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 Ryu¹, Hyun Jung Kim^2,3, Woong Bae Ji⁴, Byung Chang Kim⁵, Ji Hun Kim⁶, Sung Kyung Moon⁷, Sung Il Kang⁸, Han Deok Kwak⁹, Eun Sun Kim¹⁰, Chang Hyun Kim¹¹, Tae Hyung Kim¹², Gyoung Tae Noh¹³, Byung-Soo Park¹⁴, Hyeung-Min Park¹¹, Jeong Mo Bae¹⁵, Jung Hoon Bae¹⁶, Ni Eun Seo¹⁷, Chang Hoon Song¹⁸, Mi Sun Ahn¹⁹, Jae Seon Eo²⁰, Young Chul Yoon²¹, Joon-Kee Yoon²², Kyung Ha Lee²³, Kyung Hee Lee²⁴, Kil-Yong Lee²⁵, Myung Su Lee²⁶, Sung Hak Lee²⁷, Jong Min Lee²⁸, Ji Eun Lee²⁹, Han Hee Lee³⁰, Myong Hoon Ihn³¹, Je-Ho Jang³², Sun Kyung Jeon²⁶, Kum Ju Chae³³, Jin-Ho Choi³⁴, Dae Hee Pyo³⁵, Gi Won Ha³⁶, Kyung Su Han⁵, Young Ki Hong³⁷, Chang Won Hong⁵, Jung-Myun Kwak^,1, 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

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

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].

Table 1.

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).

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).

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.

RESULTS

DIAGNOSIS

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.

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].

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

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.

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.

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

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.

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.

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

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.

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.

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.

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

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.

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.

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

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.

SUPPLEMENTARY MATERIALS

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