Originally published as JCO Early Release 10.1200/JCO.2008.20.4552 on April 20 2009

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Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841

Mayo Clinic Jacksonville, Jacksonville, FL; Mayo Clinic Rochester, Rochester, MN; Carle Cancer Center Community Clinical Oncology Program, Urbana, IL; Southwest Oncology Group Operations Office, San Antonio, TX; Eastern Cooperative Oncology Group Data Management Office, Brookline, MA; Missouri Valley Cancer Consortium, Omaha, NE; Mayo Clinic Arizona, Scottsdale, AZ; and University of North Carolina at Chapel Hill, Chapel Hill, NC.

Corresponding author: George P. Kim, MD, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: kim.george{at}mayo.edu.

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated.

Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m² every 3 weeks) or arm B (FOLFOX4).

Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias.

Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-35269, CA-60276, CA-52352, CA-63849, CA-37417, CA-35195, CA-35101, CA-35103, CA-35448, CA-35113, and CA-35415 from the National Cancer Institute Department of Health and Human Services.

This study was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic.

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

Clinical trial information can be found for the following: NCT00005036 [ClinicalTrials.gov] .

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