title: Gemcitabine-based combinations for inoperable pancreatic cancer: have we made real progress? A meta-analysis of 20 phase 3 trials.
abstract: BACKGROUND
  Several attempts have been made at improving the efficacy of gemcitabine in advanced pancreatic cancer by combining it with other chemotherapeutic or molecularly targeted agents. However, randomized trials have produced conflicting results.
  
  
  METHODS
  All prospective, randomized, phase 3 trials that compared single-agent gemcitabine with gemcitabine-based combinations were considered eligible for the current analysis. A literature-based meta-analysis was performed, event-based relative risk ratios with 95% confidence intervals were derived through both a fixed-effect model approach and a random-effect model approach, and overall survival (OS) was explored as the primary endpoint. To estimate the magnitude of the eventual benefit, absolute differences and the number of patients needed to treat (NNT) for 1 patient to benefit were calculated. A sensitivity analysis for OS was performed according to the type of agent used in combination with gemcitabine.
  
  
  RESULTS
  Twenty trials that involved 6,296 patients were identified. No significant differences in the primary endpoint were observed in the overall population or in the sensitivity analysis. Conversely, a significant advantage was evident with regard to both progression-free survival (PFS) and the overall response rate (ORR) in the overall population, with an absolute benefit of 2.6% (NTT = 39 patients) and 3.0% (NNT = 33 patients). Platinum combinations led to the greatest absolute benefits for PFS and ORR compared with single-agent gemcitabine (10% and 6.5%, respectively), but this did not result in an OS benefit. Improvement in PFS, but not in the ORR, was correlated with an improvement in OS.
  
  
  CONCLUSIONS
  Single-agent gemcitabine remains the standard of care for patients with advanced pancreatic cancer. However, platinum/gemcitabine combinations appeared to improve PFS and the ORR and, thus, may be considered in selected patients.
authors.affiliation: Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Alain
authors.initials: A
authors.lastname: Gelibter
authors.forename: Federica
authors.initials: F
authors.lastname: Cuppone
authors.forename: Maria Simona
authors.initials: MS
authors.lastname: Pino
authors.forename: Enzo Maria
authors.initials: EM
authors.lastname: Ruggeri
authors.forename: Paolo
authors.initials: P
authors.lastname: Carlini
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nisticò
authors.forename: Edmondo
authors.initials: E
authors.lastname: Terzoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000601:surgery; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine