Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who had progressed on 5-FU/LV and irinotecan to either FOLFOX or FOLFOX and bevacizumab. Patients randomly assigned to FOLFOX and bevacizumab experienced a statistically significant improvement in PFS (7.43 months vs. 4.7 months, HR, 0.61; P < .0001) and OS (12.9 months vs. 10.8 months, HR, 0.75; P = .0011).[Level of evidence: 1iiA] Based on these two studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.
There are currently no completed randomized controlled studies evaluating whether continued use of bevacizumab in the second line or third line after progressing on a first-line bevacizumab regimen is worthwhile.
Cetuximab/Panitumumab and Second-Line Chemotherapy
Second-line chemotherapy with irinotecan in patients treated with 5-FU-leucovorin as first-line therapy demonstrated improved OS when compared to either infusional 5-FU or supportive care.[2,23,54,55] Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU/LV to bolus and infusional 5-FU/LV, single-agent oxaliplatin, or FOLFOX4. The median TTP for FOLFOX4 versus 5-FU/LV was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[Level of evidence: 1iiDiii]
Cetuximab is a partially humanized monoclonal antibody against the epidermal growth factor receptor (EGFR). For patients who have progressed on irinotecan-containing regimens, a randomized phase II study was performed of either cetuximab or irinotecan and cetuximab. The median TTP for patients receiving cetuximab was 1.5 months compared to median TTP of 4.2 months for patients receiving irinotecan and cetuximab.[Level of evidence: 3iiiDiv] On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.
The Crystal Study (EMR 62202-013 [NCT00154102]) randomly assigned 1,198 patients with stage IV colorectal cancer to FOLFIRI with or without cetuximab. The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72–0.99, P = .048 by a stratified log rank test), but not OS.[Level of Evidence: 1iiDii] Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-epidermal growth factor receptor (EGFR) antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at code on 12 or 13 of the KRAS gene). A subset analysis evaluating efficacy vis a vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among KRAS wild-type patients, the HR favored the FOLFIRI/cetuximab group (HR, 0.68; 95% CI, 0.50–0.94).