Colon Cancer

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.

View Image

Standard colectomies for adenocarcinoma of the colon.

Signs and symptoms

Colon cancer is often detected during screening procedures. 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 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

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

Adjuvant (postoperative) therapy is used in selected patients with stage II colon cancer who are at high risk of recurrence, and is standard for stage III colon cancer. Regimens used for systemic chemotherapy may include the following:

• Fluorouracil (5-fluorouracil; 5-FU)
• Capecitabine
• Oxaliplatin
• Combinations of multiple agents (eg, capecitabine or 5-FU with oxaliplatin, FOLFOX, FOLFIRI, cetuximab or panitumumab with encorafenib)

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

For metastatic colon cancer, systemic chemotherapy is standard, with neoadjuvant chemotherapy used to convert unresectable isolated liver metastases to resectable liver metastases. Biologic agents have assumed a major role, typically as targeted therapy based on genetic analysis of the tumor. Biologic agents employed to treat colon cancer include the following:

• Bevacizumab (Avastin)
• Cetuximab (Erbitux)
• Encorafenib (Braftovi)
• Entrectinib (Rozlytrek)
• Fruquintinib (Fruzaqla)
• Ipilimumab (Yervoy)
• Larotrectinib (Vitrakvi)
• Nivolumab (Opdivo)
• Panitumumab (Vectibix)
• Pembrolizumab (Keytruda)
• Ramucirumab (Cyramza)
• Regorafenib (Stivarga)
• Tucatinib (Tukysa)
• Ziv-aflibercept (Zaltrap)

See Treatment and Medication for more detail.

For more information, see Colorectal Cancer Guidelines.

Go to Oncology Decision Point Colorectal Cancer for expert commentary on treatment decisions and related guidelines.

• References

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 Overview/Epidemiology).

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 recent decades, 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)^[5]
• Oral fluoropyrimidines (ie, capecitabine)
• Biologic agents (eg, bevacizumab, cetuximab, panitumumab, pembrolizumab, nivolumab)^[1]
• 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.

• References

Pathophysiology

The colonic mucosa is a self-renewing epithelium that is structured in a very tightly regulated balance between cell proliferation at the base of a crypt, maturation as colonocytes, migration up the crypt, and extrusion of senescent and/or apoptotic cells from the upper crypt into the lumen. This entire process takes approximately 3-6 days. The transformation of normal colonic epithelium to adenomatous lesions and ultimately to colon cancer involves alterations in genes that regulate DNA repair and cell proliferation. These alterations result in disruption of the normal process of regular renewal of the epithelium, with proliferation of mutant cells and the formation of traditional adenomas or sessile serrated polyps.^[6]

Adenomatous cells are characterized by a loss of normal growth control. They continue to proliferate as they reach the top of the crypt, and they are not extruded into the lumen. Instead, they multiply and eventually fold back into the surrounding normal mucosa, inducing a response in the mesenchymal tissue that helps shape the microscopic architecture of the adenoma. The rate of growth and progression of adenomas to cancer is variable, but typically occurs in 10-15 years. Patients with heritable forms of colorectal cancer, such Lynch syndrome, otherwise known as hereditary nonpolyposis colorectal cancer (HNPCC), have a significantly more rapid rate of adenoma formation and progression to cancer.^[7]  

The conventional adenoma-carcinoma sequence is thought to be a genetically driven process characterized by the occurrence over time of successive cycles of somatic mutation and clonal expansion of cells that have acquired a survival advantage. The first mutation in this process often involves inactivating mutations of the adenomatous polyposis coli (APC) tumor suppressor gene (inherited mutations in the APC gene cause familial adenomatous polyposis [FAP], and somatic mutations in the APC gene occur in about 80% of sporadic adenomas).

Additional progressive mutations occur in cells of the adenoma, including activating mutations of the oncogenes (KRAS), and inactivating mutations of additional tumor suppressor genes (eg, TP53). Some of these individual mutations lead to clones of cells that have acquired a survival advantage over surrounding cells, leading to a clone of mutant cells. Subsequent cycles of mutation and clonal expansion ultimately lead to adenoma growth, increased severity of dysplasia, and ultimately, acquisition of the invasive and metastatic characteristics of an adenocarcinoma.

Lynch syndrome colorectal cancers also arise from or within conventional adenomas, but the process is driven by a germline mutation in one of the DNA mismatch repair genes (ie, MSH2, MLH1, MSH6, PMS2); when somatic inactivation of the remaining wild-type allele occurs in the colon, it leads to loss of DNA mismatch repair, an increased mutation rate, microsatellite instability, and a rapid progression to colorectal cancer.

An epigenetic pathway to colorectal cancer is through a serrated polyp pathway rather than via conventional adenomas. In this pathway, silencing of DNA mismatch repair genes (MLH1) or other DNA repair genes (MGMT) by methylation results in failure of DNA repair and consequently to an increased mutation rate, which can result in progression to cancer. The serrated polyp–carcinoma sequence occurs predominantly in the right colon and involves sessile serrated adenomas. These cancers show BRAF mutations, particularly BRAF V600E, and a high-level methylation of CpG islands. A second serrated polyp pathway involves tumors that arise from traditional serrated adenomas and more often have KRAS mutations; they may also have high-level CpG island methylation.^[8]

Cancer cells produce extracellular vesicles (EVs)—principally, microvesicles and exosomes—that can promote the growth, survival, invasiveness, and metastatic activity of tumors.^[9] Zhao et al reported that in an animal model of aggressive late-stage colorectal cancer, tumor-secreted EVs promoted resistance to immune checkpoint blockade. The colorectal cancer cells in this model secrete exosomes that carry immunosuppressive microRNAs; these block CD28 on T cells and CD80 on dendritic cells that infiltrate the tumors, disabling T-cell–mediated anti-tumor immune response.^[10]

Further, these authors found that intravenous injections of tumor-secreted exosomes without immunosuppressive microRNAs, in combination with immune checkpoint inhibitors, resulted in an enhanced anti-tumor immune response. This offers a potential therapeutic strategy for late-stage colorectal cancer.^[10]

• References

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.

Genetic factors

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.^[11]

Serrated polyposis syndrome (SPS) is a disorder in which multiple polyps develop in the colon and rectum. The polyps can be hyperplastic polyps, serrated serrated lesions, or traditional serrated adenomas. Individuals with SPS are at high risk for developing colorectal cancer. Some cases of SPS involve germline mutations in the RNF43 gene,^[12] but otherwise no clear genetic cause has been identified. Epigenetic and environmental factors, especially smoking, may contribute.^{[13, 14]}

Diagnostic criteria for SPS, published in 2019 by the World Health Organization (WHO) include the following two criteria^[14] :

• ≥5 serrated lesions/polyps proximal to the rectum, all being ≥5 mm in size, with ≥2 being ≥10 mm in size
• >20 serrated lesions/polyps of any size distributed throughout the large bowel, with ≥5 being proximal to the rectum

Risk of colorectal cancer appears to be lower in individuals who meet the first criteria than in those who meet the second criteria or both criteria.^[14]

Dietary and other factors

Dietary factors are the subject of intense and ongoing investigations.^[15] 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.^[16] A study by Pala et al found that high yogurt intake was also associated with a decreased risk for colorectal cancer.^[17]

A cohort study by Tabung et al that followed 121,050 adults for 26 years found that in both men and women, intake of proinflammatory diets (replete in red, processed, and organ meat, for example) was associated with a significantly higher risk of developing colorectal cancer. Risk was especially high in overweight and obese men and, paradoxically, in lean women. Risk was also increased in men and women who do not drink alcohol.^[18]

In high-income countries such as the United States, ultra-processed foods (UPFs)  provide more than half of the total dietary energy. UPFs contain ingredients that are mostly of exclusive industrial use, and they are typically high-energy-dense products that are high in sugar, unhealthy fats, and salt, and low in dietary fiber, protein, vitamins, and minerals.^[19] A systematic review and meta-analysis of UPF consumption and gastrointestinal cancer risk found that, compared with the lowest UPF consumption, the highest UPF consumption was significantly associated with an increased risk of colorectal cancer (hazard ratio 1.11).^[20]

Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with increased risk of colorectal cancer. In a study of adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors, daily administration of 20 g of weight-adjusted HFCS (the equivalent of 1 soda a day) resulted in a substantial increase in polyps that rapidly developed into advanced, high-grade dysplastic lesions. Carbon labeling showed uptake in fructose within the intestinal tumors themselves. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth.^[21]

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.^[22]

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.^[23]

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.^[24]

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 8213 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.^[25]

A nationwide cohort study from France of incident colorectal cancer in obese patients, which compared outcomes in 74,131 patients who underwent bariatric surgery with 971, 217 patients who did not have surgery, found that in the bariatric surgery cohort, risk of colorectal cancer was the same as that in the general population. In the obese patients who did not undergo bariatric surgery, the risk was 34% above that of the general population.^[26]

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 2 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.^[27]

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.^[27]

Greater adult-attained height is associated with an increased risk of colorectal cancer and adenoma, according to a systematic review and meta-analysis by Zhou et al that included 47 observational studies involving 280,644 colorectal cancer and 14,139 colorectal adenoma cases.The study found that overall, the risk of colorectal cancer is 24% higher in the tallest individuals within the highest percentile of height, compared with the shortest individuals within the lowest percentile. Every 3.9-inch (10-centimeter) increase in height was associated with a 14% higher risk for colon cancer and 6% higher odds of adenoma. Zhou et al recommend considering height as a risk factor for colorectal cancer screening.^[28]

Inflammatory bowel diseases such as ulcerative colitis and Crohn disease also increase the 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.

A matched case-control study of incident colorectal cancer cases in the United Kingdom from 1989 to 2012 found that use of oral antibiotics was associated with increased risk of colon cancer, particularly in the proximal colon. The association involved antibiotic exposure occurring more than 10 years before colon cancer diagnosis. Risk was dose dependent but was observed after even a single course of antibiotics. In addition, risk was greatest with anti-anaerobic antibiotics. The authors note that such antibiotics markedly disrupt the gut microbiome, which consists predominantly of anaerobes, and this disruption may facilitate the acquisition or development of a carcinogenic colon microbiota.^[29]

• References

Epidemiology

The incidence and mortality from colon cancer have been on a slow decline over the past several decades in the United States, with the incidence falling on average 2.4% each year and death rates falling on average 2.2% each year over 2007-2019.^[30]  However, the overall decline has been driven by a decreasing incidence in individuals age 65 years and older; rates have stabilized in those age 55-64 and have increased by 1% to 2% per year since the mid-1990s in those younger than 55 years of age.^{[31, 32]}  

Colorectal cancers remain the third most common cancer in US men and women, the third most common cause of cancer-related mortality in US men, and the fourth most common cause of cancer-related mortality in women. The American Cancer Society estimates that 107,320 new cases of colon cancer will be diagnosed in the United States in 2025. Estimates for mortality from colon and rectal cancer (the two are combined because of classification difficulties) are for 52,900 deaths in 2025.^[31]

Worldwide, colon cancer was the fourth most common cancer, with an estimated 1,142,286 million new cases in 2022, and the fifth most common cause of cancer mortality, with 538,167 deaths. Geographically, the incidence varies as much as 10-fold. The highest estimated rates are in Australia–New Zealand, Europe, and Northern America, and the lowest in south-central Asia and middle Africa. Mortality rates worldwide vary six-fold, with the highest estimated mortality rates in southern and eastern Europe and the lowest in south-central Asia and middle Africa.^[33]

An epidemiologic study from the European Union (EU) concluded that in 2018, colorectal cancer would account for the second highest number of cancer deaths, at 98,000 deaths in men and 79,400 in women. However, while the total number of colorectal deaths in the EU has risen since 2012 because of the aging population, since 2012 the age-standardized death rate has fallen by 6.7% (to 15.8 per 100,000 in men and 7.5% (to 9.2 per 100,000) in women.^[34]

A study by Sung et al that examined colorectal cancer incidence trends in younger adults versus older adults in 50 countries and territories found that from 2013 to 2017, early-onset colorectal cancer (diagnosed at ages 25 to 49 years) increased in 27 countries. The greatest annual increases occurred in New Zealand (3.97%), Chile (3.96%), Puerto Rico (3.81%), and England (3.59%). In 14 of those 27 countries and territories, rates in older adults were either stable or decreased.^[35]

Racial, sexual, and age-related disparities in incidence

Since 1989, colorectal cancer incidence rates have been higher for Blacks than for Whites in both men and women. Currently, incidence rates of colorectal cancer are 21% higher in Black men and 18% higher in Black women compared with White men and women, respectively.^[36]

Colorectal mortality rates are 44% higher in Black men and 31% higher in Black women compared with White men and women. However, from 2010 to 2019, colorectal cancer death rates declined faster in Blacks than in Whites (2.8% vs 1.8% per year), narrowing the racial disparity in both men and women.^[36]

Asians/Pacific Islanders have the lowest incidence and mortality from colorectal cancer. Hispanics have the second lowest.^[30]

The incidence of colorectal cancer is relatively equal in men and women. The American Cancer Society estimates that colon cancer will be diagnosed in 54,510 men and 52,810 women in the United States in 2025.^[31]

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 66 years.^[30]

However, in contrast to the decline in colon cancer incidence rates in persons age 55 and older, which began in the mid-1980s, rates of colon cancer in younger persons have been increasing. In adults age 20 to 39 years, colon cancer incidence rates have increased by 1.0% to 2.4% annually since the mid-1980s; in those age 40 to 54 years, the incidence has increased by 0.5% to 1.3% annually since the mid-1990s. Currently, adults born circa 1990 have double the risk of colon cancer compared with those born circa 1950. Increased obesity is one likely factor.^[32]  

From 2011 through 2016, the incidence of colorectal cancer continued to decline in those aged 65 years and older, by 3.3% annually. Rates increased by 1% annually in those aged 50 to 64 years, and rose approximately 2% annually in those younger than 50 years. The American Cancer Society estimated that 17,930 of the 147,950 individuals expected to be diagnosed with colon and rectal cancer in 2020, and 3640 of the 53,200 expected to die from the disease, would be younger than 50 years of age.^[37]  

Tumor site tends to vary by patient age. From 2012 to 2016, the proximal colon was the site of colon cancer in 23% of those under 50 years of age, 31% of those 50-64 years, and 49% of those 65 and older. Incidence trends varied by race/ethnicity: in those 50-64 years old, rates increased in Whites by 1.3% per year but decreased in Blacks by 1.6% per year, and were stable in Hispanics. In those younger than 50, rates rose by 2% annually in Whites and by 0.5% annually in Blacks.^[37]

A review of Surveillance, Epidemiology and End Results (SEER) data found that US cases of colorectal cancer in persons aged 40-49 years have increased significantly since 1995, with the greatest average annual percentage increase for distant cancers, at 2.9%, while localized and regional disease each increased < 1.5% per year. In addition, the proportion of distant colorectal cancers in this age group increased significantly from 1990-1994 to 2011–2015, from 22% to 27%, while the proportion of localized cases did not change, and the proportion of regional cases decreased. These authors point out that these results indicate a true increase in risk, because if the increase had reflected earlier detection due to wider use of screening, earlier stage at diagnosis would be expected.^[38]

• References

Prognosis

The approximate 5-year survival rate for colorectal cancer patients in the United States (all stages included) is 65%.^[30] Survival is inversely related to stage: approximate 5-year relative survival rates are as follows:

• Localized disease: 91.1%
• Regional disease: 73.7%
• Distant disease: 15.7%

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.^[39] 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^[40] :

• 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.^[41]

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^[42]

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.^[43]

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.^[44] 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.^[45]

Morikawa et al reported that in patients with colorectal cancer that tested negative for cadherin-associated protein β 1 (CTNNB1 or β-catenin), high physical activity (≥18 metabolic equivalent task [MET] hours/week) after diagnosis was associated with significantly better cancer-specific survival. No association between physical activity and survival was seen in CTNNB1–positive cases.^[46]

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.^[47]

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.^[48]

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.^[49]

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.^[50] 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.^[51]

• References

History

Because of increased emphasis on screening practices, colon cancer is now often detected before it starts to cause symptoms. In more advanced cases, common clinical presentations include iron-deficiency anemia, rectal bleeding, abdominal pain, change in bowel habits, and intestinal obstruction or perforation. Right-sided lesions are associated with younger age, and common presenting signs include bleeding and/or diarrhea. Left-sided tumors are associated with older age, and patients commonly present with bowel obstruction. 

In patients younger than 50 years old—an age group that is experiencing rising rates of colorectal cancer (see Overview/Epidemiology)—a study that used data from England's Clinical Practice Research Datalink found that abdominal pain was the most common presenting symptom of colorectal cancer. Compared with other age groups, these younger patients had the lowest percentage of typical ‘red-flag’ signs and symptoms (ie, rectal bleeding, anemia, change in bowel habits, diarrhea, abdominal mass). Instead, these patients were more likely to have presented to their primary care provider, in the year before diagnosis, with nonspecific symptoms.^[52]

Similarly, a matched case-control study of 5075 incident colorectal cancers in patients younger than 50 years identified abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia within three months to two years before diagnosis as red-flag clinical manifestations in this age group. The presence of any one of those clinical manifestations was associated with 1.94-fold higher risk; any two, with 3.59-fold higher risk, and three or more, with 6.52-fold higher risk, with stronger associations for younger ages.^[53]

• References

Physical Examination

Physical examination findings can be very nonspecific (eg, fatigue, weight loss) or normal early in the course of colon cancer. In more advanced cases, any of the following may be present:

• Abdominal tenderness
• Macroscopic rectal bleeding
• Palpable abdominal mass
• Hepatomegaly
• Ascites

• References

Approach Considerations

Because early-stage colon cancer is typically asymptomatic, screening plays a major role in the diagnosis of curable cancerous lesions, as well as the detection of precancerous lesions (adenomatous and serrated colon polyps). The decline in colorectal cancer incidence and death rates over recent decades has largely been attributed to widespread adoption of screening.^[31]

Screening guidelines endorse the use of several tests and procedures that either detect adenomatous polyps and cancer or that primarily detect cancer. However, guidelines from the American College of Gastroenterology recommend colonoscopy every 10 years, beginning at age 50 years, as the preferred screening strategy.^[54]

A suspicion of colorectal cancer diagnosis warrants rectal examination and colonoscopy with a biopsy of any suspicious lesions. The National Comprehensive Cancer Network recommends that all patients younger than 70 years of age who are diagnosed with colorectal cancer be tested for hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome); patients 70 and older should be tested only if they meet the revised Bethesda guidelines for HNPCC.^[55]

After tissue diagnosis is confirmed, laboratory studies are done with a goal of assessing patients’ organ function (liver, kidneys) in anticipation of diagnostic and therapeutic procedures and also to estimate tumor burden. Adequate imaging of the chest and abdomen should be obtained for staging purposes, ideally preoperatively.

Further workup is driven by the following:

• Clinical setting (eg, profuse bleeding and obstruction may require emergency surgery)
• Patient functional status and comorbidities
• Presenting symptoms

• References

Blood Studies

Laboratory studies are done with a goal of assessing patients’ organ function (liver, kidneys) in anticipation of diagnostic and therapeutic procedures and also to estimate tumor burden. Studies may include the following:

• Complete blood cell count
• Serum chemistries
• Liver function tests
• Kidney function tests
• Serum carcinoembryonic antigen (CEA) level

A baseline CEA level should be obtained preoperatively as it carries prognostic value and when highly elevated may indicate more advanced, disseminated disease. Increased levels of serum CEA have been associated with an adverse prognosis in patients with resectable colorectal cancer; however, this biochemical marker has not as of yet been included in colorectal cancer staging guidelines.^[56]

• References

Imaging Studies

Adequate imaging of the chest and abdomen should be obtained for staging purposes, ideally preoperatively. Abdominal/pelvic computed tomography (CT), contrast ultrasound of the abdomen/liver, and abdominal/pelvic magnetic resonance imaging (MRI) scans are appropriate for imaging the abdomen and liver, for the purpose of staging. Imaging studies may also include a chest radiograph or chest CT scan, and an abdominal barium study to better delineate the primary lesion preoperatively.

Positron emission tomography (PET) scanning is emerging as a very useful modality for staging and assessment of colorectal cancers. The newest addition, a fusion PET-CT scan, allows for detection of metastatic deposits and has the added tissue-based resolution of CT. Of note, some histologies, especially a mucinous signet-ring cell variant of colorectal cancer, may not be well visualized on a PET scan.

For more information, see Colon Cancer Imaging.

• References

Screening

The goal of colorectal cancer screening is to decrease mortality through diagnosis and treatment of precancerous lesions (adenomatous and serrated colon polyps) and early curable cancerous lesions. The evidence for the importance of early detection and removal of colorectal polyps in preventing development of invasive cancer is mostly indirect but has been corroborated by data from many trials.

Screening tests

Screening options consist of tests that detect adenomatous polyps and cancer, and tests that primarily detect cancer. Any one of these tests can be used for screening.

Tests that detect adenomatous polyps and cancer, and their recommended frequency, include the following:

• Flexible sigmoidoscopy every 5 years
• Colonoscopy every 10 years
• Double-contrast barium enema every 5 years
• Computed tomographic (CT) colonography every 5 years

Tests that primarily detect cancer, and their recommended frequency, include the following:

• Annual guaiac-based fecal occult blood test with high test sensitivity for cancer
• Annual fecal immunochemical test (FIT) with high test sensitivity for cancer
• Stool DNA test with high sensitivity for cancer, interval uncertain

A Cochrane Database review of 14 trials found that flexible sigmoidoscopy is more effective at detecting advanced adenoma and carcinoma than stool-based tests.^[57]  However, a Norwegian study determined that while the use of flexible sigmoidoscopy for screening reduced the incidence and mortality of colorectal cancer in men, it had little or no effect in women.^[58]

A case-control study using national Veterans Affairs–Medicare data concluded that colonoscopy was associated with significant reductions in colorectal cancer mortality in veterans. Mortality benefit was greater for left-sided cancer than right-sided cancer.^[59] Case patients (n= 4964) were veterans aged 52 years or older who were diagnosed with colorectal cancer in 2002 to 2008 and died of the disease by the end of 2010. Case patients were matched to four control patients (n=9856) without prior colorectal cancer. Risk of mortality from left-sided cancer was reduced in those who had undergone colonoscopy (odds ratio [OR], 0.28 [CI, 0.24 to 0.32]), as was risk for mortality from right-sided cancer (OR, 0.54 [CI, 0.47 to 0.63]).^[59]

A study by Wilschut et al found that FIT should be used at higher hemoglobin cutoff levels when colonoscopy capacity is limited. The findings suggest that FIT is more effective in terms of outcome and cost than fecal occult blood testing at all colonoscopy capacity levels.^[60]

A retrospective study in which FIT kits were mailed to patients concluded that this is an effective way to screen for colorectal cancer. In the study, the researchers mailed FIT kits to approximately 670,000 adults aged 50–70 years; 48.2% of those completed the test within 1 year. The patients who responded were mailed kits annually for the next 3 years, with response rates ranging from 75%–86%.^[61]

In the study, which comprised 98,678 persons, 20,552 were randomly assigned to screening and 78,126 to no screening. On median follow-up of 14.8 years, the absolute risks for colorectal cancer in women were 1.86% in the screening group and 2.05% in the control group (hazard ratio [HR] 0.92). In men, the corresponding risks were 1.72% and 2.50%, respectively (HR 0.66). The absolute risks for death from colorectal cancer in women were 0.60% in the screening group and 0.59% in the control group (HR 1.01); in men, the corresponding risks were 0.49% and 0.81%, respectively (HR 0.63).^[58]

Positive results on FIT screening were highest in the first round and declined in subsequent years. Overall, FIT screening identified 80% of patients with colorectal cancer diagnosed within 1 year of testing.^[61]

In a cohort study of 70,124 patients with positive FIT results, Corley et al found that patients who underwent colonoscopy within 9 months showed no increased risk for colorectal cancer or advanced-stage disease, compared with those who had colonoscopy done within a month after the positive FIT result. However, patients who did not have procedures done until 10 months or later were at significantly higher risk for cancer findings.^[62]

Patients on clopidogrel therapy are at significantly higher risk for delayed but not immediate bleeding when they have polyps removed during colonoscopy.^[63] Because interruption of clopidogrel therapy in patients with coronary artery disease increases the risk of serious ischemic events, elective colonoscopy and polypectomy should be delayed in these patients until cessation of clopidogrel therapy is considered safe.^[63]

In 2014, the FDA approved Cologuard, a colorectal cancer screening tool that detects DNA mutations and hemoglobin in stool samples. A positive result should be followed up with colonoscopy. Cologuard is recommended for screening of adults of either sex, aged 50 years or older, who are at average risk for colorectal cancer. It is not a replacement for diagnostic or surveillance colonoscopy for individuals at high risk, and its approval did not change practice guidelines that recommend screening using colonoscopy, sigmoidoscopy, or fecal occult blood testing.^[64]

In 2016, the FDA approved the first blood-based colorectal cancer screening test, Epi proColon. This is a qualitative in vitro assay for detecting methylated Septin9 DNA, which has been associated with the occurrence of colorectal cancer, in plasma obtained from whole-blood specimens. It is indicated for use in average-risk patients who have chosen not to undergo other screening methods, such as colonoscopy or stool-based tests.^[65]

Capsule colonoscopy

For capsule colonoscopy, the patient swallows a pill camera that acquires images as peristalsis propels it through the gastrointestinal tract. The images are transmitted to a recording device and then converted to a video format for viewing on a computer.

In 2014, the US Food and Drug Administration approved the PillCam COLON 2 Capsule Endoscopy System (Given Imaging Limited, Yoqneam, Israel) for use in patients in whom conventional colonoscopy with adequate preparation was conducted, but a complete evaluation of the colon was not technically possible.^[66] In multicenter trials, capsule colonoscopy has demonstrated a sensitivity of 84-89% for detection of polyps larger than 6 mm.^[67]

Screening guidelines

Multiple organizations have published guidelines on colorectal cancer screening, with recommendations on screening procedures and on screening indications and frequency, based on projected individual risks of developing colorectal cancer. For example, a 2008 joint guideline from the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommends that screening for colorectal cancer and adenomatous polyps start at age 50 years in asymptomatic men and women.^[31] However, because of rising rates of colorectal cancer in younger persons, several organizations currently recommend that screening start at age 45 years in persons at average risk.

American Cancer Society (ACS) guidelines

Current ACS guidelines on colorectal screening guidelines include the following recommendations^[68] :

• Regular screening for people at average risk should start at age 45 years
• For people in good health and with a life expectancy of more than 10 years, regular colorectal cancer screening should continue through the age of 75
• People ages 76 through 85 should make a decision with their medical provider about whether to continue screening, based on their own personal preferences, life expectancy, overall health, and prior screening history
• People over 85 should discontinue colorectal cancer screening

U.S. Preventive Services Task Force (USPSTF)

The USPSTF recommends that screening for colorectal cancer start at age 50 years and continue until age 75 years (grade A recommendation) but offers a grade B recommendation for screening adults age 45 to 49 years. For adults aged 76 to 85 years, the decision to screen should be individualized, taking into account the patient’s overall health, prior screening history, and preferences (grade C recommendation). The USPSTF advises that in those older patients, screening is more likely to benefit those who have never been screened than those who have undergone screening, and is more likely to benefit patients who are healthy enough to undergo treatment for colorectal cancer treatment and who do not have other medical conditions limiting their life expectancy.^[69]  The USPSTF does not recommend colorectal cancer screening for adults older than 85 years.^[69]

The USPSTF notes that colorectal screening is substantially underused. As part of a strategy to increase screening rates, the guidelines provide a range of screening options rather than a ranking of tests.

Screening in high-risk individuals

Screening for colorectal cancer should start at an earlier age and be more frequent and more stringent for individuals who carry an increased or high risk of developing colorectal cancer, such as persons with any of the following:

• Prior history of polyps
• Prior history of colorectal cancer
• Family history of colon cancer
• History of inflammatory bowel diseases

National Comprehensive Cancer Network guidelines specify recommendations for patients with the following high-risk syndromes^[70] :

• Lynch syndrome
• Familial adenomatous polyposis (FAP)
• Attenuated familial adenomatous polyposis (AFAP)
• MUTHYH-associated polyposis
• Peutz-Jeghers syndrome (PJS)
• Juvenile polyposis syndrome (JPS)
• Serrated polyposis syndrome (SPS)
• No syndrome, but familial risk present

Those genetically diagnosed or suspected of having hereditary familial syndromes such as hereditary nonpolyposis colon cancer syndrome or familial adenomatous polyposis should be treated as having high risk of developing colon and rectal cancer. These patients should adhere to a more intense surveillance protocol.^[71] For more information, see Familial Adenomatous Polyposis and Hereditary Colorectal Cancer.

American College of Gastroenterology (ACG) guidelines

ACG guidelines for colorectal cancer screening are as follows^[54] :

• Tests that prevent cancer are preferred over those that only detect cancer
• The preferred colorectal cancer prevention test is colonoscopy every 10 years, beginning at age 50 years, but at age 45 years in African Americans
• For patients who decline colonoscopy or another cancer prevention test, the preferred cancer detection test is FIT, conducted annually

Alternative cancer detection tests recommended in the ACG guidelines are as follows:

• Flexible sigmoidoscopy every 5-10 years
• CT colonography every 5 years, which replaces double contrast barium enema as the radiographic screening alternative for patients who decline colonoscopy

Alternative cancer detection tests in the ACG guidelines are as follows:

• Annual Hemoccult Sensa
• Fecal DNA testing every 3 years

For screening purposes, patients with one first-degree relative diagnosed with colorectal cancer or advanced adenoma at age 60 years or older are considered at average risk. For patients with a single first-degree relative diagnosed with colorectal cancer or advanced adenoma before age 60 years, or those with two first-degree relatives with colorectal cancer or advanced adenomas, the guideline recommends colonoscopy every 5 years, beginning at age 40 years or at 10 years younger than the age at diagnosis of the youngest affected relative.^[54]

 Further ACG suggestions regarding colorectal cancer screening include the following:

• Initiate colorectal cancer screening with a colonoscopy at age 40 or 10 years before the youngest affected relative, whichever is earlier, in individuals in whom a first-degree relative has had colorectal cancer or an advanced polyp before age 60 years or in whom two or more first-degree relatives have had colorectal cancer or an advanced polyp at any age; perform interval colonoscopy every 5 years.
• Consider genetic evaluation in individuals with a higher familial colorectal cancer burden (higher number and/or younger age of affected relatives).
• In individuals in whom a first-degree relative has had colorectal cancer or an advanced polyp at age 60 years or older, initiate colorectal cancer screening at age 40 or 10 years before the youngest affected relative, then resume screening according to average-risk screening recommendations.
• In individuals with a second-degree relative with colorectal cancer or an advanced polyp, follow average-risk colorectal cancer screening recommendations.
• Decide whether to continue screening beyond age 75 years on an individualized basis.
• In individuals unable or unwilling to undergo colonoscopy or FIT, consider screening with flexible sigmoidoscopy, multitarget stool DNA test, CT colonography, or colon capsule.
• Do not use the Septin 9 methylated DNA test for screening.

Colonoscopy preparation

Guidelines from the Multi-Society Task Force on Colorectal Cancer include the following recommendations for bowel cleansing before colonoscopy^[72] :

• Use of a split-dose bowel cleansing regimen (ie, roughly half of the bowel cleansing dose is given on the day of the procedure) is strongly recommended for elective colonoscopy.
• A same-day regimen is an acceptable alternative to split dosing, especially for patients undergoing an afternoon examination.
• The second dose of split preparation ideally should begin 4–6 h before the time of colonoscopy, with completion of the last dose at least 2 h before the procedure time.
• When a split-dose bowel cleansing regimen is used, diet recommendations can include either low-residue or full liquids until the evening on the day before colonoscopy 
• Selection of a bowel-cleansing regimen should take into consideration the patient's medical history; medications; and, when available, the adequacy of bowel preparation reported from prior colonoscopies.
• A split-dose regimen of 4 L polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides high-quality bowel cleansing. In healthy nonconstipated individuals, a 4-L PEG-ELS formulation produces a bowel-cleansing quality that is not superior to a lower-volume PEG formulation.
• The routine use of adjunctive agents for bowel cleansing before colonoscopy (eg, simethicone, flavored electrolyte solutions, prokinetics, spasmolytics, bisacodyl, senna, olive oil, and probioticsis) is not recommended. However, additional bowel purgatives should be considered in patients with risk factors for inadequate preparation (eg, patients with a prior inadequate preparation, history of constipation, use of opioids or other constipating medications, prior colon resection, diabetes mellitus, or spinal cord injury). 
• Although sodium phosphate (NaP) is effective and well tolerated by most patients, the risk of adverse events makes it unsuitable as a first-line agent. NaP should be avoided in elderly patients and in patients with known or suspected inflammatory bowel disease.
• Low-volume preparations or extended time delivery for high-volume preparations are recommended for patients after bariatric surgery

Postpolypectomy surveillance

A 2020 update of US Multi-Society Task Force on Colorectal Cancer guidelines provides recommendations on postpolypectomy surveillance. Screening colonoscopy findings and recommended scheduling of surveillance colonoscopy are as follows^[73] :

• Normal colonoscopy, or  < 20 hyperplastic polyps < 10 mm: 10 years
• 1–2 adenomas < 10 mm: 7–10 years
• 3–4 adenomas < 10 mm: 3–5 years
• 5–10 adenomas, adenoma ≥10 mm, or adenoma with villous component or high-grade dysplasia: 3 years
• More than 10 adenomas: 1 year, with consideration for genetic testing based on adenoma burden, age, and family history
• Piecemeal resection of adenoma ≥20 mm: 6 months, then 1 year later, then 3 years after the second examination
• 1–2 sessile serrated polyps (SSPs) < 10 mm: 5–10 years
• 3–4 SSPs < 10 mm or hyperplastic polyp ≥10 mm: 3–5 years
• 5–10 SSPs, SSP ≥10 mm, SSP with dysplasia, or traditional serrated adenoma: 3 years

In 2020, the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE) released joint guidelines for surveillance after polypectomy and colorectal cancer resection.  According to the guidelines, the criteria for high-risk for future colorectal cancer (CRC) following polypectomy comprise either of the following^[74] :

• Two or more premalignant polyps, including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia) or
• Five or more premalignant polyps

Patients who meet the high-risk criteria should undergo a single surveillance colonoscopy at 3 years.  Patients who have undergone CRC resection should have a colonoscopy at 1 year post-surgery and every 3 years thereafter.^[74]

Patients who do not meet high-risk criteria postpolypectomy should participate in national bowel screening when invited. For patients who are more than 10 years younger than the national bowel screening lower age limit, colonoscopy may be considered after 5 or 10 years and individualized to age and other risk factors.^[74]

Knudsen et al conducted a study of colorectal cancer incidence and mortality after negative screening colonoscopies, based on 195,453 participants from 3 prospective US population–based cohorts. Among the 81,151 individuals with negative colonoscopy results, there were 394 cases of colorectal cancer and 167 deaths; among the 114,302 individuals who did not receive endoscopy, there were 2229 colorectal cancer cases and 637 deaths.^[75]

In patients with negative colonoscopy screening, those with high colorectal cancer risk scores had a 10-year cumulative incidence of colorectal cancer of 0.78%. Those with intermediate risk scores did not reach that incidence until 16 years after the initial screening, and those with low risk scores did not reach it until 25 years later. The authors conclude that, “These findings provide evidence for shared decision-making between patients and physicians to consider extending the rescreening intervals after an NCS result beyond the currently recommended 10 years, particularly for individuals with a low-risk profile.”^[75]

• References

Molecular Testing

Treatment of metastatic colorectal cancer (mCRC) is increasingly guided by molecular testing of the tumor. The American Society for Clinical Pathology, the College of American Pathologists (CAP), the Association for Molecular Pathology, and the American Society of Clinical Oncology (ASCO) have issued evidence-based guidelines on colorectal cancer molecular testing.^[76]  Among the recommendations are the following:

• RAS mutational testing of colorectal carcinoma tissue should be performed for patients who are being considered for anti-EGFR therapy; this analysis must include KRAS and NRAS codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and 146 of exon 4 ("expanded" or "extended" RAS)
• BRAF V600 mutational analysis should be done in conjunction with deficient mismatch repair (dMMR)/microsatellite instability (MSI) testing for prognostic stratification
• dMMR/MSI testing must be performed in all colorectal cancers for prognostic stratification and identification of Lynch syndrome patients (BRAF mutation testing is not needed for Lynch syndrome if there is no high MSI (MSI-H) with loss of MLH1)
• Molecular marker testing (KRAS, extended RAS, BRAF, and dMMR/MSI) of the primary colorectal carcinoma tissue is acceptable; if metastatic tissue is available, that is also acceptable and is preferable in patients with metastatic disease.
• Formalin-fixed, paraffin-embedded tissue is an acceptable specimen; use of other specimens will require additional adequate validation, as would any changes in tissue processing protocols

The 2023 European Society for Medical Oncology (ESMO) guidelines for the management of mCRC include the following recommendations^[77] :

• Testing for MMR status and KRAS;NRAS exon 2, 3 and 4; and BRAF mutations is recommended in all patients at the time of mCRC diagnosis
• RAS testing is mandatory before treatment with anti-EGFR monoclonal antibodiesa and can be carried out on either the primary tumor or other metastatic sites
• BRAF mutation status should be assessed simultaneously with the evaluation of RAS, for assessing prognosis and treatment with cetuximab–encorafenib
• dMMR/MSI testing in mCRC can assist in genetic counselling for Lynch syndrome and in predicting the value of immune checkpoint inhibitor therapy
• Identification of HER2 amplification by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) is recommended in RAS wild type patients, to identify those who may benefit from HER2 blockade
• Testing of other biomarkers including ALK and ROS1 gene fusions, mutations of PIK3CA, and HER2 activating mutation,s is not recommended outside clinical trials
• In the rare event that an NTRK fusion is detected by IHC and/or comprehensive genomic analysis, treatment with larotrectinib or entrectinib is recommended
• Testing for dihydropyrimidine dehydrogenase (DPD) deficiency has to be conducted before initiating 5-FU– based chemotherapy

National Comprehensive Cancer Network (NCCN) recommendations for biomarker testing in patients with mCRC include KRAS/RAS or BRAF mutations, HER2 amplifications, and NTRK fusions. With the increasing availability of targeted biologic agents, the determination of these tumor markers provides more treatment options for these patients.^[78]

• References

Staging

The TNM staging system has become the international standard for staging of colorectal cancer. It uses the following three descriptors:

• T for primary tumor
• N for lymph nodal involvement
• M for metastasis

See Tables 1 and 2, below.^[79]

Table 1. TNM Classification for Colon Cancer

View Table

See Table

Table 2. Anatomic stage/prognostic groups

View Table

See Table

For more information, see Colon Cancer Staging.

Prognostic factors associated with staging

Patient prognosis is a function of the clinical and histopathologic stage of colon cancer at diagnosis. In addition to the well-established significance of standard pathologic features such as depth of bowel wall penetration (T), number of locoregional lymph nodes involved (N), and presence of extra-colonic metastases (M), several other factors have been proved to be of importance. These include number of harvested and processed lymph nodes, histologic grade, and evidence of lymphovascular and perineural invasion.

Features that have been shown to be associated with worse prognosis include the following:

• Bowel obstruction at diagnosis
• Ulcerative growth pattern
• Perforation
• Elevated preoperative CEA level

Molecular prognostic factors that have been investigated but not incorporated into standard clinical practice include the following:

• p53
• Loss of heterozygosity for 18q^[80]
• Mutations of deleted in colon cancer gene (DCC)
• Epidermal growth factor receptor (EGFR) gene amplification

KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect sensitivity to treatment with biologic agents directed against the epithelial growth factor receptor (EGFR).^[81] The US Food and Drug Administration (FDA) has approved a qualitative real-time polymerase chain reaction (PCR) assay, the therascreen KRAS RGQ PCR Kit, for the detection of specific KRAS mutations in the KRAS oncogene.

Deficient mismatch repair (dMMR), which is associated with high-frequency microsatellite instability (H-MSI), has been shown to be associated with better clinical outcome and lack of benefit from fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, based on a retrospective analysis of several large randomized trials of adjuvant therapy for colon cancer.^[82] In contrast, those patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability do appear to benefit from fluorouracil-based adjuvant therapy.^[83]

Testing for dMMR with H-MSI may become useful for prognosis and treatment planning in patients with resectable colon cancer. Some research also emphasizes the role of immune regulation in the development and in the natural course and prognosis of patients with colorectal cancers.^[84]

For patients aged 60-69 years with selected stage T3 or T4 colorectal cancer, prognostic factor and 5-year relapse-free survival (based on the Mayo Clinic calculator and numbers of lymph nodes analyzed^[85] ) are as follows:

• T3N0 (11-20 nodes analyzed) – 79%
• T3N0 low grade – 73%
• T3N0 (≤ 10 lymph nodes examined) – 72%
• T3N0 high grade – 65%
• T4N0 low grade – 60%
• T4N0 high grade – 51%
• T3N1 – 49%
• T3N2 – 15%

A review of Surveillance, Epidemiology, and End Results (SEER) population-based data on colon cancer by the American Joint Committee on Cancer (AJCC) Hindgut Taskforce found the following:

• T1-2N2 cancers have a better prognosis than T3-4N2 cancers
• T4bN1 and T4N2 cancers have a similar prognosis
• T1-2N1, T2N0, and T3N0 cancers have a similar prognosis
• T1-2N2a, T2N0, T3N0 (T1N2a), and T4aN0 (T2N2a) have a similar prognosis
• Prognosis for T4a lesions is better than that of T4b by N category
• The number of positive nodes affects prognosis

The Taskforce proposed the following revisions of the TN categorization for colon cancer^[86] :

• Shift T1-2N2 lesions from IIIC to IIIA/IIIB
• Shift T4bN1 from IIIB to IIIC
• Subdivide T4/N1 and T4/N2
• Revise substaging of stages II/III

Histologic subtype and metastatic patterns

In a retrospective Dutch study of autopsy results from 1675 patients with metastatic colorectal cancer and data from 88 patients with synchronous metastases from the Total Mesorectal Excision (TME) trial, Hugen et al noted that the histologic subtype and the localization of the primary tumor in colorectal cancer has a strong influence on its metastatic pattern.^{[87, 88]} Their findings include the following:

• Metastatic disease occurred more frequently and more often in multiple sites, in patients with mucinous adenocarcinoma (MC) (respectively, 33.9% and 58.6% of cases) or signet-ring cell carcinoma (SRCC) (61.2% and 70.7%) compared with those with adenocarcinoma (AC) (27.6% and 49.9%)^{[87, 88]}
• Liver metastases occurred more often in patients with AC (73.0%) or MC (52.2%) than in those with SRCC (31.7%)^[88]
• Peritoneal metastases occurred more often in patients with SRCC (51.2%) or MC (48.2%) than in those with AC (20.1%)^[88]
• Metastases to distant lymph nodes occurred in more SRCC patients (43.9%) than patients with either MC (22.3%) or AC (19.9%)^[88]
• Patients with colon cancer had a higher rate of abdominal metastases relative to those with rectal cancer, who had higher rates of extra-abdominal metastases

• References

Approach Considerations

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), but the proper use of elective colon resections in nonobstructed patients with stage IV disease is a source of continuing debate.

Adjuvant chemotherapy is standard for patients with stage III disease. Its use in stage II disease is controversial, but current guidelines recommend its use in selected patients with risk factors for recurrence.^{[1, 89]} At present, the role of radiation therapy is limited to palliative therapy for selected metastatic sites such as bone or brain metastases.

Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. Biologic agents have assumed a major role in the treatment of metastatic cases, with selection increasingly guided by genetic analysis of the tumor. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate.

For more information, see Colon Cancer Treatment Protocols.

• References

Surgical Care

Surgery is the only curative modality for localized colon cancer (stage I-III) and potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease). The general principles for all operations include removal of the primary tumor with adequate margins including areas of lymphatic drainage. Standard colectomies for adenocarcinoma of the colon are depicted in the image below.

View Image

Standard colectomies for adenocarcinoma of the colon.

For lesions in the cecum and right colon, a right hemicolectomy is indicated. During a right hemicolectomy, the ileocolic, right colic, and right branch of the middle colic vessels are divided and removed. Care must be taken to identify the right ureter, the ovarian or testicular vessels, and the duodenum. If the omentum is attached to the tumor, it should be removed en bloc with the specimen.

For lesions in the proximal or middle transverse colon, an extended right hemicolectomy can be performed. In this procedure, the ileocolic, right colic, and middle colic vessels are divided and the specimen is removed with its mesentery.

For lesions in the splenic flexure and left colon, a left hemicolectomy is indicated. The left branch of the middle colic vessels, the inferior mesenteric vein, and the left colic vessels along with their mesenteries are included with the specimen.

For sigmoid colon lesions, a sigmoid colectomy is appropriate. The inferior mesenteric artery is divided at its origin, and dissection proceeds toward the pelvis until adequate margins are obtained. Care must be taken during dissection to identify the left ureter and the left ovarian or testicular vessels.

Total abdominal colectomy with ileorectal anastomosis may be required for patients with any of the following:

• Hereditary nonpolyposis colon cancer syndrome (HNPCC; Lynch syndrome)
• Attenuated familial adenomatous polyposis (FAP)
• Metachronous cancers in separate colon segments

Total abdominal colectomy may also be indicated for some patients with acute malignant colon obstructions in whom the status of the proximal bowel is unknown.

Laparoscopic surgery

The advent of laparoscopy has revolutionized the surgical approach to colonic resections for cancers. Large prospective randomized trials have found no significant differences between open and laparoscopic colectomy with regard to intraoperative or postoperative complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical wound recurrence. Oncologic outcomes (cause-specific survival, disease recurrence, number of lymph nodes harvested) are likewise comparable.^{[90, 91, 92, 93, 94, 95]}

For example, the Clinical Outcomes of Surgical Therapy Study Group trial found no significant differences between laparoscopic-assisted colectomy (LAC) or open colectomy in terms of 5-year disease-free survival rate (69% versus 68% in the LAC and open colectomy groups, respectively) or overall survival (76% versus 75%).^[91] In a study by Lacy et al with median followup of 95 months, LAC was more effective than open colectomy, although the tendency toward higher cancer-related and overall survival did not reach statistical significance.^[94]

Surgery guidelines

American Society of Colon and Rectal Surgeons practice parameters for the management of colon cancer recommend colectomy as the primary treatment for localized resectable colon cancer.^[96] Additional recommendations are as follows:

• The extent of resection of the colon should correspond to the lymphovascular drainage of the site of the colon cancer; the lymphadenectomy should be complete and en bloc with the bowel segment
• Clinically positive lymph nodes located outside the standard field of resection that are suspected to contain metastatic disease should be biopsied or removed at the time of primary resection
• Resection of involved adjacent organs should be en bloc

National Comprehensive Cancer Network (NCCN) guidelines also recommend colectomy, with en bloc removal of regional lymph nodes, for treatment of resectable, nonobstructing colon cancer.^[78]  In addition, for clinical T4b disease, neoadjuvant chemotherapy may be considered. The NCCN states that laparoscopic-assisted colectomy may be considered, based upon the following criteria:

• The surgeon has experience performing laparoscopically assisted colorectal operations
• No locally advanced disease, acute bowel obstruction, or perforation from cancer is present
• Thorough abdominal exploration is required
•  Preoperative marking of small lesions should be considered 

NCCN recommendations for lymphadenectomy are as follows^[78] :

• Lymph nodes at the origin of feeding vessel should be identified for pathologic exam
• Clinically positive lymph nodes outside the field of resection that are considered suspicious should be biopsied or removed, if possible
• Positive nodes left behind indicate an incomplete (R2) resection
• A minimum of 12 lymph nodes need to be examined to establish N stage

European Society for Medical Oncology (ESMO) recommendations for surgical treatment of localized colon cancer include the following^[97] :

• For noninvasive adenocarcinomas (pTis—ie, intraepithelial or intramucosal), en bloc endoscopic resection of the polyp is sufficient
• Invasive carcinoma (pT1) in a polyp requires a thorough review with the pathologist and surgeon. High-risk features mandating surgical resection with lymphadenectomy include lymphatic or venous invasion, grade 3 differentiation, and significant (grade >1) tumor budding
• Laparoscopic colectomy can be safe when technical expertise is available, in the absence of contraindications
• Obstructive colon cancers can be treated in one- or two-stage procedures, as indicated

Metastatic colorectal cancer

Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate.

Medical oncologists properly note that palliative resection has major drawbacks, such as loss of performance status and risks of surgical complications that potentially lead to delay in chemotherapy. However, surgeons understand that elective operations have lower morbidity than emergent operations on patients who are receiving chemotherapy.

There is a trend toward nonsurgical management of patients with asymptomatic, surgically incurable colorectal cancer, with studies showing that fewer than 10% of these patients subsequently require surgery for obstruction or perforation.^{[98, 99]} A review by Venderbosch et al found that resection of the primary tumor appears to improve survival in patients with stage IV colorectal cancer, but these researchers concluded that prospective studies are warranted, given the potential bias of those results.^[100]

Curative-intent resections of liver metastases have significantly improved long-term survival, with acceptable postoperative morbidity, including in older patients.^[101] A study by Brouquet et al found that resection of colorectal liver metastases after a second-line chemotherapy regimen was safe and provided a modest hope for definitive cure, making this approach viable in patients with advanced colorectal liver metastases.^[102]

Hepatic arterial infusion (HAI) of chemotherapeutic agents such as floxuridine (FUDR) is a consideration following partial hepatectomy. A study by House et al found that adjuvant HAI-FUDR combined with modern systemic chemotherapy resulted in improved survival compared with adjuvant chemotherapy alone.^[103]

Colonic stents have introduced an effective method of palliation for obstruction in patients with unresectable liver metastasis. However, a study by van Hooft et al found that colonic stenting has no decisive clinical advantages compared with emergency surgery. Although it may be used as an alternative treatment in undefined sets of patients, concerns about tumor spread caused by perforations remains.^[104]

• References

Ablation

Although resection is the only potentially curative treatment for patients with colon metastases, other therapeutic options for those who are not surgical candidates include thermal ablation techniques. Cryotherapy uses probes to freeze tumors and surrounding hepatic parenchyma. It requires laparotomy and can potentially result in significant morbidity, including liver cracking, thrombocytopenia, and disseminated intravascular coagulation (DIC).

Radiofrequency ablation (RFA) uses probes that heat liver tumors and the surrounding margin of tissue to create coagulation necrosis. RFA can be performed percutaneously, laparoscopically, or through an open approach. Although RFA has minimal morbidity, local recurrence is a significant problem and correlates with tumor size.

• References

Pharmacotherapy

Analysis of a data set assembled by the Adjuvant Colon Cancer Endpoints group showed that adjuvant chemotherapy provides a significant disease-free survival benefit in stage II and III colon cancer because it reduces the recurrence rate. The benefit was particularly evident within the first 2 years of adjuvant therapy but some benefit extended to years 3-4.^[105]

The standard chemotherapy for patients with stage III and some patients with stage II colon cancer has for decades consisted of 5-fluorouracil (5-FU) in combination with adjuncts such as levamisole and leucovorin.^{[1, 2, 3, 4]} This approach was tested in several large randomized trials and was shown to reduce individual 5-year risk of cancer recurrence and death by about 30%.

Capecitabine (Xeloda) has also become a standard option. Like 5-FU, capecitabine is a fluoropyrimidine, but is given orally rather than intravenously; it undergoes a three-step enzymatic conversion to 5-FU, with the last step occurring in the tumor cell.^[1] The randomized X-ACT study demonstrated the noninferiority of capecitabine compared with 5-FU/leucovorin as adjuvant therapy for patients with stage III colon cancer, with efficacy benefits maintained at 5 years and in older patients.^[106]

The addition of oxaliplatin to fluoropyrimidine-based therapy has also become standard. A phase III trial in 1886 patients with resected stage III colon cancer reported superior overall survival with capecitabine plus oxaliplatin (XELOX, or CapeOx) versus 5-FU/leucovorin (73% vs 67%, respectively; P = 0.04) after a median follow-up of almost 7 years. The results of that study suggested that low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy.^[107] Similarly, the large MOSAIC trial demonstrated significant improvement in 5-year disease-free survival and 6-year disease-free survival for patients with stage III colon cancer when oxaliplatin was added to 5-FU/leucovorin (ie, FOLFOX4).^[108]

Elderly patients

In an observational study of 1291 patients with stage III colon cancer, 56% of whom received adjuvant chemotherapy, van Erning et al concluded that adjuvant chemotherapy should be considered in elderly patients with stage III disease. Adjuvant chemotherapy reduced the risk of distant recurrence after surgery by about half in both elderly patients and younger ones. With adjuvant chemotherapy, hazard ratios for distant recurrence were 0.50 in patients < 75 years of age and 0.57 in those 75 years and older.^[109]

Therapy duration

In the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial (n=12,834), which compared 3 versus 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or XELOX, 3-year disease-free survival in the FOLFOX 3-month arm was lower than that in the 6-month arm by 0.9% (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.00 - 1.15). To meet the prespecified noninferiority threshold, the upper limit of the 95% CI had to be 1.12 or less, so noninferiority was not established. However, shorter therapy was associated with significantly less neurotoxicity. Rates of neurotoxicity were 17% versus 48% with 3 versus 6 months, respectively, of FOLFOX; comparable figures with XELOX were 15% and 45%, respectively; P < 0.0001).^[110]

An American Society of Clinical Oncology (ASCO) guideline on adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine for patients with resected stage III colon cancer recommends offering adjuvant chemotherapy for a duration of 6 months for patients at a high risk of recurrence (T4 and/or N2). For patients at a low risk of recurrence (T1, T2, or T3 and N1), either 6 months or 3 months of chemotherapy may be offered.^[111]

For patients with stage III colon cancer, National Comprehensive Cancer Network (NCCN) guidelines also recommend basing adjuvant treatment duration on risk status, as follows^[78] :

• Low-risk stage III (pathologic stages T1-3/N1): CapeOx for 3 months or FOLFOX for 3 to 6 months 
• High-risk stage III disease (pathologic stages T4/N1-2 and anyT/N2): CapeOx for 3 to 6 months or FOLFOX for 6 months

Adjuvant therapy in stage II colon cancer

The role of adjuvant chemotherapy for stage II colon cancer is controversial.^[1] Surgery alone is usually curative for stage II colon cancer, but approximately 20-30% of these patients develop tumor recurrence and ultimately die of metastatic disease.

A large European trial (QUASAR) demonstrated small but significant benefit (3.6%) in terms of absolute 5-year survival rate for those patients who received 5-FU/leucovorin versus those in the control group.^[112] In contrast, a study by O’Connor et al found that in Medicare patients with stage II colon cancer, with or without poor prognostic features, overall survival was not substantially improved by adjuvant chemotherapy.^[113]

ASCO recommends against the routine use of adjuvant chemotherapy in patients with stage II colon cancer who are at low risk of recurrence, including in younger patients.^[89] However, ASCO recommends offering adjuvant chemotherapy to patients with stage IIB colon cancer (ie, T4) and stage IIC colon cancer (ie, lesions either penetrating visceral peritoneum or invasive of surrounding organ), with a discussion of the potential benefits and risks of harm. In addition, ASCO suggests offering adjuvant therapy to patients with stage IIA colon cancer who have any of the following high-risk factors (with consideration of the number of risk factors as part of the shared decision-making process, since the presence of more than one risk factor may increase the risk of recurrence):

• Sampling of fewer than 12 lymph nodes in the surgical specimen
• Perineural or lymphovascular invasion
• Poorly differentiated or undifferentiated tumor grade
• Intestinal obstruction
• Tumor perforation
• Grade BD3 tumor budding (≥ 10 buds)

ASCO guidelines do not routinely recommend the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy, but consider that it may be offered as a result of shared decision making. ASCO recommends against routinely offering adjuvant therapy to patients with mismatch repair deficiency/microsatellite instability (dMMR/MSI) tumors, but if the combination of dMMR/MSI and high-risk factors results in a decision to offer adjuvant therapy, ASCO recommends including oxaliplatin in the chemotherapy regimen.

A comparison of 3 versus 6 months of FOLFOX or CapeOx adjuvant chemotherapy in 1254 patients with high-risk stage II resected colorectal cancer found that neurotoxicity was approximately 5 times lower in the 3-month arm than the 6-month arm. Noninferiority of 3 months of therapy was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CapeOx or 6 months of FOLFOX therapy can be used when an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer.^[114]

Ongoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers. For example, the ECOG 5202 trial is studying the addition of bevacizumab to adjuvant therapy with 5-FU, leucovorin, and oxaliplatin in high-risk patients, with low-risk patients undergoing observation only. In this trial, high-risk patients are defined as those with microsatellite stability (MSS) or low-frequency microsatellite instability (MSI-L) and loss of heterozygosity at 18q. Low-risk patients are those with MSS or MSI-L and retention of 18q, or high-frequency MSI with or without loss of heterozygosity at 18q.

Therapy for metastatic disease

Combination regimens provide improved efficacy and prolonged progression-free survival (PFS) in patients with metastatic colon cancer. The advent of new classes of active drugs and biologics for colorectal cancer has improved the expected survival for patients with metastatic disease.

In a phase III multicenter trial in patients with advanced colorectal carcinoma refractory to fluorouracil, overall survival did not significantly differ between patients treated with FOLFOX4 (n=246) compared with irinotecan (n=245); however, FOLFOX 4 improved response rate (RR) and time to progression (TTP) compared with irinotecan (P=0.0009 for each RR and TTP). FOLFOX4 was associated with more neutropenia and paresthesias.^[115]

Although many patients with colorectal cancer are elderly, exclusion of these patients from randomized controlled trials has impeded the creation of evidence-based guidelines for this population. A study by Seymour et al demonstrated that elderly and frail patients with untreated metastatic colorectal cancer can participate in a randomized controlled trial. Study patients, who were considered unfit for full-dose chemotherapy, underwent a comprehensive health assessment and were started on chemotherapy at 80% of standard doses.^[116]

In 2015, the US Food and Drug Administration (FDA) approved trifluridine/tipiracil (Lonsurf) for metastatic colorectal cancer. Trifluridine is a nucleoside analog that inhibits cell proliferation by incorporating into DNA and interering with DNA synthesis; tipiracil inhibits the metabolism of trifluridine. The efficacy and safety of trifluridine/tipiracil were evaluated in the phase III RECOURSE trial, an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer. Patients had received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with KRAS wild-type tumors—cetuximab or panitumumab. The primary efficacy end point of the study was median overall survival, which was 7.1 months with trifluridine/tipiracil vs 5.3 months with placebo (P <  0.001). The secondary end point was PFS, which was 2 months with trifluridine/tipiracil vs 1.7 months with placebo.^[117]

In 2023, the FDA approved trifluridine/tipiracil in combination with bevacizumab for metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti–vascular endothelial growth factor (VEGF) biologic therapy, and if RAS wild-type, anti–epidermal growth factor receptor (EGFR) therapy.

Approval was based on the results from the phase III SUNLIGHT trial, in which 246 patients received either trifluridine/tipiracil plus bevacizumab (combination group) or trifluridine–tipiracil alone (FTD–TPI group). The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD–TPI group (P < 0.001). The median PFS was 5.6 months in the combination group and 2.4 months in the FTD–TPI group (P < 0.001).^[118]

Biologic agents

Targeted therapy with biologic agents, based on molecular characteristics of the tumor, have become a standard part of treatment for metastatic colon cancer. Biologic agents used for targeted therapy include monoclonal antibodies against epidermal growth factor receptors (EGFR), vascular endothelial growth factor (VEGF), and cytotoxic T-lymphocyte antigen 4 (CTL4), as well as a variety of tyrosine kinase inhibitors. Such agents include the following:

• Bevacizumab (Avastin)
• Cetuximab (Erbitux)
• Encorafenib (Braftovi)
• Entrectinib (Rozlytrek)
• Fruquintinib (Fruzaqla)
• Ipilimumab (Yervoy)
• Larotrectinib (Vitrakvi)
• Panitumumab (Vectibix)
• Ramucirumab (Cyramza)
• Regorafenib (Stivarga)
• Tucatinib (Tukysa)
• Ziv-aflibercept (Zaltrap)

Detection of microsatellite instability (MSI) has also become important for treatment for metastatic colorectal cancers. Tumors with MSI tend to respond favorably to biologic therapy with immune checkpoint inhibitors (eg, pembrolizumab, nivolumab). These tumors typically have high expression of checkpoint proteins, including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), which interfere with the body’s antitumor T-cell response. By disabling these proteins, checkpoint inhibitors enable T cells to kill tumor cells.^[119]

For patients with deficient mismatch repair (dMMR)/MSI-H tumors who are not eligible for cytotoxic combinations, National Comprehensive Cancer Network (NCCN) guidelines recommend the following as first-line immunotherapy options^[78] :

• Nivolumab
• Pembrolizumab
• Nivolumab plus ipilimumab

The NCCN recommends nivolumab with or without ipilimumab or pembrolizumab for the second- and third-line treatment of patients with dMMR/MSI-H colorectal cancer.

Besides determining the status of MMR and/or MSI, the NCCN has expanded its recommendation for biomarker testing to include KRAS/RAS or BRAF mutations, HER2 amplifications, and NTRK fusions in patients with metastatic colorectal cancer. The determination of these tumor markers provides more treatment options for these patients.^[78]

Bevacizumab

Bevacizumab is a humanized monoclonal antibody to VEGF. It was the first anti-angiogenesis drug to be approved in clinical practice and its first indication was for metastatic colorectal cancer. Approval was based on a pivotal trial that demonstrated improved PFS and overall survival when bevacizumab was added to chemotherapy with irinotecan, 5-FU, and leucovorin (IFL).

Bevacizumab, in combination with fluorouracil-based chemotherapy, is indicated for first- and second-line treatment of metastatic colorectal carcinoma. Bevacizumab is also approved for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen.

Approval for continuation treatment was based on a study that showed maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy. The risk of death was reduced by 19% for those who received bevacizumab in combination with standard chemotherapy in both the first- and second-line compared with those who received chemotherapy alone (hazard ratio [HR]=0.81, P=0.0057). PFS improved by 32% (HR=0.68, P < 0.0001).^[120]

A pooled analysis of cohorts of older patients (aged 65 years or older) from two randomized clinical trials concluded that adding bevacizumab to fluorouracil-based chemotherapy for first-line treatment of metastatic colorectal cancer improved overall survival and PFS in older patients as it does in younger patients, without increased risks of treatment in the older age group. Median overall survival improved from 14.3 months to 19.3 months with the addition of bevacizumab, while median PFS improved from 6.2 months to 9.2 months.^[121]

Results from the randomized CAIRO3 trial appear to show that, compared with observation, maintenance therapy with capecitabine and bevacizumab significantly delayed disease progression in 558 previously untreated patients with stable (or better) metastatic colorectal cancer after six cycles of induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B).^[122] Patients in both groups were treated with CAPOX-B at first progression until second progression.

At a median follow-up of 48 months, CAPOX-B was restarted in 48% of those in the maintenance treatment group and 61% of patients in the observation group.^[122] Median second progression after randomization occurred at 11.7 months in the maintenance group and 8.5 months in the observation group, and median first progression after randomization occurred at 8.5 months in the maintenance group compared with 4.1 months in the observation group. The most pronounced benefit of maintenance therapy was in patients with RAS/BRAF wild-type and BRAF V600E–mutant tumors.^[122]

In a study by Tebbutt et al, bevacizumab was found to be associated with a modestly increased risk of arterial thromboembolism (ATE). However, safety was not significantly worse in older patients or those with a history of ATE or other vascular risk factors.^[123]

Despite its role in the therapy of metastatic colon cancer, bevacizumab did not significantly prolong disease-free survival in patients with stage II and III colon cancer, when added to adjuvant chemotherapy (mFOLFOX6) in a randomized trial (NASBP C-08).^[124]

In 2017, the FDA approved Mvasi (bevacizumab-awwb) as a biosimilar to Avastin (bevacizumab), to be used in combination with fluoropyrimidine-irinotecan–based or fluoropyrimidine-oxaliplatin–based chemotherapy for the second-line treatment of patients with metastatic colorectal cancer that has progressed on a first-line bevacizumab-product–containing regimen. The approval was based on evidence from animal study data, human pharmacokinetic and pharmacodynamics data, and clinical immunogenicity data that supported Mvasi as a biosimilar to Avastin.^[125]

Cetuximab

Cetuximab is a chimeric monoclonal antibody against EGFR that is approved for treatment of KRAS mutation–negative (wild-type), EGFR-expressing, metastatic colorectal cancer. Cetuximab can be used as first-line therapy, in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin).^{[126, 127]} Additionally, cetuximab may be used as monotherapy or in combination with irinotecan (Camptosar) in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy.^[128]

KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect sensitivity to anti-EGFR treatment.^[81] The addition of anti-EGFR antibody treatment to standard chemotherapy regimens for patients with advanced colorectal cancer improves PFS for those with wild-type KRAS status, but not those with mutant KRAS.^[129]

The CRYSTAL trial, a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy with FOLFIRI, documented that only patients with wild-type KRAS derived clinical benefit from cetuximab. In patients with mutant KRAS, adding cetuximab to chemotherapy provided no clinical benefit and resulted only in unnecessary toxicity.^[127]

Based on these results, testing for KRAS mutation was added to the cetuximab indication by the European Medicines Agency (EMA). The FDA approved the use of cetuximab in combination with FOLFIRI for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer, as determined by FDA-approved tests, in 2012.

Panitumumab

Panitumumab is a fully human monoclonal antibody against EGFR. This agent was originally approved as monotherapy for patients with EGFR-expressing metastatic colorectal cancer in whom combination chemotherapy with regimens containing fluoropyrimidine, oxaliplatin, and irinotecan had failed or was not tolerated.

In 2014, the FDA approved panitumumab for first-line treatment of patients with wild-type KRAS (exon 2) metastatic colorectal carcinoma in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX4).^[130] Approval was based on results from the PRIME trial.^[131]

The PRIME trial, a phase III study, showed that patients with wild-type KRAS tumors achieved statistically significant improvement in PFS with panitumumab and FOLFOX4 versus FOLFOX4 alone (9.6 versus 8.0 months, P=0.02) and a nonsignificant improvement in OS versus FOLFOX4 alone (23.9 versus 19.7 months, P =0.07). In contrast, patients with mutant KRAS had significantly reduced PFS with panitumumab-FOLFOX4.^[131]

Thus, panitumumab becomes an option, or an alternative to cetuximab, for patients who have tumors with wild-type KRAS.^{[132, 133]} However, Hecht et al reported that adding panitumumab to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal cancer resulted in increased toxicity and decreased PFS.^[134]

Douillard and colleagues reported that in addition to KRAS mutations in exon 2, additional RAS mutations (KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15) are associated with inferior PFS and OS with panitumumab-FOLFOX4 treatment.^[135] Other mutations that involve some of the kinases downstream from KRAS (such as BRAF and PI3K) are being investigated and may result in even more selective methods to identify patients that may benefit from EGFR inhibition.

In 2017, the FDA extended approval for panitumumab for use in wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer. Approval was based on a retrospective analysis from the PRIME trial and prospective, pre-defined analyses from the phase 3 '0007 study. The '0007 study evaluated the efficacy of panitumumab plus best supportive care (BSC) versus BSC alone in patients with chemorefractory, wild-type KRAS metastatic colorectal cancer.^[136] Key secondary endpoint data showed significant improvement in overall survival (OS) of 10 months in BSC with panitumumab, versus 6.9 months with BSC alone.

In January 2025 the FDA extended approval for panitumumab for use in combination with sotorasib for the treatment of patients with KRAS G12 –mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. Approval was based on results of phase 3 CodeBreaK 300 study, in which this combination showed superior PFS compared with investigator-chosen standard-of-care treatment.^[137]

Ramucirumab

Ramucirumab is a recombinant human monoclonal antibody that binds the VEGF receptor. The FDA approved ramucirumab for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen. Approval was based on the phase III RAISE trial, in which the ramucirumab-FOLFIRI combination improved OS and PFS (13.3 months, 5.7 months, respecttively) compared with placebo-FOLFIRI (11.7 months, 4.5 months, respectively) (P = 0.023 and < 0.001, respectively).^[138]

Nivolumab

Nivolumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). In the CheckMate 142 phase II study, nivolumab, with or without ipilimumab, appeared tolerable and demonstrated clinical activity in patients with microsatellite instability–high (MSI-H) metastatic colorectal cancer. The study enrolled deficient mismatch repair (dMMR) and MSI-H colorectal cancer patients whose disease had progressed on, or who were intolerant to, at least one prior line of therapy. The investigator-assessed objective response rate (ORR) in patients receiving nivolumab (the primary endpoint) was 31%; the disease control rate was 69%.^[139]

One year after entering the trial, 48.4% of patients were still alive and disease-free. One-year OS was 73.8%. Treatment was well tolerated, with no safety signals.^[140]

CheckMate 142 brought an accelerated approval to nivolumab in 2017 for the treatment of patients 12 years or older with dMMR and MSI-H metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. In 2018, nivolumab in combination with low-dose ipilimumab also received accelerated approval for this indication. Continued approval of nivolumab for this indication may be contingent upon the outcomes of confirmatory trials.^[141]

Pembrolizumab

Pembrolizumab, which is a monoclonal antibody to PD-1, is approved for treatment of unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. It is also approved for any solid tumor that has tested positive for MSI-H or dMMR in patients who have had prior treatment and have no satisfactory alternative treatment options.^[142] The multicenter, randomized KEYNOTE-177 trial found that treatment with pembrolizumab monotherapy significantly reduced the risk of disease progression or death by 40% (HR, 0.60; 95% CI, 0.45 - 0.80; P = 0.0004), with a median PFS of 16.5 months versus 8.2 months for chemotherapy, in patients with dMMR colorectal cancers.^[142]

Regorafenib

Regorafenib, a kinase inhibitor, is approved for patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept); and, if KRAS wild type, anti-EGFR therapy (eg, cetuximab, panitumumab).^[143]

Approval was based on a multicenter trial in 760 patients with metastatic colon cancer in whom all approved standard therapies had failed. Patients were randomized in a 2:1 ratio to receive regorafenib or placebo; all patients also received best supportive care. Statistically significant benefit in OS and PFS was observed for regorafenib over placebo.^[144]

Fruquintinib

Fruquintinib (Fruzaqla), a selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, was approved by the FDA in November 2023 for adults with metastatic colorectal cancer who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

Approval was based on results of the FRESCO and FRESCO-2 trials.^{[145, 146]} OS was the major efficacy outcome in both trials. In FRESCO-2, median OS was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group (hazard ratio [HR] 0.66, P < 0.0001).^[146] In FRESCO, median OS was 9.3 months and 6.6 months (HR 0.65, P < 0.001).^[145]

Ziv-aflibercept

Ziv-aflibercept is a fusion protein that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF). This agent was approved for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen.^[147]

Approval was based on the Aflibercept Versus Placebo in Metastatic Colorectal Cancer (mCRC) After Failure of an Oxaliplatin-Based Regimen (VELOUR) trial that included 1226 patients. Results showed improved OS and PFS when ziv-aflibercept was used in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI).^[148]

A phase III trial by Van Cutsem and colleagues in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen found that the addition of ziv-aflibercept to FOLFIRI improves survival. Median survival time was 13.5 months with ziv-aflibercept plus FOLFIRI versus 12.06 months with FOLFIRI alone (P = 0.0032); PFS was 6.90 versus 4.67 months, respectively (P < 0.0001).^[149]

Larotrectinib

Larotrectinib is a highly selective inhibitor of tropomyosin receptor kinases A, B, and C (TRKA, TRKB, TRKC), which are encoded by NTRK genes. In 2018, the FDA granted tissue-agnostic approval for larotrectinib for adult and pediatric patients who meet the following criteria^[150] :

• Have solid tumors that harbor an NTRK gene fusion without a known acquired resistance mutation (note that NTRK fusions can be hard to detect and are found in only about 1% of colorectal cancers)
• Have metastatic disease or disease that has progressed after treatment
• Are likely to experience severe morbidity as a result of surgery
• Lack alternative satisfactory treatments

Therapy for BRAF V600E–positive disease

In December 2024 the FDA granted accelerated approval for the BRAF inhibitor encorafenib, in combination with cetuximab and mFOLFOX6, for first-line treatment of BRAF V600E mutation–positive metastatic colorectal cancer. Approval was based on results of the active-controlled, open-label BREAKWATER trial, in which the objective response rate with this regimen was 61%, as compared with 40% in the control arm, in which patients received mFOLFOX6, FOLFOXIRI, or CAPOX, each with or without bevacizumab. Median duration of response was 13.9 versus 11.1 months, respectively.^[151]

For advanced or metastatic colon cancer that is BRAF V600E mutation positive, NCCN guidelines include the following as second-line therapy options^[78] :

• Dabrafenib plus trametinib plus either cetuximab or panitumumab 
• Encorafenib plus either cetuximab or panitumumab, with or without binimetinib

In the open-label, phase III BEACON trial, therapy with encorafenib and the EGFR inhibitor monoclonal antibody cetuximab, with or without the MEK inhibitor binimetinib (ie, triplet or doublet therapy) provided an overall survival benefit for patients with metastatic colorectal cancer who had the BRAF V600E mutation. The BEACON trial enrolled 665 patients with BRAF V600E–mutated metastatic colorectal cancer who had disease progression after one or two previous regimens.^[152]  

Updated analysis of BEACON showed that median overall survival was 9.3 months in the triplet- and doublet-therapy groups, compared with 5.9 months for patients in the control group, who received standard-of-care therapy with cetuximab plus irinotecan or cetuximab plus FOLFIRI. The confirmed objective response rate (ORR) was 26.8% for triplet therapy, 19.5% for doublet therapy, and 1.8% for control. Thus, the increased toxicity from the addition of binimetinib can be avoided, while maintaing good outcomes.^[153]

HER2-positive disease

HER2 is overexpressed in approximately 3% of colorectal cancers overall and in 5-14% of RAS/BRAF–wild type colorectal tumors. Experimental therapeutic approaches for tumors that have HER2 overexpression have included trastuzumab plus lapatinib and trastuzumab plus pertuzumab.^[110]

In a phase II proof-of-concept study, 27 heavily pretreated patients with HER2-positive metastatic colon cancer showed good response to a therapy regimen that is commonly used to treat HER2-positive breast cancer and does not include a chemotherapy backbone. The 27 patients in the study were identified through screening of 914 patients with KRAS exon 2 (codons 12 & 13) wild-type metastatic colorectal cancer.^[154]

Most of the patients had extensive metastatic disease and distal colon tumors. Almost 75% had received at least four prior treatment regimens and had spent a median total time of 20 months on previous treatments.

Patients were treated with a combination of trastuzumab and lapatinib. At 1 year, 12 of the 27 patients (45%) were still alive. At a median follow-up of 94 weeks, one patient (4%) had achieved a complete response, seven (26%) had achieved a partial response, and disease had stabilized in 12 patients (44%).^[154]

Another regimen, tucatinib in combination with trastuzumab, was granted accelerated approval by the FDA in 2023 for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Approval was based on results from the open-label, multicenter MOUNTAINEER study in 84 patients, in which treatment with tucatinib in combination with trastuzumab yielded an overall response rate of 35% (3.6% complete response; 35% partial response), with a median duration of response of 12.4 months.^[155]

Neoadjuvant Therapy

Guidelines from the American Society of Colon and Rectal Surgeons include the following recommendations on neoadjuvant therapy for colon cancer^[96] :

• In patients with locally advanced colon cancer, neoadjuvant chemotherapy or radiotherapy can result in tumor regression and may facilitate margin-negative excision of locally advanced cancers.
• In patients with initially resectable colon cancer liver metastasis, an individualized decision should be made on neoadjuvant chemotherapy followed by surgical resection or up-front surgery.
• Patients with initially unresectable colon cancer liver metastasis should be considered for neoadjuvant chemotherapy to attempt to convert to resectability.
• Hepatic artery infusion of chemotherapy combined with systemic chemotherapy or immunotherapy may increase resectability of colon cancer liver metastasis, but should be performed only in centers with the appropriate expertise.

• References

Radiation Therapy

Although radiation therapy remains a standard modality for patients with rectal cancer, it has only a limited role in colon cancer. Radiation therapy is not used in the adjuvant setting, and in metastatic settings it is used only for palliative care in selected sites such as bone or brain metastases.

Newer, more selective ways of administering radiation therapy, such as stereotactic radiotherapy (CyberKnife) and tomotherapy, are currently being investigated. In the future, these techniques may extend the indications for radiotherapy in the management of colon cancer.

A prospective, multicenter, randomized phase III study by Hendlisz et al showed that the addition of radioembolization with yttrium-90 significantly improved time to liver progression and median time to tumor progression in patients with unresectable, chemotherapy-refractory, liver-limited metastatic colorectal cancer. The study compared treatment with fluorouracil alone with fluorouracil plus yttrium-90 resin, which was injected into the hepatic artery.^[156]  The US Food and Drug Administration (FDA) has approved yttrium-90 resin microspheres (SIR-Spheres) for the treatment of unresectable metastatic liver tumors from primary colorectal cancer in combination with adjuvant intra–hepatic artery chemotherapy with floxuridine.

• References

Diet

In a prospective cohort study that included 1575 healthcare professionals with stage I to III colorectal cancer, Song et al found that rates of colorectal cancer (CRC)–specific mortality and overall mortality were lower in patients who had higher intake of dietary fiber, especially from cereals. Survival rates were higher in patients who increased their fiber intake after diagnosis from levels before diagnosis, and in patients reporting higher intake of whole grains.^[157]

After multivariable adjustment, each 5 g increment in daily fiber intake was associated with a 22% decrease in CRC-specific mortality and a 14% decrease in all-cause mortality. In patients who increased their fiber intake after diagnosis, each 5 g increase in daily fiber intake was associated with 18% lower CRC-specific mortality. The relationship between fiber intake after diagnosis and CRC-specific mortality  reached a maximum at approximately 24 g/d, beyond which no further mortality reduction was found.^[157]

Evaluation of the source of fiber showed that cereal fiber was associated with lower CRC-specific mortality (33% per 5-g/d increment) and all-cause mortality (22%); vegetable fiber was associated with 17% lower all-cause mortality but not with significantly lower CRC-specific; no association was found for fruit fiber. Whole grain intake was associated with lower CRC-specific mortality (28% decrease in risk per 20-g/day increment), although this beneficial association fell to 23% after adjusting for fiber intake.^[157]

A prospective cohort study in 1011 patients with stage III colon cancer found that postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death. Van Blarigan et al reported that multivariable hazard ratios comparing the highest versus the lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat.^[158]

• References

Consultations

Colorectal cancer, especially early stage disease, can be cured surgically. Following diagnosis and staging, obtaining surgical consultation for the possibility of resection may be appropriate. After surgery, the stage of the tumor may be advanced depending on the operative findings (eg, lymph node involvement, palpable liver masses, peritoneal spread).

In the care of patients with colorectal cancer and isolated liver metastases, consider surgical consultation for possible resection. In some cases, resection of previously unresectable liver metastases may become feasible after cytoreduction with neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical oncologist is very important in patient care, even if the tumor is not considered resectable at the time of diagnosis. In patients with advanced disease, palliative surgery may be helpful in cases of bleeding or obstruction.

Gastroenterology (GI) consultation is critical for screening of high-risk individuals (ie, patients with a family history of colorectal cancer or polyposis syndromes) and those individuals who are found to be inappropriately iron deficient or to have occult blood on screening fecal examination. A colonoscopy or sigmoidoscopy is necessary to visualize the colon endoscopically, to obtain biopsies, or to resect polyps.

GI consultation may also be necessary in the management of advanced disease. The advent of colorectal stents allows a nonsurgical management of impending obstruction in patients who present with unresectable, metastatic disease.

GI consultation is necessary in the follow-up of patients after surgical resection and adjuvant chemotherapy. Patients must be screened for recurrent disease in the colon by colonoscopic examination at 1 year after surgery and then every 3 years.

• References

Long-Term Monitoring

Pooled analysis from several large adjuvant trials showed that 85% of colon cancer recurrences occur within 3 years after resection of primary tumor, with 95% occurring within 5 years. Therefore, patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection.^[159] Recommendations for post-treatment surveillance, from the European Society for Medical Oncology (ESMO),^[160] the American Society for Clinical Oncology (ASCO),^[159] and the National Comprehensive Cancer Network (NCCN)^[78] are compared in Table 2, below.

Table 2. Surveillance recommendations for stage II and III colon cancer

View Table

See Table

Followup should be guided by the patient’s presumed risk of recurrence and functional status. Testing at the more frequent end of the range should be considered for patients at high risk. Patients with severe comorbid conditions that make them ineligible for surgery or systemic therapy should not undergo surveillance testing.^[159]

In 2016, the US Multi-Society Task Force on Colorectal Cancer issued guidelines on colonoscopy after colorectal cancer resection, which included the following recommendations^[161] :

• Patients with colorectal cancer (CRC) should undergo high-quality perioperative clearing with colonoscopy. The procedure should be performed preoperatively, or within a 3- to 6-mo interval after surgery in the case of obstructive CRC. The goals of perioperative clearing colonoscopy are detection of synchronous cancer and detection and complete resection of precancerous polyps.
• Patients who have undergone curative resection of either colon or rectal cancer should receive their first surveillance colonoscopy 1 yr after surgery (or 1 yr after the clearing perioperative colonoscopy).
• Patients with localized rectal cancer who have undergone surgery without total mesorectal excision, those who have undergone transanal local excision (ie, transanal excision or transanal endoscopic microsurgery) or endoscopic submucosal dissection, and those with locally advanced rectal cancer who did not receive neoadjuvant chemoradiation and then surgery using total mesorectal excision techniques, are at increased risk for local recurrence. In these situations, it is suggested that patients undergo local surveillance with flexible sigmoidoscopy or endoscopic ultrasound (EUS) every 3−6 mo for the first 2−3 yr after surgery. These surveillance measures are in addition to recommended colonoscopic surveillance for metachronous neoplasia.
• In patients with obstructive CRC precluding complete colonoscopy, CT colonography (CTC) is recommended as the best alternative to exclude synchronous neoplasms. Double-contrast barium enema is an acceptable alternative if CTC is not available.

Cancer Care Ontario published guidelines for the follow-up care of survivors of stages II and III colorectal cancer, and these were endorsed by the American Society of Clinical Oncology. The recommendations include the following^[159] :

• Surveillance is especially important in the initial 2-4 years following treatment, when most recurrences occur
• Patients should be followed for 5 years, and regular reviews of medical history, physical examination, and carcinoembryonic antigen testing should be performed every 3-6 months
• Annual computed tomography (CT) scanning of the abdomen and chest should be performed for 3 years
• Pelvic CT scanning should be performed in patients with rectal cancer annually for 3-5 years
• In patients who have not received pelvic radiation, a rectosigmoidoscopy should be performed every 6 months for 2-5 years
• A surveillance colonoscopy should be performed approximately 1 year after initial surgery
• Patients should be counseled to maintain a healthy body weight, be physically active, and follow a healthy diet

• References

Prevention

Colorectal cancer prevention strategies fall into three categories:

• Screening (see Workup)
• Lifestyle measures
• Pharmacologic prevention

Lifestyle measures

Abundant epidemiologic literature suggests an association of risk for developing colorectal cancer with dietary habits, environmental exposures, and level of physical activity. For example, a prospective cohort study in the general population of two Danish cities concluded that 23% of colorectal cancer cases might have been prevented if all participants had followed recommendations for the following five lifestyle factors^[162] :

• Physical activity
• Waist circumference
• Smoking
• Alcohol intake
• Diet

A study of 79,952 men and 93,475 women who participated in the Multiethnic Cohort Study found that greater adherence to plant-based diets rich in healthy plant foods and low in less-healthy plant foods is associated with a reduced risk of colorectal cancer in men, but not in women. Plant foods designated as healthy were whole grains, fruits, vegetables, vegetable oils, nuts, legumes, and tea and coffee; those designated as less healthy were refined grains, fruit juices, potatoes, and added sugars. Benefits of a plant-based diet were greater in Japanese American, Native Hawaiian, and White groups than in African-American or Latino groups and for left colon and rectal tumors than right tumors.^[163]  

There is also evidence that diet and physical activity affect the risk for recurrence of colon cancer. A prospective observational study involving patients with stage III colon cancer from the CALGB 89803 adjuvant chemotherapy trial demonstrated adverse effect with regards to risk for recurrence and increased mortality for patients following a "Western" diet (high intake of red meat, refined grains, fat, and sweets) versus a "prudent" diet (high intake of fruits and vegetables, poultry, and fish).^[15]

In another observational study from the same cohort of patients, patients were prospectively monitored and physical activity was recorded. The study concluded that physical activity reduces the risk of recurrence and mortality in patients with resected stage III colon cancer.^[164]

Calcium and vitamin D supplementation

Although earlier data had strongly indicated that calcium supplementation can help prevent colorectal cancer, and had suggested a preventive effect of vitamin D supplementation, a randomized trial by Baron et al found that daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years.^[165]

However, a randomized trial by Barry et al suggested that vitamin D receptor genotype may affect the benefits of vitamin D3 supplementation. In their analysis of 41 single-nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes in 1702 patients with colorectal adenomas, vitamin D3 supplementation decreased risk for advanced adenomas (but not adenomas overall) by 64% in study subjects with the AA genotype at the rs7968585 SNP, but increased risk by 41% in those with one or two G alleles. The benefits of calcium supplementation were not significantly linked to genotype.^[166]

Circulating levels of 25 hydroxyvitamin D (25[OH]D) that are optimal for preventing colorectal cancer may be significantly higher than levels necessary for bone health, according to an international collaborative meta-analysis that pooled 17 cohorts. Although levels of 50 to < 62.5 nmol/L are considered adequate for bone health by the Institute of Medicine, the study found that levels of 75–< 87.5 were associated with 19% lower risk and levels of 87.5–< 100 nmol/L were associated with 27% lower risk.^[167]

For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women and 7% lower in men. In addition, the study confirmed that vitamin D deficiency increases colorectal cancer risk: 25(OH)D levels of less than 30 nmol/L were associated with a 31% greater risk compared with adequate levels.^[167]

Pharmacologic prevention

Pharmacologic prevention is based on the understanding of colorectal carcinogenesis and the availability of pharmacologic agents that are effective yet minimally toxic. The efficacy of these agents is usually first tested in high-risk populations.

Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor, was first tested in patients with familial adenomatous polyposis (FAP). Celecoxib was effective in decreasing the number and size of polyps on serial colonoscopies, which was the primary surrogate endpoint for this trial.^[168] The drug was approved for FAP patients, although it remains to be seen whether this intervention translates to reduced cancer incidence and prolonged survival.

Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened because of a high incidence of cardiovascular toxicity in trial patients, which led to the removal of rofecoxib from the market. Other nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac and nonselective cyclooxygenase inhibitors, have been tested in lower-risk populations.

Aspirin use has been shown to be effective in both primary prevention of colorectal cancer (at doses of 300 mg or more daily for about 5 years^[169] ) and secondary prevention (at doses ranging from 81 to 325 mg daily^[170] ) of colorectal adenomas. The decrease in colon cancer risk with aspirin use may vary among population subgroups. However, body mass index, physical activity, and plasma C-peptide levels were shown to not have a significant impact on aspirin’s effect on colon cancer risk.^[171]

Examination of questionnaire data collected from the Nurses’ Health Study and the Health Professionals Follow-up Study showed regular aspirin use was associated with lower risk of BRAF –wild-type colorectal cancer (multivariable hazard ratio [HR], 0.73) but not with BRAF -mutated cancer risk (multivariable HR, 1.03). Status of tumor PTGS2 expression or PIK3CA or KRAS mutation had no effect on this association.^[172]

A 2013 study showed that low-dose aspirin taken every other day lowers the risk for colorectal cancer in middle-aged women. Nearly 40,000 women aged 45 and older were randomized to low-dose aspirin (100 mg) or placebo every other day for roughly 10 years; 84% were followed for an additional 7 years after treatment ended. At followup, colorectal cancer risk was lower in the aspirin group, mostly owing to a reduction in proximal colon cancer; this reduction in risk emerged after 10 years.^[173]

American College of Gastroenterology (ACG) guidelines suggest the use of low-dose aspirin to reduce risk of colorectal cancer in individuals aged 50–69 years with a cardiovascular disease risk of 10% or higher over the next 10 years, who are not an increased risk for bleeding and are willing to take aspirin for at least 10 years. The ACG recommends against the use of aspirin as a substitute for colorectal cancer screening.^[54]

Some trials focused on combined inhibition of polyamine production and cyclooxygenase inhibition. A report from a large randomized trial of a combination of sulindac and dimethylformamine (DMFO), an inhibitor of ornithine decarboxylase (ODC), described a dramatic effect of this combination in reducing polyp recurrence in patients with prior history of colon polyps. Confirmatory trials are ongoing.^[174]

• References

Guidelines Summary

Guidelines on colorectal screening have been issued by the following organizations:

• (2024) National Comprehensive Cancer Network (NCCN)^{[175, 70]}
• (2021) American College of Gastroenterology^[54]
• (2021) U.S. Preventive Services Task Force (USPSTF)^[69]
• (2020) European Society for Medical Oncology (ESMO)^{[97, 176]}
• (2019) American College of Physicians^[177]
• (2018) American Cancer Society^[178]

Guidelines on familial risk have been issued by the following organizations:

• (2024) NCCN^[78]
• (2015) American Gastroenterological Association^[179]
• (2015) American Society of Clinical Oncology (ASCO)^[180]
• (2004) National Cancer Institute (Bethesda guidelines)^[55]

Guidelines on postpolypectomy surveillance have been issued by the following organizations:

• (2020) US Multi-Society Task Force on Colorectal Cancer^[73]
• (2020) British Society of Gastroenterology, Association of Coloproctology of Great Britain and Ireland, Public Health England^[74]

Guidelines on surgical treatment have been issued by the following organizations:

• (2024) NCCN^[78]
• (2022) American Society of Colon and Rectal Surgeons^[96]
• (2020) ESMO^[97]

Guidelines on adjuvant and neoadjuvant therapy have been issued by the following organizations:

• (2024) NCCN^[78]
• (2021) ASCO^[89]
• (2022) American Society of Colon and Rectal Surgeons^[96]
• (2020) ESMO^[182]

Guidelines on follow-up care for survivors of stage II and stage III colorectal cancer were issued by the following organizations:

• (2024) NCCN^[78]
• (2016) US Multi-Society Task Force on Colorectal Cancer^[161]
• (2015) American Society of Colon and Rectal Surgeons^[181]
• (2013) Cancer Care Ontario endorsed by ASCO^[159]
• (2013) ESMO^[160]

Guidelines on molecular testing in metastatic disease were issued by the following organizations:

• (2024) NCCN^[78]
• (2023) ESMO^[182]
• (2015) American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP),  Association for Molecular Pathology, ASCO^[183]

Guidelines on targeted therapy have been issued by the following organizations:

• (2024) NCCN^[78]
• (2023) ESMO^[182]

• References

Medication Summary

The fluoropyrimidine fluorouracil (5-fluorouracil; 5-FU) remains the backbone of chemotherapy regimens for colon cancer, both in the adjuvant and metastatic setting. In addition to 5-FU, oral fluoropyrimidines such as capecitabine (Xeloda) and, outside the United States, tegafur are used as monotherapy or in combination with oxaliplatin (Eloxatin). Some of the standard combination regimens employ prolonged continuous infusion of 5-FU (FOLFIRI, FOLFOX)^[184] or capecitabine (CAPOX, XELOX, XELIRI).^{[185, 186]} For unresectable or metastatic colon cancer, treatment increasingly includes biologic agents, typically as targeted therapy based on genetic analysis of the tumor.

See also Colon Cancer Treatment Protocols

• References

Fluorouracil (Adrucil)

• Dosing, Interactions, etc.

Clinical Context:  Fluoropyrimidine analog. Cell cycle-specific with activity in the S-phase as single agent and has for many years been combined with biochemical modulator leucovorin. It inhibits DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. Classic antimetabolite anticancer drug with chemical structure similar to endogenous intermediates or building blocks of DNA or RNA synthesis. Fluorouracil (5-fluorouracil; 5-FU) inhibits tumor cell growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular viability. These effects depend on intracellular conversion of 5-FU into 5-FdUMP, 5-FUTP, and 5-FdUTP. 5-FdUMP inhibits thymidylate synthase (key enzyme in DNA synthesis), which leads to accumulation of dUMP, which then gets misincorporated into the DNA in the form of 5-FdUTP resulting in inhibition of DNA synthesis and function with cytotoxic DNA strand breaks. 5-FUTP is incorporated into RNA and interferes with RNA processing.

• References

Capecitabine (Xeloda)

• Dosing, Interactions, etc.

Clinical Context:  Fluoropyrimidine carbamate prodrug from of fluorouracil. Capecitabine itself is inactive. Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA and to a lesser degree with RNA synthesis.

• References

Class Summary

These agents inhibit cell growth and proliferation.

• References

Leucovorin

• Dosing, Interactions, etc.

Clinical Context:  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. Current standard therapy for colon cancer involves combination chemotherapy. Binds to and stabilizes ternary complex of FdUTP (intracellular active metabolite of fluoropyrimidines) and thymidylate synthetase (TS), augmenting cytotoxic effects of fluorouracil. Used as an adjunct to fluorouracil.

• References

Class Summary

These agents counteract the toxic effects of the chemotherapeutic drug.

• References

Irinotecan (Camptosar)

• Dosing, Interactions, etc.

Clinical Context:  Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminata tree. Inactive in its parent form. Converted by the carboxylesterase enzyme to its active metabolite from, SN-38.

SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication. Current standard therapy for metastatic colon cancer is with the combination of fluorouracil, leucovorin, and irinotecan.

• References

Trifluridine/tipiracil (Lonsurf)

• Dosing, Interactions, etc.

Clinical Context:  Trifluridine is a thymidine-based nucleoside analog that incorporates into DNA, interferes with DNA synthesis, and inhibits cell proliferation. Tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. The combination product is indicated, as a single agent, or in combination with bevacizumab, for metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biologic therapy, and if RAS wild-type, an anti-EGFR therapy.

• References

Class Summary

Irinotecan is a topoisomerase I inhibitor. Trifluridine is a thymidine-based nucleoside analog that is combined with the thymidine phosphorylase inhibitor, tipiracil.

• References

Oxaliplatin (Eloxatin (DSC))

• Dosing, Interactions, etc.

Clinical Context:  Third-generation platinum-based antineoplastic agent used in combination with an infusion of fluorouracil (5-FU) and leucovorin for treatment of metastatic colorectal cancer in patients with recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. Also indicated for previously untreated advanced colorectal cancer in combination with 5-FU and leucovorin. Covalently binds to DNA with preferential binding to the N-7 position of guanine and adenine. DNA mismatch repair enzymes are unable to recognize oxaliplatin-DNA adducts in contrast with other platinum-DNA adducts as a result of their bulkier size. Forms interstrand and intrastrand Pt-DNA crosslinks that inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific with activity in all phases of the cell cycle.

• References

Class Summary

Oxaliplatin is a platinum analog.

• References

Cetuximab (Erbitux)

• Dosing, Interactions, etc.

Clinical Context:  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 treatment of KRAS mutation-negative (wild-type) EGFR-expressing, metastatic colorectal cancer for the following: 1) in combination with FOLFIRI for first-line treatment, 2) in combination with irinotecan infor disease refractory to irinotecan-based chemotherapy, and 3) as a single agent in patients who have experienced failure of oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.

• References

Bevacizumab (Alymsys, Avastin, Avzivi)

• Dosing, Interactions, etc.

Clinical Context:  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. Bevacizumab is indicated in combination with a fluoropyrimidine-based chemotherapy regimen as a first-line or second-line treatment for metastatic colorectal cancer. It is also indicated for second-line treatment in patients whose disease has progressed on a first-line bevacizumab-containing regimen. For continuation therapy, use bevacizumab in combination with a fluoropyrimidine (eg, 5-FU, capecitabine) plus irinotecan or oxaliplatin-based chemotherapy. Mvasi has been FDA-approved as a biosimilar to Avastin but not as an interchangeable product.

• References

Panitumumab (Vectibix)

• Dosing, Interactions, etc.

Clinical Context:  Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor receptor (EGFR). Indicated for wild-type KRAS (exon 2 in codons 12 or 13) metastatic colororectal carcinoma, as determined by an FDA-approved test. Indicated as second-line monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. Also indicated for use in combination with sotorasib for the treatment of KRAS G12C-mutated metastatic colorectal carcinoma, as determined by an FDA-approved test, in patients who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Also indicated as first-line therapy in combination with FOLFOX.

• References

Ipilimumab (Yervoy)

• Dosing, Interactions, etc.

Clinical Context:  Recombinant human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody. It is indicated in combination with nivolumab for adults with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

• References

Class Summary

These agents target factors responsible for deregulated cell proliferation.

• References

Ziv-aflibercept (Zaltrap)

• Dosing, Interactions, etc.

Clinical Context:  Vascular endothelial growth factor (VEGF) inhibitor; prevents VEGF from stimulating cellular responses by binding to tyrosine kinase receptors (ie, the VEGF receptors). Indicated in combination with fluorouracil/leucovorin/irinotecan (FOLFIRI) for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen.

• References

Regorafenib (Stivarga)

• Dosing, Interactions, etc.

Clinical Context:  Regorafenib is a tyrosine kinase inhibitor. It is indicated for metastatic colorectal cancer in patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept); and, if KRAS wild type, an anti-EGFR therapy (eg, cetuximab, panitumumab).

• References

Tucatinib (Tukysa)

• Dosing, Interactions, etc.

Clinical Context:  Tucatinib is a tyrosine kinase inhibitor of HER2. It inhibits the antitumor activity of HER2-expressing tumor cells and inhibits the growth of HER2-expressing tumors. The FDA granted accelerated approval for tucatinib in combination with trastuzumab for treatment of RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed after treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.

• References

Class Summary

VEGF induces endothelial cell proliferation and blood vessel permeability. Inhibiting VEGF prevents tyrosine kinase stimulation. 

• References

Ramucirumab (Cyramza)

• Dosing, Interactions, etc.

Clinical Context:  Ramucirumab specifically binds VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. It is indicated for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen.

• References

Fruquintinib

• Dosing, Interactions, etc.

Clinical Context:  Fruquintinib is a selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is indicated for metastatic colorectal cancer in adults who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therap; and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.

• References

Class Summary

Vascular endothelial growth factor (VEGF) receptor antagonists disrupt ligand-induced proliferation and migration of human endothelial cells. Angiogenesis requires the binding of signaling molecules (eg, VEGF) to receptors on the surface of normal endothelial cells. When VEGF and other endothelial growth factors bind to their receptors on endothelial cells, signals within these cells are initiated that promote the growth and survival of new blood vessels. When VEGF is bound, angiogenesis is inhibited.

• References

Pembrolizumab (Keytruda)

• Dosing, Interactions, etc.

Clinical Context:  Monoclonal antibody to programmed cell death–1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. It is indicated for unresectable or metastatic colon cancer that has tested positive for microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR), and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan.

• References

Nivolumab (Opdivo)

• Dosing, Interactions, etc.

Clinical Context:  Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits programmed cell death–1 (PD-1) activity by binding to the PD-1 receptor to block the ligands PD-L1 and PD-L2 from binding. The negative PD-1 receptor signaling that regulates T-cell activation and proliferation is therefore disrupted. This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. It is indicated for unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR), and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan in patients ≥ 12 years. Additionally, it is also indicated in combination with ipilimumab for adults.

• References

Class Summary

Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

• References

Encorafenib (Braftovi)

• Dosing, Interactions, etc.

Clinical Context:  Encorafenib inhibits in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. It is indicated in combination with cetuximab for metastatic colorectal cancer (mCRC) in patients with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy, and as first-line therapy for BRAF V600E mutation–positive mCRC, in combination with cetuximab and mFOLFOX6

• References

Class Summary

This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers.

• References

Larotrectinib (Vitrakvi)

• Dosing, Interactions, etc.

Clinical Context:  Highly selective inhibitor of the tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC. In tumor models, larotrectinib demonstrates antitumor activity in cells by activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK overexpression.

• References

Entrectinib (Rozlytrek)

• Dosing, Interactions, etc.

Clinical Context:  Selectively inhibits TRKA, TRKB, and TRKC. Indicated for adults and children aged 12 years or older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation.

• References

Class Summary

These agents inhibit tropomyosin receptor tyrosine kinases (TRKs). TRK proteins may promote cell proliferation and survival in tumor cell lines.

• References

Sotorasib (Lumakras)

• Dosing, Interactions, etc.

Clinical Context:  Forms irreversible, covalent bond with unique cysteine of KRAS G12C, locking the protein in an inactive state that prevents downstream signaling without affecting wild-type KRAS. Indicated for use in combination with panitumumab for the treatment of KRAS G12C-mutated metastatic colorectal carcinoma, as determined by an FDA-approved test, in patients who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

• References