Doctor: Perrine Crequit

Title: Cumulative and dynamic network meta-analysis

Supervisors: Philippe Ravaud, Ludovic Trinquart

Doctoral school: ED 393 Epidemiology and Biomedical Information Sciences, Université Paris Cité

Date of thesis defense: 16/11/2016

Jury: Guy Launoy, Christos Chouaid, France Mentré, Thomas Similowski, Michel Cucherat, Ludovic Trinquart, Philippe Ravaud


Systematic reviews are essential tools to synthesize available evidence for therapeutic evaluation. Multiple treatments are now frequently available for a given condition. Patients and physicians want to know which one is the best among all treatments. Thus we need to retrieve and synthesize all available evidence across all treatments and furthermore to maintain it updated when new evidence and new treatments become available. Our objective was to evaluate the limits of the current ecosystem of evidence synthesis and to develop an alternative methodology.

We have first assessed the capacity of systematic reviews to cover all available evidence of multiple treatments. We took the example of second-line treatments of advanced non-small cell lung cancer with EGFR wild-type or unknown status. We have shown that the 29 systematic reviews published in this condition up to 2015, considered collectively, failed to provide a complete and updated synthesis of all available evidence. Almost 40% of the 77 trials, of the 45 treatments, of the 54 treatment comparisons and of the 28,636 patients were always missing from systematic reviews. We have discussed the reasons why the ecosystem of evidence synthesis fails to encompass all available evidence.

We then developed a new paradigm to synthesize evidence over time called live cumulative network meta-analysis. This new concept consists in switching from a series of standard meta-analyses to a single network meta-analysis covering all treatments and systematically updated as soon as the results of a new trial become available. Live cumulative network meta- analysis is initiated with a network meta-analysis which is iteratively updated. We have described the methodological steps, developed the protocol of a proof-of-concept study applied to second-line treatments of advanced non-small cell lung cancer.

Finally, we have performed the initial network meta-analysis in this condition. We have included 98 trials including 34,179 patients and assessing 60 treatments. We have shown that nivolumab was more effective in term of overall survival compared to docetaxel HR=0.68 (IC95% 0.55-0.83), to pemetrexed HR=0.65 (0.5-0.83), to erlotinib HR=0.66 (0.51-0.84) and to gefitinib HR=0.65 (0.51-0.82). Similar results were found with pembrolizumab. In progression free survival, nivolumab had a more important treatment effect compared to the four recommended treatments.

Live cumulative network meta-analysis should become a paradigmatic shift for systematic reviews and meta-analysis in order to improve medical decision making.

Link to download the thesis (written in French)

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