Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer

The number of deaths from colorectal cancer in Japan continues to increase. Colorectal cancer deaths exceeded 50,000 in 2016. In the 2019 edition, revision of all aspects of treatments was performed, with corrections and additions made based on knowledge acquired since the 2016 version (drug therapy) and the 2014 version (other treatments). The Japanese Society for Cancer of the Colon and Rectum guidelines 2019 for the treatment of colorectal cancer (JSCCR guidelines 2019) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment and to deepen mutual understanding between healthcare professionals and patients by making these guidelines available to the general public. These guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. Controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSCCR guidelines 2019.


Guideline objectives
According to the Vital Statistics of Japan, the number of deaths from colorectal cancer in Japan has continued to increase. In 2016, the number of deaths from colorectal cancer exceeded 50,000. Many new treatment methods have been developed and their use in combination with advances in diagnostic methods has led to a steady improvement in the results of treatment. However, there are differences in treatment among medical institutions in Japan that provide medical care for patients with colorectal cancer, and the differences may lead to differences in the results of treatment.
Under such circumstances, the JSCCR guidelines 2019 for the treatment of colorectal cancer (JSCCR guidelines 2019), which are intended for doctors (general practitioners and specialists) who provide medical care for patients with colorectal cancer in various disease stages and conditions, have been prepared for the following purposes: (1) to show standard treatment strategies for colorectal cancer, (2) to eliminate disparities among institutions in terms of treatment, (3) to eliminate unnecessary treatment and insufficient treatment, and (4) to deepen mutual understanding between healthcare professionals and patients by making these guidelines available to the general public [1].
The following are expected to be achieved with these guidelines: (1) improvement of the treatment of colorectal cancer in Japan; (2) improvement of the results of treatment; (3) reduction of the human and financial burden; and (4) increased benefits for patients.
2. How to use these guidelines These guidelines were prepared by consensuses reached by the Guideline Committee of the Japanese Society for Cancer of the Colon and Rectum, based on a careful review of the evidence retrieved by the literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan and, therefore, these guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. However, these guidelines provide only general recommendations for choosing treatment strategies for colorectal cancer, and they do not control or limit treatment strategies or treatment methods that are not described herein. They can also be used as a document to explain the rationale for selecting treatment strategies and treatment methods that differ from those described therein.
The Japanese Society for Cancer of the Colon and Rectum (JSCCR) is responsible for the statements in these guidelines. However, the personnel directly in charge of treatment, not the JSCCR or the Guideline Committee, are responsible for the outcome of treatment.

Users
The users of these guidelines are mainly clinical doctors engaged in all aspects of the medical treatment of colorectal cancer. 4. How to develop these guidelines (1) Recording methods We adopted the concept from the first edition, in which the treatment policy algorithm was disclosed, a simple explanation thereof recorded, and added further comments with regard to categories requiring additional explanation. Since the 2009 edition, areas of debate have been raised as clinical questions (CQs) and included with recommendations added. In the 2016 edition, systemic therapy was the only treatment to be revised. In the 2019 edition, all aspects of the treatments were revised, with corrections and additions made to the CQs based on knowledge acquired since the 2016 version (systemic therapy) and the 2014 version (other treatments).
Efforts were made to make the expression of the CQs clear and unambiguous. When comparing multiple interventions, we did not stick to ranking everything, and kept the expression flexible to ensure that it is useful in clinical practice. The clinicopathological terms conformed to those described in the "Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, third English edition [2].
(2) Evidence level/strength of recommendations of CQs The recommendations added to CQs included the evidence level and strength of recommendations determined using the following direction.
(2-1) Evidence level Papers relating to the CQs were comprehensively collected, and the evidence indicated by individual papers relating to the critical outcomes included within the CQs was divided into groups by study design [3]. The literature level and a body of evidence (Table 1) were evaluated in reference to the GRADE* System , before determining the final CQ evidence level ( Table 2).
*GRADE: The Grading of Recommendations Assessment, Development and Evaluation  Strength of recommendations Draft recommendation statements and the strength of the recommendations were directed based on the outcomes and the level of evidence obtained from the process described above and were evaluated at a consensus meeting of the Guideline Committee. In the CQ text, the recommendations that were decided have been directly expressed, and ambiguous expressions were excluded.
The draft recommendations were evaluated from four categories (① Quality of evidence, ② Patients' views and preferences, ③ Benefits and harms, and ④ Cost effectiveness). The strength of recommendation (Table 3) was determined by vote, based on the GRADE Grid method [11]. Method 1. We selected one of the following five options and voted.
① Strong "For" intervention ② A Weak "For" intervention ③ Weak "Against" intervention ④ Strong "Against" intervention ⑤ Not graded 2. With one vote, if 70% or more of the votes were obtained in any of ① to ⑤, it was considered a final decision. If this criterion cannot be met, then the following shall be applied: -If ① + ② exceeds 50%, ③ + ④ is 20% or lower, "weakly recommend to perform." -If ③ + ④ exceeds 50%, ①+ ② is 20% or lower, "weakly recommend not to perform." 3. Items not reaching consensus after a single vote were debated once again, with the results of the first vote disclosed and additional information on the situation relating to clinical practice in Japan provided, and discussion and voting was repeated.
4. If agreement was not reached, even in the second vote, no strength of recommendation was presented in the CQ.

Literature search
At first, the literature search was performed for the clinical questions. Then, a further search was done as needed with additional search techniques.
To survey the latest literature, in addition to the papers used for reference in the previous edition, the PubMed and Ichushi-Web databases were selected for the search, and the English and Japanese literature was searched in both databases from June 2012 to February 2017. However, the start of the search period for systemic therapy was August 2016. The task of searching was performed by a medical librarian, Table 1 Rating the quality of evidence Table 2 Definition of levels of evidence (Ref. [14]) We are very confident in the effect estimate B (moderate ) We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different C (low) Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect D (very low ) We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect Strength of recommendation 1 (Strong recommendation) Strong "For" an intervention Strong "Against" an intervention 2 (Weak recommendation) Weak "For" an intervention Weak "Against" an intervention who created a search formula based on a discussion with the Committee members in charge of each item and collected literature during the search period. In addition, secondary sources such as UpToDate and literature collected by manual searching were added and critically examined as needed, and other documents such as proceedings and guidelines were included as necessary. We selected 3,295 documents from among the 16,341 documents (PubMed 9,672, ICHUSHI 6,153, hand search 516) collected during the literature search and critically reviewed all of them (Table 4).
Treatment guidelines for colorectal cancer Chapter 1: Treatment strategies for Stage 0 to Stage III colorectal cancer 1. Endoscopic treatment ( Fig. 1) General principles underlying the indications for endoscopic resection • There is little possibility of lymph node metastasis, and the size and location of the tumor make en bloc resection possible. Indication criteria for endoscopic resection: (1) Intramucosal carcinoma or carcinoma with slight submucosal invasion (2) Size does not matter (3) Any macroscopic type • Endoscopic treatment is a method of endoscopically resecting lesions in the large bowel and of collecting the resected specimens. • Endoscopic treatment methods consist of polypectomy (note 1), endoscopic mucosal resection (EMR) (note 2), and endoscopic submucosal dissection (ESD) (note 3). • In determining the indication for endoscopic treatment and the treatment method, information on the size, predicted depth of invasion, and morphology of the tumor is essential.
Comments ① Endoscopic resection is intended for both diagnosis and treatment. It consists of total excisional biopsy in which curability and the necessity of additional intestinal resection are assessed by histopathological examination of the resected specimens (CQ-1). ② cT1 deeply invasive cancer is diagnosed based on endoscopic findings, such as "fullness, erosion, ulcer, fold convergence, deformity, rigidity," as well as contrast X-ray, chromoendoscopy, image-enhanced endoscopy (e.g., NBI/BLI [27], or magnifying endoscopic observation) and endoscopic ultrasound findings. [28][29][30]. ③ En bloc resection is desirable for accurate diagnosis of the status of carcinoma invasion in the resection margin and the deepest area.
• 2 cm is the largest size of a tumor that can be easily resected en bloc by polypectomy or snare EMR [31] (CQ-2). • Colorectal ESD is an "endoscopic resection technique which enables en bloc resection of a tumor, regardless of size," which was approved for implementation  under health insurance in April 2012 with regard to "early-stage malignant tumors". Given the high likelihood of technically difficult complications (perforations), however, it should only be implemented after sufficient consideration of the level of skill of the endoscopist performing the procedure. Tumors with a diameter between 2 and 5 cm were covered by insurance. The revision of April 2018 eliminated the upper limit of the tumor diameter and the indication became early colon cancer with a maximum diameter of 2 cm or more. Early colon cancer accompanying fibrosis is even applied to tumors with a diameter of 2 cm or less (CQ-2 (1) Lymph node dissection is unnecessary for pTis cancer (D0), because pTis cancer is not accompanied by lymph node metastasis. However, D1 dissection can be performed when bowel resection is adopted.
(2) D2 dissection is necessary for pT1 cancer, because the incidence of lymph node metastasis is approximately 10% and because approximately 2% of pT1 cancer is accompanied by intermediate lymph node metastasis (Table 5). (3) Although there is insufficient evidence describing the extent of lymph node dissection for cT2 (MP) cancer, at least D2 dissection is necessary. However, D3 dissection can be performed, because about 1% of cT2 (MP) cancer is accompanied by main lymph node metastases ( Table 5) and because preoperative diagnosis of depth of invasion is not very accurate. For details of lateral lymph node dissection in rectal cancer, see (CQ-5).
[Indication criteria for sphincter preserving surgery] • Sphincter preserving surgery is indicated only when the following criteria are fulfilled: (i) resection with no oncologic remnant (both the distal and circumferential resection margins are negative = DM 0, RM 0) can be achieved, and (ii) the postoperative anal function can be maintained.
[Autonomic nerve-preserving surgery] • Considering factors such as the degree of cancer progression and the presence or absence of macroscopic nerve invasion, preservation of autonomic nerves is attempted to preserve urinary and sexual functions as much as possible, provided that curability is unaffected.
[Indications criteria for lateral lymph node dissection] • Lateral lymph node dissection is indicated when the lower border of the tumor is located distal to the peritoneal reflection and the tumor has invaded beyond the muscularis propria [40] ( ① In D1, D2, D3 dissection, the resection margin of the bowel is determined so that the pericolic/perirectal lymph node, as defined in Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma [2], is dissected. ② The extent of the pericolic/perirectal lymph node in colon cancer is defined by the positional relationship [Intersphincteric resection (ISR)] • ISR is a procedure for lower rectal cancer located close to the anus, to ensure the adequate distal margin via the removal of the internal anal sphincter and to avoid a permanent stoma. • The indication criteria for ISR are as follows: (1) able to ensure the resection with clear circumferential surgical resection margin (no infiltration to the external anal sphincter or levator ani muscles); and (2) able to ensure the adequate distal surgical margin (in general, 2 cm or more for T2/T3 tumors and 1 cm or more for T1 tumors). ISR is not recommended for cases with poorly differentiated cancer and cases in which the anal sphincter tonus is decreased. • In a systematic review of 14 papers, the R0 resection rate of patients who underwent ISR was 97.0%, the anastomotic leakage rate was 9.1%, and the local recurrence rate was 6.7%, which is reported as an acceptable result [46]. However, according to the questionnaire survey conducted by the JSCCR in 2125 cases, the 5-year survival rate of patients who underwent ISR was equivalent to that of the lower rectal cancer cases in the JSCCR colorectal cancer registry, but the 5-year local recurrence rate (including recurrence in the area of anastomosis) was relatively high at 11.5%. Obviously, the local recurrence rate becomes higher as the depth of invasion reaches deeper (4.2% at T1, 8.5% at T2, 18.1% at T3, and 36.0% at T4). The indication of ISR should be determined based on a precise preoperative diagnosis of the tumor depth. • As the extent of resection of the anal sphincter becomes wider, postoperative defecatory dysfunction (e.g., fecal incontinence) becomes a more serious problem. In particular, it has been reported that the incidence of defecatory dysfunction is high in patients who receive preoperative radiation therapy, those with anastomotic leakage, and the elderly [47-49]. • The indication of ISR should be carefully decided because the procedure is associated with a high degree of difficulty and has a great influence on the patient's QOL, including the postoperative defecatory function. In addition to tumor factors (e.g., the histological type and depth), and patient factors (e.g., age and sphincter tonus), the experience and skill of the operator should be taken into consideration.
[ • Stage IV colorectal cancer is associated with synchronous distant metastasis to any of the following organs: liver, lung, peritoneum, brain, distant lymph nodes, or other organ (e.g., bone, adrenal gland, spleen). • If both the distant metastases and the primary tumor are resectable, curative resection of the primary tumor is performed, and resection of the distant metastases is considered. • If the distant metastases are resectable but the primary tumor is unresectable, in principle, resection of the primary tumor and distant metastases is not performed, and another treatment method is selected. • If the distant metastases are unresectable but the primary tumor is resectable, the indication for the resection of the primary tumor is determined, based on the clinical symptoms of the primary tumor and the impact on the prognosis (CQ-6).
Comments ① The incidence of synchronous distant metastasis is shown in Table 9. ② Liver metastases • If resectable, liver metastases should be resected upon confirming the radicality of the primary resection. • As for the timing of resection, simultaneous resection of the primary lesion and liver metastases can be safely performed [53]. Depending on the difficulty of hepatectomy and the general condition of the patient, metachronous resection is also performed. However, it is unclear whether simultaneous resection or metachronous resection improves the longterm prognosis.
③ Lung metastases • If resectable, resection of lung metastases should be considered after resection of the primary tumor. • Metachronous resection is generally performed to remove lung metastases after primary resection.
④ Peritoneal metastases (CQ-7) • Complete resection is strongly recommended for P1. • Complete resection is recommended for P2 when easily resectable.  • The efficacy of resection of P3 has not been demonstrated.

⑤ Distant lymph node metastases
Excision of distant lymph node metastases may be considered, but no comparative clinical trials have shown a clear therapeutic effect. However, in recent years, resection of para-aortic lymph node metastases was reported to have the potential to achieve radical cure and longer survival at certain rates.
Excision of distant lymph node metastases may be considered, but no comparative clinical trials have shown a clear therapeutic effect. However, in recent years, resection of para-aortic lymph node metastases was reported to have the potential to achieve a radical cure and longer survival at certain rates [  1. Treatment strategies for liver metastases • Treatment of liver metastases is broadly divided into hepatectomy, systemic therapy, hepatic arterial infusion therapy, and thermal ablation therapy. • Hepatectomy is recommended for liver metastases when curative resection is possible. • Hepatectomy consists of systematic resection and partial (non-systematic) resection. • Indication criteria for hepatectomy (1) The patient is capable of tolerating surgery (2) The primary tumor has been controlled or can be controlled. (3) The metastatic liver tumor can be completely resected.
(4) There are no extrahepatic metastases or they can be controlled. (5) The function of the remaining liver will be adequate.
• Systemic therapy is considered for patients with unresectable liver metastases whose general condition can be maintained at a certain level or higher (PS 0 to PS 2). • Thermal ablation therapy consists of microwave ablation therapy (MCT) and radiofrequency ablation (RFA). • If the patient's general condition is poor (PS ≥ 3), or there is no effective chemotherapy, best supportive care (BSC) is provided.  [98][99][100][101][102][103][104][105][106]. ⑩ Evidence to support the efficacy of adjuvant chemotherapy after hepatectomy is not sufficient; however, imple-mentation is recommended in view of the high rate of recurrence (CQ-19). ⑪ The safety of preoperative chemotherapy for resectable liver metastases has not been established (CQ-9).
[Treatment methods other than resection] ① Systemic therapy is performed for patients with unresectable liver metastases. ② In cases of inoperable liver metastasis, hepatic arterial infusion therapy or thermal ablation therapy is not generally recommended (CQ-13, CQ-24). ③ In Japan, there are no data to support the efficacy of stereotactic body radiation therapy or brachytherapy. ④ If the patient's general condition is poor, an appropriate BSC is provided.

Treatment strategies for lung metastases
• Treatment of lung metastases consists of pneumonectomy and systemic therapy, and radiotherapy. • Pneumonectomy is considered if the metastatic lung tumor is resectable. • Pneumonectomy consists of systematic resection and partial (non-systematic) resection.
Indication criteria for pneumonectomy (1) The patient is capable of tolerating surgery.
(2) The primary tumor has been controlled or can be controlled. (3) The metastatic lung tumor can be completely resected. (4) There are no extrapulmonary metastases or they can be controlled. (5) The function of the remaining lung will be adequate.
• Systemic chemotherapy is considered for patients with unresectable lung metastases whose general condition can be maintained at a certain level or higher. • Even if the patient cannot tolerate surgery, stereotactic body radiation therapy is considered if the primary tumor and extrapulmonary metastases are controlled or can be controlled and the number of lung metastases within 5 cm in diameter is no more than three [107]. • If the patient's general condition is poor, an appropriate BSC is provided.

Comments
[Pneumonectomy] ① The efficacy of lung resection is not based on evidence derived from a cohort study or randomized controlled trial. However, good results that have not been obtained with other treatments have been shown in appropriately selected patients [97,[108][109][110][111][112][113][114][115]. ② The 5-year survival rate after pulmonary resection is 30-68% [116][117][118]. In the multicenter aggregate conducted in the JSCCR project study, the 5-year survival rate of lung resection cases was 46.7% and the cumulative 5-year relapse-free survival rate was 33.7%, while the 5-year survival rate of non-resected cases was 3.9% [116,119]. ③ In synchronous pulmonary metastasis, it is desirable to initially resect the primary lesion and evaluate local curability. Thus, in principle, metachronous resection is performed for synchronous pulmonary metastasis. ④ The number, size, location, and intra-bronchial development of metastatic lesions should be evaluated, and a procedure that enables the complete resection of the metastatic lesion with secure resection margins should be decided. ⑤ The significance of hilar/mediastinal lymph node dissection is not established. The number of metastases, bilateral lung metastasis, hilar/mediastinal lymph node metastasis, serum CEA value before lung resection, primary factor (T factor, N factor), and disease-free interval (DFI) is reported to be poor prognostic factors [112][113][114][115][116]120]. ⑥ In cases of controllable extrapulmonary metastasis (mainly liver metastasis), there are reports suggesting the efficacy of lung resection [60, 97,113,115,121,122]. ⑦ A five-year survival rate of 20-48% has been reported in patients who undergo repeat lung resection for residual lung recurrence [112,114,115,123,124]. Even for residual lung recurrence after lung resection, the indications for resection should be carefully considered according to the above-mentioned indication criteria for lung resection. ⑧ No large-scale studies have examined the efficacy of adjuvant chemotherapy after the curative resection of lung metastases (CQ-19).
3. Treatment strategies for brain metastases • Brain metastases are often detected as a part of a systemic disease, and surgical therapy or radiotherapy is considered for lesions in which treatment can be expected to be effective.
• The optimal treatment method is selected after considering the patient's general condition and status of other metastatic tumors, and evaluating the size and location of metastatic brain tumors and the number of brain lesions. • Radiotherapy is considered for patients with unresectable metastases.
[Surgical therapy] Indications criteria for brain resection [125,126] (1) The patient is capable of tolerating surgery.
(2) The primary tumor has been controlled or can be controlled. (3) The patient has a life expectancy of at least several months. (4) Resection will not cause significant neurologic symptoms. (5) There are no metastases to other organs or they can be controlled. [Radiotherapy] • The purpose of radiotherapy is to relieve symptoms, such as cranial nerve symptoms and intracranial hypertension symptoms, and to prolong survival time by reducing locoregional relapse. • Whole-brain radiotherapy is considered for patients with multiple brain metastases and for patients with a solitary brain metastasis for which surgical resection is not indicated. • Stereotactic irradiation is considered when the number of brain metastases is about no more than three or four and the maximum diameter of each metastasis does not exceed 3 cm.

Comments [Surgical therapy]
① Approximately, 90% of cases of brain metastasis involve metastasis to other organs, and the prognosis is poor, even if resection is performed [125,[127][128][129][130][131]. ② The average survival time after excision of solitary brain metastasis is reported to be 30-40 weeks [125,126,128,129,132]. However, the efficacy of surgical therapy has not been determined based on the evaluation of a suitably sized cohort. ③ The significance of adding whole-brain radiotherapy after brain metastasis resection is controversial [125].

3
[Radiotherapy] ① The symptom improvement rate is 60-80% [133,134]. ② Stereotactic irradiation achieves a local control rate of 80-90% [135]. ③ According to a systematic review, the median survival time after stereotactic irradiation, whole-brain radiotherapy, and BSC was 6.4 months, 4.4 months, and 1.8 months, respectively [136]. ④ Age, PS, number of brain metastases, and control of extracranial lesions have been reported as prognostic factors [137][138][139]. ⑤ At present, whole-brain radiotherapy is performed irrespective of the number of metastases. When a prognosis of several years can be expected, whole-brain radiotherapy in combination with stereotactic irradiation is considered [140,141]. In the case of stereotactic irradiation, single treatment is also considered as a treatment option as it can achieve a high QOL. However, surveillance at appropriate intervals by image inspection is necessary because the rate of intracranial recurrence is higher in comparison to that after whole-brain radiotherapy.

Treatment strategies for hematogenous metastases to other organs
• Resection is also considered for other hematogenous metastases, such as to the adrenal glands, skin, and spleen, if they are resectable. However, patients with such metastases often have metastasis to more than one organ, and chemotherapy or radiotherapy is often indicated. S-1 + BEV [187] CET or PANI [188,189] Second-line therapy (CQ-21) The following regimens are considered as systemic therapy for second-line therapy.
(a) For patients who are refractory or intolerant to the firstline therapy, including OX.
Comments ① When administering OX, it is necessary to pay attention to the cumulative neurotoxicity of OX. Although Grade 2 neurotoxicity which impairs tolerability was observed, if the curative effect persists, stopping OX and switching to fluoropyrimidine ± BEV/CET/PANI, etc., should be considered. If the disease progress and neurotoxicity is improved to Grade 1 or less, reintroduction of OX should be considered. ② Careful attention is required when using IRI for patients with constitutional jaundice, such as that caused by Gilbert`s syndrome, or those with high serum bilirubin or who are in a poor general condition (PS 2). Associations between genetic polymorphisms of enzymes that metabolize IRI (UGT1A1) and toxicity have been suggested. Although the maximum tolerated dose of IRI was confirmed to be 150 mg/m2 for patients with UGT1A1 homozygous (*28/*28, *6/*6, or *28/*6), grade 3 or higher neutropenia was observed in 62.5% of these patients during the first cycle [215]. ③ In Japan, the efficacy and safety of FOLFOXIRI + BEV were confirmed in the QUATTRO trial* [216]. This trial enrolled the patients of 20-75 years of age, with PS 0-1 (PS 0: 71-75 years of age), and without UGT1A1 homozygous (*28/*28, *6/*6, or *28/*6). Thus, the efficacy and safety were not confirmed among other patients. In this study, grade 3/4 neutropenia and febrile neutropenia were observed in 72.5% and 21.7% of patients, respectively. Grade 4 neutropenia and febrile neutropenia during the early cycles were higher in patients heterozygous for UGT1A1 (*28/*1, *6/*1) in comparison to wild type (*1/*1). *The QUATTRO trial, a phase II trial conducted in Japan, confirmed the efficacy and safety of FOLFOX-IRI + BEV in first-line therapy for patients with unresectable colorectal cancer.
④ The efficacy and safety of S-1 + IRI + BEV were confirmed in the TRICOLORE trial [169]. The TRI-COLORE trial, a phase III trial conducted in Japan, compared the efficacy and safety of S-1 + IRI + BEV with FOLFOX + BEV or CAPOX + BEV as first-line therapy for PS 0-1 patients with unresectable colorectal cancer. ⑤ The efficacy and safety of CAPIRI + BEV were confirmed in the AXEPT trial* [192]. * The AXEPT trial, a phase III trial conducted in Asia, compared the efficacy and safety of CAPIRI ± BEV with FOLFIRI ± BEV as second-line therapy for PS 0-2 patients with unresectable colorectal cancer.
⑥ The efficacy and safety of AFL were confirmed in the VELOUR trial* [194]. The administration of AFL is approved in combination with 5-FU, 1-LV, and IRI in Japan. As described in the package insert, the efficacy and safety of AFL in first-line therapy have not been established. *The VELOUR trial, an international cooperative phase III trial, compared the efficacy and safety of FOLFIRI + AFL with FOLFIRI + placebo as secondline therapy for PS 0-2 patients with unresectable colorectal cancer who were refractory or intolerant to prior combination therapy with fluoropyrimidine and OX.
⑦ Although hepatic arterial infusion therapy is associated with high response rates in patients with liver metastasis, it does not show any survival benefit in comparison to systemic therapy [217] (CQ-24). • Radiotherapy is used to treat patients with locally advanced rectal cancer either as adjuvant therapy after surgery to prevent recurrence or before surgery to reduce tumor volume and preserve the anal sphincter, and also as palliative care to relieve the symptoms and prolong the survival time of patients with unresectable colorectal cancer who have symptomatic lesions.

Adjuvant radiotherapy
• Adjuvant radiotherapy is classified into three categories, according to the timing of surgery and radiation therapy: preoperative radiotherapy, intraoperative radiotherapy, and postoperative radiotherapy. • The purpose of adjuvant radiotherapy is to improve the local control rate and the survival rate of rectal cancer patients. The purpose of preoperative radiotherapy includes improving the anal sphincter preservation rate and improving the resection rate. However, insufficient evidence of improved survival has been found to make this the objective of adjuvant radiotherapy. • Preoperative radiotherapy is indicated for patients with T stage clinically diagnosed as "invasion depth cT3 or deeper or cN-positive"; postoperative radiotherapy is indicated for patients with T stage pathologically diagnosed after surgery as "invasion depth pT3 or deeper or pN positive, where the existence of a surgical dissection plane positive (RM1) or penetration of the surgical dissection plane by the cancer (RMX) is unclear"; and intraoperative radiotherapy is indicated for "surgical dissection plane positive (RM1) or penetration of the surgical dissection plane by the cancer (RMX) is unclear". • Radiotherapy is delivered with a linear accelerator, with electron beams being used for intraoperative radiotherapy and photon beams for external radiotherapy.
Comments ① Preoperative radiotherapy (CQ-25) 1. Preoperative radiotherapy has the following advantages: seeding during surgery can be prevented by inactivating lesions with irradiation; a high percentage of tumor cells are normo-oxic and radiosensitive, because blood flow to the tumor is maintained; there has been little damage to the digestive tract, since the small bowel is not fixed within the pelvic cavity, thereby resulting in low radiation-induced delayed toxicity, which means a less toxic postoperative setting; improvement in the R0 resection rate and anal sphincter preservation can be expected because of tumor size reduction [228]. 2. Preoperative radiotherapy has the following disadvantages: early-stage patients may be subjected to overtreatment and postoperative complications may increase. 3. Twelve phase III clinical trials of preoperative radiotherapy (without chemotherapy) have been reported [228], and in 5 of the 12 randomized controlled trials the local control rate in the group that received preoperative radiotherapy was significantly higher than in the surgery-alone group. However, an improvement in the survival rate was observed in only 1 trial [229]. 4. Two meta-analyses of radiotherapy showed improvement in the local control rate compared to surgery alone, and improvement in the survival rate in the groups that received doses of 30 Gy or more. However, there is controversy as to whether there is improvement in the survival rate [230,231].
5. Trials of short-course radiotherapy with 5 Gy per fraction have been conducted, mainly in Europe [229,232]. Because the late effects of radiation depend on the fraction size, long-term follow-up for late adverse effects, such as anal dysfunction and bowel dysfunction, is necessary. 6. In the Dutch CKVO 95-04 trial, which compared preoperative radiotherapy (25 Gy delivered in five fractions in one week) + TME and TME alone to investigate the significance of adding short-course radiotherapy to TME, the 5-year and 10-year local control rates were significantly higher in the combination therapy group, but there was no significant difference between the two groups in the 5-year and 10-year survival rates [138, 232,233]. The incidences of sexual dysfunction and bowel dysfunction were higher in the preoperative radiation combination therapy group than in the surgery-alone group [234,235]. 7. The effect of preoperative radiotherapy in reducing the size of the primary tumor may enable sphincter preservation. When the purpose of the preoperative radiotherapy is sphincter preservation, it is desirable to perform surgery after allowing an appropriate period for the tumor to decrease in size (6-8 weeks after the completion of radiotherapy) [236]. 8. In Europe, four randomized controlled trials, including the EORTC trial, were performed to investigate the usefulness of adding chemotherapy to preoperative radiotherapy. The incidence of acute-phase adverse events was significantly higher in the preoperative chemoradiotherapy groups, but the pathologic complete response rates (pCR) were significantly higher than that in the preoperative radiotherapy alone groups. In two trials, the exception being the short-course radiotherapy trial, the local recurrence rate was significantly lower in the preoperative chemoradiotherapy group, and there was no significant difference between the two groups in terms of sphincter preservation or survival rate [237][238][239][240]. 9. In a randomized controlled trial that compared preoperative chemoradiotherapy and postoperative chemoradiotherapy, there was no significant difference in the 5-year survival rate, but the local recurrence rate and incidence of grade 3 or higher adverse events were significantly lower in the preoperative chemoradiotherapy group. Among the patients in whom abdominoperineal resection (APR) was considered necessary at the time of enrollment, the percentage of patients in whom sphincter preservation was possible was significantly higher in the preoperative chemoradiotherapy group [241].

A randomized controlled trial of 5-FU versus
Cape combination chemotherapy in the preoperative chemoradiotherapy indicated that the two drugs had the same level of efficacy and safety [242,243]. NCCN guidelines allow the use of either 5-FU or Cape as standard combination chemotherapy in the preoperative chemoradiotherapy. The indications and use of Cape as an adjuvant therapy for rectal cancer have been approved for use under health insurance in Japan as of August 2016. 11. In randomized controlled trials into the efficacy of adding OX to fluoropyrimidine as a combination chemotherapy in the preoperative chemoradiotherapy, OX increased adverse events in three trials, but demonstrated no efficacy with regard to pCR ratio, localized control ratio and survival [242,[244][245][246]; moreover, in one trial, although there was no difference in adverse events and no analysis was done into disease-free survival at the primary endpoint, the pCR ratio was significantly higher [247].

Palliative radiotherapy (a) Intrapelvic lesions (CQ-26)
• The purpose of palliative radiotherapy for intrapelvic lesions is to relieve symptoms such as pain, hemorrhage, and bowel dysfunction caused by intrapelvic tumors. • The target volume includes the tumor causing the symptoms.
[Dose and fractionation] • A total dose of 45-50 Gy is administered in 1.8-2.0 Gy fractions. • Depending on the patient's general condition, such as performance status, and the severity of the symptoms, radiotherapy may be completed in a shorter term with a larger fraction size, for example 30 Gy in 10 fractions over 2 weeks.
(b) Extrapelvic lesions 1. Bone metastases • The purpose of palliative radiotherapy for bone metastases is to achieve pain relief, prevent pathological fractures, and prevent and treat spinal cord paralysis. • The target volume includes the metastatic bone lesions causing the symptoms.
[Dose and fractionation] • Local field radiotherapy, such as 30 Gy in 10 fractions and 20 Gy in 5 fractions, is widely performed.

Brain metastases • See the section on hematogenous metastases (Chapter 4). [Dose and fractionation]
• When whole-brain radiotherapy is performed, 30 Gy in 10 fractions is the standard treatment. If long-term survival is expected, fractionated radiotherapy, such as 37.5 Gy in 15 fractions and 40 Gy in 20 fractions, is considered. • When stereotactic radiosurgery is performed, a peripheral dose of 16-25 Gy is delivered in a single fraction. • In principle, the duration of surveillance is 5 years after surgery, and the surveillance examinations should be scheduled at shorter intervals during the first 3 years after surgery. • It should be noted that there is a higher incidence of lung metastasis and local recurrence in rectal cancer than in colon cancer. • The following is an example of a surveillance schedule after curative resection of Stage I to Stage III colorectal cancer that was designed on the basis of the results of a retrospective investigation of such factors as the common sites and incidence of recurrence, the efficacy of treatment, and the clinical practice in Japan. (Figure 8) 2. Surveillance after curability B resection of colorectal cancer and after resection of recurrent tumors.
(1) The same surveillance method as for Stage III colorectal cancer is used. It should be noted that recurrence and re-recurrence are common in organs previously operated on. It should also be noted that the frequency of relapse after 5 years is relatively high. (2) In cases allocated curability B due to R1 resection, close surveillance schedule should be planned for organs in which residual cancer is suspected.  • More than 85% of the recurrences were detected within 3 years after surgery, and more than 95% of the recurrences were detected within 5 years after surgery.
• The overall incidence of recurrence more than 5 years after surgery was less than 1%. • The appearance of pulmonary recurrence tended to be slower than that of liver metastasis. • Local recurrence and lung recurrence were more frequent in rectal cancer than in colon cancer. In contrast, peritoneal recurrence was more frequent in colon cancer than in rectal cancer.
(2) Characteristics of recurrence according to pStage (Fig. 9, Tables 10, 11) 1. pStage I • The recurrence rates of colon cancer and rectal cancer were 4.4% and 7.4%, respectively. Rectal cancer was associated with a higher rate of recurrence. • The recurrence rates of pT1 cancer and pT2 cancer were 4.0%, and 7.3%, respectively. • In pStage I cases, the appearance of recurrence was delayed in comparison to pStage II and pStage III cases, and recurrence appeared after 5 years in more than 8% of patients with recurrent disease. Among all pStage I cases, the proportion of patients with recurrence after 5 years was less than 0.5%.

pStage II, pStage III
• The recurrence rates of pStage II and pStage III were 15.0% and 31.8%, respectively. • Recurrence was detected within 3 years after surgery in more than 85% of patients with recurrent disease. • The incidence of recurrence at more than 5 years after surgery in patients with pStage II and pStage III colorectal cancer was 0.3% and 1.1%, respectively.
③ Surveillance for recurrence after curability A resection of colorectal cancer • The surveillance schedule shown in Fig. 8 was prepared in consideration of the frequency of recurrence for each stage, the site and timing of recurrence, and current surveillance practices in Japan. • The diagnostic modalities and schedule density differ between the guidelines. The current surveillance methods in Japan are generally intensive in comparison to those adopted in representative guidelines from Western countries (NCCN [251], ESMO [252], ASCO [250,253], ASCRS [254].
④ Surveillance of metachronous multiple primary cancers    • "Positive vertical margin" means that carcinoma is exposed at the submucosal margin of the resected specimen. • Depth of SM invasion and the grade of budding are measured by the method described in "Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, third English edition" [2].
In cases with a positive vertical margin, the recurrence risk is estimated to be higher if follow-up is carried out in comparison to those with a negative vertical margin, since local remnant cancer is a matter of great concern. Furthermore, it is difficult to make an accurate pathological evaluation of the invasive front of the tumor on resected specimens. Although the evidence level is C, considering the balance between harm and benefit, we decided on a "strong recommendation" based on the result of the vote of the committee.
The principle for treatment of pT1 carcinomas, which are invasive carcinomas, is intestinal resection with lymph node dissection. However, some pT1 (SM) carcinomas have a very low risk of metastasis, and the purpose of these criteria is to minimize the need for additional resections that eventually result in overtreatment of such patients. While no diagnostic methods make it possible to predict lymph node metastasis (pN) without fail, the degree of risk of metastasis can be used as a basis for determining whether or not to perform additional treatment.
Factors such as the depth of submucosal invasion (SM invasion depth) [259], histological type, such as poorly differentiated adenocarcinoma, signet-ring cell carcinoma, and mucinous carcinoma [256], the presence of a poorly differentiated area and muconodules at the site of deepest invasion, budding, and lymphovascular invasion, have been reported to be risk factors for regional lymph node metastasis by pT1 (SM) carcinoma [258,260].
The above criteria for determining whether additional treatment is indicated were prepared based on the following three criteria for performing additional intestinal resection of pT1 (SM) carcinoma described in the "Japanese Classification of Colorectal Carcinoma" (2nd edition, 1980): [(1) Obvious intravascular carcinoma invasion; (2) Poorly differentiated adenocarcinoma or undifferentiated carcinoma; (3) Massive carcinoma invasion extending to the vicinity of the margin] [261]. The description of "Massive carcinoma invasion" in the 4th edition of the "Japanese Classification of Colorectal Carcinoma" was revised to the following more specific description in the 5th edition (1994): "Invasion deeper than 'very shallow invasion' (e.g., invasion exceeding approximately 200-300 µm)" [262].   Table 14 Depth of invasion of sm cancer and lymph node metastasis (modified from Ref. [259]) The lymph node metastasis rate of patients with a depth of invasion of 1000 μm or above was 12.5%

3
Subsequent case series studies in Japan have shown that "200 µm to 300 µm" can be extended to 1000 µm [263]. According to the results of the project study by the JSCCR, the lymph node metastasis rate of colorectal carcinoma with an SM invasion depth of 1000 µm or more was 12.5% (Table 14) [256,263]. However, not all cases with submucosal invasion deeper than 1,000 µm necessarily require additional surgery. Approximately, 90% of patients with a depth of invasion of 1000 µm or more did not have lymph node metastasis, and it is important to determine whether additional treatment is indicated after sufficiently considering other factors in addition to depth of SM invasion, such as whether other risk factors for lymph node metastasis are present, the physical and social background of the patient, and the patient's wishes.
It has been reported that the incidence of lymph node metastasis is 1.3% (95% confidence interval 0-2.4%) in cases with an SM invasion degree of 1,000 µm or more without risk factors for lymph node metastasis (other than the degree of SM invasion). However, in the event of metastasis or recurrence, a salvage operation cannot be indicated in many cases and cancer death may occur. These risks should be sufficiently discussed among the medical staff, including surgeons.
We added budding as a factor for considering additional treatment in the 2009 edition [264]. Furthermore, project research is currently underway into other histopathological factors. Multicenter joint research projects have produced reports providing the results of consideration into the appropriateness of these criteria [32, [265][266][267]. Regarding the criteria overseas, the European Society of Gastrointestinal Endoscopy (ESGE) Guideline recommends surgery when lymphovascular invasion, infiltration deeper than 1,000 µm, positive/nonevaluable vertical margins, or poorly differentiated tumor with submucosal invasion are diagnosed referring to JSGE guidelines [268]. CQ-2: Is endoscopic submucosal dissection (ESD) recommended for lesions with a maximum diameter of 2 cm or more?
An accurate preoperative endoscopic diagnosis is essential in endoscopic resection. Selection of EMR, piecemeal EMR, or ESD is determined after taking the operator's skill into consideration.
As a general rule, en bloc resection is recommended for suspected cancer lesions. If en bloc EMR is judged to be difficult, we recommend ESD (en bloc resection) by a skillful endoscopist.

(Recommendation 1/Evidence level B)
CQ-3: Is surveillance recommended after endoscopic resection of early colorectal cancer? ① When en bloc endoscopic resection is completed with a negative margin, then it is recommended that surveillance should be performed by endoscopic examination for approximately 1 year for the purpose of searching for any metachronous colon tumors (Recommendation 2/Evidence level B) ② When piecemeal endoscopic resection is conducted with a positive horizontal margin, then it is recommended that surveillance should be performed by endoscopic examination for approximately 6 months, as the risks for local recurrence are increased (Recommendation 1/ Evidence level C) ③ When an additional intestinal resection is not carried out for pT1 cancer, it is recommended that surveillance should be performed via endoscopic examination along with image diagnoses such as CT and tumor markers for the purpose of searching for lymph node metastasis and distant metastasis (Recommendation 1/Evidence level B) CQ-4: Is laparoscopic surgery recommended for colorectal cancer?
• Laparoscopic surgery is recommended as an option for colorectal cancer surgery (Recommendation 2/Evidence level B).
However, the patient should be instructed that the efficacy of laparoscopic surgery for transverse colon cancer and rectal cancer is not well established.
The difficulty for locally advanced cancer and patients with obesity and adhesion is high, so the indications should be determined while taking into consideration the skill of each surgical team. CQ-5: Is lateral lymph node dissection recommended for rectal cancer?
Lateral lymph node dissection is indicated when the lower border of the tumor is located distal to the peritoneal reflection and the tumor has invaded beyond the muscularis propria. The diagnostic criteria for lateral lymph node metastasis have not been established. At present, the criteria for cases where lateral lymph node dissection can be omitted are not clear.
① It is recommended that lateral lymph node dissection should be performed if a preoperative or intraoperative diagnosis reveals the presence of lateral lymph node metastasis (Recommendation 1/Evidence level C) ② Lateral lymph node dissection is recommended, even if lateral lymph node metastasis is not detected by a preoperative or intraoperative diagnosis. Although the survival benefit of lateral lymph node dissection in this group of patients is limited, it can be expected to suppress local recurrence (Recommendation 2/Evidence level B)

Comments
According to retrospective studies in Japan, lateral lymph node metastasis exists in 16-23% of cases of lower rectal cancer (Table 6) [40, [273][274][275][276]. Although the prognosis of these cases is poor, in general, 40-50% of patients with R0 resection reportedly achieved five-year survival [40, 274,[276][277][278][279][280]. The efficacy of lateral lymph node dissection is particularly high for patients with lateral nodal involvement in whom the number of lymph node metastases or the number of involved lateral lymph node station is limited [281,282]. A propensity score matching analysis of pT3/T4 lower rectal cancer cases in the 1995-2004 JSCCR colorectal cancer registry also showed that the 5-year overall survival rate of patients with lateral lymph node dissection was better than that of those without dissection (68.9% vs. 62.0%) [283]. It is considered that there is a high likelihood of achieving a survival improvement by lateral lymph node dissection. Although the evidence level is C, considering the balance between harm and benefit, this was made a "strong recommendation" based on the result of a vote by the committee. It has been reported that the incidence of lateral lymph node metastasis remains high after preoperative chemoradiation therapy if the lateral lymph nodes are enlarged before treatment. Thus, even in cases in which preoperative chemoradiotherapy is performed, the omission of lateral lymph node dissection is not recommended [284,285].
Regarding the clinical value of lateral lymph node dissection in cases without obvious lateral lymph node metastasis, the JCOG0212 study examined the non-inferiority of the mesorectal excision (ME) alone to the mesorectal excision with lateral lymph node dissection (ME + LLND) with the primary endpoints of relapse-free survival. This study was conducted for patients with no lateral lymph nodes with a short-axis diameter of 10 mm or more on preoperative CT or MRI and whose tumor was located in the rectum, with the lower tumor margin below the peritoneal reflection. As a result, the non-inferiority of ME alone to ME + LLND was not statistically proven (P value for non-inferiority = 0.0547) [286]. The frequency of local recurrence in the ME + LLND group was significantly lower than that in the ME alone group (7.4% vs. 12.6%). On the other hand, the relapsefree survival curves of the two groups were very similar, and there was no significant difference in either the overall survival rate or local recurrence-free survival rate as a secondary endpoint. Thus, the survival benefit of lateral lymph node dissection was limited in cases without lateral lymph node enlargement. Taken together, the omission of lateral lymph node dissection is not uniformly recommended, even for cases without the enlargement of lateral pelvic lymph nodes, from the viewpoint of local control. The application of lateral lymph node dissection should be determined in individual patients by comprehensively considering the balance between the expected benefits in terms of local control and survival improvement and the surgical risk and postoperative dysfunction. CQ-6: Is resection of the primary tumor recommended for patients with unresectable distant metastases?
• If symptoms exist as a result of the primary tumor, which are difficult to control using other therapies, and the resection is not significantly invasive, primary tumor resection and early systemic therapy are recommended (Recommendation 1/Evidence level C) For cases in which no symptoms are caused by the primary tumor, however, the efficacy of resecting the primary tumor has not been established. CQ-7: In cases where peritoneal metastasis is noted, is the resection of peritoneal metastasis at the same time as the primary lesion recommended?
• If the metastasis is localized (P1, P2) and the resection is not significantly invasive, then the peritoneal metastasis should be resected at the same time as the primary tumor (Recommendation 1/Evidence level C)

Comments
Some cases of long-term survival have been reported in which localized peritoneal metastasis (P1, P2) was resected alongside the primary tumor [287][288][289][290]. Simultaneous localized dissemination (P1, P2) that can be excised without excessive risk should be resected along with the primary tumor. It should be noted that it is more effective to excise localized dissemination (P1, P2) without hematogenous metastasis together with the primary tumor [291,292]. It is considered that improved survival can be highly expected. Thus, it was decided that this should be a "strong recommendation," although the evidence level is C. Comments Approximately, 20-25% of metastatic liver lesions have been reported to disappear after 6-12 courses of medication. However, even if a complete response is observed on imaging, a pathological complete response (disappearance of tumor cells) is not always obtained [293]. There is a high possibility that tumor cells will remain and it is, therefore, recommended that site of the disappearing liver metastasis be excised [294][295][296][297].
CQ-12: Is laparoscopic surgery recommended for liver metastasis of colorectal cancer?
• If a well-experienced surgical team carefully considers adaptation, the safety of laparoscopic hepatectomy for colorectal cancer liver metastasis has been confirmed to be nearly equivalent to that of laparotomy. However, with respect to efficacy, the evidence is insufficient and it is not a standard surgical procedure for liver metasta-sis of colorectal cancer (No recommendation/Evidence level D) CQ-13: Is thermal ablation therapy recommended for metastatic liver lesions?
There are few reports indicating the efficacy of thermal ablation therapy. Since thermal ablation therapy is accompanied by a high risk of local recurrence in cases of liver metastasis, resection should be initially considered wherever possible.
① As resection is the standard therapy for resectable lesions, it is not recommended as the first choice of treatment (Recommendation 1/Evidence level C) ② As systemic therapy is the standard therapy for unresectable liver metastasis, it is not recommended for unresectable lesions (Recommendation 2/Evidence level C) CQ-14: Is surgical resection recommended in cases with locally recurrent rectal cancer?
• Resection is recommended for local recurrence of rectal cancer when R0 resection is considered possible (Recommendation 2/Evidence level C) The indication of resection should be decided after considering the surgical stress, risk, and postoperative quality of life.
It is necessary to fully consider the proficiency of the individual surgical team if pelvic exenteration and bony pelvic wall resection are expected. On the other hand, in an integrated analysis of three randomized controlled trials in Europe and the United States targeting Dukes' B and Dukes' C, 5-FU + l-LV was associated with significantly better relapse-free survival and overall survival in comparison to surgery alone [301]. Subsequently, in domestic and international randomized controlled trials, the non-inferiority of Cape (X-ACT [302]) and UFT + LV (NSABP C-06 [303], JCOG 0205 [144]) to 5-FU + l-LV was shown, followed by the noninferiority of S-1 to UFT + LV (ACTS-CC [145]). From these facts, it is considered that each of the above-mentioned fluoropyrimidine monotherapies (i.e., 5-FU + l-LV, Cape, UFT + LV, S-1) has a survival benefit in comparison to surgery alone. However, its effect has been shown to be inferior to OX combination therapy, as described above.
Upon selecting the actual treatment regimen, the risk of recurrence and the expected effect in each patient should be considered (see above figure). In addition, adequate information, such as adverse events, treatment costs, and hospital visits, should be provided to each patient. It is desirable to select therapy based on comprehensive judgment, including the patient's general condition and willingness to treat.

Comments
The efficacy and safety of combination therapy with molecular targeted drugs as first-line therapy for unresectable colorectal cancer have been demonstrated for bevacizumab (BEV), cetuximab (CET) and panitumumab (PANI). On the other hand, ramucirumab (RAM), aflibercept beta (AFL) and regorafenib (REG) have not been confirmed in firstline therapy, and their concomitant use is not recommended [193,194,214].
Recently, in the pooled analysis of six RCTs (FIRE-3 trial, CALGB/SWOG 80405, PEAK, CRYSTAL, PRIME, 20050181) for RAS wild-type unresectable colorectal cancer, a correlation between the tumor location (right side or left side) and the therapeutic effect of molecular targeted drugs (BEV or anti-EGFR antibody) was reported [220]. Based on the results of the analysis, anti-EGFR antibody therapies are recommended for RAS/BRAF wild-type colon cancer when the primary lesion is on the left side, while BEV is recommended for cases in which the primary lesion is located on the right side [218]. On the other hand, BEV combination therapy is recommended for RAS or BRAF mutated colon cancer, regardless of the location of the primary lesion [218]. In BRAF-mutated colorectal cancer, FOLFOXIRI + BEV combination therapy has shown high efficacy. Thus, FOLFOXIRI + BEV is recommended as the first choice if it can be applied, considering the age, PS and comorbidities of the patient [175].
Taken together, chemotherapy in combination with BEV or anti-EGFR antibody drugs is recommended as first-line therapy for unresectable colorectal cancer, unless contraindicated. For RAS/BRAF wild-type, either BEV or anti-EGR antibody drugs should be selected considering the toxicity profile, backbone chemotherapies, patient preference, and primary tumor location. Since the efficacy of anti-EGFR antibody drugs varies according to the RAS/ BRAF genotype, it is desirable to perform mutation testing of RAS and BRAF prior to the selection of the first-line therapy.  [227].
Funding Preparation of these Guidelines was funded by the JSCCR. No financial support was received from any other organization or corporation.

Compliance with ethical standards
Conflict of interest (1) The following corporations were disclosed by self-declaration of the Guideline Committee members and Guideline Evaluation Committee members. (2) A2 Healthcare Corp., Akita Sumitomo Co., Ltd., Array Biopharma Inc., Astellas Pharma Inc., Bayer Yakuhin, Ltd., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Covidien Japan, Inc., DAIICHI SANKYO COMPANY, Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Intuitive Surgical, Inc., Japan Clinical Research Operations, Johnson & Johnson K.K., Kaigen Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mediscience Planning Inc., Merck Serono Co., Ltd., Merck Biopharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MRP Co., Ltd., MSD K.K., NanoCarrier Co., Ltd., Nippon Boehringer lngelheim Co., Ltd., Olympus Corporation, Ono pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shimadzu Corporation, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sysmex Corporation, Taiho pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited., TERUMO CORPORATION, Yakult Honsha Co., Ltd. ((2) Measures for the conflicts of interest:The Guideline Committee and the Guideline Evaluation Committee have been organized in members with a diverse range of disciplines, including surgery, internal medicine, radiology, pathology, etc., in order to minimize biased opinion. Each recommendation was made determined not on an individual opinion basis but based on voting by the whole committee members, with consensus prioritized. When voting for CQ, conflicts in relation to economic and academic interests were confirmed for each CQ, and members with conflicts of interest in the CQ abstained from voting.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.