (CRC) is frequently curable
- Histologic colon cancer types
- Adenocarcinoma: Most common colon cancer type
- Mucinous (colloid) adenocarcinoma
- Signet ring adenocarcinoma
- Scirrhous tumors
- Neuroendocrine: Tumors of this type usually have a worse prognosis than variants of adenocarcinoma
- American Joint Committee on Cancer (AJCC) colon cancer staging by TNM classification (T = primary tumor; N = regional lymph nodes; M = distant metastasis):
- For extensive details from the National Cancer Institute on AJCC staging of Colorectal Cancer, please visit www.cancer.gov
Epidemiology
Incidence/Prevalence
- Estimated new cases and death from colon cancer in the U.S. for 2013:
- 103,170 (new cases from colon cancer only)
- 51,690 (death from colon and rectal cancers combined)
- It is the third most common cancer worldwide and the second most common cause of cancer deaths in first world countries
Age
- Colorectal cancer (CRC) risk increases with advancing age and >90% cases occur in people aged
50 years
Gender
- Incidence of CRC is somewhat greater in men than in women
- Male incidence rate increases by subsite, and progressing from the cecum to the rectum
Race
- African Americans have higher incidence rates of CRC
Genetics
- 75% of cases of CRC are sporadic while the remaining 25% of cases have some genetic/family history component. Genetic mutations are the cause of inherited colon cancer risk in a small number of families
- Hereditary mutation of the APC gene is the cause of familial adenomatous polyposis (FAP) in which affected individuals carry an almost 100% risk of developing CRC
- Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition which has a 80% life-time risk for CRC. This condition comprises approximately 5% of all CRC cases
Risk factors
Non-modifiable Risk Factors
- Age: Risk of developing CRC increases with advancing age; 90% of cases occur in people 50 years of age
- Inflammatory bowel disease: Individuals with long-standing cases of ulcerative colitis or Crohn's disease have a higher risk of developing CRC
- Personal or a family history of CRC or colorectal polyps
- Inherited colon cancer-predisposition syndromes
- Hereditary non-polyposis colorectal cancer (HNPCC)
- Familial adenomatous polyposis (FAP)
- MUTYH-associated polyposis
- Peutz-Jeghers syndrome
- Turcot syndrome
- Race/Ethnicity: African Americans, Ashkenazi Jews
- Type 2 diabetes
Modifiable Risk Factors
- Alcohol consumption (may be secondary to low folate intake)
- Diet high in red or processed meats and cooking meats at very high temperatures
- Diet low in fiber, high in fat, and low in vegetables, fruits and grains increases CRC risk
- Lack of regular physical activity and sedentary lifestyle
- Overweight and obesity
- Smoking
Etiology
- Cell molecular changes and dietary factors contribute to the development of CRC
- Lifestyle factors are a significant modifiable risk factor in developing CRC
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History
- Signs of CRC are less noticeable early in the course of the disease; in more advanced stages, patients commonly present with symptoms such as:
- Abdominal pain
- Altered bowel habits
- Anemia (symptoms of – low energy, weakness, dyspnea, tachycardia)
- Involuntary weight loss
- Rectal bleeding
- Patients may also present with diarrhea or constipation. Recent change in bowel habits in an older patient should be a concern for colon cancer
- Uncommon symptoms include
- Abdominal distention
- Anorexia
- Malaise
- Nausea and vomiting
- Cancer location, size and presence of metastasis also relate to expected symptoms:
- Partial or complete bowel obstruction is more common in left sided CRC
- Large exophytic cancers can also obstruct the colonic lumen
- Partial intestinal obstruction produces symptoms such as constipation, nausea, abdominal distention, and abdominal pain. Overflow diarrhea may occur if stool moves around an obstruction intermittently
- Distal CRC may present with gross rectal bleeding
- Proximal cancer bleeding is generally occult, with patients presenting with iron deficiency anemia without any obvious etiology
- Patients with anemia may have symptoms such as low energy, weakness, fatigue, dyspnea, or tachycardia
- Cases of metastatic cancer may lead to:
- Anorexia
- Ascites
- Cachexia
- Feeling of poor health
- Involuntary weight loss
- Muscle weakness
- Specific issues with metastatic disease (bone, brain, liver, lung, and peritoneal metastasis are common)
Physical findings on examination
- Colon cancer primarily manifests signs in the advanced phase
- Pallor may be present due to anemia from GI bleeding (acute or chronic)
- Koilonychias (spoon nails), glossitis and cheilosis (cracks in corner of mouth) may be present in case of iron deficiency anemia
- Patients with hypoalbuminemia may show clinical manifestations such as peripheral edema, ascites, or anasarca
- Abdominal examination may demonstrate hypoactive or high-pitched bowel sounds along with distension in cases of obstruction
- Diffuse abdominal tenderness with peritonism can occur in cases of perforation around a malignancy
- Cases of advanced disease can rarely present with a palpable abdominal mass
- Rectal cancer may be palpable by digital rectal examination
- Other rare findings include
- Peripheral lymphadenopathy, especially a Virchow's node in the left supraclavicular space
- Hepatic enlargement due to hepatic metastases
- Temporal or intercostal muscle wasting due to cancer cachexia
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Blood test findings
Consider routine blood tests, including complete blood count (CBC), and comprehensive panel (renal, liver, electrolyte, glucose). In cases with significant hepatic dysfunction (e.g. metastatic disease to liver) an INR (Prothrombin time) is indicated.
- Complete blood count (CBC): 50% of patients with colon cancer are anemic. In patients presenting with an iron deficiency anemia of unclear cause, colon cancer is a likely cause and should be evaluated for (especially in elderly age groups)
- Chemistries and liver function tests (LFTs): Usually are normal unless metastatic disease is present
- Alkaline phosphatase levels may increase in cases of hepatic or bony metastases
- Serum lactate dehydrogenase level may be elevated in cases of colon cancer
- Patients rarely present with electrolyte abnormalities or dehydration due to diarrhea with colon cancer. Hypovolemia, Hypokalemia, or alkalosis may be occasionally seen if there is significant vomiting
- Serum carcinoembryonic antigen (CEA) level:
- Has moderate sensitivity and poor specificity
- Advanced cases of colon cancer often marked increases in CEA level
- Levels tend to be minimally elevated in patients with early and highly curable colon cancer
- This test has poor specificity as other colonic conditions and systemic disorders may also cause elevated levels
- CEA should be conducted preoperatively as it does serve some predictive value in determining cancer prognosis, with higher levels indicated the cancer is more likely to be extensive and recurrent
- CEA levels, when initially abnormal can be useful post-operatively in following the status of colon cancer and in monitoring for recurrence
Other laboratory test findings
- Histologic findings: Microscopically, colon cancers are classified as well differentiated, moderately well differentiated, or poorly differentiated. Poorly differentiated types have an unfavorable prognosis and account for approximately 20% of cases. 15% of CRCs are mucinous (colloid) due to prominent mucin accumulation inside the cell; these cases tend to be more aggressive
Radiographic findings
- Chest X-ray: Is reasonable to assess for lung metastasis
- Computed tomography (CT) scan: The standard modality for abdominal imaging in cases of colorectal cancer, CT is highly accurate in the detection of hepatic metastasis. This modality is also useful in cases of scirrhous CRC due to distinctive findings
- Barium enema: This imaging modality shows moderate sensitivity in the detection of CRC. It is however less sensitive than colonoscopy for detecting CRC and colonic polyps
- Magnetic resonance imaging (MRI): Is superior to CT in the detection of focal liver metastases and other small metastases. However, CT remains the standard modality for detection of hepatic metastases due to lower cost, greater availability, and more widespread expertise in image interpretation
- Contrast enhanced ultrasound (CEUS) of the abdomen/liver: Can be useful in evaluation for hepatic metastases
- Endoscopic ultrasound: This imaging modality can be used to evaluate the extent of rectal cancer. Endosonography has a greater accuracy for the T aspect of the TNM staging system than CT
- Fluorine-18-deoxyglucose (FDG) PET scan: Systematic reviews show inadequate evidence for routine use of FDG PET scans in primary CRC. Additionally only a small amount of evidence supports the use of FDG PET scan in the preoperative staging of recurrent and metastatic CRC
Other diagnostic test findings
- Colonoscopy: In cases of suspected CRC, colonoscopy with biopsy of suspicious lesion(s) is recommended. Colonoscopy rarely misses cases of colon cancer, and also helps to detect colonic polyps
- Flexible sigmoidoscopy: This examination is an option when colonoscopy is not available. Sigmoidoscopy markedly reduces the incidence and mortality of CRC in average-risk patients, through detection of polyps, adenoma's and carcinoma. The limitation is that this examination only examines part of the colon and malignancy or pre-malignancy may be present in unscreened portions
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General treatment items
Primary Surgical Therapy
- Standard treatment for patients with colon cancer consists of surgical resection of the affected region of colon or rectum, along with removal of primary and regional lymph nodes when localized disease (stage I-III) is present
- Laparoscopic approach has been demonstrated equivalent to standard open approach in overall survival and disease free survival
- 25-40% of the highly selected patients who develop resectable metastases in the liver and lung are cured by surgery
Adjuvant Chemotherapy- The role of adjuvant chemotherapy for patients with stage II colon cancer is controversial. Clinical trials have suggested a 2% to 4% improvement in overall survival for patients treated with adjuvant fluorouracil (5-FU)–based therapy compared with observation
- Capecitabine is increasingly being used as monotherapy or as a combined therapy with oxaliplatin and irinotecan in addition to 5-FU
- 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer before the year 2000. Since that time, it is felt that capecitabine is an equivalent alternative to 5-FU and leucovorin. Adjunctive oxaliplatin with 5-FU and leucovorin improves overall survival compared to 5-FU and leucovorin alone
Biologic agents- Bevacizumab showed improved progression-free and overall survival when added to chemotherapy (IFL, fluorouracil+irinotecan)
- Cetuximab and panitumumab are the other two biologic agents approved for colorectal cancer. Cetuximab is approved as monotherapy or in combination with irinotecan in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy
- Panitumumab is indicated as a monotherapy in cases of colorectal cancer where combined chemotherapy fails or not tolerated
Adjuvant Radiation Therapy- The role of adjuvant radiation therapy for patients with colon cancer (above the peritoneal reflection) is not well defined, although reviews suggest that radiation therapy has a role in certain high-risk subsets of colon cancer patients (T4, tumor location in immobile sites, local perforation, obstruction, and residual disease post-resection)
- Adjuvant radiation therapy has no role in the management of patients following curative resection, but may be helpful in cases of residual disease
Standard Treatment Options as per stages- Stage 0
- Local excision or simple polypectomy with clear margins
- Colon resection for larger lesions not amenable to local excision
- Stage I
- Wide surgical resection and anastomosis
- Stage II
- Wide surgical resection and anastomosis
- Adjuvant chemotherapy
- The role of adjuvant chemotherapy for patients with stage II colon cancer remains controversial
- The National Surgical Adjuvant Breast and Bowel Project (NSABP) has indicated that the reduction in risk of recurrence following adjuvant therapy in patients with stage II disease is of similar magnitude to that of patients with stage III disease treated with adjuvant therapy; however, an overall advantage has not been established
- The American Society of Clinical Oncology (ASCO) guidelines state that direct evidence from randomized controlled trials do not support use of adjuvant chemotherapy routinely for patients with stage II colon cancer
- There is an increased risk of recurrence in patients with stage II colon cancer with features such as inadequate lymph node sampling, T4 disease, involvement of the visceral peritoneum, and poorly differentiated histology
- Stage III
- Wide surgical resection and anastomosis
- Drug combinations used in this stage:
- FOLFOX4 regimen (oxaliplatin, leucovorin, and fluorouracil [5-FU])
- Levamisole regimen (5-FU and levamisole)
- Mayo Clinic or North Central Cancer Treatment Group (NCCTG) regimen (5-FU and low-dose leucovorin)
- Roswell Park or National Surgical Adjuvant Breast and Bowel Project (NSABP) regimen (5-FU and high-dose leucovorin)
- Stage IV and recurrent colon cancer
- Surgical resection of locally recurrent cancer
- Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases
- Resection of liver metastases in selected metastatic patients (5-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients
- Resection of isolated pulmonary or ovarian metastases in selected patients
- Palliative radiation therapy
- Palliative chemotherapy
- Drugs combinations used in this stage are as follow
- Arbeitsgemeinschaft Internistische Onkologie (AIO) or German AIO regimen (folic acid, 5-FU, and irinotecan)
- CAPOX regimen (Capecitabine plus oxaliplatin)
- Douillard regimen (folic acid, 5-FU, and irinotecan)
- FOLFOX4 regimen (oxaliplatin, leucovorin, and 5-FU)
- FOLFOX6 regimen (oxaliplatin, leucovorin, and 5-FU)
- FOLFIRI regimen (folic acid, 5-FU, and irinotecan)
- FUFOX regimen (oxaliplatin plus leucovorin plus 5-FU)
- FUOX regimen (5-FU plus oxaliplatin)
- IFL (or Saltz) regimen (irinotecan, 5-FU, and leucovorin)
- XELOX regimen (capecitabine plus oxaliplatin)
Medications indicated with specific doses
- Bevacizumab [IV] (Avastin)
- Capecitabine (Xeloda)
- Cetuximab [IV] (Erbitux)
- Fluorouracil [IV]
- Irinotecan [IV] (Camptosar)
- Leucovorin [IM/IV]
- Oxaliplatin [IV] (Eloxatin)
- Panitumumab [IV] (Vectibix)
Dietary or Activity restrictions
- Alcohol consumption increases CRC risk, however, this may be secondary to lower folate intake in this group
- Diet high in red or processed meats and cooking meats at very high temperatures increases CRC risk
- Diets low in fiber, high in fat, and low in vegetables, fruits and grains increases CRC risk
[Outline]
Prevention
- Data suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colonic carcinogenesis. The recommended NSAID, its dosage and duration of therapy are not known
- Screening recommendations from the American Cancer Society indicate that both males and females aged 50 years who are at average risk for developing colorectal cancer should undergo one of the following tests
- Flexible sigmoidoscopy every 5 years *
- Colonoscopy every 10 years
- Double-contrast barium enema every 5 years*
- CT colonography (virtual colonoscopy) every 5 years*
- Fecal occult blood test (FOBT) every year*†
- Fecal immunochemical test (FIT) every year*†
*Colonoscopy should be done if test results are positive.
†For FOBT or FIT used as a screening test, the take-home multiple sample method should be used. An FOBT or FIT done during a digital rectal exam in the doctor's office is not adequate for screening.
- In people carrying high risk of developing colorectal cancer, screening should be started before 50 years of age and/or such people should be screened frequently
- Patients categorized in high-risk group include those who have
- A personal history of colorectal cancer or adenomatous
- A personal history of inflammatory bowel disease (ulcerative colitis or Crohn's disease)
- A strong family history of colorectal cancer or polyps
- A known family history of a hereditary colorectal cancer syndrome such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC)
Prognosis
Survival rates for early stage colon cancers is 70% to 80%
(Table not added)
Associated conditions
- Cardiovascular disease
- Crohn's disease
- Diabetes
- Hypertension
- Obesity
- Previous cancer
- Ulcerative colitis
Pregnancy/Pediatric effects on condition
- CRC is rare during pregnancy and the reported incidence is approximately 0.002%
- CRC is rare in pediatric population and has an annual incidence of approximately 1 case/million individuals
- Children or adolescents with CRC have worse outcomes than adults
Synonyms/Abbreviations
Abbreviations
ICD-9-CM
- 153 Malignant neoplasm of colon
ICD-10-CM
- C18 Malignant neoplasm of colon
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