Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[47,48] The AIO Colorectal Study Group randomly assigned 474 patients to either FUFOX or CAPOX. The median PFS was 7.1 months for the CAPOX arm and 8.0 months for the FUFOX arm (HR, 1.17; 95% CI, 0.96–1.43: P = .117), and the HR was in the prespecified equivalence range. The Spanish Cooperative Group randomly assigned 348 patients to CAPOX or FUOX. The TTP was 8.9 months versus 9.5 months (P = .153) and met the prespecified range for noninferiority.[Level of evidence: 1iiDiii] When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.
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 with 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 with 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 (NCT00003594). 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.