1.Surgical treatment of colorectal cancer metastasis
Studies have shown that surgical resection of colorectal cancer liver metastases is potentially curative for selective patients, with a 5-year disease-free survival of up to 20%. Colorectal cancer can also develop pulmonary metastases, and most of the recommended treatment strategies for liver metastases are also applicable to pulmonary metastases, and combined hepatopulmonary resection is only suitable for highly selective patients. There are also data suggesting re-surgical resection of 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. For 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.
2.Liver treatment
Although the standard treatment for resectable metastatic disease is surgical resection, local non-surgical treatment of the liver can also be performed for a particular patient.
(1) Hepatic artery infusion (HAI)
The side effects of HAI therapy include biliary 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 therapy
Transarterial chemoembolization (TACE) includes hepatic artery cannulation to cause 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 should only be used for highly selected patients, while the latter is only suitable for patients with limited hepatic and pulmonary metastases or patients with significant symptoms or clinical trials, and should not irradiate the surgical site.
(4) Tumor ablation
Ablative therapy can be considered for patients who cannot physically tolerate resection surgery. Ablative 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.
3. Abdominal metastases
Colorectal metastases occur in about 17% of patients and only peritoneal metastases in 2% of patients, and PFS and OS are usually shorter in such patients than in patients without peritoneal metastases. Treatment is mostly palliative in nature. The committee warned that bevacizumab treatment in patients with colorectal stents increases the risk of perforation.
Cytoreductive surgery and perioperative warmed intraperitoneal chemotherapy (HIPEC) for abdominal metastases have been described with high treatment-related complications, mortality rates of 8%, and seemingly no improvement in long-term survival, and the committee currently believes that the use of cytoreductive surgery in combination 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.
4. Determination of resectability
Patients 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 should be noted that the size of the tumor alone is not a contraindication to tumor resection. The purpose of resecting liver metastases is to cure the disease and there is no benefit from debulking surgery.
5. Conversion to resectable
Most patients diagnosed with metastases have unresectable disease; however, limited metastases in 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 metastases and convert them to resectable; those with multiple metastases in the liver or lung, 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.
6. Neoadjuvant and adjuvant therapy for resectable disease
The Committee recommends that systemic chemotherapy be administered to metastatic patients after resection to remove residual disease, with a perioperative treatment period of approximately 6 months. The choice of preoperative and postoperative chemotherapy regimens is dependent on chemotherapy history and response, safety, and consistency in recommended regimens for adjuvant and neoadjuvant chemotherapy. If the tumor continues to grow at the time of neoadjuvant chemotherapy, it will be 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 should be limited to 2-3 months.
7.Chemotherapy for progressive or metastatic disease
Drugs used to treat multiply metastatic colorectal cancer can be used 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 more intense chemotherapy, one of the following five regimens is recommended: FOLFOX, FOLFIRI, CapeOX, 5-FU/LV, or FOLFOXIRI.
(1) Treatment sequence and timing
Prior to the era of targeted therapy, studies have shown that there was little difference in clinical outcomes whether strong 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) Non-recommended regimens
The IFL regimen is not recommended because of its toxicity and reduced effectiveness; the CapeIRI regimen or 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; the chance of side effects may be higher in North American patients and should be closely monitored and dose adjusted according to side effects. Recent studies have shown that hand-foot syndrome is associated with improved OS.
(4) Toxicity of irinotecan
The major ones include 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 patients who have developed toxicity.
(5) 5-FU/LV or capecitabine therapy
The guidelines recommend 5-FU/LV or capecitabine with or without bevacizumab for patients who cannot tolerate strong chemotherapy. If this less intensive therapy does not improve the patient’s functional status, it is appropriate to change to supportive therapy; if the status improves, the more intensive treatment regimen should be used as recommended above.
(6) FOLFOXIRI
This strong chemotherapy should only be used in highly selected patients who are likely to convert to resectable disease.
(7) Bevacizumab
It is a humanized monoclonal antibody that is 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 post-resection stage IV disease 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. Previous clinical studies suggested that discontinuation of anti-VEGF therapy may accelerate recurrence, make recurrent tumors more aggressive, and increase mortality, but recent findings suggest 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 have their primary or metastatic tumors tested for RAS and BRAF. 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 therapies if mutations are present. Anti-EGFR agents have no role in stage I, II, or III patients and are not recommended for testing.
KRAS mutations are early events in colorectal cancer, and there is a strong correlation between mutation status in primary and metastatic sites. Specimens from new biopsies are not required for the sole purpose of identifying RAS status unless neither primary nor metastatic specimens are present. The committee recommends that KRAS, NRAS, and BRAF testing should only be performed in CLIA-88-authorized laboratories, with no specific testing recommended. patients with RAS mutations should not receive treatment with cetuximab and panitumumab.
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 cetuximab + FOLFOX should be used with caution in the treatment of patients with resectable metastases and potentially transformable resectable patients. 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 after progression of metastatic disease is dependent on previous therapy. The committee does 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 of
① Patients receiving FOLFOX or CapeOX initial therapy with FOLFIRI or irinotecan alone or in combination with cetuximab or panitumumab (RAS wild type), bevacizumab or abciximab are also recommended options.
(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 For patients receiving FOLFOXIRI as initial therapy, cetuximab or panitumumab alone or in combination with irinotecan is the recommended choice for patients with wild-type RAS.
(12) Use of bevacizumab in non-first-line conditions
Bevacizumab was added to second-line therapy in the 2013 edition of the guideline based on the findings of the Committee and can be combined with any regimen (excluding other biologics); evidence for combination with irinotecan is lacking, but it is acceptable for patients progressing on 5-FU/LV-containing or capecitabine regimens. Bevacizumab may be added after progression if bevacizumab is 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 treatment and the patient was not on an irinotecan-containing regimen for first-line treatment.
(15) Regifenib
The Committee recommends regrafinib for third-line and beyond treatment of chemotherapy-resistant metastatic colorectal cancer. For patients with mutant RAS, regefenib is used in third-line therapy, and patients with wild-type RAS receive regefenib 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 investigations, 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, as there can be temporary negative results after chemotherapy and false positives can be formed 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 limited to hepatic metastases.
(1) Concurrent resectable hepatopulmonary metastases
Liver metastases from colorectal cancer can be resected simultaneously with the primary lesion or in stages. In the stage resection, the primary lesion is usually resected first, but nowadays it is more acceptable to resect the liver metastases first and then the primary lesion, followed by adjuvant chemotherapy. Additional data show that chemotherapy between liver and primary resection is effective in some patients.
If a patient has concurrent hepatopulmonary metastases that are resectable, the committee recommends the following options.
① concurrent or fractionated colectomy and hepatopulmonary resection followed by adjuvant chemotherapy, with FOLFOX or CapeOX preferred.
(ii) Neoadjuvant chemotherapy for 2-3 months (FOLFIRI, FOLFOX, CapeOX chemotherapy or in combination with bevacizumab, FOLFIRI, FOLFOX in combination with panitumumab, FOLFIRI in combination with cetuximab) followed by simultaneous or fractionated colectomy for colon and liver-pulmonary metastases.
(iii) Adjuvant chemotherapy (same regimen 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 available in experienced centers.
(2) Concurrent unresectable hepatopulmonary metastases
Patients should be evaluated every 2 months, and if bevacizumab is added, the last treatment should be at least 6 weeks apart from surgery, and bevacizumab should be restarted 6-8 weeks after surgery. Simultaneous or staged resection is feasible for those who have transformed into resectable disease. HAI treatment is also available in experienced centers. Ablation therapy alone or in combination with surgery is available for patients in whom all metastatic disease can be treated.
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 because 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. The treatment for non-obstructed patients is chemotherapy.
9. Treatment of non-concurrent metastatic disease
Investigation of metastatic disease includes enhanced CT or MRI, and PET/CT may also be considered to quickly identify the presence of other extrahepatic metastases, determine RAS status, and consider BRAF testing. Treatment of non-concurrent metastatic disease differs from concurrent metastatic disease in that treatment of resectable disease consists of resection and 6 months of perioperative chemotherapy, with regimens chosen based on prior chemotherapy history.
FOLFOX or CapeOX is the preferred regimen for those with no history of chemotherapy, and FLOX, capecitabine, and 5-FU/LV are also options. There are some cases where perioperative chemotherapy is not recommended, especially for those with a history of oxaliplatin chemotherapy who can be resected with the option of observation, and observation is also appropriate for tumors growing in neoadjuvant therapy. Chemotherapy is administered for unresectable disease, and HAI therapy is optional for those with only liver metastases. Patients receiving palliative chemotherapy should be evaluated with CT or MRI every 2-3 months.