R. interpreted the results of the experiments; L.E.N., R.J.V., and M.-S.G. prepared the figures; L.E.N. drafted the manuscript; L.E.N., R.J.V., J.M.C., M.-S.G., Y.I., and N.B.R. approved the final http://www.selleckchem.com/products/BI6727-Volasertib.html version of the manuscript; R.J.V., J.M.C., M.-S.G., Y.I., and N.B.R. edited and revised the manuscript. ACKNOWLEDGMENTS We thank Pere Puigserver for experimental suggestions and for reviewing the manuscript. Present address of M.-S. Gauthier: Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada H1W 4A4. Footnotes 1This article is the topic of an Editorial Focus by Mary C. Sugden and Mark J. Holness (49a).
Pancreatic adenocarcinoma is the fifth leading cause of death due to solid tumors in Western industrialized countries.

Because pancreatic adenocarcinoma is often difficult to detect in early stages, most patients are diagnosed with advanced or metastatic disease at first presentation [1,2]. The median survival of patients with locally advanced disease is 6 to 10 months, compared to 3 to 6 months for patients with metastatic disease [3]. Gemcitabine (Gemzar?; 2′,2′-difluorodeoxycytidine) is a pyrimidine antimetabolite and a specific analogue of deoxycytidine. At present, gemcitabine monotherapy remains the standard care for patients with locally advanced and metastatic pancreatic adenocarcinoma (LA/MPC) [4]. However, patients who receive this therapy have a median overall survival (OS) of only 5.65 months [5]. In an effort to increase the objective response rate (RR) and survival of LA/MPC patients, many trials have been carried out in the last ten years to evaluate gemcitabine monotherapy or combination therapy regimens.

Currently, the National Comprehensive Cancer Network (NCCN) guidelines indicate that gemcitabine combined with one other agent is the optimal treatment for LA/MPC patients with evidence of category 2B disease (recommendation based on lower-level evidence). It is unclear whether this regimen is the ideal treatment for LA/MPC or whether it should be reevaluated. Therefore, we undertook a systematic review and quantitative meta-analysis to evaluate the available evidence from relevant randomized trials. This review will summarize the various trials of gemcitabine-based chemotherapy regimens in LA/MPC and discuss how these results should affect clinical practice.

Methods Search strategy We carried out a comprehensive search of the literature for randomized controlled trials in Pubmed using the terms “chemotherapy,” “gemcitabine,” AV-951 “trials,” and “pancreatic cancer” (no limitation for language). In addition to full publications, abstracts presented at the annual meetings of the American Society of Clinical Oncology (ASCO) and the European Cancer Conference (ECCO) were included. Selection criteria To be eligible for inclusion, trials were required to be prospective, properly randomized and well designed, which we defined as matched for age, stage and performance status (PS) or Karnofsky performance status (KPS).