Gemcitabine-based combinations for inoperable pancreatic cancer: have we made real progress? A meta-analysis of 20 phase 3 trials.
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.
Bria
Emilio
E
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
Milella
Michele
M
Gelibter
Alain
A
Cuppone
Federica
F
Pino
Maria Simona
MS
Ruggeri
Enzo Maria
EM
Carlini
Paolo
P
Nisticò
Cecilia
C
Terzoli
Edmondo
E
Cognetti
Francesco
F
Giannarelli
Diana
D
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
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine