Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.
When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[Level of evidence: 1iiDiii]
Randomized phase III trials have addressed the equivalence of substituting capecitabine for infusional 5-FU. Two phase III studies have evaluated FUOX versus CAPOX.[59,60]
- 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.
Before the availability of cetuximab, panitumumab, bevacizumab, and aflibercept as second-line therapy, second-line chemotherapy with irinotecan in patients treated with 5-FU/LV as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[61,62,63,64]
Similarly, a phase III trial randomly assigned patients who progressed on irinotecan and 5-FU/LV to bolus and infusional 5-FU/LV (LV5FU2), single-agent oxaliplatin, or FOLFOX4. The 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]
Bevacizumab is a partially humanized monoclonal antibody that binds to vascular endothelial growth factor. Bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.
- After bevacizumab was approved, the BICC-C trial was amended, and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab.
- Although the primary endpoint, PFS, was not significantly different, patients receiving FOLFIRI/bevacizumab had a significantly better OS (not yet reached with a median follow-up of 22.6 months vs. 19.2 months, P = .007).
- Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL and bevacizumab.
- The patients randomly assigned to IFL and bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL and bevacizumab, as compared with 6.2 months in the group given IFL and placebo; HR for disease progression, 0.54; P < .001) and OS (20.3 months in the group given IFL and bevacizumab, as compared with 15.6 months in the group given IFL and placebo corresponding to an HR for death, 0.66; P < .001).[Level of evidence: 1iiA]
- 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 the NCCTG-N9741 trial. 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% 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.[68,69]
- 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 randomly assigned patients who had progressed on 5-FU-leucovorin 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]