Stage IV and Recurrent Rectal Cancer
The Addition of Targeted Therapy to Multiagent Chemotherapy
Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL plus bevacizumab. The patients randomly assigned to IFL plus bevacizumab experienced a significantly better PFS (10.6 months with IFL and bevacizumab compared to 6.2 months with IFL plus placebo; HR for disease progression = 0.54; P <.001) and OS (20.3 months with IFL plus bevacizumab compared to 15.6 months with IFL plus placebo; HR for death = 0.66; P <.001). Investigators from the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients who had progressed on 5-FU-leucovorin and irinotecan to either FOLFOX or FOLFOX plus bevacizumab. The results demonstrated that patients randomly assigned to FOLFOX plus bevacizumab experienced a statistically significant improvement in PFS (7.3 months vs. 4.7 months: HR for progression = 0.61; P <.0001) and OS (12.9 months vs. 10.8 months; HR for death = 0.75; P = .001).[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.
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.[2,23,47,48] Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU-leucovorin to bolus and infusional 5-FU-leucovorin (LV5FU2), single-agent oxaliplatin, or FOLFOX4. Median TTP for FOLFOX4 versus LV5FU2 was 4.6 months versus 2.7 months (stratified log-rank test, 2-sided P < .001).[Level of evidence: 1iiDiii]
Erbitux 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 erbitux or irinotecan plus erbitux. Median TTP for patients receiving erbitux was 1.5 months compared to median TTP of 4.2 months for patients receiving irinotecan and erbitux.[Level of evidence: 3iiiDiv] On the basis of this study, erbitux was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.
The Crystal Study (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).