Rectal Cancer Guidelines

Guidelines Contributor:  Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

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.

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 recommends that screening for colorectal cancer and adenomatous polyps start at age 50 years in asymptomatic men and women. ^[94]

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

American Cancer Society update

In 2018 the ACS revised its colorectal screening guidelines, advising that regular screening for people at average risk start at age 45 years. ^[95]  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.          

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 (A recommendation). For adults aged 76 to 85 years, the decision to screen should be individualized, taking into account the patient’s overall health and prior screening history (C recommendation). ^[40]

The USPSTF advises that screening is more likely to benefit older patients 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. ^[40]

The USPSTF does not recommend colorectal cancer screening for adults older than 85 years. ^[40]

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 2015, 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 ^[96] :

• Annual high-sensitivity FOBT or FIT
• Flexible sigmoidoscopy every 5 years
• High-sensitivity FOBT or FIT every 3 years plus flexible sigmoidoscopy every 5 years
• Colonoscopy every 10 years

Interval screening with fecal testing or flexible sigmoidoscopy in adults having 10-year screening colonoscopy is not recommended. Average-risk adults younger than 50 years, older than 75 years, or with an estimated life expectancy of less than 10 years should not be screened. 

American College of Gastroenterology (ACG)

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. ^[97]  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.

The ACG guidelines note that colonoscopy is the only screening modality that is both diagnostic and therapeutic. All others are two-step approaches: a positive test requires a follow-up colonoscopy. Despite that limitation, the ACG suggests that, "in some instances the 'best' screening test can be considered the one that is acceptable to the patient and gets completed." ^[97]

National Comprehensive Cancer Network (NCCN)

The National Comprehensive Cancer Network (NCCN) has released separate guidelines for average-risk and high-risk individuals. ^{[98, 34]}  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. ^[98]

The NCCN guidelines provide screening recommendations for patients at increased risk due to a personal or family history of any of the following ^[34] :

• > 10 adenomatous polyps
• ≥2 hamartomatous polyps
• ≥5 serrated polyps proximal to the sigmoid

The guidelines also specify recommendations for patients with the following high-risk syndromes ^[34] :

• 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

Individuals meeting one or more of the following criteria should receive further evaluation for high-risk syndromes:

• Individuals meeting the revised Bethesda Guidelines (Lynch syndrome)
• Family members meeting Amsterdam criteria (Lynch syndrome)
• Individuals with more than 10 adenomas detected ( MUTYH)
• Individuals with multiple GI hamartomatous polyps (PJS and JPS)
• Family members with a known high-risk syndrome associated with colorectal cancer, with or without a known mutation
• Individuals with a desmoid tumor

Screening for Familial Risk

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. ^[34]

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. ^[99]

The European Society for Medical Oncology (ESMO) guidelines for familial risk-colorectal cancer  ^[100] , which have been endorsed by the American Society of Clinical Oncology (ASCO) ^[101]  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 CRC 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. ^[102]

Revised Bethesda guidelines for Lynch syndrome and microsatellite instability

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. ^[103]

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 ^[104] :

• 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 ^[104] :

• 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 ^[105] :

• 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. ^[105]

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.

The American College of Gastroenterology has published guidelines for surveillance of patients who have had adenomas detected and removed at colonoscopy. ^[104]

These patients should have more frequent followup, as they are at increased risk for developing metachronous adenomas or colon cancer.

Colonoscopy findings and recommended scheduling of followup colonoscopy are as follows:

• No polyps – 10 years
• Small (< 10 mm) hyperplastic polyps in rectum or sigmoid – 10 years
• 1–2 small (< 10 mm) tubular adenomas – 5- 10 years
• 3–10 tubular adenomas – 3 years
• 10 adenomas – < 3 years
• One or more tubular adenomas ≥10 mm – 3 years
• One or more villous adenomas – 3 years
• Adenoma with high-grade dysplasia – 3 years

For serrated lesions, recommended surveillance intervals are as follows:

• Sessile serrated polyp(s) < 10 mm with no dysplasia – 5 years
• Sessile serrated polyp(s) ≥10 mm with no dysplasia – 3 years
• Sessile serrated polyp with dysplasia – 1 year
• Traditional serrated adenoma – 1 year
• Serrated polyposis syndrome – 1 year

The European Society of Medical Oncology offers the following recommendations for surveillance of patients with familial adenomatous polyposis (FAP) ^[100] :

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. ^[106]

Additional recommendations include:

• 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 (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. ^[107]

Additional recommendations include the following ^[107] :

• 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

Guidelines from the European Society for Medical Oncology (ESMO) include the following recommendations on management of local and locoregional rectal cancer ^[108] :

• Local excisional procedures such as transanal endoscopic microsurgery are appropriate as a single modality for early cancers (cT1N0 without adverse features such as G3, V1, L1).

• Local radiation therapy (brachytherapy or contact therapy—Papillon technique) may also be used as an alternative to local surgery, alone or combined with chemoradiotherapy.

• More advanced tumors up to and including cT2c/T3a/b should be treated with radical TME surgery because of higher risks of recurrence and the higher risk of mesorectal lymph node involvement. TME (ie, meticulous excision of all the mesorectal fat, including all lymph nodes) is the standard of care for surgery.

• For patients with locally advanced rectal cancer (LARC), treatment decisions regarding neoadjuvant therapy should be based on preoperative, MRI-predicted circumferential resection margin (≤1 mm), extramural vascular invasion, and more advanced T3 substages (T3c/T3d), which define the risk of both local recurrence and/or synchronous and subsequent metastatic disease. For resectable cancers, where there is no indication on MRI that surgery is likely to be associated with either an R2 or an R1 resection, standard TME should achieve a curative resection. The use of short-course preoperative radiotherapy or short-course preoperative radiotherapy aims to reduce local recurrence.

• The selection of preoperative approach in LARC is based more on the multidisciplinary team's decision regarding the risk of a  positive circumferential resection margin at TME. If the circumferential resection margin and/or R0 resection status are predicted to be at risk, chemoradiotherapy is advised. Otherwise, either short-course preoperative radiotherapy or chemoradiotherapy can be administered. For chemoradiotherapy, continuous intravenous infusions of 5-FU or oral capecitabine are recommended rather than bolus 5-FU [I, A].

• Preoperative radiation therapy or chemoradiotherapy reduces the rate of local recurrence without improvement of overall survival for mid/low stage II/III rectal cancers but is associated with significantly worse intestinal and sexual function after surgery.

• Upper rectal cancers (>12 cm from the anal verge) above the peritoneal reflection do not benefit from short-course preoperative radiotherapy or chemoradiotherapy and should be treated as colon cancer.

• With short-course preoperative radiotherapy in resectable cancers where downstaging is not required, ‘immediate’ surgery is recommended to take place within 7 days from the end of neoadjuvant treatment, and ideally within 0–3 days if the patient is ≥75 years (< 10 days from the first radiation fraction).

• Postoperative chemoradiotherapy could be selectively used in patients with unexpected adverse histopathological features after primary surgery (eg, positive circumferential resection margin, perforation in the tumor area, incomplete mesorectal resection, extranodal deposits or nodal deposits with extracapsular spread close to the mesorectal fascia), or in other cases with high risk of local recurrence if preoperative radiation therapy has not been given.

National Comprehensive Cancer Network (NCCN) guidelines advise that adjuvant therapy regimens for rectal cancer should include both concurrent chemotherapy/radiotherapy and adjuvant chemotherapy. Preferably, perioperative treatment should be given for a total of approximately 6 months. ^[1]

According to the NCCN, patients with stage I (T_1-2, N₀, M₀) rectal cancer without high-risk features do not require adjuvant therapy due to the high cure rate with surgical resection. High-risk patients, including those with positive margins, sm3 invasion (submucosal invasion to the lower third of the submucosal level), poorly differentiated tumor histology and those with lymphovascular invasion, should be considered for adjuvant chemotherapy and radiotherapy. ^[1]

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.

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:

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

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). ^{[109, 110, 1, 111]} 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 ^[93] :

• 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.

 In 2015, the American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) issued a provisional clinical opinion regarding gene mutation testing to predict response to anti–epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy in patients with metastatic colorectal carcinoma (mCRC). Among the recommendations are the following ^[112] :

• RAS mutational testing of colorectal carcinoma tissue should be performed in a Clinical Laboratory Improvement Amendments–certified laboratory for patients who are being considered for anti-EGFR therapy

• Analysis 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.

• Anti-EGFR MoAb therapy (currently cetuximab and panitumumab) should only be considered for treatment of patients with mCRC who are identified as having tumors with no mutations detected after extended RAS mutation analysis

The 2016 European Society of Medical Oncology (ESMO) guidelines for the management of patients with mCRC concur with the ASCP/CAP/AMP/ASCO RAS mutational testing recommendations above. Additional recommendations include ^[113] :

• Tumor  BRAF mutation status should be assessed alongside the assessment of tumor  RAS mutation status for prognostic assessment (and/or potential selection for clinical trials)

• Dihydropyrimidine dehydrogenase (DPD) testing before 5-FU administration remains an option but is not routinely recommended 

• UGT1A1 phenotyping remains an option and should be carried out in patients with a suspicion of UGT1A1 deficiency as reflected by low conjugated bilirubin and in patients where an irinotecan dose of >180 mg/m² per administration is planned 

• Thymidylate synthase (TS) activity and TSER genotyping are not recommended for use in clinical practice

• ERCC1 expression for treatment decisions involving the use of oxaliplatin is not recommended outside of clinical trial