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Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis

  • Julien EdelineEmail author
  • Laurence Crouzet
  • Boris Campillo-Gimenez
  • Yan Rolland
  • Marc Pracht
  • Anne Guillygomarc’h
  • Karim Boudjema
  • Laurence Lenoir
  • Xavier Adhoute
  • Tanguy Rohou
  • Eveline Boucher
  • Bruno Clément
  • Jean-Frédéric Blanc
  • Etienne Garin
Original Article

Abstract

Purpose

Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or 90Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population.

Methods

We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model.

Results

A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p < 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39–0.97] (p = 0.037) and 0.40 (95 % CI 0.19–0.82) (p = 0.013), respectively.

Conclusion

SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials.

Keywords

Radioembolization Vascular invasion Targeted therapy Liver-directed therapy Intra-arterial treatment Boosted SIRT 

Notes

Funding

This work was supported in part by a grant from the French National Agency for Research called “Investissements d’Avenir” n°ANR-11-LABX-0018-01.

Conflicts of interest

Etienne Garin is a consultant for BTG, manufacturer of glass microspheres. Xavier Adhoute and Jean-Frédéric Blanc participated in boards for Bayer, who produce sorafenib. The other authors have no potential conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Supplementary material

259_2015_3210_MOESM1_ESM.docx (25 kb)
Supplementary Table 1 Characteristics of the patients matched using the propensity score (DOCX 24 kb)
259_2015_3210_MOESM2_ESM.docx (25 kb)
Supplementary Table 2 Univariable and multivariable Cox proportional hazard model analysis for overall survival after matching (n = 48). (DOCX 24 kb)
259_2015_3210_Fig4_ESM.gif (20 kb)
Supplementary Figure 1

A Flowchart of the patient selection from the whole cohort to the 1:1 matching sample; B Distribution of the propensity score before matching (n = 113) and after matching (n = 48) (GIF 20 kb)

259_2015_3210_MOESM3_ESM.tif (15 mb)
High Resolution Image (TIFF 15311 kb)
259_2015_3210_Fig5_ESM.gif (49 kb)
Supplementary Figure 2

Time-varying hazard ratio for 90Y-radioembolization before matching (A) and after matching (B) (GIF 48 kb)

259_2015_3210_MOESM4_ESM.tif (27.9 mb)
High Resolution Image (TIFF 28546 kb)

References

  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. Cancer incidence and mortality worldwide 2012. International Agency for Research on Cancer. Cancer GLOBOCAN 2012. 2013.Google Scholar
  2. 2.
    Llovet JM, Bustamante J, Castells A, Vilana R, Mdel Ayuso C, Sala M, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology 1999;29:62–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol 2006;12:7561–7.PubMedCentralPubMedGoogle Scholar
  4. 4.
    European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–43.CrossRefGoogle Scholar
  5. 5.
    Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–2.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, et al. Sorafenib (BAY 43–9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 2007;59:561–74.CrossRefPubMedGoogle Scholar
  7. 7.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099–109.CrossRefPubMedGoogle Scholar
  8. 8.
    Bruix J, Raoul J-L, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;57:821–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Salem R, Lewandowski RJ, Gates VL, Nutting CW, Murthy R, Rose SC, et al. Research reporting standards for radioembolization of hepatic malignancies. J Vasc Interv Radiol 2011;22:265–78.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010;138:52–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011;54:868–78.CrossRefPubMedGoogle Scholar
  12. 12.
    Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008;47:71–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Pracht M, Edeline J, Lenoir L, Latournerie M, Mesbah H, Audrain O, et al. Lobar hepatocellular carcinoma with ipsilateral portal vein tumor thrombosis treated with yttrium-90 glass microsphere radioembolization: preliminary results. Int J Hepatol 2013;2013:827649.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Memon K, Kulik L, Lewandowski RJ, Mulcahy MF, Benson AB, Ganger D, et al. Radioembolization for hepatocellular carcinoma with portal vein thrombosis: impact of liver function on systemic treatment options at disease progression. J Hepatol 2013;58:73–80.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Kokabi N, Camacho JC, Xing M, El-Rayes BF, Spivey JR, Knechtle SJ, et al. Open-label prospective study of the safety and efficacy of glass-based yttrium 90 radioembolization for infiltrative hepatocellular carcinoma with portal vein thrombosis. Cancer 2015.Google Scholar
  16. 16.
    Iñarrairaegui M, Thurston KG, Bilbao JI, D’Avola D, Rodriguez M, Arbizu J, et al. Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2010;21:1205–12.CrossRefPubMedGoogle Scholar
  17. 17.
    Woodall CE, Scoggins CR, Ellis SF, Tatum CM, Hahl MJ, Ravindra KV, et al. Is selective internal radioembolization safe and effective for patients with inoperable hepatocellular carcinoma and venous thrombosis? J Am Coll Surg 2009;208:375–82.CrossRefPubMedGoogle Scholar
  18. 18.
    Gramenzi A, Golfieri R, Mosconi C, Cappelli A, Granito A, Cucchetti A, et al. Yttrium-90 radioembolization vs sorafenib for intermediate-locally advanced hepatocellular carcinoma: a cohort study with propensity score analysis. Liver Int 2015;35:1036–47.CrossRefPubMedGoogle Scholar
  19. 19.
    Salem R, Lewandowski RJ, Atassi B, Gordon SC, Gates VL, Barakat O, et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol 2005;16:1627–39.CrossRefPubMedGoogle Scholar
  20. 20.
    Garin E, Lenoir L, Edeline J, Laffont S, Mesbah H, Porée P, et al. Boosted selective internal radiation therapy with 90Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept. Eur J Nucl Med Mol Imaging 2013;40:1057–68.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol 2006;17:1251–78.CrossRefPubMedGoogle Scholar
  22. 22.
    Lencioni R. New data supporting modified RECIST (mRECIST) for hepatocellular carcinoma. Clin Cancer Res 2013;19:1312–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Hilgard P, Hamami M, Fouly AE, Scherag A, Müller S, Ertle J, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010;52:1741–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, Morosi C, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology 2013;57:1826–37.CrossRefPubMedGoogle Scholar
  25. 25.
    Garin E, Lenoir L, Rolland Y, Edeline J, Mesbah H, Laffont S, et al. Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results. J Nucl Med 2012;53:255–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Chiesa C, Maccauro M, Romito R, Spreafico C, Pellizzari S, Negri A, et al. Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with (90)Y microspheres: the experience of the National Tumor Institute of Milan. Q J Nucl Med Mol Imaging 2011;55:168–97.PubMedGoogle Scholar
  27. 27.
    Garin E, Rolland Y, Edeline J, Icard N, Lenoir L, Laffont S, et al. Personalized dosimetry with intensification using 90Y-loaded glass microsphere radioembolization induces prolonged overall survival in hepatocellular carcinoma patients with portal vein thrombosis. J Nucl Med 2015;56:339–46.CrossRefPubMedGoogle Scholar
  28. 28.
    Cho J-Y, Paik Y-H, Park HC, Yu JI, Sohn W, Gwak G-Y, et al. The feasibility of combined transcatheter arterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma. Liver Int 2014;34:795–801.CrossRefPubMedGoogle Scholar
  29. 29.
    Nakazawa T, Hidaka H, Shibuya A, Okuwaki Y, Tanaka Y, Takada J, et al. Overall survival in response to sorafenib versus radiotherapy in unresectable hepatocellular carcinoma with major portal vein tumor thrombosis: propensity score analysis. BMC Gastroenterol 2014;14:84.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Seyal AR, Gonzalez-Guindalini FD, Arslanoglu A, Harmath CB, Lewandowski RJ, Salem R, et al. Reproducibility of mRECIST in assessing response to transarterial radioembolization therapy in hepatocellular carcinoma. Hepatology 2015;62:1111–21.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Julien Edeline
    • 1
    • 2
    Email author
  • Laurence Crouzet
    • 1
  • Boris Campillo-Gimenez
    • 3
  • Yan Rolland
    • 4
  • Marc Pracht
    • 1
  • Anne Guillygomarc’h
    • 5
  • Karim Boudjema
    • 6
  • Laurence Lenoir
    • 7
  • Xavier Adhoute
    • 8
  • Tanguy Rohou
    • 4
  • Eveline Boucher
    • 1
  • Bruno Clément
    • 2
  • Jean-Frédéric Blanc
    • 9
  • Etienne Garin
    • 2
    • 7
  1. 1.Medical Oncology DepartmentCentre Eugene MarquisRennesFrance
  2. 2.Inserm UMR991RennesFrance
  3. 3.Clinical Research DepartmentCentre Eugene MarquisRennesFrance
  4. 4.Imaging DepartmentCentre Eugene MarquisRennesFrance
  5. 5.Hepatology DepartmentCHU PontchaillouRennesFrance
  6. 6.Hepatobiliary SurgeryCHU PontchaillouRennesFrance
  7. 7.Nuclear Medicine DepartmentCentre Eugene MarquisRennesFrance
  8. 8.Hepato-Gastroenterology DepartmentHôpital Saint-JosephMarseilleFrance
  9. 9.Hepato-Gastroenterology DepartmentHôpital Saint-AndréBordeauxFrance

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