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Colorectal liver metastasis(CLM)is common worldwide.Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials,and are now becoming standards for patients with CLM.Thedevelopment and application of anti-epidermal growth factor receptor(anti-EGFR)and anti-vascular endothelial growth factor(anti-VEGF)antibodies represents significant advances in the treatment of this disease.However,new findings continue to emerge casting doubt on the efficacy of this approach.The Kirsten ratsarcoma viral oncogene(KRAS)has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM.Whereas a recent study summarizedseveral randomized controlled trials,and showed thatpatients with the KRAS G13D mutation significantlybenefited from the addition of cetuximab in terms of progress-free survival(PFS,4.0 mo vs 1.9 mo,HR=0.51,P=0.004)and overall survival(OS,7.6 mo vs5.7 mo,HR=0.50,P=0.005).Some other studiesalso reported that the KRAS G13D mutation might notbe absolutely predictive of non-responsiveness to antiEGFR therapy.At the same time,“new”RAS mutations,including mutations in neuroblastoma RAS viral(vras)oncogene homolog(NRAS)and exons 3 and 4 of KRAS,have been suggested to be predictors of a poor treatment response.This finding was first reported by the update of the PRIME trial.The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations,panitumumab-fluorouracil,leucovorin,and oxaliplatin(FOLFOX)4 treatment led to inferior PFS(HR=1.28,95%CI:0.79-2.07)and OS(HR=1.29,95%CI:0.79-2.10),which was consistent with the findings in patients with KRAS mutations in exon 2.Then,the update of the PEAK trial and the FIRE-Ⅲtrial also supported this finding,which would reduce candidates for anti-EGFR therapy but enhance the efficacy.In firstline targeted combination therapy,the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-Ⅶtrial.Also,bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966trial.By the update and further analysis of the COIN trial and the NORDIC-Ⅶtrial,cetuximab plus FOLFOX was reported to be reliable again.But bevacizumab plus oxaliplatin-based chemotherapy was still controversial.In addition,some trials have reported that bevacizumab is not suitable for conversion therapy.The results of the FIRE-Ⅲtrial showed that cetuximab led to a significant advantage over bevacizumab in response rate(72%vs 63%,P=0.017)for evaluable population.With the balanced allocation of second-line treatment,the FIRE-Ⅲtrial was expected to provide evidence for selecting following regimens after first-line progression.There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM,although the combined regimen is often administered based on experience.Combination therapy with more than one targeted agent has been proven to provide no benefit,and even was reported to be harmful as first-line treatment by four large clinical trials.However,recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment.The mechanism of antagonism between different targeted agents deserves further study,and may also provide greater understanding of the development of resistance to targeted agents.
Colorectal liver metastasis (CLM) is common worldwide. Established therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. Development and application of anti-epidermal growth factor receptor (anti-EGFR) and The anti-vascular endothelial growth factor (anti-VEGF) antibodies have significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. Kirsten rats arcoma viral oncogene (KRAS) has been proven to be a pivotal predictor of the success of anti-EGFR treatment in CLM. Whilst a recent study summarized substantially randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Other other studies have reported that the KRAS G13D mutation may notbe absolutely predictive of non-responsiveness to antiEGFR therapy. At the same time, “new” RAS mutations, including mutations in neuroblastoma RAS viral (vras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX ) 4 treatment led to inferior PFS (HR = 1.28, 95% CI: 0.79-2.07) and OS (HR = 1.29, 95% CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2 .Then, the update of the PEAK trial and the FIRE-IIItrial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. Firstline targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII rt ial.Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. The updated and further analysis of the COIN trial and the NORDIC-Ⅶ trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial.In addition, some trials have reported that bevacizumab is not suitable for conversion therapy.The results of the FIRE-IIItrial pattern that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, p = 0.017) for evaluable population .With the balanced allocation of second-line treatment, the FIRE-III was was to provide evidence for following the regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combining therapy with more than on e targeted agent has been proven to provide no benefit, and even was was reported to be harmful as first-line treatment by four large clinical trials. Recent, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents.