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Clinical Trial
. 2009 Jun 10;27(17):2848-54.
doi: 10.1200/JCO.2008.20.4552. Epub 2009 Apr 20.

Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841

George P Kim  1 , Daniel J Sargent, Michelle R Mahoney, Kendrith M Rowland Jr, Philip A Philip, Edith Mitchell, Abraham P Mathews, Tom R Fitch, Richard M Goldberg, Steven R Alberts, Henry C Pitot
Affiliations
Clinical Trial

Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841

George P Kim et al. J Clin Oncol. .

Abstract

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/m(2) 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.

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Conflict of interest statement

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

Figures

Fig 1.
Fig 1.
Second-line therapy: overall survival (N = 491). CPT-11, irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin.
Fig 2.
Fig 2.
Second-line therapy: time to progression (N = 491). CPT-11, irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin.
See this image and copyright information in PMC

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