The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colon Cancer

The American Society of Colon and Rectal Surgeons (ASCRS) is dedicated to ensuring high-quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The Clinical Practice Guidelines Committee is composed of society members who are chosen because they have demonstrated expertise in the specialty of colon and rectal surgery. This committee was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus and develop clinical practice guidelines based on the best available evidence. While not proscriptive, these guidelines provide information on which decisions can be made and do not dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, health care workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. These guidelines should not be deemed inclusive of all proper methods of care nor exclusive of methods of care reasonably directed toward obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient. STATEMENT OF THE PROBLEM The American Cancer Society estimated that roughly 105,000 Americans would be diagnosed with colon cancer and 43,000 with rectal cancer, and that 53,200 deaths would be attributed to these cancers in the year 2020.1 In the United States, colorectal cancer remains the third most common cancer and the third most common cause of cancer-related death.2 Approximately nine of 10 patients with colorectal cancer are diagnosed at 50 years of age or older. While the incidence and mortality rate of colorectal cancer are declining for individuals older than 50 years of age, both are on the rise for those younger than 50.1 The treatment of patients with colon cancer is largely guided by the stage at presentation, emphasizing the importance of a comprehensive strategy for diagnosis, evaluation, and treatment. Surgery is the primary treatment for most patients with colon cancer, while chemotherapy is used most commonly in the adjuvant setting. In the United States cohort of the international CONCORD-2 study, five-year net (cancer-specific) survival was 90%, 70%, and 14% among those with localized, regional, or distant distribution of their colon cancer, respectively.3 Colorectal cancer screening, bowel preparation, hereditary colon cancer, enhanced recovery pathways, surveillance and survivorship after curative treatment, and prevention of thromboembolic disease, while relevant to the management of patients with colon cancer, are beyond the scope of these guidelines and are addressed in other American Society of Colon and Rectal Surgeons (ASCRS) guidelines.4–9 METHODS This guideline is based on the previous colon cancer parameter published in 2017.10 Compared with 2017, this guideline has 11 new, 10 updated, and 2 excluded recommendations (Table 1). The literature searches were performed with PubMed using a combination of specialty-specific journal titles (Appendix 1, Supplemental Digital Content 1, https://links.lww.com/DCR/B798) organized under the subject headings of Gastroenterology, Imaging, Oncology and General Medicine, and Surgery, and the Medline Subject Heading (MeSH) “colorectal neoplasm” combined with the search limits of “journal article” or “guideline” or “controlled clinical trial” or “clinical trial” or “clinical study” or “meta-analysis” or “multicenter study” or “observational study” or “practice guideline” or “randomized controlled trial” or “systematic review,” and the additional search limits of human studies, English language, and adults, and were limited to citations included in searches limited to the date range of April 8, 2015, to April 4, 2021. Additional subject-specific searches were performed with the PubMed search terms/phrases: 1) “incomplete colonoscopy” and 2) “conversion AND colorectal AND liver,” both limited to English language, journal article, and date range of August 6, 2015, to April 4, 2021, and 3) “Oncotype DX OR coloprint OR ColDx OR ctDNA OR circulating tumor DNA AND colon cancer,” limited to English language and journal article, with a date range of January 1, 2009, to June 27, 2021. An Embase query, inclusive of publication years 2017 to 2020, completed on December 2, 2020, with exclusion of titles also included in Medline/PubMed, resulted in 241 unique titles that were screened and resulted in the inclusion of 10 additional titles for the qualitative synthesis phase of the literature review. An additional 35 titles were identified from embedded references. These searches yielded a total of 7958 unique citations. A professional medical librarian provided consultation for the literature searches. The citations were then reviewed by the authors who selected the citations that they considered to be most relevant to the Clinical Practice Guideline. After screening and secondary and tertiary reviews, a total of 1921 individual citations were selected for potential inclusion in the Clinical Practice Guidelines (Appendix 2, Supplemental Digital Content 2, https://links.lww.com/DCR/B799). Emphasis was placed on prospective trials, meta-analyses, systematic reviews, and practice guidelines. Peer-reviewed observational studies and retrospective studies were included when higher quality evidence was insufficient. Ultimately, Ultimately, a total of 328 unique citations were included in the reference list. The final source material used was evaluated for methodological quality, the evidence base was examined, and a treatment guideline was formulated by the subcommittee for this guideline. A final grade of recommendation was assigned using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system (Table 2).11 When agreement was incomplete regarding the evidence base or treatment guideline, consensus from the committee chair, vice chair, and two assigned reviewers determined the outcome. Members of the ASCRS practice guidelines committee worked in joint production of these guidelines from inception to final publication. Recommendations formulated by the subcommittee were reviewed by the entire Clinical Practice Guidelines Committee. The manuscript was additionally reviewed and edited by two ad hoc committee members (M.R.W. and G.J.C.). The submission was then approved by the ASCRS executive council and peer-reviewed in Diseases of the Colon and Rectum. In general, each ASCRS Clinical Practice Guideline is updated approximately every five years. No funding was received for preparing this guideline, and the authors have declared no competing interests related to this material. This guideline conforms to the Appraisal of Guidelines for Research and Evaluation (AGREE) checklist. Table 1. - What Is New in the 2021 ASCRS Colon Cancer Clinical Practice Guidelines 2021 New Recommendations Neoadjuvant therapy #6. When neoadjuvant therapy is not included in the treatment plan, curative intent colectomy should be performed without unneeded delay. Grade of recommendation: strong recommendation based on low quality evidence, 1C. Neoadjuvant therapy #12. 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. Grade of recommendation: weak recommendations based on moderate-quality evidence, 2B Multidisciplinary discussion #21. The treatment of patients with resectable stage IV colon cancer should be individualized and based on a comprehensive multidisciplinary discussion. Grade of recommendation: strong recommendation based on moderate quality evidence, 1B. Resectable liver metastasis #22. Patients with initially resectable colon cancer liver metastasis, an individualized decision on neoadjuvant chemotherapy followed by surgical resection or up-front surgery. Grade of recommendation: weak recommendation based on moderate-quality evidence, 2B. Unresectable liver metastasis #23. Patients with initially unresectable colon cancer liver metastasis should be considered for neoadjuvant chemotherapy to attempt to convert to resectability. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. Hepatic artery infusion of chemotherapy #24. Hepatic artery infusion of chemotherapy combined with systemic chemotherapy or immunotherapy may increase resectability of colon cancer liver metastasis, but should only be performed in centers with the appropriate expertise. Strong recommendation based on moderate-quality evidence, 1B. Combined or staged liver resection #25. In patients with colon cancer and resectable liver metastasis, a single “combined” operation is generally recommended for relatively low complexity operations and sequential or “staged” operations are generally recommended for higher complexity cases. Grade of recommendation: weak recommendation based on moderate quality evidence, 2B. Lung metastasis #26. In patients with resectable colon cancer lung metastasis, resection of the lung lesions should be considered as it may prolong survival. Weak recommendation based on moderate-quality evidence, 2B. Mismatch repair #32. In patients with stage IV (dMMR or MSI-H colon cancer, immunotherapy with antibody to PD-L1 or PD-1 should be considered. Strong recommendation based on high quality evidence, 1A Timing of adjuvant chemotherapy #33. In general, and if possible, adjuvant chemotherapy should be started within 8 weeks of colon resection. Grade of recommendation: strong recommendation based on moderate quality evidence, 1B Multigene assays #34. The use of multigene assays, CDX2 expression analysis, and ctDNA may be used to complement multidisciplinary decision-making for patients with stage II or III colon cancer. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. 2021 Updated Recommendations PET/CT #4. PET/CT is generally not recommended for routine colon cancer staging but may be useful in surgical decision-making for patients with stage IV disease. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. T4b cancers #10. For resectable colon cancers that adhere to or invade adjacent organs and are being treated with curative intent, complete and en bloc resection with negative margins is recommended. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. Oophorectomy #11. Oophorectomy is typically advised for grossly abnormal ovaries or contiguous extension of colon cancer, but routine prophylactic oophorectomy is not recommended. Grade of recommendation: strong recommendation based on low-quality evidence, 1C. Malignant polyp #15. For patients with a “malignant polyp,” either endoscopic excision or oncological resection may be appropriate, and is dependent largely on polyp histopathological features and completeness of excision. Grade of recommendation: strong recommendation based on moderate quality evidence, 1B. Obstructing left-side colon cancer #17. For patients with obstructing left-sided colon cancer and curable disease, endoscopic stent decompression, or diverting colostomy, with interval colectomy, are generally preferable to emergent colectomy. Grade of recommendation: strong recommendation based on moderate quality evidence, 1B. Cancer perforation #18. In the setting of perforation or impending perforation of the colon, resection following established oncological principles with a low threshold for performing a staged procedure is recommended when feasible. Grade of recommendation: strong recommendation based on low-quality evidence, 1C. Cytoreductive surgery #27. In patients with resectable colorectal cancer peritoneal metastases, cytoreductive surgery with or without intraperitoneal chemotherapy should be considered as part of a multimodality treatment plan. Strong recommendation based on moderate quality evidence, 1B. Stage IV with asymptomatic primary tumor #28. In patients with incurable stage IV colon cancer and an asymptomatic primary colon cancer, systemic chemotherapy is recommended as the initial treatment. Grade of recommendation: strong recommendation based on moderate quality evidence, 1B. Obstructing colon cancer in palliative setting #29. In patients with an obstructing colon cancer and incurable metastatic disease, or in other scenarios in which palliation is preferred over an attempt at cure, endoscopic stent placement or fecal diversion is preferable to colectomy when life expectancy is <1 year. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B Stage II and adjuvant chemotherapy #30. In patients with microsatellite stable/mismatch repair proficient stage II colon cancer and obstruction, or perforation, or <12 lymph nodes in the resection specimen, or poor differentiation, or lymphovascular invasion, or perineural invasion, or high-level tumor budding, adjuvant chemotherapy may offer a survival benefit. Weak recommendation based on moderate quality evidence, 2B 2017 Recommendations Excluded Sentinel lymph nodes SLN mapping for colon cancer does not replace standard lymphadenectomy. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. A recommendation on this technique was excluded as its use has not been broadly adopted for clinical practice. Minimally invasive surgery Hand-assisted laparoscopic and robotic surgical techniques for right colon cancer result in oncological outcomes that are equivalent to open or straight laparoscopic techniques. Strong recommendation based on moderate-quality evidence, 1B. In 2021, hand-assisted laparoscopic and robotic colectomy techniques were included in recommendation #13: When expertise is available, a minimally invasive approach to elective colectomy for colon cancer is preferred. Grade of recommendation: strong recommendation based on high-quality evidence, 1A. ctDNA = circulating tumor DNA; dMMR = mismatch repair deficient; MSI-H = microsatellite high; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death-ligand 1; PET = positron emission tomography; SLN = sentinel lymph node Table 2. - The GRADE System - Grading Recommendations Description Benefit vs risk and burdens Methodologic quality of supporting evidence Implications 1A Strong recommendation, High-quality evidence Benefits clearly outweigh risk and burdens or vice versa RCTs without important limitations or overwhelming evidence from observational studies Strong recommendation can apply to most patients in most circumstances without reservation 1B Strong recommendation, moderate quality evidence Benefits clearly outweigh risk and burdens or vice versa RCTs with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or exceptionally strong evidence from observational studies Strong recommendation, can apply to most patients in most circumstances without reservation 1C Strong recommendation, low- or very low- quality evidence Benefits clearly outweigh risk and burdens or vice versa Observational studies or case series Strong recommendation but may change when higher-quality evidence becomes available 2A Weak recommendation, high-quality evidence Benefits closely balanced with risks and burdens RCTs without important limitations or overwhelming evidence from observational studies Weak recommendation, best action may differ depending on circumstances or patients’ or societal values 2B Weak recommendations, moderate quality evidence Benefits closely balanced with risks and burdens RCTs with important limitations (inconsistent results, methodologic flaws, indirect or imprecise) or exceptionally strong evidence from observational studies Weak recommendation, best action may differ depending on circumstances or patients’ or societal values 2C Weak recommendation, low- or very low- quality evidence Uncertainty in the estimates of benefits, risks, and burden; benefits, risk and burden may be closely balanced Observational studies or case series Very weak recommendations; other alternatives may be equally reasonable GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; RCT = randomized controlled trial.Adapted from Guyatt G, Gutermen D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174-181.11 Used with permission. Table 3. - The American Joint Committee on Cancer, Colorectal Cancer Staging System Definition of primary tumor (T) T category T criteria TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ, intramucosal adenocarcinoma (involvement of lamina propria no extension through the muscularis mucosae) T1 Tumor invades submucosa T2 Tumor invades muscularis propria T3 Tumor invades through the muscularis propria into the pericolonic tissue T4a Tumor penetrates to the surface of the visceral peritoneum (serosa) T4b Tumor invades and/or is adherent to other organs or structures Regional lymph node staging (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative N1a One regional lymph node is positive N1b Two to three regional lymph nodes are positive N1c No regional lymph nodes are positive, but there are tumor deposits in subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastases N2a Four or more regional lymph nodes are positive N2b Seven or more regional lymph nodes are positive Distant metastasis staging (M) M0 No distant metastasis M1a Metastasis confined to one organ or site is identified without peritoneal metastasis M1b Metastasis confined to two or more organs or sites is identified without peritoneal metastasis M1c Metastasis to the peritoneal surface is identified alone or with other site or organ metastases Stage T N M 0 Tis N0 M0 I 1-2 N0 M0 IIA T3 N0 M0 IIB T4a N0 M0 IIC T4b N0 M0 IIIA T1-T2 N1-N1c M0 T1 N2a M0 IIIB T3-T4a N1-N1c M0 T2-T3 N2a M0 T1-2 N2b M0 IIIC T4a N2a M0 T3-T4a N2b M0 T4b N1-N2 M0 IVA Any T Any N M1a IVB Any T Any N M1b IVC Any T Any N M1C AJCC = American Joint Committee on Cancer; RCT = randomized controlled trial EVALUATION AND RISK ASSESSMENT 1. A cancer-specific history should be obtained including disease-specific symptoms, past medical and family history, physical examination, and perioperative medical risk. Routine laboratory values, including carcinoembryonic antigen (CEA) level, should be obtained. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. Sporadic, familial (ie, no identifiable germ-line mutation), and hereditary (ie, Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis) types of colorectal cancer account for approximately 65%, 30%, and <5% of new colorectal cancers in the United States, respectively.12 The personal and family history should include documentation of premalignant lesions and cancers, age of diagnosis, and the lineage of affected first- and second-degree relatives. Patients should be asked about known hereditary cancer predisposition syndromes, previous genetic testing, and family ancestry/ethnicity that may be relevant.13 Patients with findings suggestive of an inherited susceptibility should be referred for genetic counseling given that the results may impact surgical decision-making. Among colon cancer patients younger than 50 years, up to one-third may carry a germline mutation associated with colon cancer; these patients often do not have a clinical history that is typically associated with an identified hereditary cancer syndrome, supporting the recommendation that germline testing should be strongly considered for all young-onset colon cancer patients.14 Guidelines on the management of patients with inherited colorectal cancer have been previously published by the society.6,7 In keeping with the National Cooperative Cancer Network (NCCN) guidelines, all newly diagnosed colon cancers should be evaluated for microsatellite instability (MSI) or mismatch repair protein (MMR) expression.15 Colon cancer may be asymptomatic or heralded by symptoms of fatigue, blood in the stool, abdominal pain, changes in bowel habits, or obstructive symptoms. Recent retrospective, single-institution, American studies have reported that more than 75% of colon cancer diagnoses occurred after development of symptoms, and symptomatic cancers were associated with more advanced disease compared with cancers that were identified during screening colonoscopy.16,17 Similar results, with nearly 70% of newly diagnosed cancers presenting with symptoms, were reported in a 2016 German population-based study.18 Patients’ medical fitness and nutritional status should be assessed to guide perioperative management and identify opportunities for optimization before surgery. Inquiry about alcohol consumption and smoking is also advised, as these habits have been shown to both increase the risk of developing colorectal cancer and also the risk of postoperative complications.19–22 Early mortality is infrequent among resected colon cancer patients but is more prevalent among patients with advanced age and an Eastern Cooperative Oncology Group performance status ≥2.23,24 Frail patients may benefit from preoperative, multimodality optimization (ie, prehabilitation), although the beneficial effect on postoperative complications and survival has not been firmly established.25,26 Physical examination should include assessment for an abdominal mass or surgical scars, which may influence diagnostic and treatment-related decisions. Routine serum laboratory evaluation should include a complete blood count, liver function tests, and a chemistry panel. A carcinoembryonic antigen (CEA) level should be obtained before elective surgery for colon cancer to establish a baseline value that is prognostic for recurrence and survival, and to provide a reference value for use during surveillance.27 A multivariate analysis of more than 130,000 patients included in the National Cancer Database indicated that preoperative CEA is an independent predictor of overall survival in patients with stage I to III colon cancer.28 Patients with an elevated CEA had a 62% increase in the hazard of death compared with patients with a normal preoperative CEA. Although preoperative CEA level is an independent prognostic factor, the optimal cutoff value to best determine prognostic significance is not clear.29–32 In stage IV colorectal cancer, a decrease in CEA in response to treatment with chemotherapy has been associated with improved survival.33 2. Before colectomy, histologic confirmation of invasive adenocarcinoma should be established and, when feasible, the entire colorectal mucosa should be evaluated for synchronous pathology. Grade of recommendation: strong recommendation based on low-quality evidence, 1C. When possible, the histologic diagnosis of colon cancer should be confirmed before elective surgical resection because benign processes such as diverticulitis or inflammatory bowel disease may appear grossly similar to the endoscopic or radiographic appearance of colon cancer. Colonoscopy is the preferred evaluation method under these circumstances because it offers a therapeutic opportunity to treat synchronous polyps. Endoscopic biopsy may be nondiagnostic or incongruent with the clinical impression of invasive adenocarcinoma due to sampling error, in which case repeat endoscopic biopsy may be performed in the appropriate clinical circumstance. Lesions concerning for malignancy, but without histologic confirmation (eg, possible sampling error), that are not amenable to endoscopic removal warrant oncological resection. When feasible, a complete evaluation of the colorectal mucosa is advised before surgery to detect synchronous cancers, which are reported to be present in 4% of patients with stages I to III sporadic colon cancer.34 Complete examination of the colorectal mucosa can also identify synchronous adenomas that are present in 30% to 50% of patients.35,36 Endoscopic tattooing with documentation of tattoo location (ie, distal or proximal to the tumor) should be performed routinely to facilitate intraoperative localization. In patients with a proximal cancer that cannot be passed with a colonoscope in whom an oncological resection would include the entire proximal colon (eg, obstructing distal ascending colon cancer), there is generally no need to examine the more proximal colon before colectomy. Alternatively, for patients with an endoscopically obstructing distal colon cancer (eg, sigmoid colon cancer) in whom oncological resection would spare the proximal colon, CT colonography or Fluro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) may be helpful. CT colonography is highly accurate for detecting synchronous advanced neoplasia (ie, high-grade or large adenoma or cancer) has a sensitivity of 94%, and is reported to affect the surgical plan in 2% to 21% of patients.37–39 FDG PET/CT may also be sufficient to exclude proximal synchronous neoplasia, with a negative predictive value for advanced adenoma and colon cancer of 93% and 100%, respectively.40 Alternatively, intraoperative colonoscopy to detect synchronous lesions is feasible and safe after resection of the tumor and restoration of intestinal continuity or creation of a colostomy.41–43 Postoperative colonoscopy is another option for patients in whom preoperative or intraoperative evaluation of the colon was not possible or adequate.44 Contrast enema studies have a relatively low yield for the detection colorectal mucosal pathology and therefore are generally not recommended.45 STAGING OF COLON CANCER 3. CT of the chest, abdomen, and pelvis with oral and intravenous contrast or noncontrast CT of the chest and abdominal MRI are recommended for colon cancer staging. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. CT scan of the chest, abdomen, and pelvis with intravenous iodinated and oral contrast is recommended before the elective surgical resection of colon cancer.15,46 Preoperative CT imaging permits the detection of synchronous metastases, which often requires a change in the treatment strategy and may also alter the operative plan. While the yield of chest CT in detecting colorectal cancer lung metastasis is low (6%–8%), its superiority to standard chest x-ray and ability to detect indeterminate lesions that may demonstrate malignant progression on serial examinations support its use under these circumstances.47–50 In patients with an allergy or other contraindication to the use of iodine contrast dye, a PET/CT or noncontrast chest CT with an MRI of the abdomen and pelvis are recommended alternatives.51,52 Indeterminate liver lesions identified on CT should generally be further investigated by MRI with diffusion-weighted imaging.46,53–56 4. Positron emission tomography (PET)/CT is generally not recommended for routine colon cancer staging, but may be useful in surgical decision-making for patients with stage IV disease. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. Prospective studies have not demonstrated superiority of PET/CT over standard intravenous contrast-enhanced CT in the detection of colorectal liver or peritoneal metastasis.51,57,58 At present, it is not clear if PET/CT offers an advantage to contrast-enhanced CT for the detection of colon cancer lung metastasis.59 Both the National Cooperative Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) do not recommend PET/CT in the initial staging of colorectal cancer.15,46 On the contrary, PET/CT may be recommended for patients with known metastatic colon cancer who are being considered for curative resection as the identification of otherwise unrecognized metastatic disease may alter the treatment plan. A meta-analysis of 18 studies, including more than 1000 patients with hepatic colorectal metastases showed that PET or PET/CT findings led to a change in management in 24% of patients.60 PET-CT may also be useful in the evaluation of patients with equivocal findings (eg, retroperitoneal lymphadenopathy) on CT or MRI.52 5. Colon cancer should typically be staged according to the American Joint Committee on Cancer, Tumor, Node, Metastasis (AJCC/TNM) system and should include an assessment of the completeness of surgical resection. Grade of recommendation: strong recommendation based on moderate-quality evidence, 1B. The tumor depth, nodal metastasis, and distant metastasis have been shown to be predictors of prognosis in colon cancer. These characteristics are described by the American Joint Committee on Cancer TNM staging system and are included in Table 3. The current (8th) edition expanded the definition of metastatic disease to include the M1c category for peritoneal implants, clarified the definition of tumor deposits (N1c), and also highlighted the importance of lymphovascular and perineural invasion, microsatellite instability (MSI), tumor budding, and mutations in KRAS, NRAS, and BRAF in treatment considerations.61 As with previous editions, a positive lymph node is define