Warning: fopen(/home/virtual/colon/journal/upload/ip_log/ip_log_2024-10.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 95 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 96 Colon cancer: the 2023 Korean clinical practice guidelines for diagnosis and treatment


Your browser does not support the NLM PubReader view.

Go to this page to see a list of supporting browsers.

Colon cancer: the 2023 Korean clinical practice guidelines for diagnosis and treatment

Article information

Ann Coloproctol. 2024;40(2):89-113
Publication date (electronic) : 2024 April 30
doi : https://doi.org/10.3393/ac.2024.00059.0008
Hyo Seon Ryu1orcid_icon, Hyun Jung Kim2,3orcid_icon, Woong Bae Ji4orcid_icon, Byung Chang Kim5orcid_icon, Ji Hun Kim6orcid_icon, Sung Kyung Moon7orcid_icon, Sung Il Kang8orcid_icon, Han Deok Kwak9orcid_icon, Eun Sun Kim10orcid_icon, Chang Hyun Kim11orcid_icon, Tae Hyung Kim12orcid_icon, Gyoung Tae Noh13orcid_icon, Byung-Soo Park14orcid_icon, Hyeung-Min Park11orcid_icon, Jeong Mo Bae15orcid_icon, Jung Hoon Bae16orcid_icon, Ni Eun Seo17orcid_icon, Chang Hoon Song18orcid_icon, Mi Sun Ahn19orcid_icon, Jae Seon Eo20orcid_icon, Young Chul Yoon21orcid_icon, Joon-Kee Yoon22orcid_icon, Kyung Ha Lee23orcid_icon, Kyung Hee Lee24orcid_icon, Kil-Yong Lee25orcid_icon, Myung Su Lee26orcid_icon, Sung Hak Lee27orcid_icon, Jong Min Lee28orcid_icon, Ji Eun Lee29orcid_icon, Han Hee Lee30orcid_icon, Myong Hoon Ihn31orcid_icon, Je-Ho Jang32orcid_icon, Sun Kyung Jeon26orcid_icon, Kum Ju Chae33orcid_icon, Jin-Ho Choi34orcid_icon, Dae Hee Pyo35orcid_icon, Gi Won Ha36orcid_icon, Kyung Su Han5orcid_icon, Young Ki Hong37orcid_icon, Chang Won Hong5orcid_icon, Jung-Myun Kwak,1orcid_icon, Korean Colon Cancer Multidisciplinary Committee
1Division of Colon and Rectal Surgery, Department of Surgery, Korea University College of Medicine, Seoul, Korea
2Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
3Institute for Evidence-based Medicine, Cochrane Collaboration, Seoul, Korea
4Division of Colon and Rectal Surgery, Department of Surgery, Korea University Ansan Hospital, Ansan, Korea
5Center for Colorectal Cancer, National Cancer Center, Goyang, Korea
6Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
7Department of Radiology, Kyung Hee University Hospital, Seoul, Korea
8Department of Surgery, Yeungnam University College of Medicine, Daegu, Korea
9Department of Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
10Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
11Department of Surgery, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
12Department of Radiation Oncology, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
13Department of Surgery, Ewha Womans University College of Medicine, Seoul, Korea
14Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
15Department of Pathology, Seoul National University Hospital, Seoul, Korea
16Division of Colorectal Surgery, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
17Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
18Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Korea
19Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea
20Department of Nuclear Medicine and Molecular Imaging, Korea University College of Medicine, Seoul, Korea
21Department of General Surgery, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
22Department of Nuclear Medicine and Molecular Imaging, Ajou University School of Medicine, Suwon, Korea
23Department of Surgery, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea
24Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Korea
25Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
26Department of Radiology, Seoul National University Hospital, Seoul, Korea
27Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
28Department of Surgery, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
29Department of Radiology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
30Division of Gastroenterology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
31Department of Surgery, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
32Department of Surgery, Daejeon Eulji Medical Center, Eulji University, Daejeon, Korea
33Department of Radiology, Jeonbuk National University Medical School, Jeonju, Korea
34Center for Lung Cancer, Department of Thoracic Surgery, Research Institute and Hospital, National Cancer Center, Goyang, Korea
35Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
36Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea
37Department of Surgery, National Health Insurance Service Ilsan Hospital, Goyang, Korea
Correspondence to: Jung-Myun Kwak, MD, PhD Division of Colon and Rectal Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea Email: jmkwak@korea.ac.kr
Received 2024 January 20; Revised 2024 March 11; Accepted 2024 March 18.

Abstract

Colorectal cancer is the third most common cancer in Korea and the third leading cause of death from cancer. Treatment outcomes for colon cancer are steadily improving due to national health screening programs with advances in diagnostic methods, surgical techniques, and therapeutic agents. The Korea Colon Cancer Multidisciplinary (KCCM) Committee intends to provide professionals who treat colon cancer with the most up-to-date, evidence-based practice guidelines to improve outcomes and help them make decisions that reflect their patients’ values and preferences. These guidelines have been established by consensus reached by the KCCM Guideline Committee based on a systematic literature review and evidence synthesis and by considering the national health insurance system in real clinical practice settings. Each recommendation is presented with a recommendation strength and level of evidence based on the consensus of the committee.

Keywords: Colonic neoplasms; Diagnosis; Genetics; Therapy; Humans

INTRODUCTION

Colorectal cancer is the third most common cancer in Korea. It accounts for 10.9% of all cancer deaths, the third highest mortality rate among all cancers [1]. Treatment outcomes for colon cancer have steadily improved, with a 5-year survival rate of about 72% [2]. Various diagnostic and therapeutic approaches have been proposed in recent years. Personalized precision medicine based on genetic information is also being pursued. However, the safety and effectiveness of new treatments need to be verified. In addition, there are different views on optimal drug selection, timing, treatment sequence, and duration, which need to be established based on scientific evidence. In recognition of the need for a multidisciplinary colorectal cancer guideline that reflects the latest knowledge in the Korean health insurance system and the actual situation in the field, a multidisciplinary committee composed of experts from various medical departments specializing in colorectal cancer care was organized to develop evidence-based practice guidelines for the diagnosis and treatment of colon cancer.

METHODS

Methodology

The guidelines were developed by both adapting previous guidelines and de novo development through brainstorming by the members of the development committee. These guidelines have 7 newly developed key questions (KQs) and 10 updated KQs selected from the previous version. The systematic review followed the methodology outlined by Cochrane [3]. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology was adopted to assess the quality of evidence and determine the strength of the recommendation (SoR) [4].

Synthesis of evidence

Literature search

A literature search was conducted through MEDLINE (PubMed) using primary search terms derived through discussions with methodology experts (Supplementary Material 1). A systematic literature search was conducted in MEDLINE, Embase, Cochrane, and KoreaMed databases for articles updated since the references used in the previous guideline version through August 2022 and from inception until August 2022 for de novo KQs. The retrieved articles were screened by applying inclusion and exclusion criteria in a PICOS (population, intervention, comparator, outcomes, and study design) format by at least 2 committee members assigned to each KQ. The literature selection process was reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [5] flow diagram (Supplementary Fig. 1).

Assessment of risk of bias

The quality of the literature was assessed independently by at least 2 reviewers for each KQ using assessment tools selected according to the study design (Table 1) [6–10]. Discrepancies in the assessment results were resolved by discussion. The results of the individual evidence quality assessments are presented in Supplementary Fig. 2 [11–220].

Tools for assessing risk of bias

Level of evidence

The level of evidence (LoE) was determined according to the GRADE group's criteria [4]. This assessment was done in consultation with a methodology expert and individual KQ members (Table 2).

Level of evidence

Formulation of recommendations

Investigation of the values and preferences of the target population

A 19-question survey of health outcome priorities and preferences was administered to 56 patients diagnosed and treated for colon cancer of all stages.

Strength of recommendations

Each KQ member developed draft recommendations and SoR based on the GRADE grid method by considering the strengths and limitations of the evidence, the magnitude and balance of benefits and harms, patient values and preferences, physician barriers, financial factors, and applicability in their practice setting using a summary of the evidence and the LoE [221] (Table 3).

Strengths of the recommendations and implications for clinical practice

Recommendation consensus

The draft recommendations and SoR were discussed in a development committee meeting and a consensus was reached through a blind vote of all members conducted on August 28, 2023. The internal committee recommendation grading process was attended by at least 70% of all committee members. The committee’s decision was deemed a consensus if at least 70% of the votes were cast on an individual item and at least 70% of the votes were in favor. If less than 70% of the votes were in favor, the development committee members considered amendments and a second vote was taken.

Endorsement process

External expert review

Twenty-three external experts in fields related to colon cancer diagnosis and treatment who were not members of the development committee were selected to evaluate the recommendations and assess their acceptability. They reviewed the KQs, the objectivity of the recommendation, the overall balance of benefits and harms from the evidence assessment, recommendation direction and SoR based on the strengths and limitations of the evidence.

Public hearing

Public hearings were held to survey and incorporate feedback on the direction of the recommendations and the SoRs.

Guideline update plan

When high-quality evidence is reported on new diagnostic methods, drugs, and therapies, the guideline will be revised by adding new recommendations or revising or supplementing existing recommendations. If new evidence is reported, the committee will evaluate the evidence and discuss how to revise the recommendations. If high-quality evidence is reported for un outcome with a current recommendation, the committee will consider raising the LoE for that recommendation.

RESULTS

DIAGNOSIS

Topic: Diagnosis

KQ 1. What imaging studies should be performed if liver metastases are suspected on abdominal CT for staging in a patient with colon cancer?

Recommendation 1-1.

Liver MRI is recommended if metastases localized to the liver are suspected or if liver resection is considered.

Strength of the recommendation: do (strong)

Level of evidence: low

Recommendation 1-2.

When liver metastases are suspected in patients with colon cancer, PET-CT is recommended for radical treatment decisions.

Strength of the recommendation: do (strong)

Level of evidence: low

The resection of liver metastases can improve prognosis. Determining treatment intent and resectability is important [222]. Meta-analyses have indicated that MRI outperforms CT in detecting small metastatic lesions and characterizing indeterminate lesions (Supplementary Figs. 3, 4) [11–18, 20–56, 223]. Therefore, MRI is the best option for accurately diagnosing liver metastases on a per-lesion basis. In situations where a treatment decision between curative and palliative therapy is required, it is important to determine the presence or absence of distant metastases at the patient level. PET-CT is recommended because of its high accuracy in per-patient analysis (Supplementary Fig. 5) [19, 40, 42–44, 46, 49, 50, 56]. PET-CT has the advantage of being able to accurately diagnose distant metastases to organs other than the liver. For both MRI and PET-CT, patient value and preference surveys showed that most patients were either in favor of additional testing or supportive of it at the discretion of their physicians, indicating that additional testing for an accurate diagnosis is supported by patients.

Topic: Diagnosis

KQ 2. Is the addition of PET-CT more effective than CT alone in patients with metastatic colon cancer?

Recommendation 2.

In patients with metastatic colon cancer, PET-CT is useful for detecting metastatic lesions not detected on contrast-enhanced CT. PET-CT is recommended for treatment decision-making in metastatic colon cancer.

Strength of recommendation: do (strong)

Level of evidence: very low

PET-CT has a higher diagnostic sensitivity for metastatic lesions than contrast-enhanced CT (Supplementary Fig. 6) [44, 47, 52, 60, 61, 63, 67, 71]. The concordance between PET-CT and contrast-enhanced CT for metastatic lesions ranges from 71% to 90% for liver metastases, with the concordance being lower for extrahepatic metastases than for liver metastases [47, 58, 65, 75]. Additional metastatic lesions can be detected by PET-CT. PET can also detect secondary or synchronous colon cancer [57, 58, 60, 63, 67]. PET-CT can detect additional extrahepatic metastases in 0.4 to 37.1% of cases compared to traditional diagnostics alone. PET-CT results led to treatment changes in 6.8%–53.9% of colon cancer patients [44, 47, 52, 57–75].

Topic: Diagnosis

KQ 3. What tests can be considered for proximal colon evaluation in patients with left obstructive colon cancer where evaluating the proximal colon on preoperative colonoscopy is difficult?

Recommendation 3.

In patients with left obstructive colon cancer where evaluating the proximal segment on preoperative colonoscopy is difficult, CT colonography, PET-CT, and completion colonoscopy may be considered for proximal evaluation.

Strength of recommendation: do (conditional)

Level of evidence: very low

In patients with obstructive colorectal cancer where the proximal colon could not be evaluated, CT colonography, PET-CT, and completion colonoscopy after stent insertion detected synchronous cancer in the proximal colon in 1.4%–15%, 4.1%–9.7%, and 2.5%–10% of the cases, respectively, showing very high accuracy and leading to a change in the scope of surgery or a change in treatment for those patients [76–83, 85–91, 224].

CT colonography is a CT scan without the insertion of an endoscope, which allows for the evaluation of the inner colon using computerized techniques. This technique can be useful when the entire colon cannot be evaluated due to structural causes such as colonic obstruction or other technical difficulties [225]. PET-CT can detect suspected malignant lesions even when morphologic variation is severe or direct histologic examination is difficult. In addition to detecting proximal colorectal cancer, PET-CT can help detect metastatic lesions. In addition, if a preoperative abdominal CT scan suggests a proximal colon lesion and a histologic diagnosis is needed for treatment planning, completion of the colonoscopy which refers to preoperative full colonoscopic evaluation after effective stent placement with a small-diameter endoscope should be considered. Its benefits may be significant.

Additional testing to evaluate the proximal colon should be considered in patients with obstructive colorectal cancer when feasible, as the discovery of proximal lesions may alter the scope of surgery. Failure to diagnose them may result in the need for secondary surgery or the failure of radical therapy.

INTERVENTION OR SURGERY

Topic: Surgery

KQ 4. Following the endoscopic resection of colorectal submucosal cancer (cT1N0M0) with a histopathologic diagnosis of completely resected (margin negative) submucosal adenocarcinoma, what risk factors for lymph node metastasis should be considered for additional colectomy?

Recommendation 4.

Further radical surgery should be considered in patients at high risk for lymph node metastasis, such as those with lymphovascular/perivascular involvement, poorly differentiated/undifferentiated, deep submucosal invasion, and high-tier tumor budding, even if complete resection is achieved endoscopically.

Strength of recommendation: do (strong)

Level of evidence: very low

Submucosal cancers of the colon are those in which the infiltration of cancer cells is confined to mucosal and submucosal layers. The need for further radical resection has long been debated. A lymph node metastasis rate of around 10% has been reported [226]. Tumors are generally classified as high-risk for lymph node metastasis if there is margin involvement, lymphovascular/vascular invasion, poorly differentiated/undifferentiated, deep submucosal involvement, or high-tier tumor budding, which has recently been reported to increase the risk of lymph node metastasis [92–102, 104–113, 115–119]. The presence of each risk factor is associated with a more than 3-fold increase in the odds ratio for lymph node metastasis risk (Supplementary Fig. 7) [92–95, 97–102, 105–108, 110–112, 115, 116, 118, 119]. Therefore, we recommend radical resection with lymph node dissection in high-risk patients with any 1 risk factor after endoscopic resection for submucosal cancer and surveillance rather than further radical resection in low-risk patients without all the above findings.

Limited imaging tests are currently available to determine the presence of lymph node metastases in colorectal cancer. When deciding on further radical surgery, considering the patient’s general condition and risk of lymph node metastasis is recommended. The decision should be made after full consultation with the medical team and the patient.

Topic: Surgery

KQ 5. Does D3 lymph node dissection or complete mesocolic excision/central vessel ligation contribute to reduced recurrence and improved survival in surgery for right-sided colorectal cancer without distant metastases?

Recommendation 5.

D3 lymph node dissection or complete mesocolic excision/central vessel ligation is recommended for surgery for nonmetastatic right-sided colon cancer.

Strength of recommendation: do (conditional)

Level of evidence: very low

Meta-analysis studies showed that patients who underwent extensive lymphadenectomy (D3 lymph node dissection or complete mesocolic excision/central vessel ligation) had statistically significant survival benefits over patients who did not undergo extensive lymphadenectomy, including longer overall survival (OS) (risk ratio [RR], 0.78; 95% confidence interval [CI], 0.67–0.92), better disease-free survival (DFS; RR, 0.68; 95% CI, 0.55–0.84), higher cancer-specific survival (CSS; RR, 0.27; 95% CI, 0.13–0.57), and lower recurrence rate (RR, 0.55; 95% CI, 0.43–0.70) (Supplementary Fig. 8) [120–126, 128, 227–229]. However, meta-analysis studies and prospective randomized clinical trials (RCTs) comparing short-term postoperative outcomes between extensive lymphadenectomy and no extensive lymphadenectomy did not show significant differences in outcomes related to complications such as anastomotic leakage, postoperative recovery, or reoperation [230, 231]. D3 lymph node dissection or complete mesocolic excision/central vessel ligation is recommended as it has a lower recurrence rate, a survival benefit, and minimal harm compared to no extensive lymphadenectomy.

Nonetheless, mandatory implementation of D3 lymph node dissection or complete mesocolic excision with central vessel ligation may not be recommended for early-stage colon cancer patients lacking preoperative lymph node metastases and exhibiting tumor invasion limited to the submucosal layer. Likewise, such procedures may be unsuitable for individuals at high surgical risk due to advanced age or comorbidities.

Topic: Intervention

KQ 6. Is the use of SEMS for preoperative decompression recommended in obstructive colon cancer?

Recommendation 6-1.

Preoperative stenting is not always recommended in operable obstructive right-sided colon cancer.

Strength of recommendation: do not (conditional)

Level of evidence: very low

Recommendation 6-2.

Preoperative stenting in operable obstructive left-sided colon cancer may be considered in selected cases.

Strength of recommendation: do (conditional)

Level of evidence: very low

Meta-analysis studies showed a lower rate of stoma formation in the SEMS group of patients with right-sided obstructive colon cancer than in the emergency surgery (ES) group (Supplementary Fig. 9) [129–136]. However, most studies had few cases of stoma formation in each group. Thirty-day mortality was lower in the SEMS arm, and there was no significant difference in the open conversion rate (Supplementary Fig. 9) [129–136]. In terms of oncologic outcomes, 3-year DFS was higher in the SEMS arm (RR, 1.23; 95% CI, 1.02–1.49; P=0.03), while no significant difference in 5-year DFS or 5-year OS (Supplementary Fig. 10) [129, 131–135]. The serious complication of bowel perforation may occur during SEMS insertion, although it is not frequent. In many cases of right-sided colon cancer, primary anastomosis without stoma creation is possible without preoperative decompression. In clinical practice, SEMS insertion is limited by the patient’s visit time, emergency level, and the human and material resources of the institution. Because the benefits of the procedure do not outweigh the harm it may cause and the resources it requires, SEMS insertion for preoperative decompression is not always recommended for surgically curable obstructive right-sided colon cancer.

In patients with left-sided obstructive colon cancer, the SEMS group showed significantly lower rates of stoma formation and overall complication but higher primary anastomosis rates than the ES group (Supplementary Fig. 11) [137, 138, 140–153]. Regarding oncologic outcomes, the recurrence rate in the SEMS group was significantly higher than in the ES group (RR, 1.39; 95% CI, 1.09–1.78; P=0.006) when data were analyzed by including only RCTs. Three-year DFS, 5-year DFS, 3-year OS, and 5-year OS showed substantial heterogeneity, although no significant differences were seen between the 2 groups (Supplementary Fig. 12) [137, 138, 141, 142, 145, 146, 148–152, 232]. While SEMS insertion has demonstrated superiority over ES in short-term outcomes such as the stoma formation rate, overall complications, and primary anastomosis rate in patients with left-sided obstructive colon cancer, there are concerns about recurrence. A significant difference in the recurrence rate depending on the occurrence of perforation was reported in a SEMS group [135]. In operatively curable obstructive left colon cancer, SEMS insertion may be considered by experienced interventionists in selected patients, as adequate preoperative decompression with SEMS insertion increases the likelihood of primary anastomosis without creating a stoma.

PATHOLOGY

Topic: Pathology

KQ 7. What is the appropriate number of lymph node examinations for proper lymph node staging of stage II and III colon cancer?

Recommendation 7.

For proper lymph node staging, the dissection and examinations of at least 12 lymph nodes are recommended for pathologic diagnosis.

Strength of recommendation: do (strong)

Level of evidence: low

There are limitations in that each previous study had a different patient population and that the number of lymph node examinations was decided according to various self-criteria, making it difficult to conduct a comprehensive analysis. However, most studies classified patients based on 12 lymph nodes. Thus, the present meta-analysis was performed based on 12 lymph nodes. The meta-analysis showed a significant reduction in overall mortality (hazard ratio [HR], 0.78; 95% CI, 0.72–0.85) with increases in the number of lymph nodes dissected (Supplementary Fig. 13) [154, 158, 162–164]. Lee et al. [158] found reductions in the recurrence rate with increasing numbers of lymph nodes dissected (HR, 0.59; 95% CI, 0.41–0.85). However, their study was limited by very low quality of evidence. Patient values and preferences surveys also suggest that patients would prefer to have more than 12 lymph nodes removed, as curing and minimizing recurrence are top priorities in colon cancer treatment.

Topic: Pathology

KQ 8. Should MSI testing be performed for all patients with colon cancer to screen for Lynch syndrome?

Recommendation 8.

MSI test is recommended in all patients with colon cancer to screen for Lynch syndrome.

Strength of recommendation: do (conditional)

Level of evidence: low

Microsatellite instability (MSI) testing can detect abnormalities in the number of microsatellites repeats in the sequences of patients with Lynch syndrome or sporadic tumors. It has a theoretical sensitivity of 100% for colon cancer caused by Lynch syndrome. In a meta-analysis, patients with positive MSI accounted for approximately 11% of all colon cancer patients and approximately 22% of all colon cancer patients who met the revised Bethesda guidelines criteria and required genetic testing to confirm Lynch syndrome (Supplementary Fig. 14A, B) [165–173]. Among patients ultimately diagnosed with Lynch syndrome after screening with MSI testing and genetic testing for confirmation, 22% did not meet the revised Bethesda guidelines criteria (Supplementary Fig. 14C) [165–167, 169, 173].

In a survey of patient values and preferences, 59% of patients agreed with the use of MSI testing to screen for Lynch syndrome, 30% preferred their physician’s judgment, and 7% preferred genetic testing to confirm Lynch syndrome without screening.

Topic: Pathology

KQ 9. Is KRAS, NRAS, or BRAF gene testing necessary to determine targeted therapy for EGFR as first-line chemotherapy in patients with metastatic colon cancer?

Recommendation 9.

KRAS, NRAS, and BRAF genetic testing are recommended to determine the appropriateness of EGFR-targeted therapy as first-line chemotherapy in patients with metastatic colon cancer.

Strength of recommendation: do (strong)

Level of evidence: moderate

Meta-analysis results in this study confirmed a difference in progression-free survival (PFS) with the use of anti-EGFR antibody in both KRAS wide type (WT) and mutant type (MT) tumors. In KRAS WT, the use of anti-EGFR antibody was associated with PFS benefits (HR, 0.66; 95% CI, 0.58–0.74) and OS (HR, 0.76; 95% CI, 0.67–0.86). In MT tumors, the use of targeted therapy adversely affected PFS (HR, 1.22; 95% CI, 1.06–1.41) with no significant difference in OS. The survival benefit of using anti-EGFR antibody based on KRAS testing was 24% for OS and 22% to 34% for PFS (Supplementary Fig. 15A, B) [174, 175, 177, 178]. Targeted therapy had PFS benefits in NRAS WT tumors (HR, 0.72; 95% CI, 0.58–0.89) and OS (HR, 0.77; 95% CI, 0.64–0.93), while in NRAS MT, there was no significant difference in PFS or OS (Supplementary Fig. 15C) [176]. The survival benefit of using anti-EGFR antibody with NRAS testing was 23% for OS and 28% for PFS.

Analyses showed that BRAF WT had superior PFS and OS in patients treated with targeted therapies compared to MT (Supplementary Fig. 15D) [179, 180]. However, these studies did not compare outcomes with and without targeted therapies. Thus, the survival benefit associated with BRAF testing and using targeted therapies is unknown. An analysis of randomized studies of RAS-WT/BRAF-MT patients found no difference in OS or PFS with or without anti-EGFR antibody treatment [233]. These results suggest that BRAF genetic testing can be used as a rationale for avoiding targeted therapies in BRAF MT patients undergoing first-line chemotherapy.

The sensitivity and specificity of both RAS and BRAF genetic testing are >95%. Thus, the likelihood of misusing targeted therapies due to incorrect genetic testing results is low. Although there is a cost associated with the test, 96% of patients agreed with testing in a survey on patient values and preferences. A 2012–2013 survey of more than 300 oncologists in 5 European countries found that 99.3% of the physicians performed KRAS genetic testing before using anti-EGFR antibody [234].

CHEMOTHERAPY

Topic: Chemotherapy

KQ 10. Is adjuvant chemotherapy after curative resection necessary for high-risk stage II colon cancer patients?

Recommendation 10.

Adjuvant chemotherapy after surgery is recommended for high-risk stage II colon cancer patients.

Strength of recommendation: do (conditional)

Level of evidence: low

High-risk stage Ⅱ colon cancer is defined as having at least one of the following risk factors: T4 tumor, bowel obstruction or perforation, lymphatic or vascular invasion, perineural invasion, lymph node yield of fewer than 12, poorly differentiated tumor, and positive margins. In high-risk stage II colon cancer, when comparing the adjuvant chemotherapy group to the surgery alone group, a statistically significant increase in OS was seen (HR, 0.62; 95% CI, 0.46–0.95) but no significant difference in DFS (HR, 0.76; 95% CI, 0.57–1.02) or recurrence-free survival (RFS; HR, 1.01; 95% CI, 0.79–1.29) (Supplementary Fig. 16A–C) [181–187, 235]. One prospective study reported adverse effects of adjuvant chemotherapy after surgery for high-risk stage II colon cancer that included elevated alanine aminotransferase and aspartate aminotransferase levels, decreased appetite, diarrhea, and nausea (Supplementary Fig. 16D) [186]. However, the number of events was low. In addition, such risks were not thought to outweigh the survival benefit. Curing and minimizing recurrence were top priorities for patients in the survey, with 86% of all respondents agreeing that they would accept the adverse effects of chemotherapy to improve survival outcomes.

Topic: Chemotherapy

KQ 11. Is 3 months of adjuvant chemotherapy with oxaliplatin oncologically safe for patients with stage 3 colon cancer compared to 6 months?

Recommendation 11-1.

Three months of adjuvant chemotherapy with oxaliplatin may be considered for patients with low-risk stage Ⅲ (pT1–3N1) after colon cancer surgery.

Strength of recommendation: do (conditional)

Level of evidence: low

Recommendation 11-2.

Three months of FOLFOX is not recommended as adjuvant chemotherapy for patients with high-risk stage Ⅲ (pT4 or N2) after colon cancer surgery.

Strength of recommendation: do not (conditional)

Level of evidence: low

Meta-analysis showed that in patients with stage III colon cancer, 3 months of adjuvant chemotherapy significantly reduced the incidence of peripheral neuropathy without compromising OS compared to 6 months of adjuvant chemotherapy (Supplementary Fig. 17A, B) [188, 192, 236, 237]. While RFS was not significantly different between 3 or 6 months of CAPOX (capecitabine and oxaliplatin) or FOLFOX in patients with low-risk stage III, 3 months of FOLFOX led to inferior outcomes in patients with high-risk stage III (HR, 1.37; 95% CI, 1.11–1.69) (Supplementary Fig. 17C) [189–191, 238]. Therefore, adjuvant chemotherapy for 3 months is preferred for patients with low-risk stage III, showing a significant reduction in peripheral neuropathy without affecting survival outcome. In high-risk stage III, FOLFOX showed a clear disadvantage in RFS despite a reduction in peripheral neuropathy. Therefore, FOLFOX for 3 months is not recommended given its oncologic hazard.

Topic: Chemotherapy

KQ 12. Does immunotherapy provide better response rates in patients with metastatic colon cancer with MSI-H/dMMR than conventional chemotherapy?

Recommendation 12.

Immunotherapy is recommended for patients with MSI-H/dMMR metastatic colon cancer.

Strength of recommendation: do (conditional)

Level of evidence: low

Keynote-177, a randomized phase III study, compared immunotherapy (pembrolizumab) with conventional chemotherapy (FOLFOX or FOLFIRI [folinic acid, fluorouracil, and irinotecan] ± bevacizumab or cetuximab) [194]. PFS (HR, 0.59; 95% CI, 0.45–0.79) and the overall response rate (RR, 1.36; 95% CI, 1.02–1.81) were significantly improved in the pembrolizumab arm (Supplementary Fig. 18A, B) [194]. However, OS was not significantly different between the 2 groups (HR, 0.74; 95% CI, 0.53–1.03) (Supplementary Fig. 18B) [194]. Quality of life was significantly better in the pembrolizumab arm (Supplementary Fig. 18C) [193]. Phase II studies and retrospective studies also showed improved survival with immunotherapy in patients with MSI-H/dMMR metastatic colon cancer. PFS rates of 13 months and OS of 47 months were reported with pembrolizumab or nivolumab, whereas PFS of 6 to 7 months and OS of 13 to 28 months were reported with a conventional chemotherapy [195, 239–242].

In the Keynote-177 study, the incidence of grade 3 or higher treatment-related adverse events was also significantly lower in the pembrolizumab arm (22% vs. 66%; RR, 0.30; 95% CI, 0.22–0.42) (Supplementary Fig. 18A) [194]. The CheckMate 142 and Keynote-164 studies also reported less frequent adverse events in the pembrolizumab arm than in the conventional chemotherapy arm [195, 239]. Thus, immunotherapy can reduce treatment harm and improve survival and quality of life, consistent with patient values.

However, in Korea, immunotherapy for metastatic colon cancer is not covered by national health insurance. In addition, it is expensive, resulting in economic inequalities. For this reason, we reached a consensus with a conditional recommendation. If the national health insurance system changes its policy in the future, the SoR may be upgraded.

Topic: Chemotherapy

KQ 13. In patients with locally advanced colon cancer, is the addition of neoadjuvant chemotherapy oncologically superior to surgery alone?

Recommendation 13.

Neoadjuvant chemotherapy may be considered a treatment option in patients with locally advanced colon cancer to reduce recurrence rates.

Strength of recommendation: do (conditional)

Level of evidence: low

A randomized phase III study has compared 6 weeks of neoadjuvant chemotherapy followed by surgery to 18 or 24 weeks of adjuvant chemotherapy following surgery in patients with colon cancer clinically staged as T3–4, N0–2, or M0 on imaging studies. The study found that residual disease or recurrence rates at 2 years were significantly lower in the neoadjuvant chemotherapy group (16.9% vs. 21.5%; RR, 0.72; 95% CI, 0.54–0.98), although there was no difference in OS or CSS (Supplementary Fig. 19A) [196]. No statistically significant differences in postoperative complications, including anastomotic leakage and intra-abdominal abscess were seen (Supplementary Fig. 19B) [196]. In a survey of patient values and preferences, 36% agreed with preoperative chemotherapy and 59% said it depended on their surgeon’s judgment.

Given the lack of evidence for neoadjuvant chemotherapy in nonmetastatic colon cancer and the limitations of the radiologic diagnosis of lymph node metastases, overtreatment in node-negative patients is a concern. Thus, patients selection should be done carefully.

Although neoadjuvant chemotherapy has an unclear survival benefit, it was shown to reduce recurrence rates. In a comparison of groups that did and did not receive neoadjuvant chemotherapy, no significant differences were found in terms of postoperative complications, overall treatment duration, or cost, supporting the option of preoperative chemotherapy in select patients with locally advanced colon cancer to reduce recurrence rates.

RESECTABLE METASTATIC COLON CANCER

Topic: Resectable liver metastases

KQ 14. What is the appropriate treatment for patients with resectable colon cancer liver metastases?

Recommendation 14-1.

For the radical treatment of patients with a single colon cancer liver metastasis of 3 cm or less, hepatectomy is more effective than RFA.

Strength of recommendation: do (strong)

Level of evidence: very low

Recommendation 14-2.

In patients with resectable colon cancer liver metastases, simultaneous resection versus staged resection is an option.

Strength of recommendation: do (conditional)

Level of evidence: very low

Recommendation 14-3.

In patients with resectable colon cancer liver metastases, either surgery after neoadjuvant chemotherapy or upfront surgery can be considered.

Strength of recommendation: do (conditional)

Level of evidence: very low

All previous studies comparing hepatectomy and RFA were all retrospective. Because RFA was performed in high-risk patients, the results regarding treatment complications and survival outcomes should be cautiously interpreted [199, 203, 205]. The local recurrence rate was significantly lower in the resection group than in the RFA group (RR, 0.14; 95% CI, 0.05–0.38) (Supplementary Fig. 20) [199, 203, 205]. Although few major complications have been reported, it is difficult to conclude treatment-related harms due to bias in subject selection. Given the local recurrence rate, resection is the treatment of choice for resectable colon cancer liver metastases. Other modalities such as RFA, stereotactic body radiation therapy, microwave ablation, and cryoablation may be considered depending on surgical risk. However, there is insufficient evidence on the effectiveness and side effects of those modalities.

Whether simultaneous resection is more effective than staged resection remains inconclusive, with both approaches being used in real-world practice. OS and DFS were not significantly different between simultaneous versus staged resection. Simultaneous resection was not associated with a higher risk of complications compared to staged resection in a prospective randomized study (Supplementary Fig. 21) [197, 198, 204, 209]. Patient values and preferences surveys also showed that minimizing recurrence (43.0%) and the surgeon’s judgment (39.3%) were the most important factors in deciding the timing of surgery. Clinically, the decision between simultaneous and staged resection can be made selectively based on clinical settings.

No statistical difference in 3-year DFS, 5-year DFS, or 5-year OS was found in a comparison of surgery after neoadjuvant chemotherapy versus upfront surgery (Supplementary Fig. 22A) [84, 200, 201, 206–208]. Postoperative complications tended to be higher in the surgery after neoadjuvant chemotherapy group than in the upfront surgery group. However, the difference did not appear to be significant, although some studies reported the contrary results (Supplementary Fig. 22B) [201, 202, 206–208]. In a survey of patient values and preferences, 26.8% responded that they would like to reduce the extent of surgery by receiving neoadjuvant chemotherapy, and 51.8% agreed that it was up to their surgeon. Surgery after neoadjuvant chemotherapy has the advantage of confirming chemosensitivity. However, it may make it more difficult to locate the lesion and increase the risk of postoperative complications. There is no difference in benefits or risks. Thus, either treatment can be chosen depending on the patient’s condition.

Topic: Resectable lung metastases

KQ 15. Does pulmonary metastasectomy improve survival in patients with colon cancer lung metastasis?

Recommendation 15.

Pulmonary metastasectomy is considered for patients with resectable colon cancer lung metastases.

Strength of recommendation: do (conditional)

Level of evidence: very low

Studies on pulmonary metastasectomy for colon cancer are scarce because the patient population is heterogeneous, with different indications for local and systemic treatment depending on the number and extent of metastases at diagnosis. Two treatments are often combined in practice. Nevertheless, pulmonary metastasectomy for colon cancer is widely performed in clinical practice. A meta-analysis showed a trend toward better survival in patients who underwent lung resection compared to patients treated without surgical resection (RR, 0.72; 95% CI, 0.51–1.03; P=0.07) (Supplementary Fig. 23A) [211–213], although the difference was not statistically significant. Median survival was significantly longer in patients who underwent resection than in patients treated without surgical resection (RR, 0.76; 95% CI, 0.01–1.42; P=0.02) (Supplementary Fig. 23B) [210, 211].

Pulmonary metastasectomy can be considered if the primary lesion has already been resected or is planned to be resected, pulmonary function is good, the risk of lung resection is low, and pulmonary metastatic lesions are resectable.

Topic: Resectable peritoneal metastasis

KQ 16. Do CRS and HIPEC improve survival in patients with colon cancer with peritoneal metastases?

Recommendation 16.

CRS and selective HIPEC are recommended for patients with colon cancer with resectable peritoneal metastases.

Strength of recommendation: do (conditional)

sLevel of evidence: low

Patients with colorectal cancer with peritoneal metastases typically are not expected to survive more than one year without treatment. However, even palliative chemotherapy can improve median survival from 12 months to 16 months [243]. Several studies demonstrated a significant survival benefit for patients who underwent CRS followed by HIPEC compared to palliative chemotherapy (HR, 0.55; 95% CI, 0.32–0.95) (Supplementary Fig. 24A) [215, 217–220]. When the incidence of grade 3 or higher complications was compared, no significant difference was seen between CRS followed by HIPEC and palliative chemotherapy (Supplementary Fig. 24B) [219].

However, the results recently reported from a phase III trial and prospective study that analyzed the effectiveness of CRS followed by HIPEC versus CRS alone in colorectal cancer with peritoneal metastases showed no additional survival benefit in patients who received CRS with oxaliplatin-based HIPEC compared to the CRS alone group (Supplementary Fig. 25A) [214, 244]. In a comparison of grade 3 or higher complications between the 2 groups, no difference in the rate of complications within 30 days was seen (Supplementary Fig. 25B) [214]. Therefore, in patients with colon cancer with resectable peritoneal metastases, CRS should be the cornerstone of treatment. The effectiveness of HIPEC remains unclear. Considering that high morbidity and mortality are associated with CRS, it is important to select candidates who might achieve the best outcomes.

UNRESECTABLE METASTATIC COLON CANCER

Topic: Palliative chemotherapy

KQ 17. Will second-line palliative chemotherapy improve survival and quality of life in patients with metastatic colon cancer after the failure of first-line palliative chemotherapy?

Recommendation 17.

Second-line palliative chemotherapy is recommended for patients with metastatic colon cancer that have failed first-line palliative chemotherapy to improve survival and quality of life.

Strength of recommendation: do (conditional)

Level of evidence: low

In metastatic colorectal cancer patients with disease progression after first-line palliative chemotherapy, treatment with irinotecan significantly improved survival compared with best supportive care (RR, 1.7; 95% CI, 1.24–2.35) (Supplementary Fig. 26sA) [216]. Chemotherapy was also associated with fewer tumor-related side effects and better quality of life, although it showed side effects (Supplementary Fig. 26B, C) [216]. In patients with metastatic colon cancer who have failed first-line palliative chemotherapy, the priority in deciding on second-line palliative chemotherapy is to improve survival and quality of life. Therefore, second-line chemotherapy should be considered for patients with metastatic colorectal cancer.

CONCLUSION

These guidelines emphasize the importance of a personalized treatment plan based on a multidisciplinary approach to the management of colon cancer that takes the patient’s values, preferences, and the evolving landscape of diagnostic and treatment options into consideration.

The recommended surgical technique for nonmetastatic right-sided colon cancer is complete mesocolic excision/central vessel ligation to reduce recurrence and improve survival outcomes. At least 12 lymph nodes should be examined for lymph node staging. In the management of obstructive colon cancer, decompression with preoperative stenting is not always necessary for right-sided colon cancer. However, it is recommended for left-sided colon cancer for adequate decompression with SEMS insertion. Adjuvant chemotherapy is recommended for patients with high-risk stage Ⅱ and Ⅲ after surgery. In low-risk stage Ⅲ, 3 months of adjuvant chemotherapy with oxaliplatin may also be considered.

For metastatic colon cancer, liver MRI or PET is recommended to determine resectability and radical treatment decision. MSI testing and KRAS, NRAS, or BRAF gene testing are required when considering various treatment options. Resection may be considered for resectable liver or lung metastases. CRS and selective HIPEC are recommended for resectable peritoneal metastases. Immunotherapy provides better response rate than conventional chemotherapy in metastatic colon cancer patients with MSI-H/dMMR.

Notes

Disclaimer

The 2023 Colon Cancer Korean Clinical Practice Guidelines are intended to guide the clinical practice of colon cancer based on published medical evidence for diagnosis and treatment. In actual clinical practice, the specific treatment of various clinical situations may differ from these guidelines. The guidelines should not interfere with or limit them. These guidelines do not have legal status. They are not binding. Users are responsible for patient outcomes in actual clinical practice.

Conflict of interest

Je-Ho Jang is an Editorial Board member of Annals of Coloproctology, but was not involved in in the peer reviewer selection, evaluation, or decision process of this article. To identify other potential conflicts of interest for all members who participated in the development of guidelines, we examined whether they were employed by a related company, received sponsorship or honoraria of more than KRW 10 million, conducted research funded by a specific institution or pharmaceutical company or received rights to economic benefits, or had intellectual property rights such as patents or royalties in the last 2 years. No potential conflict of interest relevant to this article was reported.

Funding

This guideline was developed with research funding provided by the National Cancer Guidelines Initiative, and the financial support had no direct or potential influence on the content or process of the guideline. The multidisciplinary committee, which included representation from 13 relevant societies, was independent of financial support. This work was also supported by the Research Fund of National Cancer Center (Goyang, Korea) (No. NCC-2112570-3).

Acknowledgments

The authors thank the Korean Cancer Management Guideline Network (KCGN) for the technical support.

Author contributions

Conceptualization: HSR, JMK, HJK, WBJ, BCK, JHK, SKM; Data curation: all authors; Formal analysis: HJK; Funding acquisition: JMK; Investigation: all authors; Methodology: HJK, WBJ; Project administration: JMK, HJK; Visualization: all authors; Writing–original draft: all authors; Writing–review & editing: HSR, JMK. All authors read and approved the final manuscript.

SUPPLEMENTARY MATERIALS

Supplementary Material 1.

Literature search terms for each key questions (KQs).

ac-2024-00059-0008-Supplementary-Material-1.pdf

Supplementary Fig. 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart for each key questions (KQs).

ac-2024-00059-0008-Supplementary-Fig-1.pptx

Supplementary Fig. 2.

Risk of bias assessment for each key questions (KQs) using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2), QUADAS-C (QUADAS-Comparative), ROBINS-I (Risk of Bias in Nonrandomized Studies of Intervention), and Cochrane RoB 2 (Risk-of-Bias Tool for Randomized Trials 2).

ac-2024-00059-0008-Supplementary-Fig-2.pptx

Supplementary Fig. 3.

Forest plots of (A) per-patient and (B) per-lesion sensitivity and specificity of computed tomography for detecting liver metastasis.

ac-2024-00059-0008-Supplementary-Fig-3.pptx

Supplementary Fig. 4.

Forest plots of (A) per-patient and (B) per-lesion sensitivity and specificity of magnetic resonance imaging for detecting liver metastasis.

ac-2024-00059-0008-Supplementary-Fig-4.pptx

Supplementary Fig. 5.

Forest plots of (A) per-patient and (B) per-lesion sensitivity and specificity of FDG positron emission tomography–computed tomography for detecting liver metastasis.

ac-2024-00059-0008-Supplementary-Fig-5.pptx

Supplementary Fig. 6.

Forest plots of sensitivity and specificity of (A) positron emission tomography–computed tomography and (B) computed tomography for detecting metastatic lesions.

ac-2024-00059-0008-Supplementary-Fig-6.pptx

Supplementary Fig. 7.

Forest plots for the association between lymph node metastasis and (A) lymphovascular invasion, (B) differentiation, (C) depth of invasion (≥1,000 μm), and (D) tumor budding.

ac-2024-00059-0008-Supplementary-Fig-7.pptx

Supplementary Fig. 8.

Forest plots of 3- and 5-year (A) recurrence rate, (B) disease-free survival, (C) overall survival, and (D) cancer-specific survival in extensive lymphadenectomy (D3 lymph node dissection or complete mesocolic extension/central vessel ligation) versus no extensive lymphadenectomy for right-sided colon cancer.

ac-2024-00059-0008-Supplementary-Fig-8.pdf

Supplementary Fig. 9.

Forest plots of (A) the stoma formation rate, (B) 30-day mortality, and (C) open conversion rate in self-expanding metallic stents versus emergency surgery for right-sided obstructive colon cancer.

ac-2024-00059-0008-Supplementary-Fig-9.pptx

Supplementary Fig. 10.

Forest plots of (A) the R0 resection rate, (B) 3-year disease-free survival, (C) 5-year disease-free survival, and (D) 5-year overall survival in self-expanding metallic stents versus emergency surgery for right-sided obstructive colon cancer.

ac-2024-00059-0008-Supplementary-Fig-10.pptx

Supplementary Fig. 11.

Forest plots of (A) the stoma formation rate, (B) primary anastomosis rate, (C) overall complication rate, and (D) 30-day mortality in self-expanding metallic stents versus emergency surgery for left-sided obstructive colon cancer.

ac-2024-00059-0008-Supplementary-Fig-11.pptx

Supplementary Fig. 12.

Forest plots of (A) 3-year disease-free survival (DFS), (B) 3-year overall survival (OS), (C) 5-year DFS, (D) 5-year OS, and (E) recurrence rate in self-expanding metallic stents versus emergency surgery for left-sided obstructive colon cancer.

ac-2024-00059-0008-Supplementary-Fig-12.pdf

Supplementary Fig. 13.

Forest plot of overall and disease-free survival in lymph node yields of more than 12 versus less than 12.

ac-2024-00059-0008-Supplementary-Fig-13.pptx

Supplementary Fig. 14.

Forest plots of (A) microsatellite instability/mismatch repair deficiency positivity, (B) positivity for revised Bethesda guidelines for Lynch syndrome in colon cancers, and (C) false-negative rate of revised Bethesda guidelines in genetically confirmed Lynch syndrome patients.

ac-2024-00059-0008-Supplementary-Fig-14.pptx

Supplementary Fig. 15.

Forest plots of progression-free survival (PFS) and overall survival (OS). (A) PFS and (B) OS according to KRAS status. (C) PFS and OS according to NRAS status. (D) PFS and OS according to BRAF status.

ac-2024-00059-0008-Supplementary-Fig-15.pdf

Supplementary Fig. 16.

Forest plots of (A) disease-free survival, (B) recurrence-free survival, (C) overall survival, and (D) adverse effects in patients receiving adjuvant chemotherapy versus no adjuvant chemotherapy for high-risk stage Ⅱ colon cancer patients.

ac-2024-00059-0008-Supplementary-Fig-16.pptx

Supplementary Fig. 17.

Forest plots of (A) overall survival and recurrence-free survival, (B) peripheral neuropathy in stage III colon cancer patients receiving 3 months versus 6 months of adjuvant chemotherapy, and (C) recurrence-free survival in patients receiving 3 months of adjuvant chemotherapy according to risk stratifications and regimens.

ac-2024-00059-0008-Supplementary-Fig-17.pdf

Supplementary Fig. 18.

Forest plots of (A) overall and progression-free survival, (B) overall response rate and grade 3 or higher adverse events, and (C) quality of life in patients with metastatic colon cancer with microsatellite instability-high/MMR protein deficiency receiving immunotherapy versus conventional chemotherapy.

ac-2024-00059-0008-Supplementary-Fig-18.pptx

Supplementary Fig. 19.

Forest plots of (A) oncologic and (B) postoperative outcomes in neoadjuvant chemotherapy followed by surgery versus upfront surgery in patients with locally advanced colon cancer.

ac-2024-00059-0008-Supplementary-Fig-19.pptx

Supplementary Fig. 20.

Forest plot of marginal recurrence and local recurrence-free survival in hepatectomy versus radiofrequency thermotherapy in patients with resectable colon cancer liver metastases.

ac-2024-00059-0008-Supplementary-Fig-20.pptx

Supplementary Fig. 21.

Forest plots of (A) oncologic outcomes and (B) postoperative complications in simultaneous versus staged resection in patients with resectable colon cancer liver metastases.

ac-2024-00059-0008-Supplementary-Fig-21.pptx

Supplementary Fig. 22.

Forest plots of (A) oncologic outcomes and (B) postoperative complications in upfront surgery versus surgery following neoadjuvant chemotherapy in patients with resectable colon cancer liver metastases.

ac-2024-00059-0008-Supplementary-Fig-22.pptx

Supplementary Fig. 23.

Forest plots of (A) overall survival and (B) median overall survival in patients with pulmonary metastasectomy with resectable colon cancer pulmonary metastases.

ac-2024-00059-0008-Supplementary-Fig-23.pptx

Supplementary Fig. 24.

Forest plots of (A) overall survival and (B) adverse events in patients with colorectal cancer peritoneal metastasis receiving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative chemotherapy.

ac-2024-00059-0008-Supplementary-Fig-24.pptx

Supplementary Fig. 25.

Forest plots of (A) overall survival and (B) adverse events in patients with colorectal cancer peritoneal metastasis receiving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone.

ac-2024-00059-0008-Supplementary-Fig-25.pptx

Supplementary Fig. 26.

Forest plots of (A) overall survival, (B) quality of life, and (C) adverse events in second-line palliative chemotherapy for metastatic colon cancer after failure of first-line palliative chemotherapy.

ac-2024-00059-0008-Supplementary-Fig-26.pptx

Supplementary materials are available from https://doi.org/10.3393/ac.2024.00059.0008.

References

1. National Cancer Information Center. Cancer in statistics [Internet]. National Cancer Information Center (Korea); c2023. [cited 2023 Oct 8]. Korean. Available from: https://www.cancer.go.kr/.
2. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018;391:1023–75.
3. Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev 2019;10:ED000142.
4. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490.
5. Moher D, Liberati A, Tetzlaff J, Altman DG, ; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6e1000097.
6. Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomized trials. BMJ 2019;366:l4898.
7. Hinneburg I. ROBINS-1: a tool andomizessing risk of bias in non-randomised studies of interventions. Med Monatsschr Pharm 2017;40:175–7.
8. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011;155:529–36.
9. Downes MJ, Brennan ML, Williams HC, Dean RS. Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS). BMJ Open 2016;6e011458.
10. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017;358:j4008.
11. Baulieu F, Bourlier P, Scotto B, Mor C, Eder V, Picon L, et al. The value of immunoscintigraphy in the detection of recurrent colorectal cancer. Nucl Med Commun 2001;22:1295–304.
12. Choi JY, Choi JS, Kim MJ, Lim JS, Park MS, Kim JH, et al. Detection of hepatic hypovascular metastases: 3D gradient echo MRI using a hepatobiliary contrast agent. J Magn Reson Imaging 2010;31:571–8.
13. Fioole B, de Haas RJ, Wicherts DA, Elias SG, Scheffers JM, van Hillegersberg R, et al. Additional value of contrast enhanced intraoperative ultrasound for colorectal liver metastases. Eur J Radiol 2008;67:169–76.
14. Haider MA, Amitai MM, Rappaport DC, O’Malley ME, Hanbidge AE, Redston M, et al. Multi-detector row helical CT in preoperative assessment of small (≤1.5 cm) liver metastases: is thinner collimation better? Radiology 2002;225:137–42.
15. Kim HJ, Kim KW, Byun JH, Won HJ, Shin YM, Kim PN, et al. Comparison of mangafodipir trisodium- and ferucarbotran-enhanced MRI for detection and characterization of hepatic metastases in colorectal cancer patients. AJR Am J Roentgenol 2006;186:1059–66.
16. Kim YK, Lee YH, Kwak HS, Kim CS, Han YM. Detection of liver metastases: gadoxetic acid-enhanced three-dimensional MR imaging versus ferucarbotran-enhanced MR imaging. Eur J Radiol 2010;73:131–6.
17. Koh DM, Brown G, Riddell AM, Scurr E, Collins DJ, Allen SD, et al. Detection of colorectal hepatic metastases using MnDPDP MR imaging and diffusion-weighted imaging (DWI) alone and in combination. Eur Radiol 2008;18:903–10.
18. Larsen LP, Rosenkilde M, Christensen H, Bang N, Bolvig L, Christiansen T, et al. Can contrast-enhanced ultrasonography replace multidetector-computed tomography in the detection of liver metastases from colorectal cancer? Eur J Radiol 2009;69:308–13.
19. Mao W, Zhou J, Qiu L, Yin H, Tan H, Shi H. The added value of dual-time-point 18F-FDG PET/CT imaging in the diagnosis of colorectal cancer liver metastases. Abdom Radiol (NY) 2020;45:1075–81.
20. Mazzoni G, Napoli A, Mandetta S, Miccini M, Cassini D, Gregori M, et al. Intra-operative ultrasound for detection of liver metastases from colorectal cancer. Liver Int 2008;28:88–94.
21. Meijerink MR, van Waesberghe JH, van der Weide L, van den Tol P, Meijer S, van Kuijk C. Total-liver-volume perfusion CT using 3-D image fusion to improve detection and characterization of liver metastases. Eur Radiol 2008;18:2345–54.
22. Schmidt J, Strotzer M, Fraunhofer S, Boedeker H, Zirngibl H. Intraoperative ultrasonography versus helical computed tomography and computed tomography with arterioportography in diagnosing colorectal liver metastases: lesion-by-lesion analysis. World J Surg 2000;24:43–8.
23. Schwartz L, Brody L, Brown K, Covey A, Tuorto S, Mazumdar M, et al. Prospective, blinded comparison of helical CT and CT arterial portography in the assessment of hepatic metastasis from colorectal carcinoma. World J Surg 2006;30:1892–901.
24. Shiozawa K, Watanabe M, Ikehara T, Matsukiyo Y, Kogame M, Kikuchi Y, et al. Comparison of contrast-enhanced ultrasonograpy with Gd-EOB-DTPA-enhanced MRI in the diagnosis of liver metastasis from colorectal cancer. J Clin Ultrasound 2017;45:138–44.
25. Soyer P, Levesque M, Caudron C, Elias D, Zeitoun G, Roche A. MRI of liver metastases from colorectal cancer vs. CT during arterial portography. J Comput Assist Tomogr 1993;17:67–74.
26. Titu LV, Breen DJ, Nicholson AA, Hartley J, Monson JR. Is routine magnetic resonance imaging justified for the early detection of resectable liver metastases from colorectal cancer? Dis Colon Rectum 2006;49:810–5.
27. Valls C, Lopez E, Gumà A, Gil M, Sanchez A, Andía E, et al. Helical CT versus CT arterial portography in the detection of hepatic metastasis of colorectal carcinoma. AJR Am J Roentgenol 1998;170:1341–7.
28. Valls C, Andía E, Sánchez A, Gumà A, Figueras J, Torras J, et al. Hepatic metastases from colorectal cancer: preoperative detection and assessment of resectability with helical CT. Radiology 2001;218:55–60.
29. Ward J, Guthrie JA, Wilson D, Arnold P, Lodge JP, Toogood GJ, et al. Colorectal hepatic metastases: detection with SPIO-enhanced breath-hold MR imaging: comparison of optimized sequences. Radiology 2003;228:709–18.
30. Akhurst T, Gönen M, Baser RE, Schwartz LH, Tuorto S, Brody LA, et al. Prospective evaluation of 18F-FDG positron emission tomography in the preoperative staging of patients with hepatic colorectal metastases. Hepatobiliary Surg Nutr 2022;11:539–54.
31. Arulampalam T, Costa D, Visvikis D, Boulos P, Taylor I, Ell P. The impact of FDG-PET on the management algorithm for recurrent colorectal cancer. Eur J Nucl Med 2001;28:1758–65.
32. Asato N, Tsurusaki M, Sofue K, Hieda Y, Katsube T, Kitajima K, et al. Comparison of gadoxetic acid-enhanced dynamic MR imaging and contrast-enhanced computed tomography for preoperative evaluation of colorectal liver metastases. Jpn J Radiol 2017;35:197–205.
33. Bartolozzi C, Donati F, Cioni D, Procacci C, Morana G, Chiesa A, et al. Detection of colorectal liver metastases: a prospective multicenter trial comparing unenhanced MRI, MnDPDP-enhanced MRI, and spiral CT. Eur Radiol 2004;14:14–20.
34. Bhattacharjya S, Bhattacharjya T, Baber S, Tibballs JM, Watkinson AF, Davidson BR. Prospective study of contrast-enhanced computed tomography, computed tomography during arterioportography, and magnetic resonance imaging for staging colorectal liver metastases for liver resection. Br J Surg 2004;91:1361–9.
35. Böhm B, Voth M, Geoghegan J, Hellfritzsch H, Petrovich A, Scheele J, et al. Impact of positron emission tomography on strategy in liver resection for primary and secondary liver tumors. J Cancer Res Clin Oncol 2004;130:266–72.
36. Coenegrachts K, De Geeter F, ter Beek L, Walgraeve N, Bipat S, Stoker J, et al. Comparison of MRI (including SS SE-EPI and SPIO-enhanced MRI) and FDG-PET/CT for the detection of colorectal liver metastases. Eur Radiol 2009;19:370–9.
37. Huguet EL, Old S, Praseedom RK, Balan KK, Gibbs P, Jamieson NV. F18-FDG-PET evaluation of patients for resection of colorectal liver metastases. Hepatogastroenterology 2007;54:1667–71.
38. Lencioni R, Donati F, Cioni D, Paolicchi A, Cicorelli A, Bartolozzi C. Detection of colorectal liver metastases: prospective comparison of unenhanced and ferumoxides-enhanced magnetic resonance imaging at 1.5 T, dual-phase spiral CT, and spiral CT during arterial portography. MAGMA 1998;7:76–87.
39. Lubezky N, Metser U, Geva R, Nakache R, Shmueli E, Klausner JM, et al. The role and limitations of 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and computerized tomography (CT) in restaging patients with hepatic colorectal metastases following neoadjuvant chemotherapy: comparison with operative and pathological findings. J Gastrointest Surg 2007;11:472–8.
40. Mainenti PP, Mancini M, Mainolfi C, Camera L, Maurea S, Manchia A, et al. Detection of colo-rectal liver metastases: prospective comparison of contrast enhanced US, multidetector CT, PET/CT, and 1.5 Tesla MR with extracellular and reticulo-endothelial cell specific contrast agents. Abdom Imaging 2010;35:511–21.
41. Motosugi U, Ichikawa T, Nakajima H, Sou H, Sano M, Sano K, et al. Imaging of small hepatic metastases of colorectal carcinoma: how to use superparamagnetic iron oxide-enhanced magnetic resonance imaging in the multidetector-row computed tomography age? J Comput Assist Tomogr 2009;33:266–72.
42. Oh JW, Oh SN, Choi JI, Choi MH, Yoo IR, Lee MA, et al. Does the gadoxetic acid-enhanced liver MRI impact on the treatment of patients with colorectal cancer? Comparison study with ¹⁸F-FDG PET/CT. Biomed Res Int 2016;2016:8412071.
43. Orlacchio A, Schillaci O, Fusco N, Broccoli P, Maurici M, Yamgoue M, et al. Role of PET/CT in the detection of liver metastases from colorectal cancer. Radiol Med 2009;114:571–85.
44. Rappeport ED, Loft A, Berthelsen AK, von der Recke P, Larsen PN, Mogensen AM, et al. Contrast-enhanced FDG-PET/CT vs. SPIO-enhanced MRI vs. FDG-PET vs. CT in patients with liver metastases from colorectal cancer: a prospective study with intraoperative confirmation. Acta Radiol 2007;48:369–78.
45. Regge D, Campanella D, Anselmetti GC, Cirillo S, Gallo TM, Muratore A, et al. Diagnostic accuracy of portal-phase CT and MRI with mangafodipir trisodium in detecting liver metastases from colorectal carcinoma. Clin Radiol 2006;61:338–47.
46. Rojas Llimpe FL, Di Fabio F, Ercolani G, Giampalma E, Cappelli A, Serra C, et al. Imaging in resectable colorectal liver metastasis patients with or without preoperative chemotherapy: results of the PROMETEO-01 study. Br J Cancer 2014;111:667–73.
47. Ruers TJ, Langenhoff BS, Neeleman N, Jager GJ, Strijk S, Wobbes T, et al. Value of positron emission tomography with [F-18]fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study. J Clin Oncol 2002;20:388–95.
48. Schulz A, Joelsen-Hatlehol ES, Brudvik KW, Aasand KK, Hanekamp B, Viktil E, et al. Preoperative detection of colorectal liver metastases: DWI alone or combined with MDCT is no substitute for Gd-EOB-DTPA-enhanced MRI. Acta Radiol 2020;61:302–11.
49. Selzner M, Hany TF, Wildbrett P, McCormack L, Kadry Z, Clavien PA. Does the novel PET/CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg 2004;240:1027–36.
50. Sivesgaard K, Larsen LP, Sørensen M, Kramer S, Schlander S, Amanavicius N, et al. Diagnostic accuracy of CE-CT, MRI and FDG PET/CT for detecting colorectal cancer liver metastases in patients considered eligible for hepatic resection and/or local ablation. Eur Radiol 2018;28:4735–47.
51. Strotzer M, Gmeinwieser J, Schmidt J, Fellner C, Seitz J, Albrich H, et al. Diagnosis of liver metastases from colorectal adenocarcinoma: comparison of spiral-CTAP combined with intravenous contrast-enhanced spiral-CT and SPIO-enhanced MR combined with plain MR imaging. Acta Radiol 1997;38:986–92.
52. Truant S, Huglo D, Hebbar M, Ernst O, Steinling M, Pruvot FR. Prospective evaluation of the impact of [18F]fluoro-2-deoxy-D-glucose positron emission tomography of resectable colorectal liver metastases. Br J Surg 2005;92:362–9.
53. Valk PE, Abella-Columna E, Haseman MK, Pounds TR, Tesar RD, Myers RW, et al. Whole-body PET imaging with [18F]fluorodeoxyglucose in management of recurrent colorectal cancer. Arch Surg 1999;134:503–13.
54. Ward J, Naik KS, Guthrie JA, Wilson D, Robinson PJ. Hepatic lesion detection: comparison of MR imaging after the administration of superparamagnetic iron oxide with dual-phase CT by using alternative-free response receiver operating characteristic analysis. Radiology 1999;210:459–66.
55. Yamada S, Kishi Y, Miyake M, Nara S, Esaki M, Shimada K. Characteristics of false-positive lesions in evaluating colorectal liver metastases on gadoxetic acid-enhanced magnetic resonance imaging. Surg Today 2022;52:1178–84.
56. Zhou N, Guo X, Sun H, Yu B, Zhu H, Li N, et al. The value of 18F-FDG PET/CT and abdominal PET/MRI as a one-stop protocol in patients with potentially resectable colorectal liver metastases. Front Oncol 2021;11:714948.
57. Akiyoshi T, Oya M, Fujimoto Y, Kuroyanagi H, Ueno M, Yamaguchi T, et al. Comparison of preoperative whole-body positron emission tomography with MDCT in patients with primary colorectal cancer. Colorectal Dis 2009;11:464–9.
58. Arulampalam TH, Francis DL, Visvikis D, Taylor I, Ell PJ. FDG-PET for the pre-operative evaluation of colorectal liver metastases. Eur J Surg Oncol 2004;30:286–91.
59. Bonanni L, de’Liguori Carino N, Deshpande R, Ammori BJ, Sherlock DJ, Valle JW, et al. A comparison of diagnostic imaging modalities for colorectal liver metastases. Eur J Surg Oncol 2014;40:545–50.
60. Briggs RH, Chowdhury FU, Lodge JP, Scarsbrook AF. Clinical impact of FDG PET-CT in patients with potentially operable metastatic colorectal cancer. Clin Radiol 2011;66:1167–74.
61. Cipe G, Ergul N, Hasbahceci M, Firat D, Bozkurt S, Memmi N, et al. Routine use of positron-emission tomography/computed tomography for staging of primary colorectal cancer: does it affect clinical management? World J Surg Oncol 2013;11:49.
62. Engelmann BE, Loft A, Kjaer A, Nielsen HJ, Berthelsen AK, Binderup T, et al. Positron emission tomography/computed tomography for optimized colon cancer staging and follow up. Scand J Gastroenterol 2014;49:191–201.
63. Fong Y, Saldinger PF, Akhurst T, Macapinlac H, Yeung H, Finn RD, et al. Utility of 18F-FDG positron emission tomography scanning on selection of patients for resection of hepatic colorectal metastases. Am J Surg 1999;178:282–7.
64. Georgakopoulos A, Pianou N, Kelekis N, Chatziioannou S. Impact of 18F-FDG PET/CT on therapeutic decisions in patients with colorectal cancer and liver metastases. Clin Imaging 2013;37:536–41.
65. Joyce DL, Wahl RL, Patel PV, Schulick RD, Gearhart SL, Choti MA. Preoperative positron emission tomography to evaluate potentially resectable hepatic colorectal metastases. Arch Surg 2006;141:1220–7.
66. Lai DT, Fulham M, Stephen MS, Chu KM, Solomon M, Thompson JF, et al. The role of whole-body positron emission tomography with [18F]fluorodeoxyglucose in identifying operable colorectal cancer metastases to the liver. Arch Surg 1996;131:703–7.
67. Lake ES, Wadhwani S, Subar D, Kauser A, Harris C, Chang D, et al. The influence of FDG PET-CT on the detection of extrahepatic disease in patients being considered for resection of colorectal liver metastasis. Ann R Coll Surg Engl 2014;96:211–5.
68. Lee JH, Lee MR. Positron emission tomography/computed tomography in the staging of colon cancer. Ann Coloproctol 2014;30:23–7.
69. Moulton CA, Gu CS, Law CH, Tandan VR, Hart R, Quan D, et al. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA 2014;311:1863–9.
70. Petersen RK, Hess S, Alavi A, Høilund-Carlsen PF. Clinical impact of FDG-PET/CT on colorectal cancer staging and treatment strategy. Am J Nucl Med Mol Imaging 2014;4:471–82.
71. Sasaki K, Kawasaki H, Sato M, Koyama K, Yoshimi F, Nagai H. Impact of fluorine-18 2-fluoro-2-deoxy-d-glucose uptake on preoperative positron emission tomography/computed tomography in the lymph nodes of patients with primary colorectal cancer. Dig Surg 2017;34:60–7.
72. Schüssler-Fiorenza CM, Mahvi DM, Niederhuber J, Rikkers LF, Weber SM. Clinical risk score correlates with yield of PET scan in patients with colorectal hepatic metastases. J Gastrointest Surg 2004;8:150–8.
73. Wiering B, Ruers TJ, Krabbe PF, Dekker HM, Oyen WJ. Comparison of multiphase CT, FDG-PET and intra-operative ultrasound in patients with colorectal liver metastases selected for surgery. Ann Surg Oncol 2007;14:818–26.
74. Wiering B, Adang EM, van der Sijp JR, Roumen RM, de Jong KP, Comans EF, et al. Added value of positron emission tomography imaging in the surgical treatment of colorectal liver metastases. Nucl Med Commun 2010;31:938–44.
75. Zhuang H, Sinha P, Pourdehnad M, Duarte PS, Yamamoto AJ, Alavi A. The role of positron emission tomography with fluorine-18-deoxyglucose in identifying colorectal cancer metastases to liver. Nucl Med Commun 2000;21:793–8.
76. Fenlon HM, McAneny DB, Nunes DP, Clarke PD, Ferrucci JT. Occlusive colon carcinoma: virtual colonoscopy in the preoperative evaluation of the proximal colon. Radiology 1999;210:423–8.
77. Flor N, Ceretti AP, Luigiano C, Brambillasca P, Savoldi AP, Verrusio C, et al. Performance of CT colonography in diagnosis of synchronous colonic lesions in patients with occlusive colorectal cancer. AJR Am J Roentgenol 2020;214:348–54.
78. Heo JH, Ryu CG, Jung EJ, Paik JH, Hwang DY. Clinical significance of preoperative virtual colonoscopy for evaluation of the proximal colon in patient with obstructive colorectal cancer. Ann Coloproctol 2017;33:130–3.
79. Hojo D, Tanaka T, Takahashi M, Murono K, Emoto S, Kaneko M, et al. Efficacy of 18-fluoro deoxy glucose-positron emission tomography computed tomography for the detection of colonic neoplasia proximal to obstructing colorectal cancer. Medicine (Baltimore) 2018;97e11655.
80. Horvat N, Raj A, Ward JM, Smith JJ, Markowitz AJ, Gollub MJ. Clinical value of CT colonography versus preoperative colonoscopy in the surgical management of occlusive colorectal cancer. AJR Am J Roentgenol 2018;210:333–40.
81. Huisman JF, Leicher LW, de Boer E, van Westreenen HL, de Groot JW, Holman FA, et al. Consequences of CT colonography in stenosing colorectal cancer. Int J Colorectal Dis 2017;32:367–73.
82. Kim JH, Kim WH, Kim TI, Kim NK, Lee KY, Kim MJ, et al. Incomplete colonoscopy in patients with occlusive colorectal cancer: usefulness of CT colonography according to tumor location. Yonsei Med J 2007;48:934–41.
83. Kim JS, Lee KM, Kim SW, Kim EJ, Lim CH, Oh ST, et al. Preoperative colonoscopy through the colonic stent in patients with colorectal cancer obstruction. World J Gastroenterol 2014;20:10570–6.
84. Kim CW, Lee JL, Yoon YS, Park IJ, Lim SB, Yu CS, et al. Resection after preoperative chemotherapy versus synchronous liver resection of colorectal cancer liver metastases: a propensity score matching analysis. Medicine (Baltimore) 2017;96e6174.
85. Lim SG, Lee KJ, Suh KW, Oh SY, Kim SS, Yoo JH, et al. Preoperative colonoscopy for detection of synchronous neoplasms after insertion of self-expandable metal stents in occlusive colorectal cancer: comparison of covered and uncovered stents. Gut Liver 2013;7:311–6.
86. Maeda C, Endo S, Mori Y, Mukai S, Hidaka E, Ishida F, et al. The ability of positron emission tomography/computed tomography to detect synchronous colonic cancers in patients with obstructive colorectal cancer. Mol Clin Oncol 2019;10:425–9.
87. Nagata K, Ota Y, Okawa T, Endo S, Kudo SE. PET/CT colonography for the preoperative evaluation of the colon proximal to the obstructive colorectal cancer. Dis Colon Rectum 2008;51:882–90.
88. Offermans T, Vogelaar FJ, Aquarius M, Janssen-Heijnen ML, Simons PC. The added clinical value of performing CT colonography in patients with obstructing colorectal carcinoma. Gastroenterol Rep (Oxf) 2018;6:210–4.
89. Park SH, Lee JH, Lee SS, Kim JC, Yu CS, Kim HC, et al. CT colonography for detection andomized tionation of synchronous proximal colonic lesions in patients with stenosing colorectal cancer. Gut 2012;61:1716–22.
90. Sánchez-Izquierdo N, Pagès M, Mayoral M, Rubello D, Colletti PM, Campos F, et al. PET/CT integrated with CT colonography in preoperative obstructive colorectal cancer by incomplete optical colonoscopy: a prospective study. Clin Nucl Med 2020;45:943–7.
91. Vitale MA, Villotti G, d’Alba L, Frontespezi S, Iacopini F, Iacopini G. Preoperative colonoscopy after self-expandable metallic stent placement in patients with acute neoplastic colon obstruction. Gastrointest Endosc 2006;63:814–9.
92. Akishima-Fukasawa Y, Ishikawa Y, Akasaka Y, Uzuki M, Inomata N, Yokoo T, et al. Histopathological predictors of regional lymph node metastasis at the invasive front in early colorectal cancer. Histopathology 2011;59:470–81.
93. Bae HJ, Ju H, Lee HH, Kim J, Lee BI, Lee SH, et al. Long-term outcomes after endoscopic versus surgical resection of T1 colorectal carcinoma. Surg Endosc 2023;37:1231–41.
94. Barel F, Cariou M, Saliou P, Kermarrec T, Auffret A, Samaison L, et al. Histopathological factors help to predict lymph node metastases more efficiently than extra-nodal recurrences in submucosa invading pT1 colorectal cancer. Sci Rep 2019;9:8342.
95. Benizri EI, Bereder JM, Rahili A, Bernard JL, Vanbiervliet G, Filippi J, et al. Additional colectomy after colonoscopic polypectomy for T1 colon cancer: a fine balance between oncologic benefit and operative risk. Int J Colorectal Dis 2012;27:1473–8.
96. Egashira Y, Yoshida T, Hirata I, Hamamoto N, Akutagawa H, Takeshita A, et al. Analysis of pathological risk factors for lymph node metastasis of submucosal invasive colon cancer. Mod Pathol 2004;17:503–11.
97. Ha RK, Han KS, Sohn DK, Kim BC, Hong CW, Chang HJ, et al. Histopathologic risk factors for lymph node metastasis in patients with T1 colorectal cancer. Ann Surg Treat Res 2017;93:266–71.
98. Han J, Hur H, Min BS, Lee KY, Kim NK. Predictive factors for lymph node metastasis in submucosal invasive colorectal carcinoma: a new proposal of depth of invasion for radical surgery. World J Surg 2018;42:2635–41.
99. Ji X, Kang M, Zhao X, Li X, Guo Y, Xie P, et al. Poorly differentiated cluster grade-a vital predictor for lymph node metastasis and oncological outcomes in patients with T1 colorectal cancer: a retrospective study. BMC Gastroenterol 2022;22:409.
100. Kim B, Kim EH, Park SJ, Cheon JH, Kim TI, Kim WH, et al. The risk of lymph node metastasis makes it unsafe to expand the conventional indications for endoscopic treatment of T1 colorectal cancer: a retrospective study of 428 patients. Medicine (Baltimore) 2016;95e4373.
101. Kitajima K, Fujimori T, Fujii S, Takeda J, Ohkura Y, Kawamata H, et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol 2004;39:534–43.
102. Lee SJ, Kim A, Kim YK, Park WY, Kim HS, Jo HJ, et al. The significance of tumor budding in T1 colorectal carcinoma: the most reliable predictor of lymph node metastasis especially in endoscopically resected T1 colorectal carcinoma. Hum Pathol 2018;78:8–17.
103. Martínez Vila C, Oliveres Montero de Novoa H, Martínez-Bauer E, Serra-Aracil X, Mora L, Casalots-Casado A, et al. A real world analysis of recurrence risk factors for early colorectal cancer T1 treated with standard endoscopic resection. Int J Colorectal Dis 2020;35:921–7.
104. Masaki T, Muto T. Predictive value of histology at the invasive margin in the prognosis of early invasive colorectal carcinoma. J Gastroenterol 2000;35:195–200.
105. Miyachi H, Kudo SE, Ichimasa K, Hisayuki T, Oikawa H, Matsudaira S, et al. Management of T1 colorectal cancers after endoscopic treatment based on the risk stratification of lymph node metastasis. J Gastroenterol Hepatol 2016;31:1126–32.
106. Naffouje SA, Lauwers G, Klapman J, Dam A, Pena L, Friedman M, et al. Malignant colon polyps: predicting lymph node metastasis following endoscopic excision. Int J Colorectal Dis 2022;37:393–402.
107. Nakadoi K, Tanaka S, Kanao H, Terasaki M, Takata S, Oka S, et al. Management of T1 colorectal carcinoma with special reference to criteria for curative endoscopic resection. J Gastroenterol Hepatol 2012;27:1057–62.
108. Nakadoi K, Oka S, Tanaka S, Hayashi N, Terasaki M, Arihiro K, et al. Condition of muscularis mucosae is a risk factor for lymph node metastasis in T1 colorectal carcinoma. Surg Endosc 2014;28:1269–76.
109. Nakajo K, Tamura S, Hiroi M, Onishi S, Yasuda N. Evaluation of the risk factors of lymph node metastasis in pT1 stage colorectal carcinoma: Indication for an endoscopic mucosal resection. Dig Endosc 2007;19:174–9.
110. Nishida T, Egashira Y, Akutagawa H, Fujii M, Uchiyama K, Shibayama Y, et al. Predictors of lymph node metastasis in T1 colorectal carcinoma: an immunophenotypic analysis of 265 patients. Dis Colon Rectum 2014;57:905–15.
111. Nishimura T, Oka S, Tanaka S, Asayama N, Nagata S, Tamaru Y, et al. Clinical significance of immunohistochemical lymphovascular evaluation to determine additional surgery after endoscopic submucosal dissection for colorectal T1 carcinoma. Int J Colorectal Dis 2021;36:949–58.
112. Ozeki T, Shimura T, Ozeki T, Ebi M, Iwasaki H, Kato H, et al. The risk analyses of lymph node metastasis and recurrence for submucosal invasive colorectal cancer: novel criteria to skip completion surgery. Cancers (Basel) 2022;14:822.
113. Sakuragi M, Togashi K, Konishi F, Koinuma K, Kawamura Y, Okada M, et al. Predictive factors for lymph node metastasis in T1 stage colorectal carcinomas. Dis Colon Rectum 2003;46:1626–32.
114. Samuolis N, Samalavicius NE, Dulskas A, Markelis R, Lunevicius R, Mickys U, et al. Surgical or endoscopic management of malignant colon polyps. ANZ J Surg 2018;88:E824–8.
115. Suh JH, Han KS, Kim BC, Hong CW, Sohn DK, Chang HJ, et al. Predictors for lymph node metastasis in T1 colorectal cancer. Endoscopy 2012;44:590–5.
116. Suh JP, Youk EG, Lee EJ, Lee JB, Lee IT, Lee DS, et al. Endoscopic submucosal dissection for nonpedunculated submucosal invasive colorectal cancer: is it feasible? Eur J Gastroenterol Hepatol 2013;25:1051–9.
117. Tominaga K, Nakanishi Y, Nimura S, Yoshimura K, Sakai Y, Shimoda T. Predictive histopathologic factors for lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma. Dis Colon Rectum 2005;48:92–100.
118. Yamamoto S, Watanabe M, Hasegawa H, Baba H, Yoshinare K, Shiraishi J, et al. The risk of lymph node metastasis in T1 colorectal carcinoma. Hepatogastroenterology 2004;51:998–1000.
119. Yasuda K, Inomata M, Shiromizu A, Shiraishi N, Higashi H, Kitano S. Risk factors for occult lymph node metastasis of colorectal cancer invading the submucosa and indications for endoscopic mucosal resection. Dis Colon Rectum 2007;50:1370–6.
120. Agalianos C, Gouvas N, Dervenis C, Tsiaoussis J, Theodoropoulos G, Theodorou D, et al. Is complete mesocolic excision oncologically superior to conventional surgery for colon cancer? A retrospective comparative study. Ann Gastroenterol 2017;30:688–96.
121. An MS, Baik H, Oh SH, Park YH, Seo SH, Kim KH, et al. Oncological outcomes of complete versus conventional mesocolic excision in laparoscopic right hemicolectomy. ANZ J Surg 2018;88:E698–702.
122. Bertelsen CA, Neuenschwander AU, Jansen JE, Tenma JR, Wilhelmsen M, Kirkegaard-Klitbo A, et al. 5-year outcome after complete mesocolic excision for right-sided colon cancer: a population-based cohort study. Lancet Oncol 2019;20:1556–65.
123. Galizia G, Lieto E, De Vita F, Ferraraccio F, Zamboli A, Mabilia A, et al. Is complete mesocolic excision with central vascular ligation safe and effective in the surgical treatment of right-sided colon cancers? A prospective study. Int J Colorectal Dis 2014;29:89–97.
124. Lieto E, Abdelkhalek M, Orditura M, Denewer A, Castellano P, Youssef TF, et al. Propensity score-matched comparison between complete mesocolic excision and classic right hemicolectomy for colon cancer. Minerva Chir 2018;73:1–12.
125. Ouyang M, Luo Z, Wu J, Zhang W, Tang S, Lu Y, et al. Comparison of outcomes of complete mesocolic excision with conventional radical resection performed by laparoscopic approach for right colon cancer. Cancer Manag Res 2019;11:8647–56.
126. Sammour T, Malakorn S, Thampy R, Kaur H, Bednarski BK, Messick CA, et al. Selective central vascular ligation (D3 lymphadenectomy) in patients undergoing minimally invasive complete mesocolic excision for colon cancer: optimizing the risk-benefit equation. Colorectal Dis 2020;22:53–61.
127. Tümay LV, Güner OS, Batı İB, Zorluoğlu A. Is complete mesocolic excision technique superior to conventional hemicolectomy technique for patients with right-sided colon cancer? Preliminary findings from a single-center retrospective analysis. Turk J Colorectal Dis 2020;30:301–10.
128. Zurleni T, Cassiano A, Gjoni E, Ballabio A, Serio G, Marzoli L, et al. Surgical and oncological outcomes after complete mesocolic excision in right-sided colon cancer compared with conventional surgery: a retrospective, single-institution study. Int J Colorectal Dis 2018;33:1–8.
129. Amelung FJ, Consten EC, Siersema PD, Tanis PJ. A population-based analysis of three treatment modalities for malignant obstruction of the proximal colon: acute resection versus stent or stoma as a bridge to surgery. Ann Surg Oncol 2016;23:3660–8.
130. Amelung FJ, Draaisma WA, Consten EC, Siersema PD, Ter Borg F. Self-expandable metal stent placement versus emergency resection for malignant proximal colon obstructions. Surg Endosc 2017;31:4532–41.
131. van den Berg MW, Sloothaak DA, Dijkgraaf MG, van der Zaag ES, Bemelman WA, Tanis PJ, et al. Bridge-to-surgery stent placement versus emergency surgery for acute malignant colonic obstruction. Br J Surg 2014;101:867–73.
132. Ji WB, Kwak JM, Kang DW, Kwak HD, Um JW, Lee SI, et al. Clinical benefits and oncologic equivalence of self-expandable metallic stent insertion for right-sided malignant colonic obstruction. Surg Endosc 2017;31:153–8.
133. Kye BH, Lee YS, Cho HM, Kim JG, Oh ST, Lee IK, et al. Comparison of long-term outcomes between emergency surgery and bridge to surgery for malignant obstruction in right-sided colon cancer: a multicenter retrospective study. Ann Surg Oncol 2016;23:1867–74.
134. Li B, Cai SL, Lv ZT, Zhou PH, Yao LQ, Shi Q, et al. Self-expandable metallic stenting as a bridge to elective surgery versus emergency surgery for acute malignant right-sided colorectal obstruction. BMC Surg 2020;20:326.
135. Morita S, Yamamoto K, Ogawa A, Naito A, Mizuno H, Yoshioka S, et al. Benefits of using a self-expandable metallic stent as a bridge to surgery for right- and left-sided obstructive colorectal cancers. Surg Today 2019;49:32–7.
136. Sakamoto T, Fujiogi M, Lefor AK, Matsui H, Fushimi K, Yasunaga H. Stent as a bridge to surgery or immediate colectomy for malignant right colonic obstruction: propensity-scored, national database study. Br J Surg 2020;107:1354–62.
137. Alcántara M, Serra-Aracil X, Falcó J, Mora L, Bombardó J, Navarro S. Prospective, controlled, randomized study of intraoperative colonic lavage versus stent placement in obstructive left-sided colonic cancer. World J Surg 2011;35:1904–10.
138. Arezzo A, Balague C, Targarona E, Borghi F, Giraudo G, Ghezzo L, et al. Colonic stenting as a bridge to surgery versus emergency surgery for malignant colonic obstruction: results of a multicentre randomized controlled trial (ESCO trial). Surg Endosc 2017;31:3297–305.
139. Arezzo A, Forcignanò E, Bonino MA, Balagué C, Targarona E, Borghi F, et al. Long-term oncologic results after stenting as a bridge to surgery versus emergency surgery for malignant left-sided colonic obstruction: a multicenter randomized controlled trial (esco trial). Ann Surg 2020;272:703–8.
140. Cheung HY, Chung CC, Tsang WW, Wong JC, Yau KK, Li MK. Endolaparoscopic approach vs conventional open surgery in the treatment of obstructing left-sided colon cancer: a randomized controlled trial. Arch Surg 2009;144:1127–32.
141. CReST Collaborative Group. Colorectal Endoscopic Stenting Trial (CReST) for obstructing left-sided colorectal cancer: randomized clinical trial. Br J Surg 2022;109:1073–80.
142. Ghazal AH, El-Shazly WG, Bessa SS, El-Riwini MT, Hussein AM. Colonic endolumenal stenting devices and elective surgery versus emergency subtotal/total colectomy in the management of malignant obstructed left colon carcinoma. J Gastrointest Surg 2013;17:1123–9.
143. Ho KS, Quah HM, Lim JF, Tang CL, Eu KW. Endoscopic stenting and elective surgery versus emergency surgery for left-sided malignant colonic obstruction: a prospective randomized trial. Int J Colorectal Dis 2012;27:355–62.
144. Pirlet IA, Slim K, Kwiatkowski F, Michot F, Millat BL. Emergency preoperative stenting versus surgery for acute left-sided malignant colonic obstruction: a multicenter randomized controlled trial. Surg Endosc 2011;25:1814–21.
145. Sloothaak DA, van den Berg MW, Dijkgraaf MG, Fockens P, Tanis PJ, van Hooft JE, et al. Oncological outcome of malignant colonic obstruction in the Dutch Stent-In 2 trial. Br J Surg 2014;101:1751–7.
146. Tung KL, Cheung HY, Ng LW, Chung CC, Li MK. Endo-laparoscopic approach versus conventional open surgery in the treatment of obstructing left-sided colon cancer: long-term follow-up of a randomized trial. Asian J Endosc Surg 2013;6:78–81.
147. van Hooft JE, Bemelman WA, Oldenburg B, Marinelli AW, Lutke Holzik MF, Grubben MJ, et al. Colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction: a multicentre randomised trial. Lancet Oncol 2011;12:344–52.
148. Gorissen KJ, Tuynman JB, Fryer E, Wang L, Uberoi R, Jones OM, et al. Local recurrence after stenting for obstructing left-sided colonic cancer. Br J Surg 2013;100:1805–9.
149. Lara-Romero C, Vilches Á, Caunedo-Álvarez Á, Hergueta-Delgado P, Lavín-Castejón I, Andrade-Bellido R, et al. Better recurrence-free survival after stent bridge to surgery compared to emergency surgery for obstructive left-sided colonic cancer in patients with stage III status of the American Joint Committee on Cancer (AJCC): a bicentric retrospective study. Int J Colorectal Dis 2019;34:1241–50.
150. Lovero R, Losurdo G, La Fortezza RF, Spirito F, Di Leo A, Andriulli A, et al. Endoscopic stenting for colorectal cancer obstruction as a bridge-to-surgery strategy. Eur J Clin Invest 2020;e13252.
151. Recuenco CB, Septiem JG, Díaz JA, Vasallo IJ, de la Madriz AA, Carneros VJ, et al. Effect of self-expandable metal stent on morbidity and mortality and oncological prognosis in malignant colonic obstruction: retrospective analysis of its use as curative and palliative treatment. Int J Colorectal Dis 2022;37:475–84.
152. Rodrigues-Pinto E, Morais R, Coelho C, Pereira P, Repici A, Macedo G. Bridge-to-surgery versus emergency surgery in the management of left-sided acute malignant colorectal obstruction: efficacy, safety and long-term outcomes. Dig Liver Dis 2019;51:364–72.
153. Tanis PJ, Paulino Pereira NR, van Hooft JE, Consten EC, Bemelman WA, ; Dutch Surgical Colorectal Audit. Resection of obstructive left-sided colon cancer at a national level: a prospective analysis of short-term outcomes in 1,816 patients. Dig Surg 2015;32:317–24.
154. Bilimoria KY, Palis B, Stewart AK, Bentrem DJ, Freel AC, Sigurdson ER, et al. Impact of tumor location on nodal evaluation for colon cancer. Dis Colon Rectum 2008;51:154–61.
155. Bui L, Rempel E, Reeson D, Simunovic M. Lymph node counts, rates of positive lymph nodes, and patient survival for colon cancer surgery in Ontario, Canada: a population-based study. J Surg Oncol 2006;93:439–45.
156. Cai Y, Cheng G, Lu X, Ju H, Zhu X. The re-evaluation of optimal lymph node yield in stage II right-sided colon cancer: is a minimum of 12 lymph nodes adequate? Int J Colorectal Dis 2020;35:623–31.
157. Johnson PM, Porter GA, Ricciardi R, Baxter NN. Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 2006;24:3570–5.
158. Lee CH, Wilkins S, Oliva K, Staples MP, McMurrick PJ. Role of lymph node yield and lymph node ratio in predicting outcomes in non-metastatic colorectal cancer. BJS Open 2018;3:95–105.
159. Moore J, Hyman N, Callas P, Littenberg B. Staging error does not explain the relationship between the number of lymph nodes in a colon cancer specimen and survival. Surgery 2010;147:358–65.
160. Prandi M, Lionetto R, Bini A, Francioni G, Accarpio G, Anfossi A, et al. Prognostic evaluation of stage B colon cancer patients is improved by an adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg 2002;235:458–63.
161. Swanson RS, Compton CC, Stewart AK, Bland KI. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10:65–71.
162. Trepanier M, Erkan A, Kouyoumdjian A, Nassif G, Albert M, Monson J, et al. Examining the relationship between lymph node harvest and survival in patients undergoing colectomy for colon adenocarcinoma. Surgery 2019;166:639–47.
163. Wang J, Kulaylat M, Rockette H, Hassett J, Rajput A, Dunn KB, et al. Should total number of lymph nodes be used as a quality of care measure for stage III colon cancer? Ann Surg 2009;249:559–63.
164. Xu Z, Berho ME, Becerra AZ, Aquina CT, Hensley BJ, Arsalanizadeh R, et al. Lymph node yield is an independent predictor of survival in rectal cancer regardless of receipt of neoadjuvant therapy. J Clin Pathol 2017;70:584–92.
165. Furukawa T, Konishi F, Shitoh K, Kojima M, Nagai H, Tsukamoto T. Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma. Cancer 2002;94:911–20.
166. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352:1851–60.
167. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–8.
168. Jiang W, Cai MY, Li SY, Bei JX, Wang F, Hampel H, et al. Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: high prevalence and unique molecular features. Int J Cancer 2019;144:2161–8.
169. Julié C, Trésallet C, Brouquet A, Vallot C, Zimmermann U, Mitry E, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 2008;103:2825–35.
170. Keränen A, Ghazi S, Carlson J, Papadogiannakis N, Lagerstedt-Robinson K, Lindblom A. Testing strategies to reduce morbidity and mortality from Lynch syndrome. Scand J Gastroenterol 2018;53:1535–40.
171. Kim MH, Kim DW, Lee HS, Bang SK, Seo SH, Park KU, et al. Universal screening for Lynch syndrome compared with pedigree-based screening: 10-year experience in a tertiary hospital. Cancer Res Treat 2023;55:179–88.
172. Musulén E, Sanz C, Muñoz-Mármol AM, Ariza A. Mismatch repair protein immunohistochemistry: a useful population screening strategy for Lynch syndrome. Hum Pathol 2014;45:1388–96.
173. Pérez-Carbonell L, Ruiz-Ponte C, Guarinos C, Alenda C, Payá A, Brea A, et al. Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer. Gut 2012;61:865–72.
174. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663–71.
175. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–705.
176. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013;369:1023–34.
177. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757–65.
178. Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29:2011–9.
179. Kaczirek K, Ciuleanu TE, Vrbanec D, Marton E, Messinger D, Liegl-Atzwanger B, et al. FOLFOX4 plus cetuximab for patients with previously untreated metastatic colorectal cancer according to tumor RAS and BRAF mutation status: updated analysis of the CECOG/CORE 1.2.002 study. Clin Colorectal Cancer 2015;14:91–8.
180. Rouyer M, François E, Sa Cunha A, Monnereau A, Bignon E, Jové J, et al. Effectiveness of first-line cetuximab in wild-type RAS metastatic colorectal cancer according to tumour BRAF mutation status from the EREBUS cohort. Br J Clin Pharmacol 2021;87:1120–8.
181. Casadaban L, Rauscher G, Aklilu M, Villenes D, Freels S, Maker AV. Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer. Cancer 2016;122:3277–87.
182. Jalaeikhoo H, Zokaasadi M, Khajeh-Mehrizi A, Rajaeinejad M, Mousavi SA, Vaezi M, et al. Effectiveness of adjuvant chemotherapy in patients with stage II colorectal cancer: a multicenter retrospective study. J Res Med Sci 2019;24:39.
183. Kim MK, Won DD, Park SM, Kim T, Kim SR, Oh ST, et al. Effect of adjuvant chemotherapy on stage II colon cancer: Analysis of Korean national data. Cancer Res Treat 2018;50:1149–63.
184. Kumar A, Kennecke HF, Renouf DJ, Lim HJ, Gill S, Woods R, et al. Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. Cancer 2015;121:527–34.
185. O’Connor ES, Greenblatt DY, LoConte NK, Gangnon RE, Liou JI, Heise CP, et al. Adjuvant chemotherapy for stage II colon cancer with poor prognostic features. J Clin Oncol 2011;29:3381–8.
186. Sadahiro S, Sakamoto K, Tsuchiya T, Takahashi T, Ohge H, Sato T, et al. Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201). BMC Cancer 2022;22:170.
187. Verhoeff SR, van Erning FN, Lemmens VE, de Wilt JH, Pruijt JF. Adjuvant chemotherapy is not associated with improved survival for all high-risk factors in stage II colon cancer. Int J Cancer 2016;139:187–93.
188. André T, Meyerhardt J, Iveson T, Sobrero A, Yoshino T, Souglakos I, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials. Lancet Oncol 2020;21:1620–9.
189. Iveson T, Kerr R, Saunders MP, Hollander NH, Tabernero J, Haydon AM, et al. Final DFS results of the SCOT study: an international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer. J Clin Oncol 2017;35:3502.
190. Sobrero A, Lonardi S, Rosati G, Di Bartolomeo M, Ronzoni M, Pella N, et al. FOLFOX or CAPOX in stage II to III colon cancer: efficacy results of the Italian three or six colon adjuvant trial. J Clin Oncol 2018;36:1478–85.
191. Souglakos J, Boukovinas I, Kakolyris S, Ziras N, Androulakis NE, Ardavanis A, et al. The Greek participitation to IDEA (International Duration Evaluation of Adjuvant Chemotherapy) study of 3 versus 6 months of adjuvant chemotherapy in stage III colon cancer: patients’ characteristics and safety analysis. J Clin Oncol 2017;35:740.
192. Yoshino T, Yamanaka T, Oki E, Kotaka M, Manaka D, Eto T, et al. Efficacy and long-term peripheral sensory neuropathy of 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy for colon cancer: the ACHIEVE phase 3 randomized clinical trial. JAMA Oncol 2019;5:1574–81.
193. Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, et al. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:665–77.
194. Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022;23:659–70.
195. Le DT, Diaz LA Jr, Kim TW, Van Cutsem E, Geva R, Jäger D, et al. Pembrolizumab for previously treated, microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Eur J Cancer 2023;186:185–95.
196. Morton D, Seymour M, Magill L, Handley K, Glasbey J, Glimelius B, et al. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J Clin Oncol 2023;41:1541–52.
197. Boudjema K, Locher C, Sabbagh C, Ortega-Deballon P, Heyd B, Bachellier P, et al. Simultaneous versus delayed resection for initially resectable synchronous colorectal cancer liver metastases: a prospective, open-label, randomized, controlled trial. Ann Surg 2021;273:49–56.
198. Fei F, Zhou Z, Shen Y, Su Z. Comparison of the effects and prognosis of concurrent and staged resections for the treatment of resectable colorectal cancer liver metastasis. Am J Transl Res 2021;13:3634–41.
199. Aloia TA, Vauthey JN, Loyer EM, Ribero D, Pawlik TM, Wei SH, et al. Solitary colorectal liver metastasis: resection determines outcome. Arch Surg 2006;141:460–7.
200. Chen FL, Wang YY, Liu W, Xing BC. Neoadjuvant chemotherapy improves overall survival in resectable colorectal liver metastases patients with high clinical risk scores: a retrospective, propensity score matching analysis. Front Oncol 2022;12:973418.
201. Hirokawa F, Ueno M, Nakai T, Kaibori M, Nomi T, Iida H, et al. Neoadjuvant chemotherapy versus upfront surgery for resectable liver metastases from colorectal cancer: a multicenter, propensity score-matched cohort study. J Gastrointest Surg 2022;26:772–81.
202. Kawaguchi D, Hiroshima Y, Matsuo K, Endo I, Koda K, Tanaka K. Hepatic resection after prehepatectomy chemotherapy for metastatic colorectal cancer: a propensity-matched analysis. Anticancer Res 2016;36:4725–30.
203. Lee BC, Lee HG, Park IJ, Kim SY, Kim KH, Lee JH, et al. The role of radiofrequency ablation for treatment of metachronous isolated hepatic metastasis from colorectal cancer. Medicine (Baltimore) 2016;95e4999.
204. Moug SJ, Smith D, Leen E, Roxburgh C, Horgan PG. Evidence for a synchronous operative approach in the treatment of colorectal cancer with hepatic metastases: a case matched study. Eur J Surg Oncol 2010;36:365–70.
205. Park IJ, Kim HC, Yu CS, Kim PN, Won HJ, Kim JC. Radiofrequency ablation for metachronous liver metastasis from colorectal cancer after curative surgery. Ann Surg Oncol 2008;15:227–32.
206. Park SH, Shin JK, Lee WY, Yun SH, Cho YB, Huh JW, et al. Clinical outcomes of neoadjuvant chemotherapy in colorectal cancer patients with synchronous resectable liver metastasis: a propensity score matching analysis. Ann Coloproctol 2021;37:244–52.
207. Strowitzki MJ, Schmidt T, Keppler U, Ritter AS, Mahmoud S, Klose J, et al. Influence of neoadjuvant chemotherapy on resection of primary colorectal liver metastases: a propensity score analysis. J Surg Oncol 2017;116:149–58.
208. Ueno M, Komeda K, Kosaka H, Nakai T, Nomi T, Iida H, et al. Prognostic impact of neoadjuvant chemotherapy in patients with synchronous colorectal liver metastasis: a propensity score matching comparative study. Int J Surg 2021;94:106106.
209. Wu Y, Mao A, Wang H, Fang G, Zhou J, He X, et al. Association of simultaneous vs delayed resection of liver metastasis with complications and survival among adults with colorectal cancer. JAMA Netw Open 2022;5e2231956.
210. Balhareth AS, AlQattan AS, Alshaqaq HM, Alkhalifa AM, Al Abdrabalnabi AA, Alnamlah MS, et al. Survival and prognostic factors of isolated pulmonary metastases originating from colorectal cancer: an 8-year single-center experience. Ann Med Surg (Lond) 2022;77:103559.
211. Milosevic M, Edwards J, Tsang D, Dunning J, Shackcloth M, Batchelor T, et al. Pulmonary metastasectomy in colorectal cancer: updated analysis of 93 randomized patients: control survival is much better than previously assumed. Colorectal Dis 2020;22:1314–24.
212. Siebenhüner AR, Güller U, Warschkow R. Population-based SEER analysis of survival in colorectal cancer patients with or without resection of lung and liver metastases. BMC Cancer 2020;20:246.
213. Zhang GQ, Taylor JP, Stem M, Almaazmi H, Efron JE, Atallah C, et al. Aggressive multimodal treatment and metastatic colorectal cancer survival. J Am Coll Surg 2020;230:689–98.
214. Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:256–66.
215. Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737–43.
216. Cunningham D, Pyrhönen S, James RD, Punt CJ, Hickish TF, Heikkila R, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413–8.
217. Elias D, Lefevre JH, Chevalier J, Brouquet A, Marchal F, Classe JM, et al. Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin. J Clin Oncol 2009;27:681–5.
218. Franko J, Ibrahim Z, Gusani NJ, Holtzman MP, Bartlett DL, Zeh HJ 3rd. Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer 2010;116:3756–62.
219. Gervais MK, Dubé P, McConnell Y, Drolet P, Mitchell A, Sideris L. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis arising from colorectal cancer. J Surg Oncol 2013;108:438–43.
220. Razenberg LG, van Gestel YR, Creemers GJ, Verwaal VJ, Lemmens VE, de Hingh IH. Trends in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of synchronous peritoneal carcinomatosis of colorectal origin in the Netherlands. Eur J Surg Oncol 2015;41:466–71.
221. Jaeschke R, Guyatt GH, Dellinger P, Schünemann H, Levy MM, Kunz R, et al. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ 2008;337:a744.
222. House MG, Ito H, Gönen M, Fong Y, Allen PJ, DeMatteo RP, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg 2010;210:744–55.
223. Koh DM, Collins DJ, Wallace T, Chau I, Riddell AM. Combining diffusion-weighted MRI with Gd-EOB-DTPA-enhanced MRI improves the detection of colorectal liver metastases. Br J Radiol 2012;85:980–9.
224. Kim WS, Lee HS, Lee JM, Kwak MS, Hwang SW, Park SH, et al. Fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography for the detection of proximal synchronous lesions in patients with obstructive colorectal cancer. J Gastroenterol Hepatol 2017;32:401–8.
225. Kim SH. CT colonography. J Korean Med Assoc 2007;50:33–50.
226. Nivatvongs S. Surgical management of early colorectal cancer. World J Surg 2000;24:1052–5.
227. Tan MN, Liu B, Lin NS, Liu HM, Loong TH, How KY, et al. Propensity-score-matched analysis of D2 and D3 right hemicolectomy for colon cancer. ANZ J Surg 2022;92:2577–84.
228. Zenger S, Aytac E, Gurbuz B, Ozben V, Ozoran E, Baca B, et al. Metastasis to lymph nodes around the vascular tie worsens long-term oncological outcomes following complete mesocolic excision and conventional colectomy for right-sided colon cancer. Tech Coloproctol 2021;25:309–17.
229. Giani A, Bertoglio CL, Mazzola M, Giusti I, Achilli P, Carnevali P, et al. Mid-term oncological outcomes after complete versus conventional mesocolic excision for right-sided colon cancer: a propensity score matching analysis. Surg Endosc 2022;36:6489–96.
230. Anania G, Davies RJ, Bagolini F, Vettoretto N, Randolph J, Cirocchi R, et al. Right hemicolectomy with complete mesocolic excision is safe, leads to an increased lymph node yield and to increased survival: results of a systematic review and meta-analysis. Tech Coloproctol 2021;25:1099–113.
231. Karachun A, Panaiotti L, Chernikovskiy I, Achkasov S, Gevorkyan Y, Savanovich N, et al. Short-term outcomes of a multicentre randomized clinical trial comparing D2 versus D3 lymph node dissection for colonic cancer (COLD trial). Br J Surg 2020;107:499–508.
232. Kim HJ, Choi GS, Park JS, Park SY, Jun SH. Higher rate of perineural invasion in stent-laparoscopic approach in comparison to emergent open resection for obstructing left-sided colon cancer. Int J Colorectal Dis 2013;28:407–14.
233. Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer 2015;51:587–94.
234. Han van Krieken J, Kafatos G, Bennett J, Mineur L, Tomášek J, Rouleau E, et al. Panitumumab use in metastatic colorectal cancer and patterns of RAS testing: results from a Europe-wide physician survey and medical records review. BMC Cancer 2017;17:798.
235. Li D, Jiang Z, Xiang L, Yang C, Long F, Liu W. A retrospective study based on SEER database: not all high-risk factors are equal for stage II colon cancer. Transl Cancer Res 2022;11:689–98.
236. Petrelli F, Labianca R, Zaniboni A, Lonardi S, Galli F, Rulli E, et al. Assessment of duration and effects of 3 vs 6 months of adjuvant chemotherapy in high-risk stage II colorectal cancer: a subgroup analysis of the TOSCA randomized clinical trial. JAMA Oncol 2020;6:547–51.
237. Yoshino T, Oki E, Misumi T, Kotaka M, Manaka D, Eto T, et al. Final analysis of 3 versus 6 months of adjuvant oxaliplatin and fluoropyrimidine-based therapy in patients with stage III colon cancer: the randomized phase III ACHIEVE trial. J Clin Oncol 2022;40:3419–29.
238. Petrelli F, Rulli E, Labianca R, Lonardi S, Rosati G, Dotti K, et al. Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial. Ann Oncol 2021;32:66–76.
239. Overman MJ, Lenz HJ, Andre T, Aglietta M, Wong MK, Luppi G, et al. Nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): five-year follow-up from CheckMate 142. J Clin Oncol 2022;40:3510.
240. Cohen R, Meurisse A, Pudlarz T, Bennouna J, Tournigand C, De La Fouchardiere C, et al. One-year duration of nivolumab plus ipilimumab in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): long-term follow-up of the GERCOR NIPICOL phase II study. J Clin Oncol 2022;40:13.
241. Saberzadeh Ardestani B, Jones JC, Hubbard JM, McWilliams RR, Halfdanarson TR, Shi Q, et al. Efficacy of pembrolizumab as first-line therapy in patients with mismatch repair–deficient metastatic colorectal cancer in relation to the metastatic site. J Clin Oncol 2023;41:57.
242. Ghaus A, Pheely A, Murdock V, Shareef H, Samuel LM, Clive S, et al. Real-world experience of pembrolizumab in microsatellite instability-high CRC: a Scottish multicenter analysis. J Clin Oncol 2022;40:54.
243. Franko J, Shi Q, Meyers JP, Maughan TS, Adams RA, Seymour MT, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016;17:1709–19.
244. Baratti D, Kusamura S, Azmi N, Guaglio M, Montenovo M, Deraco M. Colorectal peritoneal metastases treated by perioperative systemic chemotherapy and cytoreductive surgery with or without mitomycin C-based HIPEC: a comparative study using the Peritoneal Surface Disease Severity Score (PSDSS). Ann Surg Oncol 2020;27:98–106.

Article information Continued

© 2024 The Korean Society of Coloproctology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Recommendation Recommendation strength Level of evidence Method
Diagnosis
 KQ 1. What imaging studies should be performed if liver metastases are suspected on abdominal computed tomography (CT) for staging in a patient with colon cancer? Updated
  1-1. Liver magnetic resonance imaging (MRI) is recommended if metastases localized to the liver are suspected or if liver resection is considered. Do (strong) Low
  1-2. When liver metastases are suspected in patients with colon cancer, positron emission tomography (PET)-CT is recommended for radical treatment decisions. Do (strong) Low
 KQ 2. Is the addition of PET-CT more effective than CT alone in patients with metastatic colon cancer? Updated
  2. In patients with metastatic colon cancer, PET-CT is useful for detecting metastatic lesions not detected on contrast-enhanced CT. PET-CT is recommended for treatment decision-making in metastatic colon cancer. Do (strong) Very low
 KQ 3. What tests can be considered for proximal colon evaluation in patients with left obstructive colon cancer where evaluating the proximal colon on preoperative colonoscopy is difficult? Updated
  3. In patients with left obstructive colon cancer where the proximal segment is difficult to evaluate on preoperative colonoscopy, CT colonography, PET-CT, and completion colonoscopy may be considered for proximal evaluation. Do (conditional) Very low
Intervention or surgery
 KQ 4. Following the endoscopic resection of colorectal submucosal cancer (cT1N0M0) with a histopathologic diagnosis of completely resected (margin negative) submucosal adenocarcinoma, what risk factors for lymph node metastasis should be considered for additional colectomy? Updated
  4. Further radical surgery should be considered in patients at high risk for lymph node metastasis, such as those with lymphovascular/perivascular involvement, poorly differentiated/undifferentiated, deep submucosal invasion, and high-tier tumor budding, even if complete resection is achieved endoscopically. Do (strong) Very low
 KQ 5. Does D3 lymph node dissection or complete mesocolic excision/central vessel ligation contribute to reduced recurrence and improved survival in surgery for right-sided colorectal cancer without distant metastases? De novo
  5. D3 lymph node dissection or complete mesocolic excision/central vessel ligation is recommended for nonmetastatic right-sided colon cancer. Do (conditional) Very low
 KQ 6. Is the use of self-expanding metallic stents (SEMS) for preoperative decompression recommended in obstructive colon cancer? De novo
  6-1. Preoperative stenting is not always recommended in operable obstructive right-sided colon cancer. Do not (conditional) Very low
  6-2. Preoperative stenting in operable obstructive left-sided colon cancer may be considered in selected cases. Do (conditional) Very low
Pathology
 KQ 7. What is the appropriate number of lymph node examinations for proper lymph node staging of stage II and III colon cancer? Updated
  7. For proper lymph node staging, the dissection and examinations of least 12 lymph nodes are recommended for pathologic diagnosis. Do (strong) Low
 KQ 8. Should microsatellite instability (MSI) testing be performed for all colon cancer patients to screen for Lynch syndrome? De novo
  8. MSI test is recommended for all patients with colon cancer to screen for Lynch syndrome. Do (conditional) Low
 KQ 9. Is KRAS, NRAS, or BRAF gene testing necessary to determine targeted therapy for epidermal growth factor receptor (EGFR) as first-line chemotherapy in patients with metastatic colon cancer? Updated
  9. KRAS, NRAS, and BRAF genetic testing are recommended to determine the appropriateness of EGFR-targeted therapy as first-line chemotherapy in patients with metastatic colon cancer. Do (strong) Moderate
Chemotherapy
 KQ 10. Is adjuvant chemotherapy after curative resection necessary for high-risk stage II colon cancer patient? Updated
  10. Adjuvant chemotherapy after surgery is recommended for high-risk stage II colon cancer patients Do (conditional) Low
 KQ 11. Is 3 months of adjuvant chemotherapy with oxaliplatin oncologically safe for patients with stage III colon cancer compared to 6 months? De novo
  11-1. Three months of adjuvant chemotherapy with oxaliplatin may be considered for patients with low-risk stage Ⅲ (pT1–3N1) after colon cancer surgery. Do (conditional) Low
  11-2. Three months of FOLFOX (folinic acid, fluorouracil and oxaliplatin) is not recommended as adjuvant chemotherapy in patients with high-risk stage Ⅲ (pT4 or N2) after colon cancer surgery. Do not (conditional) Low
 KQ 12. Does immunotherapy provide a better response rate in patients with metastatic colon cancer with MSI-high (MSI-H)/ MMR protein deficiency (dMMR) than conventional chemotherapy? De novo
  12. Immunotherapy is recommended for patients with MSI-H/dMMR metastatic colon cancer. Do (conditional) Low
 KQ 13. In patients with locally advanced colon cancer, is the addition of neoadjuvant chemotherapy oncologically superior to surgery alone? Updated
  13. Neoadjuvant chemotherapy may be considered a treatment option for patients with locally advanced colon cancer to reduce recurrence rates. Do (conditional) Low
Resectable metastastic colon cancer
 KQ 14. What is the appropriate treatment for patients with resectable colon cancer liver metastases? Updated
  14-1. For theradical treatment of patients with a single colon cancer liver metastasis of 3 cm or less, hepatectomy is more effective than radiofrequency thermotherapy (RFA). Do (strong) Very low
  14-2. In patients with resectable colon cancer liver metastases, simultaneous resection versus staged resection is an option. Do (conditional) Very low
  14-3. In patients with resectable colon cancer liver metastases, either surgery after neoadjuvant chemotherapy or upfront surgery can be considered. Do (conditional) Very low
 KQ 15. Does pulmonary metastasectomy improve survival in patients with colon cancer lung metastasis? Updated
  15. Pulmonary metastasectomy is considered for resectable colon cancer lung metastases. Do (conditional) Very low
 KQ 16. Do cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival in patients with colon cancer with peritoneal metastases? De novo
  16. CRS and selective HIPEC are recommended for patients with colon cancer with resectable peritoneal metastases Do (conditional) Low
Unresectable metastatic colon cancer
 KQ 17. Is second-line palliative chemotherapy recommended for improving survival and quality of life in patients with metastatic colon cancer after the failure of first-line palliative chemotherapy? Updated
  17. Second-line palliative chemotherapy is recommended for patients with metastatic colon cancer that have failed first-line palliative chemotherapy to improve survival and quality of life. Do (conditional) Low

Table 1.

Tools for assessing risk of bias

Study type Tool
Randomized controlled study Cochrane RoB 2 [6]
Nonrandomized controlled study ROBINS-I [7]
Diagnostic study QUADAS-2 [8]
Cross-sectional study QUADAS-C [9]
Systematic review AMSTAR 2 [10]

RoB, Risk-of-Bias Tool for Randomized Trials; ROBINS-I, Risk of Bias in Nonrandomized Studies of Intervention; QUADAS, Quality Assessment of Diagnostic Accuracy Studies; QUADAS-C, QUADAS-Comparative; AMSTAR, A Measurement Tool to Assess Systematic Reviews.

Table 2.

Level of evidence

Level of evidence Definition
High High evidence from a well-conducted RCT/meta-analysis with low risk of bias in study design and conduct, or from an observational study with no bias in study design or conduct and an effect size rated as very large
Moderate Evidence from an RCT/meta-analysis with bias in study design and conduct, or from an observational study with no bias in study design or conduct and a large effect size
Low Evidence from an RCT/meta-analysis with study design and conduct flaws raised in more than one item, or from an observational study with no study design or conduct flaws
Very low Evidence from observational studies with study design and conduct flaws, case reports, or poorly systematized observational studies

RCT, randomized controlled trial.

Table 3.

Strengths of the recommendations and implications for clinical practice

Strength of recommendation Definition
Strong recommendation Strongly recommended in most clinical situations, given the benefits and harms of the treatment, level of evidence, values and preferences, and resources
Conditional recommendation The use of these treatments may depend on the clinical situation or patient/societal values. They might be used selectively or conditionally
Conditional against In some situations or conditions, implementation is not recommended because harms of the treatment may outweigh its benefits based on the clinical situation and/or patient/social value
Strong against It is not recommended in most clinical situations because the harms of the treatment outweigh the benefits, considering the clinical situation and/or patient/social value