XELOX vs. FOLFOX-4 for metastatic colorectal cancer treatment

Treatment methods compared in two phase-3 studies.

Issue: May 25, 2008

XELOX treatment was found to be noninferior to FOLFOX-4 as a first-line treatment for metastatic colorectal cancer, and the addition of bevacizumab only slightly improved progression-free survival, according to findings published in the Journal of Clinical Oncology.

The researchers from various U.S. and international sites initially set out to evaluate how capecitabine (Xeloda, HLR) plus oxaliplatin (XELOX) compared with fluorouracil, folinic acid and oxaliplatin (FOLFOX-4) as a first-line treatment against metastatic colorectal cancer; however, the study was later amended after phase-3 data for bevacizumab (Avastin, Genentech) became available.

During the studies, the researchers enrolled patients (n=2,304) aged 18 years or older who had histologically confirmed colorectal cancer, unresectable metastatic disease, an ECOG performance status of ≤1 and a life expectancy of longer than three months. The patients were randomly assigned to either receive XELOX or FOLFOX-4 treatment; 1,401 of those patients were then also assigned to receive either bevacizumab or placebo.

Taking into account the pooled XELOX and FOLFOX-4 treatment arms results, median progression-free survival was calculated to be eight months vs. 8.5 months (HR=1.04; 97.5% CI, 0.93-1.16). Median overall survival for the XELOX arm was 19.8 months compared with 19.6 months for the FOLFOX-4 arm (HR=0.99; 97.5% CI, 0.88-1.12).

In the updated second study, median progression-free survival was 9.4 months for patients receiving bevacizumab and eight months for patients receiving placebo (HR=0.83; 97.5% CI, 0.72-0.95). Patients receiving bevacizumab had a median overall survival of 21.3 months compared with 19.9 months for patients receiving placebo (HR=0.89; 97.5% CI, 0.76-1.03). The patients’ response rates were also similar between groups. – by Cara Dickinson

This is a study that evolved during its enrollment. It started out as a straightforward FOLFOX vs. XELOX comparison and wound up as a more complex comparison of FOLFOX/XELOX with or without bevacizumab. The study results confirm the noninferiority of XELOX compared with FOLFOX; however, when bevacizumab was added to the oxaliplatin combinations, although there was a small benefit in terms of progression-free survival to the bevacizumab group, it was not nearly of the same increment as we have seen with bevacizumab in other studies. There was also no increase in response rate when bevacizumab was added compared with the other nonbevacizumab arms, which is distinctly different from other studies.

These results raise questions about the value of adding bevacizumab in these combinations. It may just be that bevacizumab can elevate lesser therapies to a certain threshold, but perhaps there is a limit to its effect. FOLFOX and XELOX may just be good enough on their own so that the added benefit of bevacizumab is significant but not quite as dramatic. It is also possible that these results were somewhat skewed because the treatment that was given was not contemporary. In general, patients with colon cancer receiving bevacizumab combination always get more therapy compared with the combination without bevacizumab because they receive treatment longer. In this study, there was no difference in the duration of therapy, which is probably because when the patients developed oxaliplatin neuropathy, all treatment was discontinued. This pattern of care may have diminished the effect of bevacizumab on progression-free survival, although it is worth emphasizing that there was no difference in response rate, which should have been unaffected by this in management of patients.

To conclude, FOLFOX and XELOX appear equivalent, with the caveat that the dosing of capecitabine in European patients (who made up the majority of patients in this study) is probably different than for American patients. The bevacizumab component of the study does raise the concern that bevacizumab may not add nearly as much to FOLFOX as we would have thought, and this challenges the current marketing and conventional wisdom.

– Alan Paul Venook, MD

HemOnc Today Editorial Board member

For more information:

Cassidy J, Clarke S, Díaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26:2006-2012.

Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019.