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Clinical Study

Sorafenib alone vs. sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial

British Journal of Cancer (2019) | Download Citation

Abstract

Background

Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients.

Methods

Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate.

Results

Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1–51); median number of GEMOX cycles was 7 (1–16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8–6.8) and 13.5 (7.5–16.2) months, and 4.6 (3.9–6.2) months and 14.8 (12.2–22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand–foot syndrome (5%/18).

Conclusions

Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.

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Acknowledgements

We thank all the patients and their families for their trust and participation in the study. We thank the PRODIGE group and also Bayer Health Care for financial support. We thank Professor Boris Guiu (Montpellier University Hospital, Univ. Montpellier) for his radiologic review of all CT-scan data, Catherine Fiess (Clinical Research and Innovation Department, Montpellier Cancer Institute, Univ. Montpellier) for her work as clinical research assistant and project manager, and Sylvain Boudon (Biometrics Unit, Montpellier Cancer Institute, Univ. Montpellier) for data management. This research was supported by the SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553. The study received funding from Bayer Health care. Bayer Health care was not involved in data collection, analysis and interpretation, or in the writing of the manuscript.

Author contributions

Conception and design: E.A., G.P.P., M.Y. and V.B. Acquisition of data: E.A., J.M.P., Y.B., J.F.S., P.M., J.F.B., O.B., M.R., G.P.P., M.Y. and V.B. Analysis and interpretation of data: E.A., S.T., S.P., H.F., G.P.P., M.Y. and V.B. Drafting and critical revision of the manuscript: E.A., S.T., H.F., G.P.P., M.Y. and V.B. Final approval of the manuscript: E.A., S.T., J.M.P., Y.B., J.F.S., P.M., J.F.B., O.B., M.R., S.P., H.F., G.P.P., M.Y. and V.B.

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Affiliations

  1. Institut du Cancer de Montpellier (ICM), Université de Montpellier, Montpellier, France

    • Eric Assenat
    • , Simon Thézenas
    • , Sylvain Poujol
    • , Hélène de Forges
    •  & Marc Ychou
  2. Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France

    • Eric Assenat
    •  & Georges-Philippe Pageaux
  3. Centre Hospitalier Universitaire de Toulouse, Toulouse, France

    • Jean-Marie Peron
  4. Bergonié Institute, Bordeaux, France

    • Yves Bécouarn
  5. Centre Hospitalier Universitaire de Marseille, Marseille, France

    • Jean-François Seitz
  6. Centre Hospitalier Universitaire de Lyon, Lyon, France

    • Philippe Merle
  7. Saint-André Hospital, Bordeaux, France

    • Jean-Frédéric Blanc
  8. Centre Hospitalier Universitaire de Reims, Reims, France

    • Olivier Bouché
  9. Centre Hospitalier Universitaire de Béziers, Béziers, France

    • Mohamed Ramdani
  10. Gustave Roussy, Villejuif, France

    • Valérie Boige

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Competing interests

E.A. reports personal fees from Bayer, Sirtex, Novartis, Ipsen and Sanofi, and travel and expenses from Bayer and Ipsen, outside the submitted work. P.M. reports personal fees from Bayer outside the submitted work. J.F.B. reports personal fees from Bayer, outside the submitted work. O.B. reports personal fees (board and speaker) from Amgen, Roche, Merck Sereno, Bayer, and from Pierre Fabre, Novartis and Lilly, outside the submitted work. All other authors have nothing to disclose regarding the present study.

Ethics approval and consent to participate

All patients signed an informed consent before entering the study. The study protocol was approved by an ethical review board (Comité de Protection des Personnes Sud Méditerrannée IV, September 2nd, 2008; EudraCT number: 2008-000123-26) and was conducted in accordance with the good clinical practice and Declaration of Helsinki guidelines.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Eric Assenat.

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DOI

https://doi.org/10.1038/s41416-019-0443-4