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Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 5041-5042 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.7158
Comments on Final Report of the AIO Colorectal Cancer Group Study: Fluorouracil/Oxaliplatin Versus Capecitabine/OxaliplatinF. Hoffmann-La Roche Ltd, Pharmaceutical Division, Pharma Business Oncology, Basel, Switzerland To the Editor: Following the publication of the article by Porschen et al,1 which reported final results from a randomized phase III trial of CAPOX (capecitabine plus weekly oxaliplatin) versus FUFOX (infusional fluorouracil/folinic acid plus oxaliplatin) in first-line metastatic colorectal cancer by the German Arbeitsgemeinschaft Internistische Onkologie (AIO) study group, I feel compelled to write and correct some of the factual inaccuracies in the article. In the Abstract and Discussion sections, the authors state that CAPOX resulted in slightly inferior efficacy than FUFOX. However, inferiority cannot be concluded statistically from the outcomes reported by Porschen et al1 because no rejection of the null hypothesis (ie, noninferiority could not be shown) does not automatically lead to an acceptance of the hypothesis that CAPOX is inferior to FUFOX. It is common knowledge that in order to test the inferiority of two regimens, an adequately designed superiority study has to be performed, and only a positive outcome of such a study can prove this hypothesis. In the discussion, some of the values quoted from other studies and illustrated in Table 3 are incorrect. In the NO16966 study, overall survival should be 18.8 months for XELOX (capecitabine plus 3-weekly oxaliplatin) versus 17.7 months for FOLFOX-4 (infusional fluorouracil/folinic acid plus oxaliplatin intent-to-treat population), and the patient numbers should be 317 in each group.2 For the French study, the response rate presented for XELOX versus FOLFOX should be 42% versus 46% (ie, the primary end point–response rate in the per-protocol population, independent review committee evaluation).3 Instead, Porschen et al1 selected a secondary end point (response rate in the intent-to-treat population), which had a statistically inconclusive result, without making this clear in the footnote to Table 3 in their article. Also in the Discussion, the authors suggest that bevacizumab offers benefit when added to XELOX but not to FOLFOX-4 according to the NO16966 study. This needs to be clarified. The preplanned comparisons showed no difference in progression-free survival (PFS) and overall survival: XELOX versus FOLFOX-4 (7.3 v 7.7 months and 18.8 v 17.7 months, respectively), and XELOX plus bevacizumab versus FOLFOX-4 plus bevacizumab (9.3 v 9.4 months and 21.4 v 21.2 months, respectively). As shown by Saltz et al,4 the FOLFOX-4 plus placebo group had a longer time interval between the end of adjuvant chemotherapy to relapse compared with the other arms (769 v 597 to 660 days) despite stratification for key prognostic factors, suggesting that there was an imbalance due to a better prognosis in some patients in this arm. This led to an unusually high PFS in this subgroup of patients (median, 8.6 months) compared with the original FOLFOX-4 arm (median, 7.6 months). This imbalance was not present in the XELOX plus placebo group or in the other groups in the study (XELOX, XELOX plus bevacizumab, FOLFOX-4, FOLFOX-4 plus bevacizumab). Porschen et al1 simply compared the XELOX plus placebo versus FOLFOX-4 plus placebo Kaplan-Meier PFS curves and concluded incorrectly for the whole study that bevacizumab improves efficacy only when added to XELOX but not to FOLFOX-4. This is not the case as the primary end point showed a statistically significant increase in PFS for bevacizumab in combination with chemotherapy. In addition, in a second-line study, Giantonio et al5 showed clearly that addition of bevacizumab to FOLFOX-4 improves PFS and overall survival versus FOLFOX-4 alone. I hope that the Journal sees fit to issue a corrected version of the article by Porschen et al1 with the factual inaccuracies listed above corrected. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Thomas Buechele, F. Hoffmann-La Roche Ltd (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Porschen R, Arkenau H-T, Kubicka S, et al: Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: A final report of the AIO colorectal study group. J Clin Oncol 25
: 4217
-4223, 2007 2. Cassidy J, Clarke S, Diaz-Rubio E, et al: XELOX compared to FOLFOX4: Survival and response results from XELOX-1/ NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25 : 18s , 2007 (suppl; abstr 4030) 3. Bennouna J, Ducreux M, Hebbar M, et al: Preliminary efficacy findings from a randomized phase III study of capecitabine + oxaliplatin (XELOX) vs. infusional 5-FU/LV + oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer (MCRC). 2007 Gastrointestinal Cancer Symposium Progaram/Proceedings, ASCO, 2007 , pp (abstr 272) 4. Saltz L, Clarke S, Diaz-Rubio E, et al: Bevacizumab (Bev) in combination with XELOX or FOLFOX4: Updated efficacy results from XELOX-1/ NO16966, a randomized phase III trial in first-line metastatic colorectal cancer. J Clin Oncol 25 : 18s , 2007 (suppl; abstr 4028) 5. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25
: 1539
-1544, 2007
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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