Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-fluorouracil and infusional 5-fluorouracil alone in advanced pancreatic carcinoma patients
Authors: C. Alliot
Journal: Annals of Oncology (2004)

Advanced pancreatic carcinoma carries a poor prognosis, with a median survival ∼3–6 months. In a randomized phase II study of patients with advanced pancreatic carcinoma, Ducreux and colleagues evaluated oxaliplatin 130 mg/m2 alone, oxaliplatin with 5-fluororuacil (5-FU) (1000 mg/m2 days 1–4) and 5-FU alone [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 (81) Google Scholar]. Combination chemotherapy gave the best results, with a response rate of 10%, median time to progression of 4.2 months and median survival of 9 months. Nevertheless, this study is questionable in several aspects. The first point is the choice of the single-agent arms, which led to short survivals (2.4 and 3.4 months with 5-FU and oxaliplatin, respectively), confirming its inefficacy. The current study started in November 1997, despite the fact that after the publication of Burris et al. [2.Burris H.A. Moore M.J. Andersen J. et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomised trial.J Clin Oncol. 1997; 15: 2403-2413Crossref PubMed Scopus (5166) Google Scholar] in June 1997, gemcitabine rapidly became the standard care. Moreover, gemcitabine administered at fixed dose rate seems to be even more efficacious. Although combinations of 5-FU and cisplatin have frequently been used in patients with good general status in France, 5-FU alone has not been administered for many years. Despite an inevitable selection of relatively favourable cases, several recent studies have demonstrated that 5-FU alone gives no responses and does not prolong survival [2.Burris H.A. Moore M.J. Andersen J. et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomised trial.J Clin Oncol. 1997; 15: 2403-2413Crossref PubMed Scopus (5166) Google Scholar, 3.Ducreux M. Rougier P. Pignon J.P. et al.A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma.Ann Oncol. 2002; 13: 1185-1191Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. Moreover, both continuous infusion and modulation by leucovorin have failed to increase the efficacy of 5-FU [4.Rubin J. Gallagher J.G. Schroeder G. et al.Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma.Cancer. 1996; 78: 1888-1891Crossref PubMed Scopus (48) Google Scholar, 5.Lokich J. Chawla P.L. Brooks J. et al.Chemotherapy in pancreatic carcinoma: 5-fluorouracil (5FU) and 1,3,bis-(2 chloroethyl)-1-nitrosourea (BCNU).Ann Surg. 1974; 179: 450-456Crossref PubMed Scopus (18) Google Scholar]. It gives no advantage in combination with gemcitabine [6.Berlin J.D. Catalano P. Thomas J.P. et al.Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group trial E2297.J Clin Oncol. 2002; 20: 3270-3275Crossref PubMed Scopus (701) Google Scholar]. Above all, continuous infusion is extremely restrictive for patients with a very short life expectancy. Given synergies with many drugs, it is also true that oxaliplatin gives higher response rates in combination, typically in tumors with higher chemosensitivity such as colorectal carcinoma or ovarian carcinomas. Nevertheless, a phase II study of the combination of gemcitabine and oxaliplatin showed modest results, with a median time to progression of 4.5 months, suggesting no evidence of superiority over gemcitabine alone [7.Alberts S.R. Townley P.M. Goldberg R.M. et al.Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II.Ann Oncol. 2003; 14: 580-585Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Although oxaliplatin is usually included in the FOLFOX regimen, Ducreux and colleagues [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 (81) Google Scholar] have created a new variant, increasing the confusion. A tremendous number of phase II studies exploring doublets with various combinations of old and new drugs including taxanes, irinotecan, platinum compounds or fluoropyrimidines have been published since the end of the 1990s, showing, at best, marginal improvements. The evolution of this proliferation of phase II studies to phase III studies would take decades. Given the poor prognosis and low probability of obtaining significant improvements with the current cytotoxic drugs, quality of life should remain one of the primary objectives for pancreatic carcinoma. In this regard, the oral route as well as regimens compatible with home chemotherapy should be preferred. A certain number of factors that are predictive of response to chemotherapy, such as CA 19-9, serum albumin, total bilirubin, C-reactive protein or performance status, might be applied. Since the vast majority of the patients do not benefit from current costly regimens, while on the other hand there are good responders with prolonged survival and an increasing variety of drugs, studies should be orientated towards molecular predictive factors of response to a given drug.