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).
Despite the lack of direct data, in standard practice, bevacizumab was added to FOLFOX as a standard first-line regimen based on the results of NCCTG-N9741. Subsequently, in a randomized phase III study, patients with untreated, stage IV colorectal cancer were randomly assigned in a 2 × 2 factorial design to CAPOX versus FOLFOX4, then to bevacizumab versus placebo. PFS was the primary endpoint. In this trial, 1,401 patients were randomly assigned, and the median PFS was 9.4 months for patients receiving bevacizumab and 8.0 months for the patients receiving placebo (HR, 0.83; 97.5% confidence interval [CI], 0.72–0.95; P = .0023).[Level of evidence: 1iiDiii] Median OS was 21.3 months for patients receiving bevacizumab and 19.9 months for patients receiving placebo (HR, 0.89; 97.5% CI, 0.76–1.03, P = .077). The median PFS (intention-to-treat analysis) was 8.0 months in the pooled CAPOX-containing arms versus 8.5 months in the FOLFOX4-containing arms (HR, 1.04; 97.5% CI, 0.93–1.16), with the upper limit of the 97.5% CI being below the predefined noninferiority margin of 1.23.[51,52] The effect of bevacizumab on OS is likely to be less than what was seen in the original Hurwitz study.
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]