The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Surveillance and Survivorship Care of Patients After Curative Treatment of Colon and Rectal Cancer

STATEMENT OF THE PROBLEM More than 140,000 people in the United States are diagnosed annually with colorectal cancer (CRC), and 5% to 40% of patients treated with curative intent develop a recurrence, typically within 5 years.1–3 The optimal strategy for detecting recurrence would minimize cost and harm, such as psychosocial stress and unnecessary testing, and maximize survival and quality of life (QoL). Although surveillance recommendations include periodically taking a history, performing a physical examination, and evaluating laboratory blood testing, imaging studies, and endoscopy, surveillance approaches should be tailored, to a degree, by recurrence risk, incorporating clinicopathologic factors like disease stage, treatment regimen, and patient factors.4 CRC survivors compose the second largest group of cancer survivors, with ≈1.5 million survivors living in the United States.5 The number of CRC survivors is increasing, in part because of the rising incidence of early onset CRC.6 The optimal follow-up care for this growing population of posttreatment cancer survivors is unclear.7–10 Depending on the definition used, an individual may be considered a cancer survivor from the time of diagnosis, during and immediately after treatment, and for the rest of his or her life. Recognizing that CRC treatment has multiple potential late and long-term consequences, survivors should be assessed for these sequelas and treated to improve their QoL. In 2006, the Institute of Medicine released a report highlighting the need to improve the care provided to cancer survivors and increasing awareness regarding the medical, functional, and psychosocial needs related to survivorship.11,12 Although it is important to formalize CRC survivorship care and improve the transition from treatment to survivorship, the scientific evidence specific to CRC remains limited, and recommendations are often extrapolated from research regarding other cancer populations. However, generalizing survivorship goals and management strategies across heterogeneous groups of cancer survivors may result in inferior management of CRC-specific treatment-related effects. Physical and psychosocial treatment effects that impact QoL are among the long-term challenges faced by CRC survivors, and recognizing and addressing these forms the basis for tailored CRC-specific survivorship care models. The American College of Surgeons Commission on Cancer, updated in 2020, includes standards for survivorship care as part of their cancer center accreditation.13 In addition, the National Comprehensive Cancer Network (NCCN) now has a comprehensive guideline for survivorship care, which encompasses assessment and treatment of late and long-term effects of cancer therapy, as well as guidelines regarding appropriate preventive health recommendations for patients with cancer.10 Acknowledging the increasing importance of cancer survivorship care, a section dedicated to survivorship was added to this update of the previously published surveillance practice guideline. Methodology These guidelines were built in part on the American Society of Colon and Rectal Surgeons (ASCRS) Practice Guideline for the Surveillance of Patients After Curative Treatment of Colon and Rectal Cancer published in 2015.14 A systematic, organized search of MEDLINE, PubMed, EMBASE, and the Cochrane Database of Collected Reviews was performed restricted to the English language. Because the past parameter included information on risk and surveillance, searches related to these topics were limited to the interval January 1, 2014, to October 6, 2020. Searches related to survivorship included articles published January 1, 1950, to October 6, 2020, because this topic was not included in the previous guideline (Fig. 1). Search terms regarding risk assessment included key words: colorectal cancer, recurrence, risk colon cancer, rectal cancer, colorectal neoplasm, surveillance, strategies, intensity, cure, CEA, CT, colonoscopy, endoscopy, proctoscopy, ERUS, and follow-up. Medical Subject Headings included colorectal neoplasms, colonic neoplasms, rectal neoplasms, neoplasm recurrence, local, neoplasms, second primary, and neoplasm metastasis. Search terms regarding surveillance included colon cancer, rectal cancer, colorectal neoplasm, surveillance, strategies, intensity, cure, CEA, CT, colonoscopy, endoscopy, proctoscopy, ERUS, follow-up, colorectal neoplasms, colonic neoplasms, rectal neoplasms, neoplasm recurrence, local, neoplasms, second primary, and neoplasm metastasis. Search terms regarding survivorship included key words colon cancer, rectal cancer, colorectal cancer, quality of life, HRQOL, well being, wellbeing, satisfaction, life satisfaction, personal satisfaction, Health-Related Quality of Life, satisfaction, life satisfaction, personal satisfaction, fatigue, neuropathy, bowel dysfunction, sexual dysfunction, urinary dysfunction, and symptoms.FIGURE 1.: Preferred Reporting Items for Systematic Reviews and Meta-analyses literature search flow sheet.Directed searches using embedded references from primary articles and existing guidelines were performed in selected circumstances. The 2860 screened articles were evaluated for their level of evidence, favoring clinical trials, meta-analysis/systematic reviews, comparative studies, and large registry retrospective studies over single institutional series, retrospective reviews, and peer-reviewed observational studies. Peer-reviewed observational studies and retrospective studies were included when higher-quality evidence was insufficient. A final list of 130 sources was evaluated for methodologic quality, the evidence base was examined, and a treatment guideline was formulated by the subcommittee for this guideline. The final grade of recommendation and level of evidence for each statement were determined using the Grades of Recommendation, Assessment, Development, and Evaluation system (Table 1).15 When agreement was incomplete regarding the evidence base or treatment guideline, consensus from the committee chair, vice chair, and 2 assigned reviewers determined the outcome. Members of the ASCRS Clinical 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. Reflecting the evidence presented and notwithstanding the significant differences between colon cancer and rectal cancer, the term colorectal cancer (CRC) appears throughout these guidelines; when the literature specifically relates to colon cancer or rectal cancer, these terms were used. TABLE 1. - The GRADE system: grading recommendations Grade 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 Adapted with permission from Chest. 2006;129:174-181.GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; RCT = randomized controlled trial. The guideline was peer reviewed by Diseases of the Colon & Rectum, and the final guideline was approved by the ASCRS Executive Council. In general, each ASCRS Clinical Practice Guideline is updated every 5 years. This guideline conforms to the Appraisal of Guidelines Research and Evaluation checklist. A. Risk Assessment and Stratification 1. Surveillance after resection of nonmetastatic colon or rectal cancer should be tailored to the relative risk of recurrence based on clinical and pathologic prognostic indicators. Grade of recommendation: Weak recommendation based on low-quality evidence, 2C. There is a growing body of evidence linking poor oncologic outcomes like increased recurrence risk and worse overall survival (OS) and disease-free survival (DFS) to particular pathologic and molecular CRC features. Consideration of additional surveillance beyond what is typically advised based on stage alone may be justified in patients with signet ring cell adenocarcinoma (SRCC), negative nodes but with lymphovascular invasion (LVI), perineural invasion or tumor budding, a poorly differentiated tumor, or elevated CEA. Although there is evidence demonstrating that these features are associated with worse outcomes, suggesting that increased surveillance may improve outcomes under these circumstances, there are limited data supporting which specific strategy should be used or whether increased surveillance will actually impact outcomes for these patients. Secco et al16 reported a study that stratified 358 patients based on risk factors for CRC recurrence and randomly assigned patients to surveillance based on risk versus minimal surveillance. The strategies and definitions of risk from this 2002 publication are outdated now, but the authors demonstrated that high-risk patients who underwent more intensive follow-up underwent more curative metastasectomies and that patients who underwent "risk-adapted" surveillance had better 5-year survival than those who had minimal surveillance (50% vs 32%; p < 0.01). In this study, intensive follow-up was defined as office visits and CEA testing every 3 months for 2 years, every 4 months in year 3, and every 6 months in years 4 and 5, whereas abdominal and pelvic ultrasounds were performed every 6 months for 3 years and then yearly in years 4 and 5, and chest x-rays were performed yearly. Since this study, minimal follow-up groups have not been included in trials evaluating surveillance strategies for CRC. Patients with primary colorectal SRCC adenocarcinomas or mucinous adenocarcinomas (MAC) have inferior survival rates and higher rates of recurrence in comparison with non-SRCC, non-MAC patients.17 In a series of 22 patients with SRCC, 20 patients (91%) presented with stage III or IV disease.18 The mean survival time was 52.7 ± 11.0 months (95% CI, 31.2–74.2 mo) in patients who underwent an R0 resection (n = 11) and 18.0 ± 6.7 months (95% CI, 4.8–31.2 mo) in the others (n = 11). In the 15 patients who died during the follow-up period, the mean progression-free survival was only 11.8 ± 3.5 months (95% CI, 4.9–18.7 mo). One recent study of 8005 patients with colon cancer treated with resection between 2007 and 2015 compared outcomes between 7502 patients with classic adenocarcinoma, 428 patients with MAC, and 75 patients with SRCC. The 5-year OS for patients with classic adenocarcinoma, MAC, and SRCC was 82.0%, 64.2%, and 64.2% (p < 0.001), whereas the 5-year DFS was 71.6%, 64.3%, and 54.4% (p < 0.001), demonstrating that MAC and SRCC both convey a higher risk of recurrence.19 Reported recurrences occurred most commonly in the liver, lungs, and peritoneum. Patients with LVI and/or perineural invasion are at increased risk for local and distant recurrence after resection for CRC. In a data set of 126 patients who underwent resection of a T4 rectal cancer, extramural vascular invasion was associated with reduced OS (p = 0.007) and DFS (p = 0.002).20 In addition, in a single-institution cohort of 860 patients with resected stage I CRC, LVI was an independent risk factor for reduced recurrence-free survival (HR = 2.6 (95% CI, 1.097–6.531); p = 0.03).21 Poor differentiation on pathologic evaluation of a patient's tumor is also a negative prognostic factor. Cao et al22 assessed prognostic features across 1412 CRCs and identified that poor differentiation, as well as perineural invasion and BRAF mutation, were independent prognostic factors for OS on Cox regression analysis. In a single-institution retrospective review, Hogan et al23 evaluated 379 patients who underwent segmental resection for colonic adenocarcinoma and 148 patients who underwent operations for rectal adenocarcinoma. On multivariable analysis, patients with colon cancer with LVI were at higher risk for local recurrence (HR = 1.9; p = 0.002), and patients with rectal cancer with LVI had a higher incidence of systemic recurrence (HR = 2.57; p = 0.002) and reduced OS (HR = 2.32; p = 0.04). LVI was also associated with reduced DFS after both colon and rectal resections (HR = 1.49; p = 0.02 and HR = 2.69; p < 0.001). In another single-institution retrospective series of 1437 consecutive patients who underwent resection for stage II or III CRC, LVI and perineural invasion were each associated with diminished OS and DFS.24 Elevated CEA levels before or after CRC resection are also predictive of a poor prognosis. A post hoc analysis of 3769 resected stage III CRC patients from the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) and Pan-European Trials in Alimentary Tract Cancer-8 revealed that postoperative CEA levels ≥5.0 ng/mL were associated with reduced DFS and OS.25 In this analysis, the median time between surgery and postoperative CEA measurement was 4.3 weeks. In a series of 572 patients who underwent colon cancer resection for node-negative disease between 1985 and 1993 at a single institution, an elevated preoperative CEA was a significant predictor of worse survival at a median follow-up of 35 months.26 Similarly, in a larger retrospective cohort of 965 patients who underwent resection for stage III CRC, a preoperative CEA level >3.0 ng/mL was associated with reduced DFS (HR = 4.6 (95% CI, 2.0–10.4)) and reduced OS (HR = 3.9 (95% CI, 1.1–13.8)).27 High-grade tumor budding is predictive of a poor prognosis in the setting of stage II colon adenocarcinoma, suggesting that patients with this poor prognostic indicator may also benefit from increased surveillance. In a single-institution retrospective series, 200 patients who underwent resection for stage II colon adenocarcinoma were divided into low-grade (n = 131) and high-grade (n = 69) tumor budding based on histopathology assessment using hematoxylin and eosin staining.28 Overall recurrence rates were significantly lower in patients with low-grade tumor budding compared with high-grade tumor budding (10% vs 41%; p < 0.001). High-grade tumor budding was also associated with developing liver metastasis and peritoneal metastasis (p < 0.001 and p = 0.003). Five- and ten-year survival rates differed significantly between patients with low-grade tumor budding (93.9% and 90.6%) and those with high-grade tumor budding (73.9% and 67.8%). Further demonstrating the deleterious effect of aggressive tumor budding, the stage II patients with high-grade tumor budding had similar survival rates when compared with a cohort of 226 patients with stage III colon cancer (including high and low tumor budding) from the same institution. In another series of 138 patients with stage II colon cancer evaluated retrospectively, T3 tumors were divided into no or minimal tumor budding (BD-1, n = 111) and moderate or severe tumor budding (BD-2, n = 27).29 The recurrence rates in the BD-1 and BD-2 groups were 4.5% and 48.0% (p < 0.001), and the 5-year disease-specific survival rates were 98.0% and 74.0% (p < 0.001). A recent prospective multicenter study evaluating the prognostic impact of tumor budding in stage II colon cancer enrolled 991 patients from 123 institutions and categorized patients by tumor budding grade (BD-1, n = 376; BD-2, n = 331; BD-3, n = 284).30 Higher (ie, worse) BD classification was predictive of decreased relapse-free survival (BD-1, BD-2, and BD-3 survival rates were 90.9%, 85.1%, and 74.4%; p < 0.001) and significantly correlated with recurrence in liver, lungs, and peritoneum. Patients with rectal cancer with risk factors such as positive distal or circumferential margins, poor response to neoadjuvant chemoradiotherapy, or positive lymph nodes also have a higher risk of recurrence and should typically be considered for increased surveillance.31–33 Baik et al,31 in a retrospective review of patients with rectal cancer, compared 460 patients with a negative circumferential margin with 44 patients with a positive margin and found that a positive margin was an independent risk factor for reduced, cancer-specific, 5-year survival (72.5% vs 26.9%; p < 0.001). In addition, Shiraishi et al,33 in a retrospective review of 102 patients who underwent neoadjuvant chemotherapy for rectal cancer, found that 5-year recurrence-free survival was 81.1% in those who responded well to neoadjuvant therapy (>60% reduction in tumor volume measured by MRI) and 49.0% in poor responders (p = 0.001). Based on the aforementioned studies, there are multiple, definable factors that increase a given patient's risk of recurrence. Whether more intensive surveillance in the subset of patients with increased risk of recurrence translates into improved survival is not known; thus, additional research, ideally with randomized controlled trials, is needed. 2. A risk-adapted surveillance strategy should be considered for patients with nonmetastatic colon or rectal cancer who did not receive guideline-recommended cancer treatment. Grade of recommendation: Weak recommendation based on moderate quality evidence, 2B. Patients who receive guideline-based cancer care should typically undergo recommended protocolized surveillance. Meanwhile, patients in whom care guidelines were not followed have an increased risk of recurrence and may benefit from increased surveillance, but this concept has not been well-studied. Inadequate lymph node retrieval (<12) after segmental colectomy for colon adenocarcinoma is associated with an increased likelihood of recurrence and should be considered a high-risk marker. In a secondary analysis of 1585 patients enrolled in the Intergroup Trial INT0089 evaluating adjuvant chemotherapy in patients with high-risk stage II/III colon cancer, mathematical modeling was used to determine the number of lymph nodes needed to be truly predictive of lymph node negativity and predicted a <25% probability of node positivity if >18 nodes are examined for T1/T2 tumors or if >10 nodes are examined for T3/T4 tumors.34,35 A more mature analysis of the same trial but with 3411 patients with colon cancer reaffirmed that the number of retrieved lymph nodes is of prognostic significance.36 Similarly, an analysis of the Veterans Affairs Central Cancer Registry database consisting of 5823 patients with stage I to III colon cancer revealed that OS increased with the number of lymph nodes harvested.37 A retrospective analysis of the National Cancer Database including 35,787 patients with T3N0 resected colon cancers from 1985 to 1991 compared 5-year survival rates stratified by the number of examined lymph nodes and found that survival was 49.8% for patients with 1 to 7 lymph nodes, 56.2% for patients with 8 to 12 lymph nodes, and 63.4% for patients with ≥13 lymph nodes (p < 0.001).38 Whether the survival difference was attributable to surgical, pathologic, or patient-related factors is not known. Given these data, patients with colon cancer with inadequate nodal sampling are at risk for worse survival and may benefit from increased surveillance. Omitting chemotherapy or radiotherapy in situations where it would have been recommended according to established, stage-based guidelines or not completing chemotherapy or radiotherapy (eg, because of treatment toxicity) may also justify altering a patient's surveillance strategy.39,40 The MOSAIC trial, a multicenter study of 2246 patients with stage II and III colon cancer published in 2009, randomized stage III patients to adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or leucovorin and 5-fluorouracil, and the FOLFOX group had significantly improved 5-year DFS (73.3% vs 67.4%) and 10-year OS (67.1% vs 59.0%).41,42 Given that the control arm received demonstrably inferior chemotherapy and experienced decreased survival supports the recommendation to consider increased surveillance in patients who receive less than the recommended chemotherapy. Similarly, multiple trials show that radiation improves local recurrence rates for stage II and III rectal cancer.43,44 For example, in the Dutch Colorectal Cancer trial, patients were randomly assigned to alone or preoperative and at years, the patients who received alone had a local recurrence of whereas the patients who had and radiation had a local recurrence of Patients in whom preoperative or postoperative radiation in the setting of stage II or III rectal cancer was but are at increased risk of recurrence, local recurrence, which may justify increased surveillance in these patients. surveillance may also be considered in patients rectal cancer treatment did not include a high-quality given the data that local In addition, of surveillance is recommended for patients with rectal cancer treated who are as clinical the factors into regarding recurrence risk and of surveillance can be for are to improve and patients' of the of risk factors on recurrence. For example, et using data from patients with CRC, an risk to the risk of recurrence 1 year after surgery patient stage, and treatment Surveillance Surveillance is recommended for patients with stage II and III colon or rectal cancer who have resection with curative Grade of recommendation: Strong recommendation based on high-quality evidence, The of surveillance is to improve survival early of There have now been randomized controlled trials evaluating the importance of surveillance for patients after resection of colon and rectal cancer and the of of follow-up in this One early study that a survival benefit to surveillance was reported by Secco et in statement 1 and published in randomized 358 CRC patients to risk-adapted follow-up based on prognostic risk factors or minimal follow-up and demonstrated improved survival in high-risk patients who underwent intensive than minimal follow-up (50% survival for high-risk patients who underwent intensive follow-up vs survival for those who underwent minimal p < the study by Secco et al16 was before the of in follow-up study demonstrating a survival benefit to surveillance, published in by et was a multicenter trial that randomized patients with resected stage II or III CRC to or intensive surveillance. surveillance patients underwent blood liver and blood cell and clinical every 3 months in years 1 and then every 6 months in years 3 to 5, as well as a at years 1 and The surveillance patients had blood and clinical on the same but had abdominal or liver every 6 months in years 1 and 2 and annually in years 3 to 5, and chest annually for 5 years. Although OS and tumor recurrence were not between the 2 study analysis that was not to these outcomes improved survival in patients with stage II CRC (HR = (95% CI, p = and in patients with rectal cancer (HR = (95% CI, p = related to intensive surveillance. More recent randomized controlled trials surveillance have not demonstrated significant differences in survival related to intensive follow-up compared with less intensive However, outcomes between trials is because study such in studies, the for more intensive follow-up groups are often to the less intensive follow-up groups in more recent The and trials, the most trials what should be included in surveillance and at what were published the ASCRS Surveillance Clinical Practice Guidelines and are in in statement 6 (Table TABLE 2. - of of the and trials versus surveillance of Patients Trial = = visits Colon a Colon liver 12 and visits Colon 6, 6, 6, a Colon and visits Rectal a and 12 12 and 4 visits Rectal 6, 6, 6, a liver and and 8 survival difference diagnosed recurrences a mean of Overall survival difference difference are in = of and trial = chest = = = was in but were not by the for the trial in the group included CEA, blood cell and with rectal cancer in underwent rectal at office the of surveillance, the of should because these may be the of CRC recurrence. In randomized studies, to of patients with CRC were at the time of their of Although can determine whether a cancer has of patients with CRC recurrence have The definition of between studies but commonly includes abdominal change in bowel blood in abdominal and Patients should be regarding the of for potential recurrence and to should these Surveillance is recommended for patients with stage IV colon or rectal cancer who have therapy with curative Grade of recommendation: Strong recommendation based on low-quality evidence, The of surveillance in stage IV patients remains because most studies regarding follow-up and surveillance for survivors of colon or rectal cancer patients with stage IV Meanwhile, the potential for long-term survival after curative intent therapy under these circumstances, in selected is well in patients with or The optimal and of surveillance for