Response to the letter “Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU and infusional 5-FU alone in advanced pancreatic carcinoma patients”, by C. Allior (Ann. Oncol 2004; 15: 1576–1577)
Authors: M. Ducreux, E. Mitry, M. Ould-Kaci, V. Boige, J.F. Seitz, R. Bugat, J.L. Breau, O. Bouché, P.L. Etienne, J.M. Tigaud, F. Morvan, E. Cvitkovic, P. Rougier
Journal: Annals of Oncology (2004)

The authors thank Dr Alliot for his thoughtful letter, and agree with most of his considerations, discussion and well thought-out approach to the possibility of finding molecular predictive factors for specific drugs or regimens. Nonetheless, some misconceptions and/or misunderstandings need to be clarified with respect to the timing and rationale for the published study [1.Ducreux M. Mitry E. Ould-Kaci M. et al.Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone in advanced pancreatic carcinoma patients.Ann Oncol. 2004; 15: 467-473Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar], so that his comments can be considered in the correct context. Most of the authors of our paper are indeed firm advocates of the fixed rate gemcitabine infusion, which was first prospectively assessed in a comparative trial reported in abstract form in 1999 by Tempero et al. [2.Tempero M. Plunkett W. van Haperen Ruiz et al.Randomized phase II trial of dose intense gemcitabine by standard infusion vs fixed dose rate in metastatic pancreatic adenocarcinoma.Proc Am Soc Clin Oncol. 1999; 18 (Abstr): 273aGoogle Scholar] as a more efficient (more active, less toxic) way to administer this agent. This led one of the participants to design the optimal GEMOX (gemcitabine–oxaliplatin) (E.C.) combination later adopted by the GERCOR group in its studies on this disease [3.Louvet C. André T. Lledo G. et al.Gemcitabine combined with oxaliplatin (GEMOX) combination in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study.J Clin Oncol. 2002; 20: 1512-1518Crossref PubMed Scopus (210) Google Scholar]. Gemcitabine was not approved for the treatment of pancreatic cancer in France until April 1998, given its minimal benefit over what we consider suboptimal (bolus) administration of 5-fluorouracil (5-FU). On the other hand, our choice of infusional 5-FU (a better way of giving 5-FU, before capecitabine became available) as a control was based on its proven marginal activity in pancreatic cancer reported for a number of published phase III studies (of which, one is referenced in our manuscript: Maisey et al. [4.Maisey N. Chau I. Cunningham D. et al.Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer.J Clin Oncol. 2002; 20: 3130-3136Crossref PubMed Scopus (111) Google Scholar]). Given that our study was initiated at the time that identification of oxaliplatin–5-FU synergy was resulting in an overhaul of the treatment and natural history of advanced colon cancer, and that its activity had been reported in many other settings, we had no other alternative than to choose the correct ethical control to benchmark the combination activity exploration beyond a single-arm phase II trial, which also allowed us to obtain at the same time, once and for all, single-agent data on oxaliplatin activity in pancreatic cancer. We consider that although the results of our trial are modest and have been published in full relatively late, they provide valuable information to many colleagues, and will allow oncologists to avoid needless ‘second guessing’. The excellent safety profile of the oxaliplatin–5-FU combination provides a valid alternative for the small but prevalent population of patients who cannot be treated with gemcitabine due to its pulmonary toxicity, a short time interval with radiotherapy, or who have failed gemcitabine–platinum-based therapies. In summary, given that gemcitabine was not available in France at the time of the conception of this study, we considered (and still do) that the study presented was one of the best alternatives available for the treatment of pancreatic cancer patients within a clinical research initiative. Its results were beneficial to a small proportion of long-term responding patients during its conduct, and the oncologic community through its reporting.