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Holmium-166 Radioembolization in Hepatocellular Carcinoma: Feasibility and Safety of a New Treatment Option in Clinical Practice

  • Clinical Investigation
  • Interventional Oncology
  • Published:
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Abstract

Purpose

To investigate clinical feasibility, technical success and toxicity of 166Ho-radioembolization (166Ho-RE) as new approach for treatment of hepatocellular carcinomas (HCC) and to assess postinterventional calculation of exact dosimetry through quantitative analysis of MR images.

Materials and Methods

From March 2017 to April 2018, nine patients suffering from HCC were treated with 166Ho-RE. To calculate mean doses on healthy liver/tumor tissue, MR was performed within the first day after treatment. For evaluation of hepatotoxicity and to rule out radioembolization-induced liver disease (REILD), the Model for End-Stage Liver Disease (MELD) Score, the Common Terminology Criteria for Adverse Events and specific laboratory parameters were used 1-day pre- and posttreatment and after 60 days. After 6 months, MR/CT follow-up was performed.

Results

In five patients the right liver lobe, in one patient the left liver lobe and in three patients both liver lobes were treated. Median administered activity was 3.7 GBq (range 1.7–5.9 GBq). Median dose on healthy liver tissue was 41 Gy (21–55 Gy) and on tumor tissue 112 Gy (61–172 Gy). Four patients suffered from mild postradioembolization syndrome. No significant differences in median MELD-Score were observed pre-, posttherapeutic and 60 days after 166Ho-RE. No deterioration of liver function and no indicators of REILD were observed. One patient showed a complete response, four a partial response, three a stable disease and one a progressive disease at the 6 months follow-up.

Conclusion

166Ho-RE seems to be a feasible and safe treatment option with no significant hepatotoxicity for treatment of HCC.

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References

  1. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, et al. The Burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol. 2017;3(12):1683–91. https://doi.org/10.1001/jamaoncol.2017.3055.

    Article  PubMed Central  Google Scholar 

  2. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(5 Suppl 1):S5–16.

    Article  PubMed  Google Scholar 

  3. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;99:99. https://doi.org/10.1016/j.jhep.2018.03.019.

    Article  Google Scholar 

  4. Levi Sandri GB, Ettorre GM, Giannelli V, Colasanti M, Sciuto R, Pizzi G, et al. Trans-arterial radio-embolization: a new chance for patients with hepatocellular cancer to access liver transplantation, a world review. Transl Gastroenterol Hepatol. 2017;2:98. https://doi.org/10.21037/tgh.2017.11.11.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ettorre GM, Levi Sandri GB, Laurenzi A, Colasanti M, Meniconi RL, Lionetti R, et al. Yttrium-90 radioembolization for hepatocellular carcinoma prior to liver transplantation. World J Surg. 2017;41(1):241–9. https://doi.org/10.1007/s00268-016-3682-z.

    Article  PubMed  Google Scholar 

  6. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.

    Article  PubMed  Google Scholar 

  7. Nijsen JF, Zonnenberg BA, Woittiez JR, Rook DW, Swildens-van Woudenberg IA, van Rijk PP, et al. Holmium-166 poly lactic acid microspheres applicable for intra-arterial radionuclide therapy of hepatic malignancies: effects of preparation and neutron activation techniques. Eur J Nucl Med. 1999;26(7):699–704.

    Article  CAS  PubMed  Google Scholar 

  8. Zielhuis SW, Nijsen JF, Krijger GC, van het Schip AD, Hennink WE. Holmium-loaded poly(l-lactic acid) microspheres: in vitro degradation study. Biomacromol. 2006;7(7):2217–23. https://doi.org/10.1021/bm060230r.

    Article  CAS  Google Scholar 

  9. Nijsen F, Rook D, Brandt C, Meijer R, Dullens H, Zonnenberg B, et al. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study. Eur J Nucl Med. 2001;28(6):743–9.

    Article  CAS  PubMed  Google Scholar 

  10. Vente MA, Nijsen JF, de Wit TC, Seppenwoolde JH, Krijger GC, Seevinck PR, et al. Clinical effects of transcatheter hepatic arterial embolization with holmium-166 poly(l-lactic acid) microspheres in healthy pigs. Eur J Nucl Med Mol Imaging. 2008;35(7):1259–71. https://doi.org/10.1007/s00259-008-0747-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zielhuis SW, Nijsen JF, Seppenwoolde JH, Bakker CJ, Krijger GC, Dullens HF, et al. Long-term toxicity of holmium-loaded poly(l-lactic acid) microspheres in rats. Biomaterials. 2007;28(31):4591–9. https://doi.org/10.1016/j.biomaterials.2007.07.012.

    Article  CAS  PubMed  Google Scholar 

  12. Smits ML, Elschot M, van den Bosch MA, van de Maat GH, van het Schip AD, Zonnenberg BA, et al. In vivo dosimetry based on SPECT and MR imaging of 166Ho-microspheres for treatment of liver malignancies. J Nucl Med. 2013;54(12):2093–100. https://doi.org/10.2967/jnumed.113.119768.

    Article  CAS  PubMed  Google Scholar 

  13. van de Maat GH, Seevinck PR, Elschot M, Smits ML, de Leeuw H, van Het Schip AD, et al. MRI-based biodistribution assessment of holmium-166 poly(l-lactic acid) microspheres after radioembolisation. Eur Radiol. 2013;23(3):827–35. https://doi.org/10.1007/s00330-012-2648-2.

    Article  PubMed  Google Scholar 

  14. Smits ML, Nijsen JF, van den Bosch MA, Lam MG, Vente MA, Mali WP, et al. Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. Lancet Oncol. 2012;13(10):1025–34. https://doi.org/10.1016/S1470-2045(12)70334-0.

    Article  CAS  PubMed  Google Scholar 

  15. Salem R, Thurston KG. Radioembolization with 90-yttrium 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(8):1251–78. https://doi.org/10.1097/01.rvi.0000233785.75257.9a.

    Article  PubMed  Google Scholar 

  16. Smits ML, Nijsen JF, van den Bosch MA, Lam MG, Vente MA, Huijbregts JE, et al. Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial. J Exp Clin Cancer Res. 2010;29:70. https://doi.org/10.1186/1756-9966-29-70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sangro B, Martinez-Urbistondo D, Bester L, Bilbao JI, Coldwell DM, Flamen P, et al. Prevention and treatment of complications of selective internal radiation therapy: expert guidance and systematic review. Hepatology. 2017;66(3):969–82. https://doi.org/10.1002/hep.29207.

    Article  PubMed  Google Scholar 

  18. Mahnken AH, Spreafico C, Maleux G, Helmberger T, Jakobs TF. Standards of practice in transarterial radioembolization. Cardiovasc Intervent Radiol. 2013;36(3):613–22. https://doi.org/10.1007/s00270-013-0600-8.

    Article  PubMed  Google Scholar 

  19. Nijsen JF, Seppenwoolde JH, Havenith T, Bos C, Bakker CJ, van het Schip AD. Liver tumors: MR imaging of radioactive holmium microspheres—phantom and rabbit study. Radiology. 2004;231(2):491–9. https://doi.org/10.1148/radiol.2312030594.

    Article  PubMed  Google Scholar 

  20. Seevinck PR, van de Maat GH, de Wit TC, Vente MA, Nijsen JF, Bakker CJ. Magnetic resonance imaging-based radiation-absorbed dose estimation of 166Ho microspheres in liver radioembolization. Int J Radiat Oncol Biol Phys. 2012;83(3):e437–44. https://doi.org/10.1016/j.ijrobp.2011.12.085.

    Article  CAS  PubMed  Google Scholar 

  21. Sangro B, Gil-Alzugaray B, Rodriguez J, Sola I, Martinez-Cuesta A, Viudez A, et al. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer. 2008;112(7):1538–46. https://doi.org/10.1002/cncr.23339.

    Article  PubMed  Google Scholar 

  22. Kamath PS, Kim WR, Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797–805. https://doi.org/10.1002/hep.21563.

    Article  PubMed  Google Scholar 

  23. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60. https://doi.org/10.1055/s-0030-1247132.

    Article  CAS  PubMed  Google Scholar 

  24. Prince JF, van den Bosch M, Nijsen JFW, Smits MLJ, van den Hoven AF, Nikolakopoulos S, et al. Efficacy of radioembolization with (166)Ho-microspheres in salvage patients with liver metastases: a phase 2 study. J Nucl Med. 2018;59(4):582–8. https://doi.org/10.2967/jnumed.117.197194.

    Article  CAS  PubMed  Google Scholar 

  25. Kennedy A, Nag S, Salem R, Murthy R, McEwan AJ, Nutting C, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys. 2007;68(1):13–23. https://doi.org/10.1016/j.ijrobp.2006.11.060.

    Article  PubMed  Google Scholar 

  26. Sangro B, Inarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol. 2012;56(2):464–73. https://doi.org/10.1016/j.jhep.2011.07.012.

    Article  PubMed  Google Scholar 

  27. Kennedy AS, Kleinstreuer C, Basciano CA, Dezarn WA. Computer modeling of yttrium-90-microsphere transport in the hepatic arterial tree to improve clinical outcomes. Int J Radiat Oncol Biol Phys. 2010;76(2):631–7. https://doi.org/10.1016/j.ijrobp.2009.06.069.

    Article  CAS  PubMed  Google Scholar 

  28. Lam MG, Goris ML, Iagaru AH, Mittra ES, Louie JD, Sze DY. Prognostic utility of 90Y radioembolization dosimetry based on fusion 99mTc-macroaggregated albumin-99mTc-sulfur colloid SPECT. J Nucl Med. 2013;54(12):2055–61. https://doi.org/10.2967/jnumed.113.123257.

    Article  CAS  PubMed  Google Scholar 

  29. Furuse J, Ishii H, Nagase M, Kawashima M, Ogino T, Yoshino M. Adverse hepatic events caused by radiotherapy for advanced hepatocellular carcinoma. J Gastroenterol Hepatol. 2005;20(10):1512–8. https://doi.org/10.1111/j.1440-1746.2005.03916.x.

    Article  PubMed  Google Scholar 

  30. Lau WY, Kennedy AS, Kim YH, Lai HK, Lee RC, Leung TW, et al. Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres. Int J Radiat Oncol Biol Phys. 2012;82(1):401–7. https://doi.org/10.1016/j.ijrobp.2010.08.015.

    Article  PubMed  Google Scholar 

  31. Kennedy AS, Nutting C, Coldwell D, Gaiser J, Drachenberg C. Pathologic response and microdosimetry of (90)Y microspheres in man: review of four explanted whole livers. Int J Radiat Oncol Biol Phys. 2004;60(5):1552–63. https://doi.org/10.1016/j.ijrobp.2004.09.004.

    Article  CAS  PubMed  Google Scholar 

  32. Campbell AM, Bailey IH, Burton MA. Tumour dosimetry in human liver following hepatic yttrium-90 microsphere therapy. Phys Med Biol. 2001;46(2):487–98.

    Article  CAS  PubMed  Google Scholar 

  33. Ng SC, Lee VH, Law MW, Liu RK, Ma VW, Tso WK, et al. Patient dosimetry for 90Y selective internal radiation treatment based on 90Y PET imaging. J Appl Clin Med Phys. 2013;14(5):212–21. https://doi.org/10.1120/jacmp.v14i5.4371.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gulec SA, Mesoloras G, Dezarn WA, McNeillie P, Kennedy AS. Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: the tumor selectivity of the treatment as a function of tumor to liver flow ratio. J Transl Med. 2007;5:15. https://doi.org/10.1186/1479-5876-5-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fajardo LF, Colby TV. Pathogenesis of veno-occlusive liver disease after radiation. Arch Pathol Lab Med. 1980;104(11):584–8.

    CAS  PubMed  Google Scholar 

  36. Bayraktar UD, Seren S, Bayraktar Y. Hepatic venous outflow obstruction: three similar syndromes. World J Gastroenterol. 2007;13(13):1912–27.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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(5):1826–37. https://doi.org/10.1002/hep.26014.

    Article  CAS  PubMed  Google Scholar 

  38. Golfieri R, Bilbao JI, Carpanese L, Cianni R, Gasparini D, Ezziddin S, et al. Comparison of the survival and tolerability of radioembolization in elderly vs. younger patients with unresectable hepatocellular carcinoma. J Hepatol. 2013;59(4):753–61. https://doi.org/10.1016/j.jhep.2013.05.025.

    Article  PubMed  Google Scholar 

  39. Bittermann T, Makar G, Goldberg DS. Early post-transplant survival: interaction of MELD score and hospitalization status. J Hepatol. 2015;63(3):601–8. https://doi.org/10.1016/j.jhep.2015.03.034.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Garwood ER, Fidelman N, Hoch SE, Kerlan RK Jr, Yao FY. Morbidity and mortality following transarterial liver chemoembolization in patients with hepatocellular carcinoma and synthetic hepatic dysfunction. Liver Transpl. 2013;19(2):164–73. https://doi.org/10.1002/lt.23552.

    Article  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  Google Scholar 

  42. Salem R, Gordon AC, Mouli S, Hickey R, Kallini J, Gabr A, et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2016;151(6):1155–63. https://doi.org/10.1053/j.gastro.2016.08.029.

    Article  PubMed  Google Scholar 

  43. Mantry PS, Mehta A, Madani B, Mejia A, Shahin I. Selective internal radiation therapy using yttrium-90 resin microspheres in patients with unresectable hepatocellular carcinoma: a retrospective study. J Gastrointest Oncol. 2017;8(5):799–807. https://doi.org/10.21037/jgo.2017.08.03.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sangro B, Bilbao JI, Boan J, Martinez-Cuesta A, Benito A, Rodriguez J, et al. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2006;66(3):792–800. https://doi.org/10.1016/j.ijrobp.2006.05.065.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

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This study was not supported by any funding.

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Authors and Affiliations

  1. Institute and Policlinic for Diagnostic and Interventional Radiology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany

    Christoph G. Radosa, Verena Plodeck, Jens P. Kühn & Ralf-Thorsten Hoffmann

  2. Department of Gynecology and Obstetrics, Saarland University Hospital, Kirrbergerstraße 100, 66421, Homburg, Germany

    Julia C. Radosa

  3. Department of Nuclear Medicine, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany

    Sabine Grosche-Schlee, Klaus Zöphel & Jörg Kotzerke

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  1. Christoph G. Radosa
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Correspondence to Ralf-Thorsten Hoffmann.

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Conflict of interest

R.-T. Hoffmann participates as proctor, advisory board member and received speaker’s honoraria from Sirtex and Terumo. The other authors declare no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by local ethics committee. In addition, it is a retrospective study, and for this type of study, formal consent is not required.

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Informed consent was obtained from all individual participants included in the study.

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Radosa, C.G., Radosa, J.C., Grosche-Schlee, S. et al. Holmium-166 Radioembolization in Hepatocellular Carcinoma: Feasibility and Safety of a New Treatment Option in Clinical Practice. Cardiovasc Intervent Radiol 42, 405–412 (2019). https://doi.org/10.1007/s00270-018-2133-7

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