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Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer

Jim Cassidy, Stephen Clarke, Eduardo Díaz-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Mikhail Lichinitser, Tsai-Shen Yang, Fernando Rivera, Felix Couture, Florin Sirzén, Leonard Saltz

From the Beatson Oncology Centre, Glasgow, United Kingdom; University of Sydney and Sydney Cancer Centre, Sydney, Australia; Hospital Clínico San Carlos, Madrid; Hospital Marques De Valdecilla, Santander, Spain; Vienna University Medical School, Vienna, Austria; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Cancer Care Manitoba, St Boniface General Hospital, Winnipeg, Manitoba; Cross Cancer Institute, Edmonton, Alberta; CHUQ L'Hotel-Dieu De Quebec, Quebec, Canada; Russian Cancer Research Center, Moscow, Russian Federation; Chang-Gung Memorial Hospital, Taipei, Taiwan; F. Hoffmann-La Roche, Basel, Switzerland; and the Memorial Sloan Kettering Cancer Center, New York, NY

Corresponding author: Jim Cassidy, MD, Glasgow University, Garscube Estate, Switchback Rd, Glasgow, Scotland, G61 1BD; e-mail: j.cassidy{at}beatson.gla.ac.uk

Purpose To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to fluorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as first-line therapy in metastatic colorectal cancer (MCRC).

Patients and Methods The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 x 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecified primary end point for the noninferiority analysis was progression-free survival.

Results The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 x 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4–containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4.

Conclusion XELOX is noninferior to FOLFOX-4 as a first-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients.

Supported by Roche.

Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29- October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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