Skip to main content

Advertisement

SpringerLink
Log in

Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study.

Methods

Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism.

Results

The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity.

Conclusion

188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.

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
Fig. 4

Similar content being viewed by others

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  PubMed  Google Scholar 

  2. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    Article  CAS  PubMed  Google Scholar 

  3. Vilgrain V, Bouattour M, Sibert A, Lebtahi R, Ronot M, Pageaux G-P, et al. SARAH: a randomised controlled trial comparing efficacy and safety of selective internal radiation therapy (with yttrium-90 microspheres) and sorafenib in patients with locally advanced hepatocellular carcinoma. J Hepatol. 2017;66:S85–6.

    Article  Google Scholar 

  4. Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux G-P, 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;18:1624–36.

    Article  CAS  PubMed  Google Scholar 

  5. Chow PKH, Gandhi M, Tan S-B, 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.

    Article  CAS  PubMed  Google Scholar 

  6. Raoul JL, Guyader D, Bretagne JF, Duvauferrier R, Bourguet P, Bekhechi D, et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med. 1994;35:1782–7.

    CAS  PubMed  Google Scholar 

  7. Noiret N, Garin E, Lepareur N, Ardisson V. Composition for treating liver cancer in humans based on rhenium-188 and method for preparing such a composition [Internet]. 2011 [cited 2017 Oct 11]. Available from: https://www.google.com/patents/EP2536438A1?hl=fr&cl=en

  8. Lepareur N. Vectorisations active et passive de radiopharmaceutiques du technetium-99m et du rhénium-188 pour l’imagerie médicale et la thérapie [Internet]. Rennes 1; 2003 [cited 2017 Jul 10]. Available from: http://www.theses.fr/2003REN10110

  9. Garin E, Noiret N, Malbert C, Lepareur N, Roucoux A, Caulet-Maugendre S, et al. Development and biodistribution of 188Re-SSS lipiodol following injection into the hepatic artery of healthy pigs. Eur J Nucl Med Mol Imaging. 2004;31:542–6.

    Article  CAS  PubMed  Google Scholar 

  10. Garin E, Noiret N, Malbert C-H, Lepareur N, Roucoux A, Dazord L, et al. Development of 99mTc labelled lipiodol: biodistribution following injection into the hepatic artery of the healthy pig. Nucl Med Commun. 2004;25:291–7.

    Article  CAS  PubMed  Google Scholar 

  11. Garin E, Denizot B, Noiret N, Lepareur N, Roux J, Moreau M, et al. 188Re-SSS lipiodol: radiolabelling and biodistribution following injection into the hepatic artery of rats bearing hepatoma. Nucl Med Commun. 2004;25:1007–13.

    Article  CAS  PubMed  Google Scholar 

  12. Garin E, Rakotonirina H, Lejeune F, Denizot B, Roux J, Noiret N, et al. Effect of a 188 re-sss lipiodol/131i-lipiodol mixture, 188 re-sss lipiodol alone or 131i-lipiodol alone on the survival of rats with hepatocellular carcinoma. Nucl Med Commun. 2006;27:363–9.

    Article  CAS  PubMed  Google Scholar 

  13. Lepareur N, Ardisson V, Noiret N, Boucher E, Raoul J-L, Clément B, et al. Automation of labelling of Lipiodol with high-activity generator-produced 188Re. Appl Radiat Isot. 2011;69:426–30.

    Article  CAS  PubMed  Google Scholar 

  14. Lepareur N, Ardisson V, Noiret N, Garin E. (188)re-SSS/Lipiodol: development of a potential treatment for HCC from bench to bedside. Int J Mol Imaging. 2012;2012:278306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 188RE-SSS lipiodol to treat hepatocellular carcinomas — full text view.ClinicalTrials.gov [Internet]. 2016 [cited 2016 Jun 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT01126463

  16. Jaszczak RJ, Greer KL, Floyd CE Jr, Harris CC, Coleman RE. Improved SPECT quantification using compensation for scattered photons. J Nucl Med. 1984;25:893–900.

    CAS  PubMed  Google Scholar 

  17. Snyder WS, Ford MR, Warner GG, Watson SB. MIRD Pamphlet #11: S, Absorbed dose per unit cumulated activity for selected radionuclides and organs. 1975 [cited 2017 Oct 10]; Available from: https://www.scienceopen.com/document?vid=a0909e6e-4b0b-469b-b9c7-09c8dac3fc37

  18. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF, et al. MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med. 1999;40:37S–61S.

    CAS  PubMed  Google Scholar 

  19. Zanzonico PB, Divgi C. Patient-specific radiation dosimetry for radionuclide therapy of liver tumours with intrahepatic artery rhenium-188 lipiodol. Semin Nucl Med. 2008;38:S30–9.

    Article  PubMed  Google Scholar 

  20. Sgouros G. Bone marrow dosimetry for radioimmunotherapy: theoretical considerations. J Nucl Med. 1993;34:689–94.

    CAS  PubMed  Google Scholar 

  21. Lambert B, Bacher K, Defreyne L, Gemmel F, Van Vlierberghe H, Jeong JM, et al. 188Re-HDD/lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial. J Nucl Med. 2005;46:60–6.

    CAS  PubMed  Google Scholar 

  22. Lambert B, Bacher K, De Keukeleire K, Smeets P, Colle I, Jeong JM, et al. 188Re-HDD/lipiodol for treatment of hepatocellular carcinoma: a feasibility study in patients with advanced cirrhosis. J Nucl Med. 2005;46:1326–32.

    CAS  PubMed  Google Scholar 

  23. Lambert B, Bacher K, Defreyne L, Van Vlierberghe H, Jeong JM, Wang RF, et al. (188)re-HDD/lipiodol therapy for hepatocellular carcinoma: an activity escalation study. Eur J Nucl Med Mol Imaging. 2006;33:344–52.

    Article  CAS  PubMed  Google Scholar 

  24. Lambert B, Bacher K, Defreyne L. Rhenium-188 based radiopharmaceuticals for treatment of liver tumours. Q J Nucl Med Mol Imaging. 2009;53:305–10.

    CAS  PubMed  Google Scholar 

  25. Bernal P, Raoul J-L, Stare J, Sereegotov E, Sundram FX, Kumar A, et al. International Atomic Energy Agency-sponsored multination study of intra-arterial rhenium-188-labeled lipiodol in the treatment of inoperable hepatocellular carcinoma: results with special emphasis on prognostic value of dosimetric study. Semin Nucl Med. 2008;38:S40–5.

    Article  PubMed  Google Scholar 

  26. Bernal P, Raoul J-L, Vidmar G, Sereegotov E, Sundram FX, Kumar A, et al. Intra-arterial Rhenium-188 Lipiodol in the treatment of inoperable hepatocellular carcinoma: results of an IAEA-sponsored multination study. Int J Radiat Oncol. 2007;69:1448–55.

    Article  CAS  Google Scholar 

  27. Boschi A, Uccelli L, Duatti A, Colamussi P, Cittanti C, Filice A, et al. A kit formulation for the preparation of 188Re-lipiodol: preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma. Nucl Med Commun. 2004;25:691–9.

    Article  CAS  PubMed  Google Scholar 

  28. Knapp FF. Continued availability of the tungsten-188/rhenium-188 generator to enhance therapeutic utility of 188Re. Int J Nucl Med Res [Internet]. 2017 [cited 2018 Dec 7]; Available from: http://www.cosmosscholars.com/special-issues-ijnmr/46-abstracts/ijnmr/724-abstract-continued-availability-of-the-tungsten-188-rhenium-188-generator-to-enhance-therapeutic-utility-of-188re

  29. Pillai MR, Dash A, Knapp FF. Rhenium-188: availability from the 188W/188Re generator and status of current applications. Curr Radiopharm. 2012;5:228–43.

    Article  CAS  PubMed  Google Scholar 

  30. Kan Z, Ivancev K, Hägerstrand I, Chuang VP, Lunderquist A. In vivo microscopy of the liver after injection of lipiodol into the hepatic artery and portal vein in the rat. Acta Radiol. 1989;30:419–25.

    Article  CAS  PubMed  Google Scholar 

  31. Park C, Choi SI, Kim H, Yoo HS, Lee YB. Distribution of Lipiodol in hepatocellular carcinoma. Liver. 1990;10:72–8.

    Article  CAS  PubMed  Google Scholar 

  32. Celler A, Esquinas PL. Personalized dosimetry for 188 Re radionuclide therapies based on post-treatment SPECT/CT scans. 2017 [cited 2017 Aug 24]; Available from: http://cosmosscholars.com/phms/index.php/ijnmr/article/view/776

  33. Fernández E, Luis P. Quantitative measurements of Rhenium-188 for radionuclide therapies [Internet]. University of British Columbia; 2017 [cited 2017 Aug 24]. Available from: https://open.library.ubc.ca/cIRcle/collections/ubctheses/24/items/1.0348703

Download references

Acknowledgements

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

We are grateful to Prof Mario Marengo, from Bologna University, for his help with the calibration settings for 188Re.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Cancer Institute Eugène Marquis, Avenue de la Bataille Flandres-Dunkerque, CS 44229, 35042, Rennes, cedex, France

    Kostas Delaunay, Sophie Laffont, Xavier Palard & Etienne Garin

  2. University of Rennes 1, Rennes, France

    Kostas Delaunay, Julien Edeline, Xavier Palard, Éric Bellissant & Etienne Garin

  3. Department of Medical Oncology, Cancer Institute Eugène Marquis, Rennes, France

    Julien Edeline, Samuel Le Sourd & Marc Pracht

  4. INSERM INRA UMR 1241 NuMeCan, University of Rennes 1, Rennes, France

    Julien Edeline, Nicolas Lepareur & Etienne Garin

  5. Department of Medical Imaging, Cancer Institute Eugène Marquis, Rennes, France

    Yan Rolland

  6. INSERM UMR 1099 LTSI, University of Rennes 1, Rennes, France

    Yan Rolland

  7. Radiopharmacy, Cancer Institute Eugène Marquis, Rennes, France

    Nicolas Lepareur, Christelle Bouvry & Valérie Ardisson

  8. ENSCR, CNRS, ISCR [(Institut des Sciences Chimiques de Rennes)] - UMR 6226, University of Rennes, F-35000, Rennes, France

    Nicolas Noiret

  9. INSERM CIC 1414 Clinical Investigation Center, Rennes, France

    Éric Bellissant

  10. Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmaco-epidemiology and Drug Information Center, Rennes University Hospital, Rennes, France

    Éric Bellissant

Authors
  1. Kostas Delaunay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julien Edeline
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Rolland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicolas Lepareur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sophie Laffont
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xavier Palard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christelle Bouvry
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Samuel Le Sourd
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marc Pracht
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Valérie Ardisson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nicolas Noiret
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Éric Bellissant
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Etienne Garin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Etienne Garin.

Ethics declarations

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 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest

Yan Rolland, Julien Edeline, and Etienne Garin are consultants for BTG UK Ltd.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Delaunay, K., Edeline, J., Rolland, Y. et al. Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization. Eur J Nucl Med Mol Imaging 46, 1506–1517 (2019). https://doi.org/10.1007/s00259-019-04277-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-019-04277-9

Keywords

Search

Navigation