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Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 5043-5045 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4676
Capecitabine Plus Oxaliplatin in Metastatic Colorectal CancerCancer Research UK, Department of Medical Oncology, University of Glasgow, Glasgow, Scotland To the Editor: Capecitabine, an oral fluoropyrimidine, is one of a number of new agents that has emerged for the treatment of colorectal cancer in the last decade. It has been approved as monotherapy in both the metastatic and adjuvant settings on the basis of successful phase III trials.1-3 The next logical step was to test capecitabine as the fluoropyrimidine component in combination regimens. To this end, five phase III noninferiority trials were undertaken to evaluate capecitabine-oxaliplatin regimens in the first- and second-line treatment of metastatic colorectal cancer (Table 1 details the trial regimens discussed). 4-8 Four of these studies4,6-8 used the XELOX regimen (oxaliplatin 130 mg/m2 on day 1 plus capecitabine 1,000 mg/m2 twice daily for 14 days every 3 weeks), which was selected by the manufacturer for development because of its efficacy, convenience, and manageable tolerability profile.9 The remaining study5 used an alternative regimen, CAPOX, in which the oxaliplatin dose is split and given on days 1 and 8.
The final results of two of these trials were published recently in the Journal.5,6 Díaz-Rubio et al6 described a randomized comparison of XELOX versus FUOX, an infusional fluorouracil-oxaliplatin regimen developed by the Spanish Treatment of Digestive Tumors group. Porschen et al,5 on behalf of the Arbeitsgemeinschaft Internistische Onkologie (AIO) Colorectal Study Group, reported a randomized comparison of CAPOX versus FUFOX, an infusional regimen of fluorouracil/folinic acid developed by the AIO. In both trials, the upper limit of the 95% CI exceeded the predefined noninferiority margin, but the lower limit of the 95% CI was less than 1.00, which means that the results with regard to noninferiority were inconclusive. Inferiority, as suggested by Porschen et al5 in their conclusions, cannot be concluded statistically from this outcome 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, 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.
I would also question the validity of the outcome reported by Porschen et al5 given the sample size calculation described. It is confusing that in the text the authors refer to one-sided 95% CIs whereas in the graphs they present two-sided 90% CIs. The power of the study was 80% for a one-sided test with an Another point worthy of comment is that there was an imbalance of restaging in the study performed by the AIO Colorectal Study Group5—an issue that was raised in two previous presentations of this study13,14 but not considered in the published article. Tumor assessments were generally performed earlier in the CAPOX arm than in the FUFOX arm, particularly during the first 20 weeks (median staging interval, 10 v 11 weeks). This tumor evaluation bias could have distorted the comparison of progression-free survival (PFS) in favor of FUFOX and caused the separation of PFS curves observed at week 21. I think that to gain a balanced perspective on the efficacy of capecitabine in this setting, the findings from all the relevant phase III trials need to be considered, rather than focusing solely on the first two published trials. Final results are also now available for the two other phase III trials in the first-line setting—NO16966, which compared XELOX versus FOLFOX-4,4 and a study conducted by a group of French investigators, which compared XELOX versus FOLFOX-6.7 Both trials demonstrated that XELOX was noninferior to the comparator FOLFOX regimen (Table 1). The results of the final phase III study (NO16967), which compared XELOX versus FOLFOX-4 in the second-line setting, also demonstrated noninferiority of the XELOX regimen.8 Of the four trials conducted in the first-line setting, I think it is important to recognize the relative size of NO16966,4 which had a patient population almost twice as large as that of all the other trials combined. NO16966 was started as a multinational, randomized two-arm comparison of XELOX versus FOLFOX-4. The protocol was subsequently amended to a 2 x 2 factorial (four-arm) design, and bevacizumab or placebo were added to the treatment arms. The study sought to address two questions: first, the noninferiority of XELOX ± bevacizumab/placebo versus FOLFOX-4 ± bevacizumab/placebo; and second, the superiority of bevacizumab versus placebo plus oxaliplatin-based chemotherapy (ie, XELOX or FOLFOX-4). The final results of the primary analysis, which involved more than 2,000 patients, clearly demonstrated the noninferiority of XELOX ± bevacizumab/placebo versus FOLFOX-4 ± bevacizumab/placebo. Some may argue that it is inappropriate to compare this result with the other phase III studies because approximately one third of the NO16966 study population received concurrent bevacizumab. However, the NO16966 study protocol also included a predefined statistical comparison of the nonbevacizumab-containing arms (n = 1,335), and this also clearly demonstrated noninferiority of XELOX versus FOLFOX-4 (Table 1). My point is that these two recently published trials are only the first of five trials. Their findings should not be viewed in isolation, but with consideration for the complete trial program. Overall, considering that statistical confidence is in part determined by sample size, the results of NO16966, together with the other data available, should serve to give us clinical confidence that XELOX is noninferior to infusional fluorouracil-oxaliplatin regimens. XELOX is emerging as an effective regimen for the treatment of patients with metastatic colorectal cancer, and one that offers the unique benefits of an oral fluoropyrimidine. As we move toward individualized therapy, the properties offered by XELOX should be considered alongside those of the other regimens available to us so that we select the one that suits our patient's needs best. 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: None Consultant or Advisory Role: Jim Cassidy, Roche (C), Sanofi-Synthelabo (C) Stock Ownership: None Honoraria: Jim Cassidy, Roche, Sanofi-Synthelabo Research Funding: Jim Cassidy, Roche Expert Testimony: None Other Remuneration: None
REFERENCES
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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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value of 5%. However, it is recommended that noninferiority studies should use a two-sided test with an 
