Colorectal Cancer Guidelines

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

• American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology
• U.S. Preventive Services Task Force (USPSTF)
• American College of Physicians (ACP)
• American College of Gastroenterology (ACG)
• National Comprehensive Cancer Network (NCCN)

While all the guidelines recommend routine screening for colorectal cancer and adenomatous polyps in asymptomatic adults, they differ with regard to frequency of screening and age at which to discontinue screening, as well as the preferred screening method. Although the customary age for starting screening in persons at average risk has been 50 years, the increasing incidence of colorectal cancer in younger people has prompted several organizations to lower the recommended starting age to 45 years. For high-risk patients, the recommendations differ regarding the age at which to begin screening, as well as the frequency and method of screening.

In contrast, a 2019 guideline on colorectal cancer screening from an international panel of experts recommends using risk calculations to guide screening, with screening limited to patients with an elevated level of risk.

American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology

A joint guideline developed by the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology, published in 2008, recommends that screening for colorectal cancer and adenomatous polyps start at age 50 years in asymptomatic men and women. ^[1]

In addition, individuals with any of the following colorectal cancer risk factors should undergo colonoscopy at an earlier age and more frequently than average risk individuals:

• Family history of colorectal cancer or polyps
• Family history of a hereditary colorectal cancer syndrome such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC)
• Personal history of colorectal cancer
• Personal history of chronic inflammatory bowel disease (ulcerative colitis or Crohn disease)

Screening options for average-risk adults 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 (FOBT) 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

In 2017 the US Multi-Society Task Force on Colorectal Cancer issued updated screening recommendations that divide screening tests into three tiers, based upon their effectiveness. ^[2]

Tier 1 tests consist of the following:

• Colonoscopy every 10 years
• Annual FIT

Tier 2 tests consist of the following:

• CT colonography every 5 years
• FIT–fecal DNA every 3 years
• Flexible sigmoidoscopy every 5–10 years

Tier 3 testing is capsule colonoscopy every 5 years. Septin 9 testing is not recommended.

Suggested timing of initial screening and intervals for subsequent testing for different risk populations are as follows:

• For patients at average risk, testing with a tier 1 test should begin at age 45 years for African Americans and at age 50 for patients of all other races.

• For patients with a family history of colorectal cancer or advanced adenoma that was diagnosed before age 60 years in one first-degree relative or at any age in two first-degree relatives, testing should begin with colonoscopy at an age10 years younger than the youngest age at diagnosis of a first-degree relative, or age 40, to be repeated every 5 years.

• In patients with one first-degree relative with colorectal cancer, advanced adenoma, or an advanced serrated lesion diagnosed at age 60 or older, screening should begin with a tier 1 test at age 40 and continue at the same intervals as in average-risk patients.

• Colonoscopy screening should be discontinued in patients aged 75 or older with prior negative screening tests or whose life expectancy is less than 10 years, or in those 85 years or older without prior screening.

In 2018 the ACS revised its colorectal screening guidelines, advising that regular screening for people at average risk start at age 45 years. ^[3]  Additional ACS recommendations include the following:

• 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.

In 2021, the US Multi-Society Task Force on Colorectal Cancer revised its colorectal screening guidelines, suggesting that screening begin at age 45 in individuals at average risk. The Task Force does not recommend screening after age 85 years. ^[4]

U.S. Preventive Services Task Force (USPSTF)

In May 2021 the USPSTF revised its colorectal screening guidelines. While maintaining its grade A recommendation of screening for colorectal cancer in all adults aged 50 to 75 years, the USPSTF added a grade B recommendation for screening in 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 (C recommendation). ^{[5, 6]} The USPSTF advises that in 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. ^[6]

The USPSTF does not recommend colorectal cancer screening for adults older than 85 years. ^[6]

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.

Stool-based screening tests and intervals are as follows:

• Guaiac-based fecal occult blood test (FOBT), every year
• Fecal immunochemical test (FIT), every year
• FIT-DNA, every 1 or 3 years

Direct visualization screening tests and intervals are as follows:

• Colonoscopy, every 10 years
• Computed tomographic (CT) colonography, every 5 years
• Flexible sigmoidoscopy, every 5 years
• Flexible sigmoidoscopy with FIT; sigmoidoscopy every 10 years, with FIT every year

American College of Physicians (ACP)

In 2019, the American College of Physicians recommended that average-risk adults aged 50 to 75 years should be screened for colorectal cancer by one of the following strategies ^[7] :

• FIT or high-sensitivity FOBT or FIT every 2 years
• Colonoscopy every 10 years
• Flexible sigmoidoscopy every 10 years plus FIT every 2 years

Clinicians should discontinue screening for colorectal cancer in average-risk adults older than 75 years or in adults with a life expectancy of 10 years or less. ^[7]

American College of Gastroenterology

American College of Gastroenterology (ACG) 2021 guidelines recommend colorectal cancer screening in average-risk individuals of age 50 to 75 years, and suggest screening in average-risk individuals of age 45 to 49 years. The ACG recommends colonoscopy and FIT as the primary modalities for colorectal cancer screening. ^[8]  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 Septin 9 for screening.

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (NCCN) has released separate guidelines for average-risk and high-risk individuals. ^{[9, 10]} For average individuals, the recommendations are nearly identical to those of the joint American Cancer Society (ACS), US Multi-Society Task Force on Colorectal Cancer, and American College of Radiology. However, in 2021 the NCCN lowered the age for starting screening in average-risk individuals from 50 years to 45 years. ^[9]

The NCCN criteria for average risk are as follows ^[9]

• Age ≥45 y
• No history of adenoma, sessile serrated polyp, or colorectal cancer
• No history of inflammatory bowel disease
• Negative family history for colorectal cancer or confirmed advanced adenoma (ie, high-grade dysplasia, ≥1 cm, villous or tubulovillous histology) or an advanced sessile serrated polyp (≥1 cm, any dysplasia)

The NCCN guidelines provide screening recommendations for patients at increased risk due to any of the following ^[9] :

• Personal history of adenoma or sessile serrated polyp
• Personal history of colorectal cancer
• Inflammatory bowel disease (ulcerative colitis, Crohn's disease)
• Positive family history

The guidelines also specify recommendations for patients with the following high-risk syndromes ^[10] :

• Lynch syndrome (hereditary nonpolyposis colorectal cancer)
• Classic familial adenomatous polyposis (FAP)
• Attenuated familial adenomatous polyposis (AFAP)
• MUTHYH-associated polyposis (MAP)
• Peutz-Jeghers syndrome (PJS)
• Juvenile polyposis syndrome (JPS)
• Serrated polyposis syndrome (SPS)
• Colonic adenomatous polyposis of unknown etiology
• Cowden syndrome/PTEN hamartoma tumor syndrome
• Li-Fraumeni syndrome

Individuals meeting one or more of the following criteria should receive further evaluation for polyposis syndromes ^[10] :

• Individuals with more than 10 adenomas detected (FAP, AFAP, MAP, and other rare genetic causes of multiple adenomatous polyps)
• Individuals with more than 2 hamartomatous polyps (PJS, JPS and Cowden/PTEN hamartoma tumor syndrome)
• Individuals with 5 or more serrated polyps proximal to the rectum
• Family members with a known high-risk syndrome associated with colorectal cancer, with or without a known mutation
• Individuals with a desmoid tumor, hepatoblastoma, cribriformmorular variant of papillary thyroid tumor (FAP, AFAP, MAP)

Risk-based screening

An international panel of experts has published colorectal cancer screening guidelines that recommend risk-based screening for adults aged 50-79 years with no prior screening, no symptoms of colorectal cancer, and a life expectancy of at least 15 years. ^[11] For individuals with an estimated 15-year colorectal cancer risk below 3%, the panel suggests no screening (weak recommendation). For individuals with an estimated 15-year risk above 3%, the panel suggests screening with one of the following options:

• FIT every year
• FIT every 2 years
• A single sigmoidoscopy
• A single colonoscopy 

Calculation of 15-risk for colorectal cancer can be made using the online QCancer calculator. (Note that this calculator was developed for the United Kingdom population.)

Lynch Syndrome

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Guidelines for Lynch syndrome screening have been developed by the National Cancer Institute (Bethesda guidelines) and the NCCN. ^[12]

Because cancers with MSI account for approximately 15% of all colorectal cancers, in 1996 the National Cancer Institute developed the Bethesda guidelines for the identification of individuals with HNPCC who should be tested for MSI. These guidelines were most recently revised in 2002. ^[13]

Th NCCN criteria for the evaluation of Lynch syndrome (LS) include the following ^[10] :

• Known LS pathogenic variant in family
• Personal history of colorectal, endometrial, or other LS-associated cancer
• Family history of a first-degree relative with colorectal or endometrial cancer diagnosed before age 50
• Family history of a first-degree relative with colorectal or endometrial cancer and another synchronous or metachronous LS-related cancer
• Family history of 2 or more first-degree or second-degree relatives with LS-related cancer, including 1 or more diagnosed before age 50
• Family history of 3 or more first-degree or second-degree relatives with LS-related cancers

The American Gastroenterological Association recommends testing all patients with colorectal cancer for Lynch syndrome. The tumor should be tested for MSI or with immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 proteins. ^[14]

The European Society for Medical Oncology (ESMO) guidelines for familial risk-colorectal cancer ^[15] , which have been endorsed by the American Society of Clinical Oncology (ASCO) ^[16] includes the following recommendations:

• Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all patients with colorectal cancer. As an alternate strategy, tumor testing should be carried out in individuals with colorectal cancer younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines

• If loss of MLH1/PMS2 protein expression is observed, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be conducted to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.

• If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1).

• Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis.

The American College of Gastroenterology recommendations are in general agreement with ESMO. ^[17]

A 2020 update of US Multi-Society Task Force on Colorectal Cancer guidelines provides recommendations on postpolypectomy surveillance. The recommendations assume high-quality baseline colonoscopy, defined as meeting all the following criteria: ^[18]

• Adequate bowel preparation
• Performance by a colonoscopist with adequate adenoma detection rate
• Complete examination to the cecum
• Attention to complete polyp excision

Screening colonoscopy findings and recommended scheduling of surveillance colonoscopy are as follows ^[18] :

• 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 post-polypectomy and post–colorectal cancer resection surveillance guidelines.  According to the guidelines, the criteria for high-risk for future colorectal cancer (CRC) following polypectomy comprise either of the following ^[19] :

• Two or more premalignant polyps, including at least one advanced colorectal polyp (defined as a serrated polyp at least 10 mm in size or containing any grade of dysplasia, or an adenoma 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. ^[19]

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. ^[19]

The European Society of Medical Oncology offers the following recommendations for surveillance of patients with familial adenomatous polyposis (FAP) ^[15] :

Classic FAP

• Colon and rectum: Sigmoidoscopy (or colonoscopy) every 1 to 2years, starting at age 10 to 11 years and continued lifelong in mutation carriers. Once adenomas are detected, annual colonoscopy until colectomy. Surgery is indicated if there are large numbers of adenomas, including adenomas showing a high degree of dysplasia.

• Gastroduodenal adenomas: Gastroduodenal endoscopy starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage.

• Thyroid cancer:  Consider annual cervical ultrasonography starting at age 25 to 30 years.

• Desmoid tumors: Consider baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan in presence of risk factors (positive family history for desmoids and site of the mutation in APC).

Attenuated FAP

• Colon and rectum: Colonoscopy every 1 to 2 years, starting at age 18 to 20 years and continued lifelong in mutation carriers. Once adenomas are detected, colonoscopy should be carried out annually.

• Gastroduodenal adenomas: Gastroduodenal endoscopy starting when colorectal polyposis is diagnosed or at age 25 to 30 years, whichever comes first. Surveillance intervals are based on the Spigelman stage.

• Thyroid cancer: Annual cervical ultrasonography may be considered starting at age 25 to 30 years.

• Desmoid tumors: A baseline CT scan or MRI should be considered if risk factors (positive family history for desmoids and site of the mutation in APC).

The American Society of Colon and Rectal Surgeons recommends that patients with familial adenomatous polyposis (FAP) or with personal or family risk factors for FAP be referred to center registries and genetic counselors with experience in the multidisciplinary management of these individuals. ^[20]

Additional recommendations include the following:

• Prophylactic colectomy or proctocolectomy should be routine; the frequency and type of surgery should depend on the severity of the polyposis phenotype
• Use of chemoprevention as primary therapy is not recommended
• Small tubular adenomas with mild dysplasia can be kept under surveillance, but adenomas with severe dysplasia must be removed
• Duodenectomy or pancreaticoduodenectomy is recommended for persistent or recurrent severe dysplasia in the papilla or duodenal adenomas
• Clinically inert tumors should be treated with sulindac or not treated at all
• Slowly growing or mildly symptomatic tumors may be treated with less toxic regimens such as sulindac and tamoxifen or with vinblastine and methotrexate
• Rapidly growing tumors need aggressive therapy with either very-high-dose tamoxifen or antisarcoma-type chemotherapy
• Radiation is an option if collateral damage is not a major concern

 

The 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. ^[21]

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. ^[12] 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 ^[12] :

• 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

The American Society of Colon and Rectal Surgeons (ASCRS) defines rectal cancer as cancer located within 15 cm of the anal verge by rigid proctoscopy. ASCRS 2013 revised management guidelines and practice parameters recommend that patients with low-risk, early-stage rectal cancer be treated with primary surgical therapy. Treatment of locally advanced or high-risk disease should include neoadjuvant radiation or chemoradiation followed by surgery. ^[22]

Additional recommendations include the following ^[22] :

• Local excision for T1 tumors absent high risk factors
• Total mesorectal excision (TME) for curative resection of tumors of the middle and lower thirds of the rectum
• In the absence of clinical involvement, extended lateral lymph node dissection (LLND) is not necessary in addition to TME
• For tumors of the upper third of the rectum, a tumor-specific mesorectal excision should be used.
• For T4 rectal cancers, resection of involved adjacent organs should be performed with an en bloc technique.
• Oophorectomy is advised for grossly abnormal ovaries or contiguous extension of a rectal cancer, but routine prophylactic oophorectomy is not necessary
• Laparoscopic TME has comparable outcomes with open TME

The 2018 European Society for Medical Oncology (ESMO) guidelines include the following key surgical recommendations ^[23] :

• Only patients with cT1N0 should be considered for transanal endoscopic microsurgery (TEM), although TEM for more advanced T-stage may be appropriate for patients at high surgical risk after discussion with the patient.
• More advanced tumors up to and including cT2c/T3a/b should be treated by radical total mesorectal excision (TME) surgery because of higher risks of recurrence and the higher risk of mesorectal lymph node involvement
• In rare situations, local excision can be an option in patients with a cT1 tumor or in elderly or fragile patients. TEM is then the procedure of choice.
• Robotic-assisted rectal cancer surgery provides some technical advantages for surgeons compared with conventional laparoscopy, but is still under evaluation.
• For cT2 tumors < 4 cm, local excision after preoperative RT/CRT has been considered as alternative management to abdominal surgery

 

The American Society of Clinical Oncology (ASCO) recommends against the routine use of adjuvant chemotherapy for patients with stage II colon cancer who are at low risk of recurrence, including in younger patients. ^[24] 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 recommends including oxaliplatin in the chemotherapy regimen if the combination of dMMR/MSI and high-risk factors results in a decision to offer adjuvant therapy. In patients who are candidates for adjuvant doublet chemotherapy, the duration of adjuvant oxaliplatin-containing chemotherapy may be 3 or 6 months. ^[24]

National Comprehensive Cancer Network (NCCN) guidelines recommend the use of as many chemotherapy drugs as possible to maximize the effect of adjuvant therapies for colon and rectal cancer. ^{[12, 25]}

According to the NCCN, stage I (T_1-2, N₀, M₀) rectal cancer patients do not require adjuvant therapy due to their high cure rate with surgical resection. High-risk patients, including those with poorly differentiated tumor histology and those with lymphovascular invasion, should be considered for adjuvant chemotherapy and radiotherapy.

The NCCN guidelines recommend combination therapy with infusional fluorouracil, folinic acid, and oxaliplatin (FOLFOX) as reasonable for patients with high-risk or intermediate-risk stage II disease; however, FOLFOX is not indicated for good- or average-risk stage II rectal cancer.

Adjuvant chemotherapy is encouraged for eligible patients with stage III disease. NCCN recommendations for stage III treatment vary according to risk status. For low-risk stage III colon cancer (T1-3, N1), preferred treatments are as follows ^[12] :

• Capecitabine plus oxaliplatin (CapeOx) for 3 months  or
• FOLFOX for 3–6 months (category 1 for 6 months)

For high-risk stage III colon cancer (T4, N1-2; T any, N2), preferred treatment recommendations include the following:

• CapeOx for 3–6 months (category 1 for 6 mo) or
• FOLFOX for 6 months (category 1) 

For both low-risk and high-risk colon cancer, other options include capecitabine or 5-fluorouracil (5-FU) for 6 months.

For more information on chemotherapy regimens, see Colon Cancer Treatment Protocols. For the majority of patients with stage II or stage III rectal cancer, the NCCN recommends the use of ionizing radiation to the pelvis along with adjuvant chemotherapy. Either of the two following sequences of therapy may be used ^[25] :

• Chemoradiation therapy preoperatively and chemotherapy postoperatively
• Chemotherapy followed by chemoradiation therapy, followed by resection

The NCCN advises that the total duration of perioperative therapy, including chemoradiation therapy and chemotherapy, should not exceed 6 months.

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

• Cancer Care Ontario endorsed by American Society of Clinical Oncology (ASCO)
• European Society of Medical Oncology (ESMO)
• National Comprehensive Cancer Network (NCCN)
• American Society of Colon and Rectal Surgeons (ASCRS)

All four guidelines agree that patients with resected colon cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection, and that surveillance should include regular reviews of medical history, physical examination, and carcinoembryonic antigen assays, as well as colonoscopy and abdominal and chest computed tomography (CT ^{[26, 27, 12, 28]} The frequency of the surveillance testing differs as shown in the table below.

Table.1 (Open Table in a new window)

In 2016, the US Multi-Society Task Force on Colorectal Cancer issued guidelines on colonoscopy after colorectal cancer resection, which included the following recommendations ^[29] :

• 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.

Guidelines on molecular biomarker testing for the evaluation of colorectal cancer (CRC) from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology include the following recommendations ^[30] :

• Patients with CRC who are being considered for anti–epidermal growth factor receptor (EGFR) therapy must receive RAS mutational testing, which should include KRAS and NRAS codons 12 and 13 of exon 2, 59 and 61 of exon 3, and 117 and 146 of exon 4 (“expanded” or “extended” RAS).
• BRAF p.V600 ( BRAF c.1799 [p.V600]) position mutational analysis should be performed in CRC tissue in selected patients for prognostic stratification.
• BRAF p.V600 mutational analysis should be performed in deficient mismatch repair (dMMR) tumors with loss of MLH1 to evaluate for Lynch syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome.
• Clinicians should order mismatch repair (MMR) status testing in patients with CRC to identify patients at high risk for Lynch syndrome and/or for prognostic stratification.
• Tissues from metastatic or recurrent CRC tumors are the preferred specimens for treatment-predictive biomarker testing and should be used if such specimens are available and adequate. In their absence, primary tumor tissue is an acceptable alternative and should be used.
• Formalin-fixed, paraffin-embedded (FFPE) tissue is an acceptable specimen for molecular biomarker mutational testing in colorectal carcinoma. Use of other specimens (eg, cytology specimens) will require additional adequate validation, as would any changes in tissue-processing protocols.
• Laboratories must validate the performance of immunohistochemistry (IHC) testing for CRC molecular biomarkers (currently IHC testing for MLH1, MSH2, MSH6, and PMS2) in accordance with best laboratory practices.
• Laboratories should use CRC molecular biomarker testing methods that are able to detect mutations in specimens with at least 5% mutant allele frequency, taking into account the analytical sensitivity of the assay (limit of detection [LOD]) and tumor enrichment (eg, microdissection).

The 2023 European Society for Medical Oncology (ESMO) guidelines for the management of patients with metastatic CRC (mCRC) include the following recommendations on biomarker testing ^[31] :

• Testing for MMR status and for mutations in KRAS; NRAS exon 2, 3, and 4: and BRAF is recommended in all patients at the time of mCRC diagnosis.
• RAS testing is mandatory before treatment with anti-EGFR monocloal antibodies, 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 prognostic assessment and for the option of treatment with cetuximab-encorafenib.
• dMMR/microsatellite instability (MSI) testing in mCRC can assist in genetic counselling for Lynch syndrome.
• dMMR/MSI testing is also recommended as the initial molecular workup in mCRC for its predictive value for the use of immune checkpoint inhibitors (ICIs).
• Identification of HER2 amplification by IHC or FISH is recommended in RAS wild type patients to detect those who may benefit from HER2 blockade
• Testing of other biomarkers—including ALK and ROS1 gene fusions, mutations of PIK3CA, and HER2 activating mutations—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-fluorouracil (5-FU)–based chemotherapy.

Guidelines on the treatment of metastatic colorectal cancer (mCRC) have been published by the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO). ^{[32, 31]}

ASCO guidelines

The ASCO guidelines, published in 2023, include the following recommendations ^[32] :

• Doublet (FOLFOX or FOLFIRI) backbone chemotherapy should be offered as first-line treatment for initially unresectable, microsatellite stable (MSS) or proficient mismatch repair (pMMR) mCRC. (Capecitabine plus oxaliplatin may be substituted for FOLFOX at the clinical discretion of the treating provider, and in shared decision making with the patient.)
• Triplet (FOLFOXIRI) backbone chemotherapy may be offered as first-line therapy to selected patients with initially unresectable MSS or pMMR mCRC. Shared decision making is recommended: survival and recurrence outcomes are improved with triplet chemotherapy compared with doublet chemotherapy, but grade 3 or greater adverse events are more frequent.
• Note that in the evidence base for the above recommendations, all patients received the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab in addition to the doublet or triplet chemotherapy backbone.
• Pembrolizumab should be offered as first-line therapy to patients with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) mCRC.
• Anti-EGFR therapy plus doublet chemotherapy should be offered as first-line therapy for MSS or pMMR left-sided RAS wild-type mCRC
• Encorafenib plus cetuximab should be offered to patients with previously treated BRAF V600E–mutant mCRC that has progressed after at least one previous line of therapy.
• Cytoreductive surgery (CRS) plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; these patients should have been deemed amenable to complete resection of colorectal peritoneal metastases, regardless of previous treatment, and should have no extraperitoneal metastases.
• Oxaliplatin-based hyperthermic intraperitoneal chemotherapy is not recommended as an addition to CRS for treatment of patients with colorectal peritoneal metastases.
• Surgery with or without perioperative chemotherapy should be offered to patients who are candidates for potentially curative resection of liver metastases.

ESMO guidelines

The ESMO guidelines, updated in 2023, include the following recommendations on treatment of potentially resectable mCRC ^[31] :

• In patients with resectable metastases and with favorable prognostic criteria and a good surgical approach, perioperative systemic treatment may not be needed.
• In patients with resectable metastases, the use of perioperative oxaliplatin-based chemotherapy is recommended when the prognostic situation is unclear.
• Anti-EGFR monoclonal antibodies in left-sided RAS wild type mCRC should be used as conversion therapy, when complete resection is the aim.
• In patients with right-sided and RAS-mutant disease, FOLFOXIRI–bevacizumab and, to a lesser extent, a cytotoxic doublet–bevacizumab should be considered the best choice depending on patients’ ability to tolerate triplet chemotherapy.
• Patients unresponsive to first-line chemotherapy should not be denied resection or ablation of metastases, since the outcome of resected patients after second-line treatment could be also favorable. Intra-arterial chemotherapy could be an option in such patients, not only to recover a response but also to achieve liver resection.
• In case of a peritoneal metastasis only, complete cytoreductive surgery should be carried out. The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) cannot be considered outside of clinical trials.

The ESMO guidelines include the following recommendations on first-line therapy of mCRC ^[31] :

• Determining the RAS mutational status on a tumor biopsy  (or through a liquid biopsy if no tumor sample is available) is mandatory to guide the best treatment decision.
• Use of a biologic agent in combination with chemotherapy is recommended, unless contraindicated
• In the majority of patients, first-line treatment will consist of a chemotherapy doublet (eg, FOLFOX, FOLFIRI, CapeOx) that can be combined with an anti-VEGF or anti-EGFR monoclonal antibody (eg, FOLFIRI–cetuximab,  FOLFOX4–panitumumab, modified FOLFOX6–panitumumab).
• In RAS wild type and BRAF wild type left-sided tumors, a chemotherapy double plus an anti-EGFR monoclonal antibody is the preferred option. Due to increased adverse effects and lack of efficacy, combination with cetuximab–capecitabine or bolus 5-FU-based chemotherapy is not recommended
• In RAS wild type right-sided tumors, chemotherapy ± bevacizumab is the preferred option, although if a higher response is needed for conversion therapy, a doublet with cetuximab or panitumumab can be used.
• Anti-EGFR monoclonal antibodies can be combined with the doublets FOLFOX or FOLFIRI.
• Bevacizumab can be combined with single fluoropyrimidines, irinotecan, or oxaliplatin-based doublet chemotherapy
• Combining anti-VEGF and anti-EGFR monoclonal antibodies is not recommended.
• A triplet with FOLFOXIRI plus bevacizumab could also be an option for selective patients with good performance status (PS) and without comorbidities. Triplets including FOLFOXIRI should not be used in patients > 75 years old, with PS2 or in patients with significant comorbidities.
• In selected cases, when downstaging is the objective or in right-sided colon cancer with BRAF V600E mutations, a triplet (FOLFOXIRI), which can be combined with bevacizumab, should be considered, but a doublet plus bevacizumab could provide similar outcomes.
• Triplets with FOLFOXIRI and anti-EGFR monoclonal antibodies are not recommended.
• In patients with comorbidities or older age, or with metastatic disease not amenable to a curative treatment strategy and no significant disease-related symptoms, monotherapy with a fluoropyrimidine ± bevacizumab can be used. In frail or elderly patients unable to tolerate chemotherapy, whose tumors are left-sided and RAS wild type, monotherapy with anti-EGFR monoclonal antibodies can be considered.
• In patients who experience cardiotoxicity and/or hand-foot syndrome on 5-FU or capecitabine-based chemotherapy, S-1 may be used as an alternative.
• Patients should receive all available treatments during the course of the disease [I, B].
• In dMMR/MSI-H mCRC, pembrolizumab has demonstrated benefit over standard chemotherapy and targeted agents in the first-line setting and it is recommended as standard of care.

The ESMO guidelines include the following recommendations on maintenance therapy of mCRC ^[31] :

• After first-line chemotherapy based on oxaliplatin–bevacizumab, maintenance therapy with a fluoropyrimidine and bevacizumab could be considered in patients with non-progressive mCRC after at least 4 months of treatment.
• After first-line chemotherapy based on oxaliplatin plus anti-EGFR monoclonal antibodies, maintenance therapy with a fluoropyrimidine plus anti-EGFR monoclonal antibodies could be considered in patients with non-progressive mCRC.
• When FOLFIRI is used in first-line treatment, irinotecan can be continued as full therapy until disease progression.
• A successful initial induction therapy regimen should be reintroduced if progressive disease develops during maintenance therapy.

The ESMO guidelines include the following recommendations on second-line therapy for mCRC ^[31] :

• In patients who received oxaliplatin-based first-line therapy, second-line treatment with an irinotecan-based regimen or monotherapy is recommended. In patients treated with irinotecan-based first-line therapy, an oxaliplatin-based regimen (FOLFOX or CapeOx) can be used for second-line therapy, if not contraindicated.
• In patients with RAS wild type mCrC not previously treated with an anti-EGFR monoclonal antibody, treatment with chemotherapy (FOLFIRI or irinotecan) and cetuximab or panitumumab could be considered for left-sided colon tumors. For right-sided tumors, second-line therapy with an anti-angiogenic agent combined with chemotherapy is recommended.
• In patients previously treated with irinotecan–fluoropyrimidine-based chemotherapy alone, FOLFOX–bevacizumab is recommended.
• A second-line treatment with an antiangiogenic agent combined with chemotherapy, regardless of whether the first-line regimen included bevacizumab, should be used, independently of the RAS mutational status and the primary tumor location.
• Bevacizumab can be combined with a fluoropyrimidine-doublet with oxaliplatin or irinotecan, depending on the first-line chemotherapy backbone.
• Aflibercept or ramucirumab in combination with FOLFIRI could be used as an alternative to bevacizumab with FOLFIRI in patients progressing on first-line treatment with oxaliplatin-based chemotherapy.
• For BRAF V600E–mutated, previously treated mCRC, encorafenib–cetuximab is recommended as the best option for second-line therapy.
• For dMMR/MSI-H tumors progressing after first-line chemotherapy, ipilimumab–nivolumab is recommended.

The ESMO guidelines include the following recommendations on third-line and further-line therapy for mCRC ^[31] :

• Reintroduction of the initial induction therapy can be considered after second-line therapy, as long as the disease did not progress during the induction course of first-line chemotherapy.
• Either regorafenib or trifluridine–tipiracil, if available, is recommended in patients previously treated with fluoropyrimidines, oxaliplatin, irinotecan, and biologics; or in earlier lines of therapy following oxaliplatin and irinotecan regimen failure, depending on local approvals.
• For BRAF V600E–mutated, previously treated mCRC, encorafenib–cetuximab is recommended as the best third-line option.
• In RAS wild type and BRAF wild type mCRC not previously treated with EGFR antibodies, cetuximab or panitumumab is recommended foir monotherapy.
• In irinotecan-refractory mCRC, cetuximab–irinotecan is recommended over cetuximab alone.
• With disease refractory to an anti-EGFR antibody, administering an alternative anti-EGFR antibody is not recommended.
• In mCRC maintaining RAS wild type status, rechallenge with anti-EGFR monoclonal antibodies may be an option in selected patients.
• In HER2-positive mCRC, treatment with HER2 dual blockade is optionally recommended, especially in RAS wild type tumors.

The ESMO guidelines include the following recommendations on followup ^[31] :

• For patients receiving active treatment, radiologic evaluation should be carried out every 8-12 weeks, including (in most cases) CT scan or MRI, as well as the measurement of CEA levels.
• Patients with a radically resected metastatic disease with potential for cure merit more intense monitoring initially with radiologic assessment with CT (or MRI) and measurement of CEA levels every 3 months during the first 2 years and every 6 months thereafter.