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Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: pp. 5045-5046 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4841
In ReplyHospital Bremen East, Bremen, Germany
Medical School Hannover, Hannover, Germany
University Salzburg, Salzburg, Austria
University Clinic, Ulm, Germany
Private Oncology Clinic Hildesheim, Germany
Robert-Rössle-Clinic, Helios Clinic, Charité Berlin-Buch, Berlin, Germany
Hospital Maria Hilf, Mönchengladbach, Germany
Mayo Clinic, Rochester, MN
WISP, Research Institute, Langenfeld, Germany
Ruhr-University Bochum, Bochum, Germany
Martin-Luther-University, Halle, Germany Throughout the last few years, different randomized phase II and III trials have investigated the role of oxaliplatin in combination with either capecitabine or infusional fluorouracil. The goal of these studies was to show noninferiority of the oral versus the infusional combination. It was thought that capecitabine was more convenient for patients and thus their preferred choice. Currently, two phase III trials have been published in this Journal.1-2 A smaller phase II study has been published recently and reports of other studies have been communicated at various meetings.3-6 We greatly appreciate the comments and questions raised by Dr Cassidy. He summarized the results of the published Arbeitsgemeischaft Internistische Onkologie (AIO) and Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) phase III trials, the results of the Roche (Grenzach-Wyhlen, Germany) investigator study NO16966 including a subgroup analysis, and the results of a French phase II trial. In his analysis, he did not include the results of the randomized American TREE-1 trial and results of the randomized Italian FOCA trial. We agree with Dr Cassidy's conclusion that capecitabine plus oxaliplatin (CAPOX)/capecitabine plus oxaliplatin (XELOX) has comparable clinical efficacy compared with infusional fluorouracil (FU) plus folinic acid plus oxaliplatin/oxaliplatin plus leucovorin plus FU (FOLFOX)/infusional FU plus oxaliplatin, and we support his notion that the combination of capecitabine and oxaliplatin with or without a biologic agent is a valuable alternative to infusional fluorouracil based regimens in the first- and second-line setting for patients with metastatic colorectal cancer. However, in this context we have to draw the reader's attention on results that have been consistently found in the communicated phase II and III trials. In most first-line trials,response rate (RR) and progression-free survival (PFS) trended inferior in the oral combination cohort. These findings were also seen in the other randomized phase II trials, TREE-1 and FOCA. TREE-1 demonstrated RR, time to treatment failure, and PFS for CAPOX to be inferior to mFOLFOX (29% v 39%; 4.4 v 6.4 months and 5.9 v 8.7 months). The same applied for the FOCA trial, where the RR was 43.5% for the oral combination and 48.2% for the infusional combination (RR was the primary end point). In the French study mentioned by Dr Cassidy, a difference of 4.7% in RR in favor for FOLFOX6 compared to XELOX was observed. The primary end point of this study was best RR of the per protocol (PP) treated population assessed by an independent review committee. The upper limit of the 95% CI was 14.4% and just below the noninferiority margin of 15%. For the intention-to-treat population (ITT), the upper limit of the 95% CI was 16.2% and above the noninferiority margin. Similar to the Spanish TTD trial, our study found a comparable clinical outcome for CAPOX; however, the limit of the one-sided 95% CI in both studies breached the prespecified limit for noninferiority, which did not permit the exclusion of a relevant inferiority.
A noninferiority hypothesis is one-sided in nature, and thus, the application of a two-sided test, as recommended by Dr Cassidy, would be a rather illogical procedure. Moreover, the one-sided 95% CI of our primary objective corresponds well with the two-sided 90% CI, as the latter provides the boundaries of both the one-sided 95% CIs (the lower one not referring to our primary objective, but nevertheless presented, as the reader would ask for this information). The In fact, the "inconclusiveness" result of our study was not related to "power" or "one-/two-sided items," but rather the actually detected hazard ratio (HR) of 1.17, which unexpectedly diverged from the 1.0 anticipated by our group when designing this study. For example, in order to distinguish a true HR of 1.17 from the 1.23 noninferiority boundaries defined in the NO16966 trial, one would require a study with more than 10,000 patients, which is obviously not feasible. Finally, the imbalance in restaging, mentioned by Dr Cassidy, could not explain the observed differences in PFS which were confirmed in a sensitivity analysis. We agree with Dr Cassidy that the two published trials should not be viewed in isolation and that different treatment schedules used in these studies may have influenced the outcome. In addition, statistical considerations were different in both studies; moreover, the outcome of his own (larger) study showed clearly noninferiority for XELOX with regards to PFS. A preliminary meta-analysis, based on the currently published data of the randomized trials comparing XELOX/CAPOX versus infusional fluorouracil combined with oxaliplatin, supports Dr Cassidy's findings, (Fig 1; fixed effect model).
With the exception of the Italian phase II trial, there was no striking interstudy heterogeneity, even though considering the fact that the "standard" therapy was different in each of the five trials. The pooled estimation for PFS (HR, 1.07) suggested a slightly higher efficacy of the fluorouracil regimens. However, the upper limit of the 95% CI (1.16) was clearly within the range that is generally accepted as nonrelevantly inferior. Even the upper limit of the CI in an alternatively calculated random effects model, allocating somewhat more weight to the smaller trial amounted to 1.20 and still remained within that range. We appreciated Dr Cassidy's valuable comments, and we hope our meta-analysis is helpful in this context to clarify the efficacy of CAPOX/XELOX in comparison with infusional fluorouracil/oxaliplatin-based regimens in colorectal cancer. AUTHORS' 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: None Stock Ownership: None Honoraria: Rainer Porschen, Roche, Sanofi-Aventis; Stefan Kubicka, Roche, Sanofi-Aventis; Axel Grothey, Roche, Sanofi-Aventis; Ullrich Graeven, Roche, Sanofi-Aventis; Albrecht Kretzschmar, Roche; Hans-Joachim Schmoll, Roche, Sanofi-Aventis Research Funding: Rainer Porschen, Roche, Sanofi-Aventis; Stefan Kubicka, Roche, Sanofi-Aventis Expert Testimony: None Other Remuneration: None
ACKNOWLEDGMENTS Hans-Joachim Schmoll is writing on behalf of the Arbeitsgemeinschaft Internistische Onkologie (AIO) Colorectal Study Group. REFERENCES
1. Porschen R, Arkenau HT, 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
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-4223, 2007 2. Diaz-Rubio E, Tabernero J, Gomez-Espana A, et al: Phase III study of capecitabine plus oxaliplatin versus continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: Final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors trial. J Clin Oncol 25
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-4230, 2007 3. Ducreux M, Bennouna J, Hebbar M, et al: Efficacy and safety findings from a randomized phase II study of capecitabine + oxaliplatin (XELOX) vs infusional 5-FU/LV + oxaliplatin (FOLFOX-6) as firstline treatment for metastatic colorectal camcer (MCRC). 2007 Gastronintestinal Cancers Symposium Program/Proceedings, 2007 , 220 (abstr 272) 4. Hochster HS, Welles L, Hart L, et al: Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first line treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 studies. J Clin Oncol 23 : 16 , 2005 (abstr 3515) 5. Martoni AA, Pinto C, Di Fabio F, et al: Capecitabine plus oxaliplatin (xelox) versus protracted 5-fluorouracil venous infusion plus oxaliplatin (pvifox) as first-line treatment in advanced colorectal cancer: A GOAM phase II randomised study (FOCA trial). Eur J Cancer 42 : 3161 -3168, 2006[CrossRef][Medline] 6. Cassidy J, Clarke S, Diaz-Rubio E, et al: XELOX compared to FOLFOX4: Survival and response results from XELOX-1/NO166966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25 : 18s , 2007 (abstr 4030) 7. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials. Stat Med 18:1905-1942, 1999 8. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352
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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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error and power levels are a different matter,
