Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab. In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab. The median PFS was 9.4 months in the group receiving cetuximab and 10.7 months in the group not receiving cetuximab (P = .01). In a subset analysis, cetuximab-treated patients with tumors bearing a mutated KRAS gene had significantly decreased PFS compared with cetuximab-treated patients with wild type KRAS tumors (8.1 mo. vs. 10.5 mo.; P = .04). Cetuximab-treated patients with mutated KRAS tumors had a significantly shorter PFS compared with patients with mutated KRAS tumors not receiving cetuximab (8.1 mo. vs. 12.5 mo.; P = .003) as well as OS (17.2 mo. vs. 24.9 mo.; P = .03).[Level of evidence: 1iiDiii]
Panitumumab is a fully humanized antibody against the EGFR. In a phase III trial that has not yet been reported, patients with chemotherapy refractory colorectal cancer were randomly assigned to panitumumab or best supportive care. Patients receiving panitumumab experienced improved OS. Despite the preliminary nature of this study, the FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.
Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared to FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic colon cancer (11.4 months vs. 10.0 months, HR = 1.27; 95% CI, 1.06-1.52).[Level of evidence: 1iiDiii]
Second-line and third-line chemotherapy
Approximately 15% to 25% of colorectal cancer patients will present with liver metastases at diagnosis, and another 25% to 50% will develop metaschronous hepatic metastasis following resection of the primary tumor.[55,56,57] Although only a small proportion of patients with liver metastasis are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy provide a number of treatment options.
For patients with hepatic metastasis considered to be resectable (based on a limited number of lesions, intrahepatic locations of lesions, lack of major vascular involvement, absent or limited extrahepatic disease, and sufficient functional hepatic reserve), a negative-margin resection has resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[17,21,58,59,60,61] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.
Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease. Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide long-term tumor control.[62,63,64,65,66,67,68] Radiofrequency ablation and cryosurgical ablation remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.[69,70,71]