NCCN Colon Cancer Guidelines (2015.2 latest version) 2015-03-23 Lotus Under the Moon NCCN updated its colon cancer guidelines in March 2015, first look~ I. Important updates: 1. Testing for RAS gene status, including KRAS exon 2 and non-exon 2 and NRAS, and also testing for BRAF gene status, with or without RAS mutations. 2. FOLFOX+Cetuximab as a treatment option with the following caveat: Data on the treatment of potentially resectable liver metastatic disease remain controversial. 3. For resectable metastatic disease, the total duration of perioperative treatment does not exceed 6 months. II. Overview The United States ranks fourth in colorectal cancer diagnoses and second in deaths due to cancer, with data showing a downward trend in incidence and mortality. Improvements in incidence and mortality are determined by cancer prevention, early diagnosis, and better treatment. Clinicians should make the following points clear when using the guidelines: 1. Staging in the guidelines is by TNM stage; 2. All recommended grades are 2A unless otherwise noted. iii. Risk assessment Approximately 20% of colon cancers have familial aggregation, and first-degree relatives of patients with newly diagnosed colorectal cancer adenocarcinoma or adenoma are at increased risk of colorectal cancer. Genetic susceptibility to colorectal cancer includes well-defined genetic syndromes such as Lynch syndrome and familial adenomatous polyp growths. Family history and risk assessment are recommended for all colon cancer patients. 1. Lynch syndrome is the most common hereditary colon cancer susceptibility syndrome, accounting for 2-4% of all colorectal cancers. It is caused by mutations in DNA mismatch repair genes (MMR), including MLH1, MSH2, MSH6 and PMS2. Current methods to detect Lynch syndrome are immunohistochemical analysis of MMR protein expression and analysis of microsatellite instability (MSI). If MLH1 protein is absent by immunohistochemistry, BRAF mutations, which can cause MLH1 promoter methylation affecting protein expression, are also detected. The NCCN supports MMR testing for all patients younger than 70 years of age or older than 70 years of age who meet the Bethesda guidelines. Additional testing should be performed on stage II patients. Other risk factors for colorectal cancer Patients with inflammatory bowel disease are at increased risk for colorectal cancer. other possible risk factors include smoking, consumption of red and processed meat, alcohol consumption, diabetes, low physical activity, metabolic syndrome, obesity or high BMI. smoking, metabolic syndrome, obesity or consumption of red and processed meat may be associated with poor prognosis, and a family history of colorectal cancer is associated with a relatively good prognosis. data are still The data are controversial. IV. Staging The seventh edition of the AJCC staging manual has made some adjustments to the staging of colon cancer. stage II disease is divided into IIA and IIB, and IIC based on T3 or T4, and the degree of T4 invasion. n1 and n2 are also further subdivided to reflect the prognostic impact of the number of involved lymph nodes. Tumor deposition in subplasma, mesenteric, non-peritoneal pericolonic or perirectal tissues is defined as N1c. It is subdivided into M1a and M1b according to whether distant metastases are confined to 1 or multiple tissues or organs. v. Pathology The pathology report should include the following: cancer grading, penetration depth, extension to adjacent organs, number of regional lymph nodes, number of positive lymph nodes, presence of distant metastases, distal and proximal cut margins and circumferential cut margins, presence of lymphovascular invasion, perineural invasion, extra nodal tumor deposits. p “and “yp” in TNM staging refer to pathological staging, neoadjuvant treatment and post-operative pathological staging. 1. Margins The circumferential cutaneous margin (CRM) in rectal cancer is the deepest tumor infiltration and the closest epithelial soft tissue to the tumor, produced by blunt or sharp separation of the posterior peritoneal surface. The transverse colon is a colon entirely surrounded by peritoneum, and the mesenteric resection margin is the CRM. in the 7th edition of AJCC, it is recommended that surgeons should assess the completeness of resection, R0 is complete tumor resection with negative margin; R1 is incomplete tumor resection with positive microscopic margin; R2 is incomplete resection with positive sarcoid margin. 2. lymph nodes The NCCN committee recommends testing at least 12 lymph nodes, and for T4 damage testing more lymph nodes would be more reasonable. A diagnosis of N0 with fewer than 12 lymph nodes is considered a high risk factor. Extracellular tumor deposits, also known as peri-tumor deposits or satellite nodes, are scattered deposits of tumor in the adipose tissue surrounding the tumor’s colorectum and are not counted in the total number of lymph nodes involved, and the location of the deposits should be within the lymphatic drainage area of the primary tumor. Most deposits are thought to be from lymphovascular invasion or perineural invasion. The number of extra nodal deposits should be entered in the pathology report and has an impact on DFS and OS. 4. perineural invasion Perineural invasion is associated with poor prognosis and is a high risk factor for systemic recurrence. VI. Role of vitamin D in colorectal cancer Some studies have shown that vitamin D deficiency may increase the incidence of colorectal cancer and that vitamin D supplementation reduces the risk of colorectal cancer. There are no studies testing whether vitamin D supplementation improves patient outcomes. Due to the lack of high-level evidence, the committee does not recommend routine testing of vitamin D levels or vitamin D supplementation for patients with colorectal cancer. vii. Adenocarcinoma of the small bowel and appendix Because adenocarcinoma of the small bowel and appendix is extremely rare, there are no specific NCCN guidelines. Localized small bowel adenocarcinoma is amenable to surgical resection, but the common and appropriate perioperative treatment for local and distant recurrence is unclear. There are limited data on progressive small bowel adenocarcinoma, and treatment with CapeOX and FOLFOX may be attempted. Data on appendiceal adenocarcinoma are also scarce, with most patients receiving debulking surgery combined with systemic and intraperitoneal therapy. Some studies have shown that response rates for patients with progressive disease receiving combination chemotherapy are similar to those of patients with progressive colorectal cancer, with regimens containing fluorouracil being the most commonly used. The committee recommends that systemic chemotherapy for adenocarcinoma of the small bowel and appendix be performed in reference to the colon cancer regimen. VIII. Clinical presentation and treatment of nonmetastatic disease 1. Diagnosis and treatment of malignant polyps Malignant polyps are defined as cancer invading the submucosa. polyps that do not invade the submucosa do not show regional lymph node metastasis if they are carcinoma in situ. The need for further surgical excision after endoscopic removal of adenomatous polyps or adenomas requires evaluation of pathological findings and consultation with the patient. Whether invasive carcinoma is found within a tipped or untipped polyp (adenoma), if the resection is complete and the histologic features are good, no further surgery is required. Good histologic features include grade 1 or 2, no vascular lymphatic invasion, and negative cut margins. Colonic resection is also feasible for completely removed, single clot-free polyps with good histologic features and negative cut margins because of the significantly higher incidence of negative outcomes for clot-free polyps, including recurrence, mortality, and hematogenous metastases. If the specimen is fragmented, the margins cannot be evaluated, or if the specimen has poor histologic features, colectomy, whole lymph node dissection, or optional laparoscopic resection is recommended. Poor histologic features include grade 3 or 4, vascular lymphatic invasion, and positive margins. Positive margins can be defined as the presence of tumor within 1-2 mm of the cross-sectional margin or tumor cells within the thermal ablation cross-section. All patients with resected polyps should undergo a full colonoscopy to exclude other polyps and endoscopic follow-up. chemotherapy is not recommended for stage I patients. PET/CT is not a routine baseline examination, but can be considered if CT or MRI shows suspicious abnormalities that cannot be determined. Consider it, especially if the findings may change the treatment strategy. PET/CT is not recommended for lesions smaller than 1 cm. In the case of resectable colon cancer producing complete bowel obstruction, colon resection and complete removal of regional lymph nodes should be performed, followed by colon resection after diversion or stenting if required. Stenting is usually used for distal damage, and stenting can remove proximal colonic pressure to facilitate anastomosis for elective colectomy. If the colon cancer is locally unresectable or the patient cannot tolerate surgery, chemotherapy is recommended for conversion to resectable state. (1) Surgical treatment For resectable non-metastatic colon cancer, the preferable surgical treatment is colectomy and whole resection of regional lymph nodes. The procedure of colon resection needs to be based on the location of the tumor and the regional lymph nodes contained in the resected bowel and arterial arch. Other lymph nodes such as the lymph nodes at the beginning of the vein that feeds the tumor and suspicious lymph nodes outside the resection area should also be removed and biopsied if possible. Surgery should be performed for curative purposes as much as possible, and those positive lymph nodes that are not resected should be resected for R2. (2) Laparoscopic colectomy The committee recommends that laparoscopic colectomy is only feasible with experienced surgeons and that total abdominal exploration is part of the procedure. It is not recommended for obstruction, perforation, or clear invasion of surrounding structures by the tumor. Laparoscopic surgery is not recommended for patients at high risk of abdominal adhesions and should be converted to open surgery if adhesions are found intraoperatively. Adjuvant chemotherapy for resectable colon cancer (1) Adjuvant chemotherapy is of great benefit. The choice of chemotherapy is mainly based on the stage of disease: ① Stage I patients do not need any adjuvant therapy ② Low-risk stage II patients can be enrolled in clinical trials, either for observation or for consideration of capecitabine or 5-FU/LV therapy. FOLFOX is not recommended for the treatment of stage II patients without high-risk factors. Adjuvant chemotherapy with regimens including 5-FU/LV, capecitabine, FOLFOX, CapeOX, or FLOX should be considered for stage II patients with high risk factors, including T4, poor differentiation (except MSI-H), lymphovascular invasion, perineural invasion, intestinal obstruction, perforation or perforation in close proximity to the tumor, indeterminate or positive margins, or less than 12 lymph nodes. observation may also be considered. Adjuvant chemotherapy at 6 months postoperatively is recommended for stage III patients with regimens including FOLFOX (preferred), CapeOX (preferred), FLOX, 5-FU/LV, and capecitabine for patients who are not candidates for oxaliplatin therapy. The committee does not recommend bevacizumab, cetuximab, panitumumab, and irinotecan for adjuvant treatment of nonmetastatic disease. (5) Stage II patients with MSI-H have a good prognosis and will not benefit from adjuvant 5-FU therapy. The committee recommends that MMR should be performed in stage II patients, and poorly differentiated pathological types are not considered high risk factors if accompanied by MSI-H. (2) Multigene analysis Several multigene analyses are available that hold promise for providing prognostic and predictive information to help decide whether to pursue adjuvant chemotherapy in patients with stage II or III disease.Oncotype DX examines seven genes at risk of recurrence and five reference genes to classify patients as low, intermediate, or high risk of recurrence. The trial showed that it did have significance for relapse, OS, and DFS in stage II or III patients, but did not predict whether adjuvant chemotherapy would be beneficial. ColoPrint for 18 genetic tests classified prognosis as low and high risk, and the risk of recurrence confirmed by ColoPrint was independent of other risk factors such as T-stage, perforation, number of lymph nodes, and tumor grade. coIDx was used to detect high risk of recurrence in stage II colon cancer, and the risk of recurrence confirmed by CoIDx was independent of other risk factors. Although the above tests can obtain additional assessments of recurrence risk, the committee questioned their value and there is no evidence to predict the potential benefit of chemotherapy, so polygenic testing is not currently recommended to determine whether to administer adjuvant chemotherapy. (3) Adjuvant chemotherapy in elderly patients As the use of adjuvant chemotherapy declines as patients age, questions about the safety and efficacy of chemotherapy in older patients are difficult to answer. Cohort studies have shown that older patients can benefit from adjuvant therapy, and some studies have shown similar benefits and toxicity of 5-FU/LV adjuvant therapy in older and younger patients. The committee cautioned stage II and III patients over 70 years of age that the therapeutic benefit of adding oxaliplatin to 5-FU/LV has not been demonstrated. (4) Timing of adjuvant therapy Some studies have shown a 14% reduction in OS for every four-week delay in chemotherapy, so adjuvant chemotherapy should be started as early as the patient can afford. (5) Adjuvant radiotherapy Radiotherapy administered in conjunction with 5-FU-containing chemotherapy should only be used for highly selected patients, such as T4 tumors penetrating to fixed structures or recurrence. The radiotherapy area includes the tumor bed. Intraoperative radiotherapy is suitable for patients who need incremental radiotherapy, or if intraoperative radiotherapy is not possible, external irradiation in increments of 10-20 Gy or brachytherapy can be used. Preoperative combined 5-FU radiotherapy helps resectability and confocal radiotherapy should be used. Intensity-modulated radiotherapy can reduce toxicity to normal tissues and should be applied in special cases such as reirradiation for recurrent patients. IX. Principles of treatment of metastatic disease Metastases occur in 50%-60% of patients and unresectable liver metastases in 80%-90% of patients. Metastatic disease often appears after regional treatment, with the liver being the most frequently involved site, and 20%-34% of patients have concurrent liver metastases. Patients with liver metastases who do not undergo surgery have a low 5-year survival rate. Some clinicopathological factors such as extrahepatic metastases, more than 3 tumors, and DFS less than 12 months have poor prognosis. 1. Surgery for colorectal cancer metastases Studies have shown that surgical resection of colorectal cancer liver metastases in selective patients is potentially curative, with a 5-year disease-free survival of up to 20%. Colorectal cancer can also develop pulmonary metastases, and most recommended treatment strategies for liver metastases are also applicable to pulmonary metastases, with combined hepatopulmonary resection only being appropriate for highly selective patients. There are also data suggesting re-surgical resection for metastatic lesions with recurrent hepatic recurrence, but 5-year survival decreases with each surgery, and the presence of extrahepatic disease at the time of surgery is an independent poor prognostic factor. Simultaneous resection or staged resection is feasible for both primary and metastatic lesions that are resectable. In unresectable metastases and in the absence of acute obstruction of the primary tumor, palliative resection of the primary site is a rare indication and chemotherapy is the treatment of choice. Although the standard treatment for resectable metastatic disease is surgical resection, local non-surgical treatment of the liver may also be performed for a particular patient. (The side effects of HAI therapy include biliary tract toxicity. The committee believes that HAI therapy is appropriate for elective patients and should only be used where there is extensive experience with both surgical and oncologic treatment. (2) Arterial Embolization Treatment Transarterial chemoembolization (TACE) includes hepatic artery cannulation causing obstruction to facilitate local administration of chemotherapy. The available evidence is insufficient to recommend TACE for the treatment of liver metastases from colorectal cancer, except in clinical trials. (3) Radiotherapy Radiotherapy includes either intra-arterial placement of radioactive particles for embolization or confocal external irradiation. The former is only used for highly selected patients, while the latter is only suitable for patients with limited hepatopulmonary metastases or patients with significant symptoms or clinical trials, and should not irradiate the surgical site. (4) Tumor ablation Ablation may be considered for patients who are physically unable to tolerate resection, and ablation techniques include radiofrequency ablation, microwave ablation, and cold ablation. The committee does not recommend ablative therapy as a substitute for surgery in resectable patients. Surgery or ablation or ablation combined with surgery is not recommended for patients whose lesions cannot be completely removed. About 17% of patients have colorectal metastases and 2% have only peritoneal metastases, and PFS and OS are usually shorter in these patients than in those without metastases. Treatment is mostly palliative in nature. The committee warned that patients treated with bevacizumab using colorectal stents are at increased risk of perforation. Studies have been done describing cytoreductive surgery and perioperative warmed intraperitoneal chemotherapy (HIPEC) for abdominal metastases with high treatment-related complications, mortality of 8%, and seemingly no improvement in long-term survival, and the committee currently believes that the use of cytoreductive surgery combined with HIPEC for diffuse abdominal metastases is only appropriate for clinical trials. However, the committee also recognized the need for additional trials to confirm this treatment. A patient diagnosed with potentially resectable colorectal cancer should undergo a multidisciplinary evaluation, including a surgical consultation to assess resectability status. The criteria for determining the resectability of a patient with metastatic disease are complete resection of all disease with negative margins and adequate liver function. Preoperative portal embolization of the affected liver may be performed to increase liver preservation in those with inadequate residual liver function. It is important to note that tumor size alone is not a contraindication to tumor resection, and that the purpose of resection of liver metastases is to cure the disease without the benefit of debulking surgery. 5. conversion to resectable Most patients diagnosed with metastases have unresectable disease; however, limited metastases to the liver that involve key structures are feasible for surgical resection after tumor regression, and such patients should be highly considered for chemotherapy to reduce the metastases and convert them to resectable; those with multiple metastases to the liver or lungs, where chemotherapy alone cannot obtain R0 resection, should be considered unresectable lesions that cannot be converted. Any chemotherapy regimen used to treat metastatic disease can be used for conversion therapy, with the aim not to remove micrometastases but to try to obtain tumor regression. Importantly irinotecan and oxaliplatin containing regimens can cause hepatic steatohepatitis and sinusoidal liver injury. To reduce hepatotoxicity, it is recommended that this be performed as soon as surgery is available. For chemotherapy for initial unresectable disease, the committee recommends reassessment of disease every two months. The committee recommends that systemic chemotherapy be administered to metastatic patients after resection to remove residual disease for approximately 6 months of perioperative treatment. The choice of preoperative and postoperative chemotherapy regimens is dependent on chemotherapy history and response, safety, and consistency between adjuvant and neoadjuvant chemotherapy recommendations. If the tumor continues to grow at the time of neoadjuvant chemotherapy, it is switched to another regimen or observed. The appropriate sequence of chemotherapy is unclear. Resectable patients should undergo hepatic resection followed by postoperative adjuvant chemotherapy or perioperative chemotherapy. Possible advantages of preoperative chemotherapy are: earlier treatment of micrometastatic disease, determination of response to chemotherapy, and avoidance of local treatment in patients with early disease progression. The disadvantage is that if progression or complete remission occurs during treatment, the opportunity for surgery may be missed. Therefore, preoperative chemotherapy patients need frequent evaluation and close communication between multidisciplinary specialists and patients to optimize preoperative treatment strategies and appropriate timing for surgical intervention. Other risk of preoperative chemotherapy is hepatotoxicity, so neoadjuvant chemotherapy is best limited to 2-3 months. 7. Chemotherapy for progressive or metastatic disease Drugs for the treatment of multiple metastatic colorectal cancers can be used either in combination or alone, including 5-FU/LV, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, abciximab, and regifinib. Treatment selection is based on the purpose of treatment, type and duration of previous treatment, and toxicity of the treatment drug. If the patient’s physical status, etc. can tolerate stronger chemotherapy, one of the following five regimens is recommended: FOLFOX, FOLFIRI, CapeOX, 5-FU/LV, or FOLFOXIRI. (1) Treatment order and timing Before the era of targeted therapy, studies have shown that there was little difference in clinical outcomes whether stronger chemotherapy or weaker chemotherapy was given first. For metastatic disease, all of the above regimens are equal, with no priority recommendation, nor for initial treatment with biologics. (2) Not recommended regimens The IFL regimen is not recommended because of its toxicity and reduced effectiveness; the CapeIRI regimen or the CapeIRI/bevacizumab regimen is not recommended for first-line treatment of metastatic colorectal cancer; the combination of biological agents is not recommended because it does not improve outcomes but increases toxicity. (3) Toxicity of Capecitabine The committee noted that: patients with decreased creatinine clearance can develop drug accumulation, so dose adjustment should be made; the incidence of hand-foot syndrome is higher than 5-FU/LV; North American patients may have a higher chance of side effects and should be closely monitored and the dose adjusted according to side effects. A recent study showed that hand-foot syndrome was associated with improved OS. (4) Irinotecan Toxicity The main toxicity includes early and late diarrhea, dehydration and severe neutropenia. Irinotecan is caused by the inactivation of an enzyme called UGT1A1, which is involved in bilirubin conversion and can lead to elevated indirect bilirubin in deficiency. Therefore, caution should be exercised when using irinotecan in the presence of UGT1A1 deficiency or when indirect bilirubin is elevated. Some UGT1A1 deficiencies lead to decreased metabolic inactivation of irinotecan, drug accumulation, and increased toxicity. The maximum tolerated dose of irinotecan is 850 mg, 700 mg, and 400 mg for the following phenotypes *1/*1, *1/28, and *28/*28, respectively. UGT1A1 testing is not recommended for patients who have developed toxicity because the patient will require dose reduction regardless of the results. (5) 5-FU/LV or capecitabine therapy For patients who cannot tolerate strong chemotherapy, the guidelines recommend treatment with 5-FU/LV or capecitabine, with or without bevacizumab. If such less intense therapy does not improve the patient’s functional status, it is appropriate to change to supportive therapy; if the status improves, a more intense regimen as recommended above should be used. (6) FOLFOXIRI This strong chemotherapy should only be used in highly selected patients who are likely to convert to resectable disease. (7) Bevacizumab is a humanized monoclonal antibody used to block tumor angiogenesis. Studies have shown benefit of bevacizumab for first-line treatment of metastatic colorectal cancer, and there are no data clarifying whether bevacizumab should be used in the perioperative treatment of resectable metastatic disease. The committee does not recommend bevacizumab for the adjuvant treatment of stage IV disease after resection unless a response to bevacizumab therapy is seen with neoadjuvant therapy. The FDA agreed to add a warning to the bevacizumab insert that there is a risk of necrotizing fasciitis, which can sometimes be fatal, usually secondary to wound healing complications, gastrointestinal perforation, or fistula formation following bevacizumab administration. The use of bevacizumab may interfere with wound healing. The committee recommends a minimum of 6 weeks between elective surgery and the last bevacizumab treatment. Former clinical studies showed that discontinuation of anti-VEGF therapy may accelerate recurrence, make recurrent tumors more aggressive, and increase mortality, but recent findings show no rebound effect. (8) Cetuximab and panitumumab Both are monoclonal antibodies that act on EGFR to inhibit its downstream signaling. They can be treated with serious infusion reactions including allergy; they can also produce skin toxicity, which is associated with treatment response and survival; in addition, both can cause venous thrombosis and other serious side effects. (9) KRAS, NRAS, BRAF The committee strongly recommends that patients with metastatic colorectal cancer should be tested for RAS and BRAF in primary or metastatic tumors. recommending RAS testing does not imply a preference for a particular regimen in first-line therapy. Early establishment of RAS status is beneficial to ensure continuity of therapy and to consider other treatments if mutations are present. Anti-EGFR agents have no role in stage I, II, or III patients and testing is not recommended. KRAS mutation is an early event in colorectal cancer and there is a strong correlation between mutation status in primary and metastatic sites. Specimens from new biopsies are not needed if only to clarify RAS status, unless neither primary nor metastatic specimens are present. The committee recommends that KRAS, NRAS, and BRAF testing should be performed only in CLIA-88-authorized laboratories, with no specific test recommended. patients with RAS mutations should not receive cetuximab- and panitumumab-containing therapy. The committee recommends BRAF testing for the diagnosis of stage IV disease. The committee concluded that there is no evidence that anti-EGFR therapy can be used based on BRAF mutation status. Some studies have shown an association between BRAF mutations with particularly high-risk clinicopathologic features and proximal tumors, T4 tumors, and poor differentiation. (10) Cetuximab + FOLFOX Based on the results of CALGB/SWOG80405, the committee recommends that cetuximab + FOLFOX may be used for the initial treatment of progressive or metastatic disease. The committee cautioned that cetuximab may be harmful when used in the perioperative setting and that caution should be exercised when treating patients with resectable metastases and potentially transformable resectable patients with cetuximab + FOLFOX. The committee considered the addition of cetuximab, panitumumab, or bevacizumab to chemotherapy to be equivalent options in metastatic cancer, first-line therapy, and RAS wild-type. (11) Post-progression therapy Treatment of metastatic disease after progression is dependent on previous therapy. The committee did not recommend mitomycin, interferon, paclitaxel, methotrexate, pemetrexed, sunitinib, sorafenib, erlotinib, or gemcitabine, either as a single agent or in combination. And there are studies showing no objective response present with capecitabine alone in patients progressing after 5-FU treatment. The recommended treatment choices after progression on first-line 5-FU/LV-containing or capecitabine regimens are based primarily on the initial treatment regimen: ① Patients receiving initial therapy with FOLFOX or CapeOX, FOLFIRI or irinotecan alone or in combination with cetuximab or panitumumab (RAS wild-type), bevacizumab or abciximab are also recommended choices. (ii) Patients receiving the FOLFIRI regimen as initial therapy, FOLFOX or CapeOX or in combination with bevacizumab; cetuximab or panitumumab in combination with irinotecan; single-agent cetuximab or panitumumab is also a recommended option. (iii) For patients receiving 5-FU/LV or capecitabine monotherapy, second-line treatment options include FOLFOX, CapeOX, FOLFIRI, single-agent irinotecan, or irinotecan in combination with oxaliplatin. All of these regimens can be combined with bevacizumab or abciximab. ④ Patients receiving FOLFOXIRI as initial therapy, cetuximab or panitumumab alone or in combination with irinotecan are the recommended options for patients with wild-type RAS. (12) Application of bevacizumab in non-first-line conditions Bevacizumab was added to second-line therapy in the 2013 edition of the guidelines based on the findings committee and can be combined with any regimen (excluding other biologics); evidence for combination with irinotecan is lacking but is acceptable for patients progressing on 5-FU/LV-containing or capecitabine regimens. Bevacizumab may be added after progression if bevacizumab was not used in initial therapy. (13) Cetuximab and panitumumab in non-first-line conditions The Committee does not recommend switching to another after failure of cetuximab or panitumumab therapy. (14) Abciximab The most common side effects of this drug are weakness, diarrhea, hypertension, venous thrombosis, and infection. The committee considered abciximab in combination with FOLFIRI or irinotecan to be appropriate for second-line therapy and the patient was not on an irinotecan-containing regimen for first-line therapy. (15) Regefenib The committee recommended regefenib for third-line and beyond in chemotherapy-resistant metastatic colorectal cancer. For patients with mutant RAS, regrafinib is used in third-line therapy, and patients with wild-type RAS receive regrafinib as third- or fourth-line therapy. The most common grade 3 or higher side effects are hand-foot skin reactions, fatigue, hypertension, diarrhea, rash, and, to a lesser extent, lethal hepatotoxicity. 8. Treatment of concurrent metastatic disease Adequate workup, including RAS, should be performed in cases with suspected metastatic colon adenocarcinoma, and BRAF testing should be considered in wild-type cases. Routine PET/CT is not recommended and is optional in certain potentially surgically curable patients to determine if there are other metastases; it is also not used to assess response to chemotherapy because there can be temporary negative results after chemotherapy and also false positives due to infection or surgical inflammation. Included in the criteria for potential surgical curability are patients who have been converted to surgically curable with preoperative chemotherapy. Curative resection is not possible for most patients with extrahepatic metastases, and translational resection is more appropriate for patients with metastases limited to the liver. (1) Resectable simultaneous hepatopulmonary metastases Colorectal cancer liver metastases can be resected simultaneously with the primary site or in a fractionated fashion, in which the primary site is usually resected first, but nowadays it is more acceptable to resect the liver metastases first and then the primary site, followed by adjuvant chemotherapy. Additional data show that chemotherapy between liver and primary resection is effective in some patients. If the patient has both liver and lung metastases that are resectable, the committee recommends the following options: ① Simultaneous or fractionated colectomy and hepatopulmonary resection followed by adjuvant chemotherapy, FOLFOX or CapeOX preferred; ② Neoadjuvant chemotherapy for 2-3 months (FOLFIRI, FOLFOX, CapeOX chemotherapy or in combination with bevacizumab, FOLFIRI, FOLFOX in combination with panitumumab (FOLFIRI, FOLFOX in combination with panitumumab, FOLFIRI, FOLFOX in combination with cetuximab), followed by simultaneous or fractionated resection of colon and liver and lung metastases; (3) adjuvant chemotherapy (same protocol as above) and resection of metastatic lesions after colon resection. Neoadjuvant chemotherapy and adjuvant chemotherapy should not exceed a total of 6 months. For cases with liver metastases only, HAI therapy is also feasible in experienced centers. (2) Concurrent unresectable hepatopulmonary metastases In patients with possible transformation, a high response rate chemotherapy regimen should be selected and patients should be evaluated every 2 months, with at least 6 weeks between the last treatment and surgery if bevacizumab therapy is added, and 6-8 weeks after surgery before restarting bevacizumab therapy. Simultaneous or staged resection is feasible for those with conversion to resectable disease. HAI therapy is also feasible in experienced centers. Ablative therapy alone or in combination with surgery is available for patients in whom all metastatic disease is treatable. Patients who do not respond to treatment should continue to receive chemotherapy, with regimens that refer to those for metastatic disease; noncurative debulking surgery or ablation is not recommended; chemotherapy is recommended for those with only liver or lung metastases that cannot be surgically removed; the committee believes that the risks of resection of asymptomatic primary tumors in unresectable cases far outweigh the benefits. Palliative resection is only appropriate for impending obstruction or acute bleeding. Removal of the primary tumor does not reduce the risk of perforation with bevacizumab, as perforation of the colon and primary focus is rare. (3) Concomitant abdominal metastases Palliative surgical resection, including colectomy, diverting colectomy, bypass or stenting, followed by chemotherapy should be performed in patients with abdominal metastases that are likely to produce obstruction soon.