© 2004 European Society for Medical Oncology
Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-fluorouracil and infusional 5-fluorouracil alone in advanced pancreatic carcinoma patients
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
]. 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] 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, 3]. Moreover, both continuous infusion and modulation by leucovorin have failed to increase the efficacy of 5-FU [4, 5]. It gives no advantage in combination with gemcitabine [6]. 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]. Although oxaliplatin is usually included in the FOLFOX regimen, Ducreux and colleagues [1] 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.
Hematology/Oncology Division, General Hospital of Annemasse, rue du Jura, Ambilly, BP 525, 74107 Annemasse Cedex, France
* Email: alliotcfr{at}yahoo.fr
References
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: 467–473.
2. Burris HA, Moore MJ, 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: 2403–2413.
3. Ducreux M, Rougier P, Pignon JP et al. A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma. Ann Oncol 2002; 13: 1185–1191.
4. Rubin J, Gallagher JG, Schroeder G et al. Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma. Cancer 1996; 78: 1888–1891.[CrossRef][Web of Science][Medline]
5. Lokich J, Chawla PL, Brooks J et al. Chemotherapy in pancreatic carcinoma: 5-fluorouracil (5FU) and 1,3,bis-(2 chloroethyl)-1-nitrosourea (BCNU). Ann Surg 1974; 179: 450–456.[Web of Science][Medline]
6. Berlin JD, Catalano P, Thomas JP 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: 3270–3275.
7. Alberts SR, Townley PM, Goldberg RM et al. Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II. Ann Oncol 2003; 14: 580–585.
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