9. Principles of treatment of metastatic disease
7. Chemotherapy for progressive or metastatic disease
(9) KRAS, NRAS, BRAF
The committee strongly recommends that patients with metastatic colorectal cancer should be tested for RAS, 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 recommended 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 after progression of metastatic disease 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 of.
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 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 are also recommended options.
(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 In patients receiving FOLFOXIRI as initial therapy, cetuximab or panitumumab alone or in combination with irinotecan is the recommended option 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 of the study 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 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 for 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 false positives can also 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, 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 in combination with cetuximab) followed by simultaneous or fractionated colectomy and hepatopulmonary resection of colon and liver metastases.
(iii) Adjuvant chemotherapy (same regimen as above) and resection of metastatic lesions after colectomy. Neoadjuvant 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
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 6-8 weeks after surgery before restarting bevacizumab treatment. 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 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.