Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

Open Access 02-08-2022 | Hepatocellular Carcinoma | Original Article

Addition of Y-90 radioembolization increases tumor response and local disease control in hepatocellular carcinoma patients receiving sorafenib

Authors: Osman Öcal, Kerstin Schütte, Christoph J. Zech, Christian Loewe, Otto van Delden, Vincent Vandecaveye, Chris Verslype, Bernhard Gebauer, Christian Sengel, Irene Bargellini, Roberto Iezzi, Alexander Philipp, Thomas Berg, Heinz J. Klümpen, Julia Benckert, Maciej Pech, Antonio Gasbarrini, Holger Amthauer, Peter Bartenstein, Bruno Sangro, Peter Malfertheiner, Jens Ricke, Max Seidensticker

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 13/2022

Abstract

Purpose

To compare the treatment response and progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients who received sorafenib treatment either alone or combined with radioembolization (RE).

Methods

Follow-up images of the patients treated within a multicenter phase II trial (SORAMIC) were assessed by mRECIST. A total of 177 patients (73 combination arm [RE + sorafenib] and 104 sorafenib arm) were included in this post-hoc analysis. Response and progression characteristics were compared between treatment arms. Survival analyses were done to compare PFS and post-progression survival between treatment arms. Multivariate Cox regression analysis was used to compare survival with factors known to influence PFS in patients with HCC.

Results

The combination arm had significantly higher objective response rate (61.6% vs. 29.8%, p < 0.001), complete response rate (13.7% vs. 3.8%, p = 0.022), and a trend for higher disease control rate (79.2% vs. 72.1%, p = 0.075). Progression was encountered in 116 (65.5%) patients and was more common in the sorafenib arm (75% vs. 52.0%, p = 0.001). PFS (median 8.9 vs. 5.4 months, p = 0.022) and hepatic PFS were significantly better in the combination arm (9.0 vs. 5.7 months, p = 0.014). Multivariate analysis confirmed the treatment arm as an independent predictor of PFS.

Conclusion

In advanced HCC patients receiving sorafenib, combination with RE has an additive anticancer effect on sorafenib treatment resulting in a higher and longer tumor response. However, the enhanced response did not translate into prolonged survival. Better patient selection and superselective treatment could improve outcomes after combination therapy.

El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264-73.e1. https://doi.org/10.1053/j.gastro.2011.12.061.PubMedCrossRef

De Toni EN, Schlesinger-Raab A, Fuchs M, Schepp W, Ehmer U, Geisler F, et al. Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study. Gut. 2020;69(1):168–76. https://doi.org/10.1136/gutjnl-2018-318193.PubMedCrossRef

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. https://doi.org/10.1056/NEJMoa0708857.PubMedCrossRef

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. https://doi.org/10.1016/s1470-2045(08)70285-7.PubMedCrossRef

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905. https://doi.org/10.1056/NEJMoa1915745.PubMedCrossRef

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(3):868–78. https://doi.org/10.1002/hep.24451.PubMedCrossRef

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(5):1741–9. https://doi.org/10.1002/hep.23944.PubMedCrossRef

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(1):52–64. https://doi.org/10.1053/j.gastro.2009.09.006.PubMedCrossRef

Salem R, Johnson GE, Kim E, Riaz A, Bishay V, Boucher E, et al. Yttrium-90 radioembolization for the treatment of solitary, unresectable HCC: the LEGACY study. Hepatology. 2021;74(5):2342–52. https://doi.org/10.1002/hep.31819.PubMedCrossRef

10.

Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017;18(12):1624–36. https://doi.org/10.1016/s1470-2045(17)30683-6.PubMedCrossRef

11.

Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, et al. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018;36(19):1913–21. https://doi.org/10.1200/jco.2017.76.0892.PubMedCrossRef

12.

Ricke J, Klümpen HJ, Amthauer H, Bargellini I, Bartenstein P, de Toni EN, et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol. 2019;71(6):1164–74. https://doi.org/10.1016/j.jhep.2019.08.006.PubMedCrossRef

13.

Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. https://doi.org/10.1016/s0140-6736(16)32453-9.PubMedCrossRef

14.

Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. https://doi.org/10.1056/NEJMoa1717002.PubMedPubMedCentralCrossRef

15.

Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–96. https://doi.org/10.1016/s1470-2045(18)30937-9.PubMedCrossRef

16.

Llovet JM, Lencioni R. mRECIST for HCC: performance and novel refinements. J Hepatol. 2020;72(2):288–306. https://doi.org/10.1016/j.jhep.2019.09.026.PubMedCrossRef

17.

Riaz A, Gabr A, Abouchaleh N, Ali R, Al Asadi A, Mora R, et al. Radioembolization for hepatocellular carcinoma: statistical confirmation of improved survival in responders by landmark analyses. Hepatology. 2018;67(3):873–83. https://doi.org/10.1002/hep.29480.PubMedCrossRef

18.

Gillmore R, Stuart S, Kirkwood A, Hameeduddin A, Woodward N, Burroughs AK, et al. EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization. J Hepatol. 2011;55(6):1309–16. https://doi.org/10.1016/j.jhep.2011.03.007.PubMedCrossRef

19.

Kudo M, Ueshima K, Chiba Y, Ogasawara S, Obi S, Izumi N, et al. Objective response by mRECIST is an independent prognostic factor for overall survival in hepatocellular carcinoma treated with sorafenib in the SILIUS trial. Liver Cancer. 2019;8(6):505–19. https://doi.org/10.1159/000503032.PubMedPubMedCentralCrossRef

20.

Öcal O, Schinner R, Schütte K, de Toni EN, Loewe C, van Delden O, et al. Early tumor shrinkage and response assessment according to mRECIST predict overall survival in hepatocellular carcinoma patients under sorafenib. Cancer Imaging. 2022;22(1):1. https://doi.org/10.1186/s40644-021-00439-x.PubMedPubMedCentralCrossRef

21.

Heinemann V, Stintzing S, Modest DP, Giessen-Jung C, Michl M, Mansmann UR. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur J Cancer. 2015;51(14):1927–36. https://doi.org/10.1016/j.ejca.2015.06.116.PubMedCrossRef

22.

Takahashi A, Moriguchi M, Seko Y, Shima T, Mitsumoto Y, Takashima H et al. Early tumor shrinkage as a predictive factor for outcomes in hepatocellular carcinoma patients treated with lenvatinib: a multicenter analysis. Cancers (Basel). 2020;12(3). https://doi.org/10.3390/cancers12030754.

23.

Ricke J, Steffen IG, Bargellini I, Berg T, Jaureguizar JIB, Gebauer B, et al. Gadoxetic acid-based hepatobiliary MRI in hepatocellular carcinoma. JHEP Rep. 2020:100173. https://doi.org/10.1016/j.jhepr.2020.100173.

24.

Ronot M, Bouattour M, Wassermann J, Bruno O, Dreyer C, Larroque B, et al. Alternative response criteria (Choi, European association for the study of the liver, and modified Response Evaluation Criteria in Solid Tumors [RECIST]) versus RECIST 1.1 in patients with advanced hepatocellular carcinoma treated with sorafenib. Oncologist. 2014;19(4):394–402. https://doi.org/10.1634/theoncologist.2013-0114.PubMedPubMedCentralCrossRef

25.

Edeline J, Boucher E, Rolland Y, Vauléon E, Pracht M, Perrin C, et al. Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer. 2012;118(1):147–56. https://doi.org/10.1002/cncr.26255.PubMedCrossRef

26.

Lee JS, Choi HJ, Kim BK, Park JY, Kim DY, Ahn SH, et al. The modified Response Evaluation Criteria in Solid Tumors (RECIST) yield a more accurate prognoses than the RECIST 1.1 in hepatocellular carcinoma treated with transarterial radioembolization. Gut Liver. 2020;14(6):765–74. https://doi.org/10.5009/gnl19197.PubMedPubMedCentralCrossRef

27.

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(4):1111–21. https://doi.org/10.1002/hep.27915.PubMedCrossRef

28.

Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut. 2021;70(1):204–14. https://doi.org/10.1136/gutjnl-2020-321702.PubMedCrossRef

29.

Zhang X, Wang J, Shi J, Jia X, Dang S, Wang W. Cost-effectiveness of atezolizumab plus bevacizumab vs sorafenib for patients with unresectable or metastatic hepatocellular carcinoma. JAMA Netw Open. 2021;4(4):e214846. https://doi.org/10.1001/jamanetworkopen.2021.4846.PubMedPubMedCentralCrossRef

30.

Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862–73. https://doi.org/10.1016/j.jhep.2021.11.030.PubMedCrossRef

31.

Kudo M. Sequential therapy for hepatocellular carcinoma after failure of atezolizumab plus bevacizumab combination therapy. Liver Cancer. 2021;10(2):85–93. https://doi.org/10.1159/000514312.PubMedPubMedCentralCrossRef

32.

Garin E, Tselikas L, Guiu B, Chalaye J, Edeline J, de Baere T, et al. Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol Hepatol. 2021;6(1):17–29. https://doi.org/10.1016/s2468-1253(20)30290-9.PubMedCrossRef

33.

Hermann A-L, Dieudonné A, Ronot M, Sanchez M, Pereira H, Chatellier G, et al. Relationship of tumor radiation–absorbed dose to survival and response in hepatocellular carcinoma treated with transarterial radioembolization with 90Y in the SARAH study. Radiology. 2020;296(3):673–84.PubMedCrossRef

34.

Tai D, Loke K, Gogna A, Kaya NA, Tan SH, Hennedige T, et al. Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209–678): a single arm, single centre, phase 2 trial. Lancet Gastroenterol Hepatol. 2021;6(12):1025–35. https://doi.org/10.1016/s2468-1253(21)00305-8.PubMedCrossRef

35.

Gil-Alzugaray B, Chopitea A, Iñarrairaegui M, Bilbao JI, Rodriguez-Fraile M, Rodriguez J, et al. Prognostic factors and prevention of radioembolization-induced liver disease. Hepatology. 2013;57(3):1078–87. https://doi.org/10.1002/hep.26191.PubMedCrossRef

36.

Currie BM, Nadolski G, Mondschein J, Dagli M, Sudheendra D, Stavropoulos SW, et al. Chronic hepatotoxicity in patients with metastatic neuroendocrine tumor: transarterial chemoembolization versus transarterial radioembolization. J Vasc Interv Radiol. 2020;31(10):1627–35. https://doi.org/10.1016/j.jvir.2020.05.019.PubMedCrossRef

37.

Ricke J, Schinner R, Seidensticker M, Gasbarrini A, van Delden OM, Amthauer H, et al. Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma. J Hepatol. 2021. https://doi.org/10.1016/j.jhep.2021.07.037.PubMedCrossRef

38.

Iñarrairaegui M, Pardo F, Bilbao JI, Rotellar F, Benito A, D’Avola D, et al. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol. 2012;38(7):594–601. https://doi.org/10.1016/j.ejso.2012.02.189.PubMedCrossRef

39.

Tohme S, Sukato D, Chen HW, Amesur N, Zajko AB, Humar A, et al. Yttrium-90 radioembolization as a bridge to liver transplantation: a single-institution experience. J Vasc Interv Radiol. 2013;24(11):1632–8. https://doi.org/10.1016/j.jvir.2013.07.026.PubMedCrossRef

40.

Garlipp B, Amthauer H, Kupitz D, Grosser OS, Jürgens J, Damm R, et al. The impact of unilateral 90Y-radioembolization on functional changes in the contralateral hepatic lobe: the prospective, open-label RadioEmbolization, Volumetry, and Liver FuncTion Measurements (REVoluTion) study. Ann Surg Open. 2021;2(3):e095.CrossRef

41.

Ogushi K, Chuma M, Uojima H, Hidaka H, Numata K, Kobayashi S, et al. Safety and efficacy of lenvatinib treatment in Child-Pugh A and B patients with unresectable hepatocellular carcinoma in clinical practice: a multicenter analysis. Clin Exp Gastroenterol. 2020;13:385–96. https://doi.org/10.2147/ceg.S256691.PubMedPubMedCentralCrossRef

42.

Marrero JA, Kudo M, Venook AP, Ye SL, Bronowicki JP, Chen XP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65(6):1140–7. https://doi.org/10.1016/j.jhep.2016.07.020.PubMedCrossRef

43.

Lee S, Kim BK, Kim SU, Park SY, Kim JK, Lee HW, et al. Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study. J Gastroenterol Hepatol. 2014;29(7):1463–9. https://doi.org/10.1111/jgh.12542.PubMedCrossRef

44.

Pressiani T, Boni C, Rimassa L, Labianca R, Fagiuoli S, Salvagni S, et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol. 2013;24(2):406–11. https://doi.org/10.1093/annonc/mds343.PubMedCrossRef

45.

Schütte K, Schinner R, Fabritius MP, Möller M, Kuhl C, Iezzi R, et al. Impact of extrahepatic metastases on overall survival in patients with advanced liver dominant hepatocellular carcinoma: a subanalysis of the SORAMIC trial. Liver Cancer. 2020:1–16. https://doi.org/10.1159/000510798.

Title: Addition of Y-90 radioembolization increases tumor response and local disease control in hepatocellular carcinoma patients receiving sorafenib
Authors: Osman Öcal
Kerstin Schütte
Christoph J. Zech
Christian Loewe
Otto van Delden
Vincent Vandecaveye
Chris Verslype
Bernhard Gebauer
Christian Sengel
Irene Bargellini
Roberto Iezzi
Alexander Philipp
Thomas Berg
Heinz J. Klümpen
Julia Benckert
Maciej Pech
Antonio Gasbarrini
Holger Amthauer
Peter Bartenstein
Bruno Sangro
Peter Malfertheiner
Jens Ricke
Max Seidensticker
Publication date: 02-08-2022
Publisher: Springer Berlin Heidelberg
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Sorafenib
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 13/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05920-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Addition of Y-90 radioembolization increases tumor response and local disease control in hepatocellular carcinoma patients receiving sorafenib

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 13/2022

Optical molecular imaging and theranostics in neurological diseases based on aggregation-induced emission luminogens

Noninvasive photoacoustic computed tomography/ultrasound imaging to identify high-risk atherosclerotic plaques

Hetero-bivalent agents targeting FAP and PSMA

18F-FDG PET/CT findings of mesenchymal hamartoma of the liver in an adolescent

The value of FDG PET/CT imaging in outcome prediction and response assessment of lymphoma patients treated with immunotherapy: a meta-analysis and systematic review

Innate immune cells and myelin profile in multiple sclerosis: a multi-tracer PET/MR study