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Colon Cancer

  • Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
 
Updated: May 07, 2016
 

Practice Essentials

Colon cancer is the most common type of gastrointestinal cancer. It is a multifactorial disease process, with etiology encompassing genetic factors, environmental exposures (including diet), and inflammatory conditions of the digestive tract.

Surgery currently is the definitive treatment modality.[1] The image below depicts standard colectomies for adenocarcinoma of the colon.

Standard colectomies for adenocarcinoma of the col Standard colectomies for adenocarcinoma of the colon.

See Cutaneous Clues to Diagnosing Metastatic Cancer, a Critical Images slideshow, to help identify various skin lesions that are cause for concern.

Signs and symptoms

Colon cancer is now often detected during screening procedures. Other common clinical presentations include the following:

  • Iron-deficiency anemia
  • Rectal bleeding
  • Abdominal pain
  • Change in bowel habits
  • Intestinal obstruction or perforation

Physical findings may include the following:

  • Early disease: Nonspecific findings (fatigue, weight loss) or none at all
  • More advanced disease: Abdominal tenderness, macroscopic rectal bleeding, palpable abdominal mass, hepatomegaly, ascites

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Complete blood count
  • Chemistries and liver function tests
  • Serum carcinoembryonic antigen

Imaging studies that may facilitate staging include the following:

  • Chest radiography
  • Chest computed tomography
  • Abdominal barium study
  • Abdominal/pelvic CT
  • Contrast ultrasonography of the abdomen and liver
  • Abdominal/pelvic MRI
  • Positron emission tomography, including fusion PET-CT scan

Other procedures that may be warranted include the following:

  • Colonoscopy
  • Sigmoidoscopy
  • Biopsy of suspicious lesions
  • Double-contrast barium enema

Current TNM classification is as follows:

  • Tx – No description of tumor extent possible, because of incomplete information
  • Tis – In situ carcinoma; tumor involves only muscularis mucosa
  • T1 – Cancer has grown through muscularis mucosa and extends into submucosa
  • T2 – Cancer has grown through submucosa and extends into muscularis propria
  • T3 – Cancer has grown through muscularis propria and into outermost layers of colon but not through them; it has not reached any nearby organs or tissues
  • T4a – Cancer has grown through serosa (visceral peritoneum)
  • T4b – Cancer has grown through wall of colon and is attached to or invades nearby tissues or organs
  • Nx – No description of lymph node involvement possible, because of incomplete information
  • N0 – No cancer in nearby lymph nodes
  • N1a – Cancer cells found in 1 nearby lymph node
  • N1b – Cancer cells found in 2-3 nearby lymph nodes
  • N1c – Small deposits of cancer cells found in areas of fat near lymph nodes, but not in lymph nodes themselves
  • N2a – Cancer cells found in 4-6 nearby lymph nodes
  • N2b – Cancer cells found in 7 or more nearby lymph nodes
  • M0 – No distant spread seen
  • M1a – Cancer has spread to 1 distant organ or set of distant lymph nodes
  • M1b – Cancer has spread to more than 1 distant organ or set of distant lymph nodes, or has spread to distant parts of the peritoneum

Staging is as follows:

Table 1. TNM Staging System for Colon Cancer (Open Table in a new window)

Stage Primary Tumor (T) Regional Lymph Node (N) Remote Metastasis (M)
Stage 0 Carcinoma in situ (Tis) N0 M0
Stage I Tumor may invade submucosa (T1) or muscularis propria (T2) N0 M0
Stage II Tumor invades muscularis (T3) or adjacent organs or structures (T4) N0 M0
Stage IIA T3 N0 M0
Stage IIB T4a N0 M0
Stage IIC T4b N0 M0
Stage IIIA T1-4 N1-2 M0
Stage IIIB T1-4 N1-2 M0
Stage IIIC T3-4 N1-2 M0
Stage IVA T1-4 N1-3 M1a
Stage IVB T1-4 N1-3 M1b

See Workup for more detail.

Management

Surgery is the only curative modality for localized colon cancer (stage I-III). Surgical resection potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease). Surgical options include the following:

  • Right hemicolectomy: For lesions in the cecum and right colon
  • Extended right hemicolectomy: For lesions in the proximal or middle transverse colon
  • Left hemicolectomy: For lesions in the splenic flexure and left colon
  • Sigmoid colectomy: For sigmoid colon lesions
  • Total abdominal colectomy with ileorectal anastomosis: For selected patients with hereditary nonpolyposis colon cancer, attenuated familial adenomatous polyposis, metachronous cancers in separate colon segments, or acute malignant colon obstructions with unknown status of the proximal bowel

Other therapeutic options for patients who are not surgical candidates include the following:

  • Cryotherapy
  • Radiofrequency ablation
  • Hepatic arterial infusion of chemotherapeutic agents

Regimens used for systemic chemotherapy may include the following:

  • 5-Fluorouracil (5-FU)
  • Capecitabine
  • Tegafur
  • Oxaliplatin
  • Irinotecan
  • Combinations of multiple agents (eg, capecitabine or 5-FU with oxaliplatin, 5-FU with leucovorin and oxaliplatin)

Regimens used for adjuvant (postoperative) chemotherapy commonly include 5-FU with leucovorin or capecitabine, either alone or in combination with oxaliplatin.[2, 3, 4]

Biologic agents employed to treat colon cancer include the following:

  • Bevacizumab (Avastin)
  • Cetuximab (Erbitux)
  • Panitumumab (Vectibix)
  • Ramucirumab (Cyramza)
  • Regorafenib (Stivarga)
  • Ziv-aflibercept (Zaltrap)

See Treatment and Medication for more detail.

Next

Background

Invasive colorectal cancer is a preventable disease. Early detection through widely applied screening programs is the most important factor in the recent decline of colorectal cancer in developed countries (see Deterrence/Prevention).

Full implementation of screening guidelines[5] could cut mortality rate from colorectal cancer in the United States by an estimated additional 50%; even greater reductions are estimated for countries where screening tests may not be widely available at present. New and more comprehensive screening strategies are also needed.

Fundamental advances in understanding the biology and genetics of colorectal cancer are taking place. This knowledge is slowly making its way into the clinic and being employed to better stratify individual risks of developing colorectal cancer, discover better screening methodologies, allow for better prognostication, and improve the ability to predict benefit from new anticancer therapies.

In the past 10 years, an unprecedented advance in systemic therapy for colorectal cancer has dramatically improved outcome for patients with metastatic disease. Until the mid-1990s, the only approved agent for colorectal cancer was 5-fluorouracil. Since then, new agents in a variety of classes have become available, including the following:

  • Cytotoxic agents (eg, irinotecan, oxaliplatin) [6]
  • Oral fluoropyrimidines (ie, capecitabine and tegafur)
  • Biologic agents (eg, bevacizumab, cetuximab, panitumumab) [7]
  • Most recently, anti-angiogenic agents (ie, ziv-aflibercept, regorafenib)

Although surgery remains the definitive treatment modality, these new agents will likely translate into improved cure rates for patients with early-stage disease (stage II and III) and prolonged survival for those with stage IV disease. Further advances are likely to come from the development of new targeted agents and from better integration of systemic therapy with other modalities such as surgery, radiation therapy, and liver-directed therapies.

An image depicting standard colectomies for adenocarcinoma of the colon can be seen below.

Standard colectomies for adenocarcinoma of the col Standard colectomies for adenocarcinoma of the colon.

For more information, see Colorectal Cancer Guidelines.

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Pathophysiology

Genetically, colorectal cancer represents a complex disease, and genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Sequence of molecular and genetic events leading to transformation from adenomatous polyps to overt malignancy has been characterized by Vogelstein and Fearon.[8]

The early event is a mutation of APC (adenomatous polyposis gene), which was first discovered in individuals with familial adenomatous polyposis (FAP). The protein encoded by APC is important in the activation of oncogene c-myc and cyclin D1, which drives the progression to malignant phenotype. Although FAP is a rare hereditary syndrome accounting for only about 1% of cases of colon cancer, APC mutations are very frequent in sporadic colorectal cancers.

In addition to mutations, epigenetic events such as abnormal DNA methylation can also cause silencing of tumor suppressor genes or activation of oncogenes. These events compromise the genetic balance and ultimately lead to malignant transformation.

Other important genes in colon carcinogenesis include the KRAS oncogene, chromosome 18 loss of heterozygosity (LOH) leading to inactivation of SMAD4 (DPC4), and DCC (deleted in colon cancer) tumor suppression genes. Chromosome arm 17p deletion and mutations affecting the p53 tumor suppressor gene confer resistance to programmed cell death (apoptosis) and are thought to be late events in colon carcinogenesis.

A subset of colorectal cancers is characterized with deficient DNA mismatch repair. This phenotype has been linked to mutations of genes such as MSH2, MLH1, and PMS2. These mutations result in so-called high frequency microsatellite instability (H-MSI), which can be detected with an immunocytochemistry assay. H-MSI is a hallmark of hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome), which accounts for about 6% of all colon cancers. H-MSI is also found in about 20% of sporadic colon cancers.

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Etiology

Colorectal cancer is a multifactorial disease process. Genetic factors, environmental exposures (including diet), and inflammatory conditions of digestive tract are all involved in the development of colorectal cancer.

Although much about colorectal cancer genetics remains unknown, current research indicates that genetic factors have the greatest correlation to colorectal cancer. 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 colon cancer by age 40 years.

Hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome) poses about a 40% lifetime risk for developing colorectal cancer; individuals with this syndrome are also at increased risk for urothelial cancer, endometrial cancer, and other less common cancers. Lynch syndrome is characterized by deficient mismatch repair (dMMR) due to inherited mutation in one of the mismatch repair genes, such as hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, and possibly other undiscovered genes.

HNPCC is a cause of about 6% of all colon cancers. Although the use of aspirin may reduce the risk of colorectal neoplasia in some populations, a study by Burn et al found no effect on the incidence of colorectal cancer in carriers of Lynch syndrome with use of aspirin, resistant starch, or both.[9]

Dietary factors are the subject of intense and ongoing investigations.[10] Epidemiologic studies have linked increased risk of colorectal cancer with a diet high in red meat and animal fat, low-fiber diets, and low overall intake of fruits and vegetables. A study by Aune et al found that a high intake of fiber was associated with a reduced risk of colorectal cancer. In particular, cereal fiber and whole grains were found to be effective.[11] A study by Pala et al found that high yogurt intake was also associated with a decreased risk for colorectal cancer.[12]

Factors associated with lower risk include folate intake, calcium intake, and estrogen replacement therapy. However, most of these studies were retrospective epidemiologic studies and have yet to be validated in prospective, placebo-controlled, interventional trials.

Obesity and lifestyle choices such as cigarette smoking, alcohol consumption, and sedentary habits have also been associated with increased risk for colorectal cancer. A meta-analysis of prospective cohort studies found a modest but significant elevation of colorectal cancer risk in current smokers; risk was higher for men and for rectal cancers than colon cancers, and persisting in former smokers.[13]

In a large prospective study, Cho and colleagues reported that high alcohol consumption was associated with elevated risk for colorectal cancer, in individuals with a family history of the disease. The association was significant only for the highest alcohol intake category of 30 g or more daily; no significant linear trend was evident. In comparison with nondrinkers with no family history, individuals who consumed 30 g/d or more and who had a family history of colorectal cancer had a relative risk for colon cancer of 2.80.[14]

Current screening guidelines recommend that clinicians be aware of increased colorectal cancer risk in patients who smoke or are obese, but do not highlight the increased risk in patients with diabetes. A meta-analysis of case-control and cohort studies identified diabetes as an independent risk factor for colon and rectal cancer. Subgroup analyses confirmed the consistency of the findings across study type and population. This information may have an impact on screening guidelines and on building risk models of colorectal cancer.[15]

Association between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses. Jacobs et al pooled data from 8,213 participants in seven prospective studies and found that BMI was significantly related to most histologic characteristics of metachronous adenomas in men but not in women. The researchers concluded that body size may affect colorectal carcinogenesis at comparatively early stages, particularly in men.[16]

Activation of the WNT signaling pathway, which most often results from APC loss, plays a critical role in the development of colorectal cancer, and CTNNB1 (β-catenin) is a major mediator of the WNT pathway. WNT-CTNNB1 signaling also appears to be involved in obesity, glucose metabolism, and metabolic diseases such as obesity and type II diabetes. Consequently, Morikawa et al hypothesized that the association of obesity and physical activity with colorectal cancer risk might differ by tumor subtypes according to CTNNB1 status.[17]

Using a molecular pathological epidemiology database, these researchers determined that risk of CTNNB1-negative cancer was significantly higher with greater BMI and lower with increased physical activity level. These researchers found no association between either BMI or physical activity level and CTNNB1-positive cancer risk.[17]

Inflammatory bowel diseases such as ulcerative colitis and Crohn disease also carry an increased risk of developing colorectal adenocarcinoma. The risk for developing colorectal malignancy increases with the duration of inflammatory bowel disease and the greater extent of colon involvement.

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Epidemiology

Although the incidence and mortality from colon cancer have been on a slow decline over the past 20 years in the United States, colorectal cancers remain the third most common cancer and the third most common cause of cancer-related mortality in the US. The American Cancer Society estimates that 95,270 new cases of colon cancer will be diagnosed in the United States in 2016. Estimates for mortality from colon and rectal cancer (the two are combined because of classification difficulties) are for 49,190 deaths in 2016.[18]

Worldwide, colorectal cancer is the second most common in cancer in women (614,000 cases, 9.2% of all cancers) and the third most common in men (746,000 cases, 10.0% of the total). Geographically, the incidence varies as much as 10-fold. The highest estimated rates are in Australia/New Zealand (per 100,000 population, 44.8 in men and 32.2 in women), and the lowest in Western Africa (per 100,000 population, 4.5 in men and 3.8 in women).[19]

Mortality is lower (694,000 deaths, 8.5% of the total) with more deaths (52%) in the less-developed regions of the world, reflecting a poorer survival in these regions. There is less variability in mortality rates worldwide (six-fold in men, four-fold in women), with the highest estimated mortality rates in both sexes in Central and Eastern Europe (20.3 per 100,000 for men, 11.7 per 100,000 for women), and the lowest in Western Africa (3.5 and 3.0, respectively).

Racial, sexual, and age-related disparities in incidence

Recent trends in the United States suggest a disproportionally higher incidence and death from colon cancer in African Americans than in whites. Hispanics have the lowest incidence and mortality from colorectal cancer.

The incidence of colorectal cancer is relatively equal in men than in women. The American Cancer Society estimates that colon cancer will be diagnosed in 47,710 men and 47,560 women in the United States in 2016.[18]

Age is a well-known risk factor for colorectal cancer, as it is for many other solid tumors. The timeline for progression from early premalignant lesion to malignant cancer ranges from 10-20 years. Median age at diagnosis is 68 years.[20]

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Prognosis

The approximate 5-year survival rate for colorectal cancer patients in the United States (all stages included) is 65%.[20] Survival is inversely related to stage: approximate 5-year survival rates are 95% for patients with stage I disease, 60% for those with stage III disease, and 10% for those with stage IV (metastatic) disease (see Staging).

A study by Chua et al found that approximately one in every three patients who undergo resection for colorectal liver metastases become actual 5-year survivors.[21] Of those, approximately half survive 10 years and are cured of colorectal liver metastases. A multivariate analysis of 1001 patients who underwent potentially curative resection of liver metastases identified five factors as independent predictors of worse outcome[22] :

  • Size greater than 5 cm
  • Disease-free interval of less than a year
  • More than one tumor
  • Primary lymph-node positivity
  • Carcinoembryonic antigen (CEA) level greater than 200 ng/mL

Aggarwal et al found that circulating tumor cells measured at baseline after the initiation of new therapy in patients with metastatic colorectal cancer independently predicted survival; in patients with a baseline carcinoembryonic antigen (CEA) value of 25 ng/mL or higher, those with low baseline levels of circulating tumor cells (< 3) had longer survival. Both the number of circulating tumor cells and the CEA level measured at 6-12 weeks independently predicted survival.[23]

Research suggests a role for intra-tumoral immune response as a predictor of clinical outcome in patients with colorectal cancer, in addition to more traditional pathological and molecular markers. Katz et al reported that in patients with colorectal liver metastases, high numbers of T regulatory cells relative to CD4 or CD8 T cells predicted poor outcome[24]

A study by Yothers et al found that black patients with resected stage II and stage III colon cancer had worse overall and recurrence-free survival compared with white patients who underwent the same therapy. Five-year overall survival rate was 68.2% for blacks and 72.8% for whites; the three-year recurrence-free survival was 68.4% in blacks and 72.1% in whites.[25]

A study by Campbell et al found that prediagnosis body mass index (BMI) is an important predictor of survival among patients with nonmetastatic colorectal cancer, whereas postdiagnosis BMI is not.[26] A separate study from Campbell et al found that spending 6 or more hours per day sitting was associated with higher all-cause mortality compared with sitting less than 3 hours per day. The study concluded that increased recreational physical activity in patients with colorectal carcinoma reduces mortality.[27]

A review of eight trials by Rothwell et al found that allocation to aspirin reduced death caused by cancer. Benefit was apparent after 5 years of follow-up. The 20-year risk of cancer death was also lower in the aspirin group for all solid cancers. A latent period of 5 years was observed before risk of death was decreased for esophageal, pancreatic, brain, and lung cancers. A more delayed latent period was observed for stomach, colorectal, and prostate cancer. The overall effect on 20-year risk of cancer death was greatest for adenocarcinomas.[28]

A study by Burn et al found that 600 mg of aspirin per day for a mean of 25 months reduced cancer incidence after 55.7 months among known carriers of hereditary colorectal cancer. However, further studies are needed to determine the optimum dose and duration of treatment.[29]

Patients with preexisting mental disorders have an overall higher mortality rate than their counterparts. This higher mortality rate can be attributed to a lack of surgery, chemotherapy, and radiation therapy, especially in patients with psychotic disorders and dementia. Improved public health initiatives are needed to improve colon cancer detection and treatment in older adults with mental disorders.[30]

A study by Phipps et al found that smoking is also associated with increased mortality after colorectal cancer diagnosis, especially in patients whose cancer has high microsatellite instability.[31] A study by Dehal et al found that patients with colorectal cancer and type 2 diabetes mellitus have a higher risk of mortality than those without, most notably a higher risk due to cardiovascular disease.[32]

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Contributor Information and Disclosures
Author

Tomislav Dragovich, MD, PhD Chief, Section of Hematology and Oncology, Banner MD Anderson Cancer Center

Tomislav Dragovich, MD, PhD is a member of the following medical societies: American Association for Cancer Research, SWOG, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Coauthor(s)

Vassiliki L Tsikitis, MD Associate Professor of Surgery, Department of Surgery, Division of General and Gastrointestinal Surgery, Oregon Health and Science University School of Medicine

Vassiliki L Tsikitis, MD is a member of the following medical societies: American College of Surgeons, American Society of Colon and Rectal Surgeons, Association for Academic Surgery, Society for Surgery of the Alimentary Tract, SWOG, Association of Women Surgeons, Pacific Coast Surgical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center

N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society

Disclosure: Nothing to disclose.

Additional Contributors

Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

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Standard colectomies for adenocarcinoma of the colon.
Table 1. TNM Staging System for Colon Cancer
Stage Primary Tumor (T) Regional Lymph Node (N) Remote Metastasis (M)
Stage 0 Carcinoma in situ (Tis) N0 M0
Stage I Tumor may invade submucosa (T1) or muscularis propria (T2) N0 M0
Stage II Tumor invades muscularis (T3) or adjacent organs or structures (T4) N0 M0
Stage IIA T3 N0 M0
Stage IIB T4a N0 M0
Stage IIC T4b N0 M0
Stage IIIA T1-4 N1-2 M0
Stage IIIB T1-4 N1-2 M0
Stage IIIC T3-4 N1-2 M0
Stage IVA T1-4 N1-3 M1a
Stage IVB T1-4 N1-3 M1b
Table 1. TNM Staging System for Colon Cancer
Stage Primary Tumor (T) Regional Lymph Node (N) Remote Metastasis (M)
Stage 0 Carcinoma in situ (Tis) N0 M0
Stage I Tumor may invade submucosa (T1) or muscularis propria (T2) N0 M0
Stage II Tumor invades muscularis (T3) or adjacent organs or structures (T4) N0 M0
Stage IIA T3 N0 M0
Stage IIB T4a N0 M0
Stage IIC T4b N0 M0
Stage IIIA T1-4 N1-2 M0
Stage IIIB T1-4 N1-2 M0
Stage IIIC T3-4 N1-2 M0
Stage IVA T1-4 N1-3 M1a
Stage IVB T1-4 N1-3 M1b
Table 2. Surveillance recommendations for stage II and III colon cancer
Parameter Organization
ESMO [JSMO](2013) ASCO (2013) NCCN (2016)
History and physical exam Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y Every 3-6 mo for 3 y, then every 6 mo to 5 y Every 3-6 mo for 2 y, then every 6 mo to 5 y
CEA Every 3-6 mo for 3 y, then every 6 -12 mo at 4 and 5 y Every 3 mo for 3 y* Every 3-6 mo for 2 y, then every 6 mo to 5 y
Chest CT* Every 6-12 mo for first 3 y Every 1 y for 3 y Every 1 y for 5 y
Colonoscopy** At y 1 after surgery, and every 3-5 y thereafter At 1 y, then every 5 y, dictated by the findings on the previous colonoscopy At 1 y, 3 y, then every 5 y if negative
Abdominal CT* Every 6-12 mo for first 3 y Every 1 y for 3 y Every 6-12 mo for up to 5 y; scans to include chest and pelvis
ESMO = European Society of Medical Oncology; JSMO = Japanese Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; CEA = carcinoembryonic antigen; CT = computed tomography



* For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors).



**Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 1 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp > 1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y.



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