Skip to main content

Advertisement

SpringerLink
Log in

Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child–Pugh B cirrhosis

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background and aims

There is limited data regarding the role for systemic treatment in patients with Hepatocellular Carcinoma with Child–Pugh B cirrhosis.

Methods

PRODIGE 21 was a multicentric prospective non-comparative randomized trial. Patients were randomized to receive sorafenib (Arm A), pravastatin (Arm B), sorafenib–pravastatin (Arm C) combination, or best supportive care (Arm D). Primary endpoint was time to progression (TTP), secondary endpoints included safety and overall survival (OS).

Results

160 patients were randomized and 157 patients were included in the final analysis. 86% of patients were BCLC C and 55% had macrovascular invasion. The safety profiles of the drugs were as expected. Median TTP was 3.5, 2.8, 2.0 and 2.2 months in arms A, B, C and D, respectively, but analysis was limited by the number of patients deceased without radiological progression (59%). Median OS was similar between the four arms: 3.8 [95% CI: 2.4–6.5], 3.1 [95% CI: 1.9–4.3], 4.0 [95% CI: 3.2–5.5] and 3.5 months [95% CI: 2.2–5.4] in arms A, B, C and D, respectively. Median OS was 4.0 months [95% CI: 3.3–5.5] for patients treated with sorafenib, vs 2.9 months [95% CI: 2.2–3.9] for patients not treated with sorafenib. In patients with ALBI grade 1/2, median OS was 6.1 months [95% CI: 3.8–8.3] in patients treated with sorafenib vs 3.1 months [95% CI: 1.9–4.8] for patients not treated with sorafenib.

Conclusion

In the overall Child–Pugh B population, neither sorafenib nor pravastatin seemed to provide benefit. In the ALBI grade 1/2 sub-population, our trial suggests potential benefit of sorafenib.

Clinical trial registration

The study was referenced in clinicaltrials.gov (NCT01357486).

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424

    Article  Google Scholar 

  2. Bertuccio P, Turati F, Carioli G, et al. Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol 2017;67:302–309

    Article  Google Scholar 

  3. Galle PR, Forner A, Llovet JM, et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69:182–236

    Article  Google Scholar 

  4. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatol Baltim Md 2018;67:358–380

    Article  Google Scholar 

  5. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatol Baltim Md 2018;68:723–750

    Article  Google Scholar 

  6. EASL, EORTC, others. EASL–EORTC Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–943

    Article  Google Scholar 

  7. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 2015;33:550–558

    Article  Google Scholar 

  8. Ogasawara S, Chiba T, Ooka Y, et al. Liver function assessment according to the Albumin-Bilirubin (ALBI) grade in sorafenib-treated patients with advanced hepatocellular carcinoma. Invest New Drugs 2015;33:1257–1262

    Article  CAS  Google Scholar 

  9. Edeline J, Blanc J-F, Johnson P, et al. A multicentre comparison between Child Pugh and Albumin-Bilirubin scores in patients treated with sorafenib for Hepatocellular Carcinoma. Liver Int Off J Int Assoc Study Liver 2016;36:1821–1828

    CAS  Google Scholar 

  10. Kuo Y-H, Wang J-H, Hung C-H, et al. Albumin-Bilirubin grade predicts prognosis of HCC patients with sorafenib use. J Gastroenterol Hepatol 2017;32:1975–1981

    Article  CAS  Google Scholar 

  11. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390

    Article  CAS  Google Scholar 

  12. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet Lond Engl 2018;391:1163–1173

    Article  CAS  Google Scholar 

  13. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Lond Engl 2017;389:56–66

    Article  CAS  Google Scholar 

  14. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54–63

    Article  CAS  Google Scholar 

  15. Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:282–296

    Article  CAS  Google Scholar 

  16. McNamara MG, Slagter AE, Nuttall C, et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer Oxf Engl 1990;2018(105):1–9

    Google Scholar 

  17. Marrero JA, Kudo M, Venook AP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 2016;65:1140–1147

    Article  CAS  Google Scholar 

  18. Zhou Y-Y, Zhu G-Q, Wang Y, et al. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget 2016;7:21753–21762

    Article  Google Scholar 

  19. Kawata S, Yamasaki E, Nagase T, et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 2001;84:886–891

    Article  CAS  Google Scholar 

  20. Lersch C, Schmelz R, Erdmann J, et al. Treatment of HCC with pravastatin, octreotide, or gemcitabine–a critical evaluation. Hepatogastroenterology 2004;51:1099–1103

    CAS  PubMed  Google Scholar 

  21. Jouve J-L, Lecomte T, Bouché O, et al. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol 2019;71:516–522

    Article  CAS  Google Scholar 

  22. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30:52–60

    Article  CAS  Google Scholar 

  23. Labeur TA, Achterbergh R, Takkenberg B, Van Delden O, Mathôt R, Klümpen H-J. Sorafenib for patients with hepatocellular carcinoma and Child-Pugh B liver cirrhosis: lessons learned from a Terminated Study. Oncologist 2019. https://doi.org/10.1634/theoncologist.2019-0718

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hollebecque A, Cattan S, Romano O, et al. Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Ther 2011;34:1193–1201

    Article  CAS  Google Scholar 

  25. Pressiani T, Boni C, Rimassa L, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol Off J Eur Soc Med Oncol 2013;24:406–411

    Article  CAS  Google Scholar 

  26. Kudo M. Nivolumab in Patients with Child-Pugh B Advanced Hepatocellular Carcinoma (aHCC) in the CheckMate-040 Study. AASLD Annu Meet 2018;LB-2

  27. Durand F, Valla D. Assessment of prognosis of cirrhosis. Semin Liver Dis 2008;28:110–122

    Article  CAS  Google Scholar 

  28. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–649

    Article  CAS  Google Scholar 

  29. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698–711

    Article  Google Scholar 

Download references

Acknowledgements

We thank the FFCD operational team (statisticians, data managers and CRAs): Karine Le Malicot, Fadil Masskourri, Caroline Choine, Florence Guiliani, Nouredine Lasmi, Guillaume Arnould, Nathan Guiet, Morgane Maury-Nègre, Hicham Fattouh, Nicolas Le Provost, Jérémie Bez, and Cécile Girault. We also thank research teams at each participating center.

List of FFCD Investigators/collaborators: Prodige 21: Evelyne Boucher (Centre Eugène Marquis, Rennes), Marie Talarmin (Centre Eugène Marquis, Rennes), Samuel Le Sourd (Centre Eugène Marquis, Rennes), Julien Vergniol (CHU Bordeaux, Pessac), Alice Gagnaire (Hôpital François Mitterrand, Dijon), Laurent Bedenne (Hôpital François Mitterrand, Dijon), Jean-Louis Jouve (Hôpital François Mitterrand, Dijon), Patrick Hillon (Hôpital François Mitterrand, Dijon), Côme Lepage (Hôpital François Mitterrand, Dijon), Anne Minello (Hôpital François Mitterrand, Dijon), Hélène Barraud (CHU Nancy-Brabois, Vandoeuvre Les Nancy), Thierry Lecomte (Hôpital Trousseau, Tours), Jean-Pierre Barbieux (Hôpital Trousseau, Tours), Patrice Wolff (CHU Carémeau, Nîmes), Valérie Phoutthasang (CHU Carémeau, Nîmes), Christine Belletier (Centre Paul Strauss, Strasbourg), Isabelle Archambeaud (CHU Hôtel Dieu, Nantes), Tamara Matysiak Budnik (CHU Hôtel Dieu, Nantes), Matthieu Schnee (CHD Vendée, La Roche-Sur-Yon), Muriel Duluc (CHU la TIMONE, Marseille), Emmanuelle Norguet Monnereau (CHU la TIMONE, Marseille), Jaafar Bennouna (Centre René Gauducheau, Saint-Herblain), Sandrine Hiret (Centre René Gauducheau, Saint-Herblain), Michel Gatineau (Groupe Hospitalier Saint Joseph, Paris), Mohamed Ramdani (Centre Hospitalier, Béziers), Yann Le Bricquir (Centre Hospitalier, Béziers), Nathalie Ganne-Carrie (Hôpital Jean Verdier, Bondy), Valérie Bourcier (Hôpital Jean Verdier, Bondy), Christophe Pilette (Centre Hospitalier, Le Mans), Barbara Dauvois (Hôpital de La Source, Orléans), Mathieu Baconnier (CH Annecy Genevois, Pringy), Pierre Michel (CHU Charles Nicolle, Rouen), Philippe Thevenet (Centre Hospitalier, Saint Malo), Hélène Cosme-Gassmann (Centre Hospitalier, Sens), François Habersetzer (Hôpital Civil, Strasbourg), Camélia Coltescu (Hôpital Civil, Strasbourg), Mathieu Pauwels (Centre Hospitalier, Abbeville), Sophie Nahon Brissonneau (Centre Hospitalier du Pays d'Aix, Aix-en-Provence), Joëlle Egreteau (Centre Hospitalier Bretagne Sud Le Scorff, Lorient), Jérôme Desrame (Hôpital Privé Jean Mermoz, Lyon), Dominique Auby (Hôpital Layné, Mont de Marsan), Patrick Texereau (Hôpital Layné, Mont de Marsan), Pierre-Luc Etienne (Centre CARIO – HPCA, Plérin), Louis-Marie Dourthe (Clinique Sainte Anne, Strasbourg), Youssef Tazi (Clinique Sainte Anne, Strasbourg).

Funding

The study was funded by the ‘‘Programme Hospitalier de Recherche Clinique” (PHRC) in 2010 (Institut National du Cancer [INCa], Grant PHRC10_04-02). Pravastatin was supplied by Sanofi, France.

Author information

Authors and Affiliations

  1. Hepatology, CHU Bordeaux, (HOPITAL SAINT-ANDRE-CHU), 1 Rue Jean Burguet, 33000, Bordeaux, France

    Jean-Frédéric Blanc

  2. CH Saint Jean, Perpignan, France

    Faiza Khemissa

  3. CHU Nancy-Brabois, Vandoeuvre les Nancy, France

    Jean-Pierre Bronowicki

  4. FFCD, Dijon, France

    Carole Monterymard

  5. CHU Tours Hôpital Trousseau, Tours, France

    Jean-Marc Perarnau

  6. Hôpital Duchenne, Boulogne-Sur-Mer, France

    Vincent Bourgeois

  7. CHU Carémeau, Nîmes, France

    Stéphane Obled

  8. Centre Paul Strauss, Strasbourg, France

    Meher Ben Abdelghani

  9. CHU Hôtel Dieu, Nantes, France

    Isabelle Mabile-Archambeaud

  10. CHD Vendée, La Roche-Sur-Yon, France

    Roger Faroux

  11. CHU la TIMONE, Marseille, France

    Jean-François Seitz

  12. Centre Hospitalier de Meaux, Meaux, France

    Christophe Locher

  13. ICO Centre René Gauducheau, Saint-Herblain, France

    Hélène Senellart

  14. Centre Hospitalier Auxerre, Auxerre, France

    Anne-Laure Villing

  15. CH de la Côte Basque, Bayonne, France

    Franck Audemar

  16. AP-HP Hôpital Henri Mondor, Créteil, France

    Charlotte Costentin

  17. Groupe Hospitalier Saint Joseph, Paris, France

    Gaël Deplanque

  18. Faculté de Médecine, INSERM U1231, Université de Bourgogne, Franche-Comté, Dijon, France

    Sylvain Manfredi

  19. Centre Eugène Marquis, Rennes, France

    Julien Edeline

Authors
  1. Jean-Frédéric Blanc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faiza Khemissa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Pierre Bronowicki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carole Monterymard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Marc Perarnau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vincent Bourgeois
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stéphane Obled
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Meher Ben Abdelghani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isabelle Mabile-Archambeaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roger Faroux
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean-François Seitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christophe Locher
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hélène Senellart
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Anne-Laure Villing
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Franck Audemar
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Charlotte Costentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Gaël Deplanque
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Sylvain Manfredi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Julien Edeline
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the PRODIGE 21 collaborators

  • Evelyne Boucher
  • , Marie Talarmin
  • , Samuel Le Sourd
  • , Julien Vergniol
  • , Alice Gagnaire
  • , Laurent Bedenne
  • , Jean-Louis Jouve
  • , Patrick Hillon
  • , Côme Lepage
  • , Anne Minello
  • , Hélène Barraud
  • , Thierry Lecomte
  • , Jean-Pierre Barbieux
  • , Patrice Wolff
  • , Valérie Phoutthasang
  • , Christine Belletier
  • , Isabelle Archambeaud
  • , Tamara Matysiak Budnik
  • , Matthieu Schnee
  • , Muriel Duluc
  • , Emmanuelle Norguet Monnereau
  • , Jaafar Bennouna
  • , Sandrine Hiret
  • , Michel Gatineau
  • , Mohamed Ramdani
  • , Yann Le Bricquir
  • , Nathalie Ganne-Carrie
  • , Valérie Bourcier
  • , Christophe Pilette
  • , Barbara Dauvois
  • , Mathieu Baconnier
  • , Pierre Michel
  • , Philippe Thevenet
  • , Hélène Cosme-Gassmann
  • , François Habersetzer
  • , Camélia Coltescu
  • , Mathieu Pauwels
  • , Sophie Nahon Brissonneau
  • , Joëlle Egreteau
  • , Jérôme Desrame
  • , Dominique Auby
  • , Patrick Texereau
  • , Pierre-Luc Etienne
  • , Louis-Marie Dourthe
  •  & Youssef Tazi

Corresponding author

Correspondence to Jean-Frédéric Blanc.

Ethics declarations

Conflict of interest

Jean-Frédéric Blanc received honoraria from Bayer, Ipsen, Roche, outside the submitted work. Jean-Pierre Bronowicki received honoraria from Bayer outside the submitted work. Julien Edeline received honoraria from Roche, Bayer, Eisai, Ipsen, MSD, BMS, AstraZeneca, BTG, Amgen, Beigene, outside the submitted work.

Ethical approval

This study was approved by an ethic committee and conducted under the principles of the declaration of Helsinki. The trial was approved by the Ethics Committee ‘Comité de protection des personnes Sud Ouest et Outre Mer III’ on the 23/02/2020.

Informed consent

All patients provided written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Members of the PRODIGE 21 collaborators are listed in the Acknowledgement section.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 14 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blanc, JF., Khemissa, F., Bronowicki, JP. et al. Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child–Pugh B cirrhosis. Hepatol Int 15, 93–104 (2021). https://doi.org/10.1007/s12072-020-10120-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-020-10120-3

Keywords

Search

Navigation