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Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis

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Abstract

Background

It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC).

Objective

The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single-agent gemcitabine in the first-line treatment of unresectable LA/MPC.

Methods

We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016.

Results

Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine-based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue.

Conclusions

Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine-based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC.

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Authors and Affiliations

  1. Department of Pathology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China

    Xiu-Wei Zhang

  2. Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China

    Yu-Xiang Ma, Yang Sun, Yu-Bo Cao & Chong-An Xu

  3. Center for Translational Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, China

    Qin Li

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Contributions

CAX participated in the design and conception. contribute to data analysis and manuscript writing. and YHW performed experiments. YXM, YS and YBC performed data acquisition, data analysis and data interpretation. YXM and YS performed statistical analysis. YWZ and QL participated in editing the manuscript. YBC and XWZ contributed to quality control of data and algorithms. XWZ and CAX participated in drafting the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chong-An Xu.

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Zhang, XW., Ma, YX., Sun, Y. et al. Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis. Targ Oncol 12, 309–321 (2017). https://doi.org/10.1007/s11523-017-0486-5

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