Clinical Application of Trans-Arterial Radioembolization in Hepatic Malignancies in Europe: First Results from the Prospective Multicentre Observational Study CIRSE Registry for SIR-Spheres Therapy (CIRT)

Thomas Helmberger, Rita Golfieri, Maciej Pech, Thomas Pfammatter, Dirk Arnold, Roberto Cianni, Geert Maleux, Graham Munneke, Olivier Pellerin, Bora Peynircioglu, Bruno Sangro, Niklaus Schaefer, Niels de Jong, José Ignacio Bilbao, On behalf of the CIRT Steering Committee, On behalf of the CIRT Principal Investigators, Jean-Pierre Pelage, Derek M Manas, Frank T Kolligs, Samer Ezziddin, Ralph Peters, Thomas Albrecht, Olivier D'Archambeau, Tugsan Balli, Sadik Bilgic, Alan Bloom, Roberto Cioni, Roman Fischbach, Patrick Flamen, Laurent Gerard, Gerd Grözinger, Marcus Katoh, Michael Koehler, Jan Robert Kröger, Christiane Kuhl, Franco Orsi, Murat Ozgun, Peter Reimer, Maxime Ronot, Axel Schmid, Alessandro Vit, Thomas Helmberger, Rita Golfieri, Maciej Pech, Thomas Pfammatter, Dirk Arnold, Roberto Cianni, Geert Maleux, Graham Munneke, Olivier Pellerin, Bora Peynircioglu, Bruno Sangro, Niklaus Schaefer, Niels de Jong, José Ignacio Bilbao, On behalf of the CIRT Steering Committee, On behalf of the CIRT Principal Investigators, Jean-Pierre Pelage, Derek M Manas, Frank T Kolligs, Samer Ezziddin, Ralph Peters, Thomas Albrecht, Olivier D'Archambeau, Tugsan Balli, Sadik Bilgic, Alan Bloom, Roberto Cioni, Roman Fischbach, Patrick Flamen, Laurent Gerard, Gerd Grözinger, Marcus Katoh, Michael Koehler, Jan Robert Kröger, Christiane Kuhl, Franco Orsi, Murat Ozgun, Peter Reimer, Maxime Ronot, Axel Schmid, Alessandro Vit

Abstract

Purpose: To address the lack of prospective data on the real-life clinical application of trans-arterial radioembolization (TARE) in Europe, the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) initiated the prospective observational study CIRSE Registry for SIR-Spheres® Therapy (CIRT).

Materials and methods: Patients were enrolled from 1 January 2015 till 31 December 2017. Eligible patients were adult patients treated with TARE with Y90 resin microspheres for primary or metastatic liver tumours. Patients were followed up for 24 months after treatment, whereas data on the clinical context of TARE, overall survival (OS) and safety were collected.

Results: Totally, 1027 patients were analysed. 68.2% of the intention of treatment was palliative. Up to half of the patients received systemic therapy and/or locoregional treatments prior to TARE (53.1%; 38.3%). Median overall survival (OS) was reported per cohort and was 16.5 months (95% confidence interval (CI) 14.2-19.3) for hepatocellular carcinoma, 14.6 months (95% CI 10.9-17.9) for intrahepatic cholangiocarcinoma. For liver metastases, median OS for colorectal cancer was 9.8 months (95% CI 8.3-12.9), 5.6 months for pancreatic cancer (95% CI 4.1-6.6), 10.6 months (95% CI 7.3-14.4) for breast cancer, 14.6 months (95% CI 7.3-21.4) for melanoma and 33.1 months (95% CI 22.1-nr) for neuroendocrine tumours. Statistically significant prognostic factors in terms of OS include the presence of ascites, cirrhosis, extra-hepatic disease, patient performance status (Eastern Cooperative Oncology Group), number of chemotherapy lines prior to TARE and tumour burden. Thirty-day mortality rate was 1.0%. 2.5% experienced adverse events grade 3 or 4 within 30 days after TARE.

Conclusion: In the real-life clinical setting, TARE is largely considered to be a part of a palliative treatment strategy across indications and provides an excellent safety profile.

Level of evidence: Level 3.

Trial registration: ClinicalTrials.gov NCT02305459.

Keywords: Hepatocellular carcinoma; Liver; Metastasis; Observational study; Radioisotope brachytherapy; Registries; Therapeutic embolization; Trans-arterial radioembolization; Yttrium-90.

Conflict of interest statement

JB and GM received speaker fees and proctor fees from SIRTEX Medical, BP received proctor fees from SIRTEX Medical, MP reported grants from Bayer and SIRTEX during the course of the study, OP is shareholder of GOGITh-SAS, NdJ is an employee of CIRSE, BS received grants, personal fees and non-financial support from SIRTEX Medical and BMS, grants and personal fees from Onxeo, personal fees and non-financial support from Astra Zeneca, Bayer, Ipsen, and BTG, and personal fees from Lilly, Eisai and Roche. DA is on the advisory board of Terumo, Boston Scientific, SIRTEX Medical Europe and Biocompatibles. RC, RG, TH, NS, TP and GM declared no conflict of interest. All authors report no conflict of interest directly related to the submitted work.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves per indication of overall survival in months after TARE, including at risk patients per interval

References

    1. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 doi: 10.1093/annonc/mdw235.
    1. Valle JW, Borbath I, Khan SA, et al. Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 doi: 10.1093/annonc/mdw324.
    1. Giammarile F, Bodei L, Chiesa C, et al. EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds. Eur J Nucl Med Mol Imaging. 2011 doi: 10.1007/s00259-011-1812-2.
    1. Galle PR, Forner A, Llovet JM, et al. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 doi: 10.1016/j.jhep.2018.03.019.
    1. Dufour JF, Greten TF, Raymond E, et al. Clinical practice guidelines EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma european organisation for research and treatment of cancer. J Hepatol. 2012 doi: 10.1016/j.jhep.2011.12.001.
    1. Benson AB, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) Colon Cancer, Version 4.2020. NCCN website. 15 June 2020. Accessed 24 August 2020.
    1. Benson AB, D’Angelica MI, Abbott DE, et al. NCCN Clinical practice guidelines in oncology (NCCN Guidelines ®) Hepatobiliary Cancers, Version 5.2020. NCCN website. 4 August 2020. Accessed 24 August 2020.
    1. Sangro B, Salem R. Transarterial chemoembolization and radioembolization. Semin Liver Dis. 2014 doi: 10.1055/s-0034-1394142.
    1. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010 doi: 10.1053/j.gastro.2009.09.006.
    1. Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study. Hepatology. 2013 doi: 10.1002/hep.26014.
    1. Hilgard P, Hamami M, El Fouly A, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology. 2010 doi: 10.1002/hep.23944.
    1. Sangro B, Carpanese L, Cianni R, et al. Survival after Yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: A European evaluation. Hepatology. 2011 doi: 10.1002/hep.24451.
    1. Mancini R, Carpanese L, Sciuto R, et al. A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90Yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: Preliminary results on toxicity and response rates. In Vivo (Brooklyn). 2006.
    1. Sofocleous CT, Garcia AR, Pandit-Taskar N, et al. Phase i trial of selective internal radiation therapy for chemorefractory colorectal cancer liver metastases progressing after hepatic arterial pump and systemic chemotherapy. Clin Colorectal Cancer. 2014 doi: 10.1016/j.clcc.2013.11.010.
    1. Gulec SA, Pennington K, Wheeler J, et al. Yttrium-90 microsphere-selective internal radiation therapy with chemotherapy (Chemo-SIRT) for colorectal cancer liver metastases: An in vivo double-arm-controlled phase II trial. Am J Clin Oncol Cancer Clin Trials. 2013 doi: 10.1097/COC.0b013e3182546c50.
    1. Martin LK, Cucci A, Wei L, et al. Yttrium-90 radioembolization as salvage therapy for colorectal cancer with liver metastases. Clin Colorectal Cancer. 2012 doi: 10.1016/j.clcc.2011.12.002.
    1. Hendlisz A, Van Den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010 doi: 10.1200/JCO.2010.28.5643.
    1. Vilgrain V, Pereira H, Assenat E, 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 doi: 10.1016/S1470-2045(17)30683-6.
    1. Wasan HS, Gibbs P, Sharma N, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017 doi: 10.1016/S1470-2045(17)30457-6.
    1. Sharma RA, Wasan HS, Van Hazel GA, et al. Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer. J Clin Oncol. 2018 doi: 10.1200/jco.2017.35.15_suppl.3507.
    1. Chauhan N, Mulcahy MF, Salem R, et al. Therasphere yttrium-90 glass microspheres combined with chemotherapy versus chemotherapy alone in second-line treatment of patients with metastatic colorectal carcinoma of the liver: Protocol for the EPOCH phase 3 randomized clinical trial. J Med Internet Res. 2019 doi: 10.2196/11545.
    1. Chow PKH, Gandhi M, Tan SB, et al. SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018 doi: 10.1200/JCO.2017.76.0892.
    1. Saxena A, Meteling B, Kapoor J, Golani S, Morris DL, Bester L. Is Yttrium-90 radioembolization a viable treatment option for unresectable, chemorefractory colorectal cancer liver metastases? A large single-center experience of 302 patients. Ann Surg Oncol. 2015 doi: 10.1245/s10434-014-4164-x.
    1. Kennedy AS, Ball D, Cohen SJ, et al. Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for 90Y resin microspheres. J Gastrointest Oncol. 2015 doi: 10.3978/j.issn.2078-6891.2014.109.
    1. Rognoni C, Ciani O, Sommariva S, et al. Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma: Systematic review and meta-analyses. Oncotarget. 2016 doi: 10.18632/oncotarget.11644.
    1. Levillain H, Duran Derijckere I, Ameye L, et al. Personalised radioembolization improves outcomes in refractory intra-hepatic cholangiocarcinoma: a multicenter study. Eur J Nucl Med Mol Imaging. 2019 doi: 10.1007/s00259-019-04427-z.
    1. Riby D, Mazzotta AD, Bergeat D, et al. Downstaging with radioembolization or chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2020 doi: 10.1245/s10434-020-08486-7.
    1. Cucchetti A, Cappelli A, Mosconi C, et al. Improving patient selection for selective internal radiation therapy of intra-hepatic cholangiocarcinoma: a meta-regression study. Liver Int. 2017 doi: 10.1111/liv.13382.
    1. Sangro B, Maini CL, Ettorre GM, et al. Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies. Eur J Nucl Med Mol Imaging. 2018 doi: 10.1007/s00259-018-3968-5.
    1. Bargellini I, Mosconi C, Pizzi G, et al. Yttrium-90 radioembolization in unresectable intrahepatic cholangiocarcinoma: results of a multicenter retrospective study. Cardiovasc Intervent Radiol. 2020 doi: 10.1007/s00270-020-02569-4.
    1. Sposito C, Mazzaferro V. The SIRveNIB and SARAH trials, radioembolization vs. sorafenib in advanced HCC patients: reasons for a failure, and perspectives for the future. HepatoBiliary Surg Nutr. 2018. 10.21037/hbsn.2018.10.06
    1. White J, Carolan-Rees G, Dale M, et al. Analysis of a national programme for selective internal radiation therapy for colorectal cancer liver metastases. Clin Oncol. 2019;31(1):58–66. doi: 10.1016/j.clon.2018.09.002.
    1. White J, Carolan-Rees G, Dale M, et al. Yttrium-90 transarterial radioembolization for chemotherapy-refractory intrahepatic cholangiocarcinoma: a prospective. Observational Study. J Vasc Interv Radiol. 2019;30(8):1185–1192. doi: 10.1016/j.jvir.2019.03.018.
    1. Kuei A, Saab S, Cho SK, Kee ST, Lee EW. Effects of Yttrium-90 selective internal radiation therapy on non-conventional liver tumors. World J Gastroenterol. 2015 doi: 10.3748/wjg.v21.i27.8271.
    1. Barbier CE, Garske-Román U, Sandström M, Nyman R, Granberg D. Selective internal radiation therapy in patients with progressive neuroendocrine liver metastases. Eur J Nucl Med Mol Imaging. 2016 doi: 10.1007/s00259-015-3264-6.
    1. Puippe G, Pfammatter T, Schaefer N. Arterial therapies of non-colorectal liver metastases. Visz Gastrointest Med Surg. 2015;31(6):414–422. doi: 10.1159/000441689.
    1. Helmberger T, Arnold D, Bilbao JI, et al. Clinical application of radioembolization in hepatic malignancies: Protocol for a prospective multicenter observational study. J Med Internet Res. 2020 doi: 10.2196/16296.
    1. Kurilova I, Beets-Tan RGH, Flynn J, et al. Factors affecting oncologic outcomes of 90Y radioembolization of heavily pre-treated patients with colon cancer liver metastases. Clin Colorectal Cancer. 2019 doi: 10.1016/j.clcc.2018.08.004.
    1. Damm R, Seidensticker R, Ulrich G, et al. Y90 Radioembolization in chemo-refractory metastastic, liver dominant colorectal cancer patients: outcome assessment applying a predictive scoring system. BMC Cancer. 2016 doi: 10.1186/s12885-016-2549-x.
    1. Sofocleous CT, Violari EG, Sotirchos VS, et al. Radioembolization as a salvage therapy for heavily pretreated patients with colorectal cancer liver metastases: factors that affect outcomes. Clin Colorectal Cancer. 2015 doi: 10.1016/j.clcc.2015.06.003.
    1. Barat M, Cottereau A-S, Kedra A, et al. The Role of Interventional Radiology for the Treatment of Hepatic Metastases from Neuroendocrine Tumor: An Updated Review. J Clin Med. 2020 doi: 10.3390/jcm9072302.
    1. Jia Z, Wang W. Yttrium-90 radioembolization for unresectable metastatic neuroendocrine liver tumor: a systematic review. Eur J Radiol. 2018 doi: 10.1016/j.ejrad.2018.01.012.
    1. Zuckerman DA, Kennard RF, Roy A, Parikh PJ, Weiner AA. Outcomes and toxicity following Yttrium-90 radioembolization for hepatic metastases from neuroendocrine tumors—a single-institution experience. J Gastrointest Oncol. 2019 doi: 10.21037/jgo.2018.10.05.
    1. Bale R, Putzer D, Schullian P. Local treatment of breast cancer liver metastasis. Cancers (Basel). 2019 doi: 10.3390/cancers11091341.
    1. Gordon AC, Gradishar WJ, Kaklamani VG, et al. Yttrium-90 radioembolization stops progression of targeted breast cancer liver metastases after failed chemotherapy. J Vasc Interv Radiol. 2014 doi: 10.1016/j.jvir.2014.07.007.
    1. Jakobs TF, Hoffmann RT, Fischer T, et al. Radioembolization in patients with hepatic metastases from breast cancer. J Vasc Interv Radiol. 2008 doi: 10.1016/j.jvir.2008.01.009.
    1. Rowcroft A, Loveday BPT, Thomson BNJ, Banting S, Knowles B. Systematic review of liver directed therapy for uveal melanoma hepatic metastases. HPB. 2020 doi: 10.1016/j.hpb.2019.11.002.
    1. Gibbs P, Do C, Lipton L, et al. Phase II trial of selective internal radiation therapy and systemic chemotherapy for liver-predominant metastases from pancreatic adenocarcinoma. BMC Cancer. 2015 doi: 10.1186/s12885-015-1822-8.
    1. Michl M, Haug AR, Jakobs TF, et al. Radioembolization with yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: Efficacy, safety and prognostic factors. Oncol. 2014 doi: 10.1159/000355821.
    1. Tulokas S, Mäenpää H, Peltola E, et al. Selective internal radiation therapy (SIRT) as treatment for hepatic metastases of uveal melanoma: a Finnish nation-wide retrospective experience. Acta Oncol (Madr). 2018 doi: 10.1080/0284186X.2018.1465587.
    1. Edeline J, Touchefeu Y, Guiu B, et al. Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2020 doi: 10.1001/jamaoncol.2019.3702.
    1. Feretis M, Solodkyy A. Yttrium-90 radioembolization for unresectable hepatic metastases of breast cancer: a systematic review. World J Gastrointest Oncol. 2020 doi: 10.4251/wjgo.v12.i2.228.
    1. Xing M, Prajapati HJ, Dhanasekaran R, et al. Selective internal yttrium-90 radioembolization therapy (90Y-SIRT) versus best supportive care in patients with unresectable metastatic melanoma to the liver refractory to systemic therapy: Safety and efficacy cohort study. Am J Clin Oncol Cancer Clin Trials. 2017 doi: 10.1097/COC.0000000000000109.
    1. Al-Adra DP, Gill RS, Axford SJ, Shi X, Kneteman N, Liau SS. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol. 2015 doi: 10.1016/j.ejso.2014.09.007.
    1. Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015 doi: 10.1002/jso.23781.
    1. Ricke J, Sangro B, Amthauer H, et al. The impact of combining Selective Internal Radiation Therapy (SIRT) with Sorafenib on overall survival in patients with advanced hepatocellular carcinoma: the soramic trial palliative cohort. J Hepatol. 2018 doi: 10.1016/s0168-8278(18)30424-0.
    1. Abdallah MA, Wongjarupong N, Hassan MA, et al. The efficacy, safety, and predictors of outcomes of transarterial radioembolization for hepatocellular carcinoma: a retrospective study. Expert Rev Gastroenterol Hepatol. 2020 doi: 10.1080/17474124.2020.1777856.
    1. Salem R, Gabr A, Riaz A, et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1000-patient 15-year experience. Hepatology. 2018 doi: 10.1002/hep.29691.
    1. Abouchaleh N, Gabr A, Ali R, et al. 90 Y radioembolization for locally advanced hepatocellular carcinoma with portal vein thrombosis: Long-term outcomes in a 185-patient cohort. J Nucl Med. 2018 doi: 10.2967/jnumed.117.199752.
    1. Reimer P, Virarkar MK, Binnenhei M, Justinger M, Schön MR, Tatsch K. Prognostic factors in overall survival of patients with unresectable intrahepatic cholangiocarcinoma treated by means of yttrium-90 radioembolization: results in therapy-naïve patients. Cardiovasc Intervent Radiol. 2018 doi: 10.1007/s00270-017-1871-2.
    1. Köhler M, Harders F, Lohöfer F, et al. Prognostic factors for overall survival in advanced intrahepatic cholangiocarcinoma treated with yttrium-90 radioembolization. J Clin Med. 2019;9(1):56. doi: 10.3390/jcm9010056.
    1. Hickey R, Lewandowski RJ, Prudhomme T, et al. 90Y radioembolization of colorectal hepatic metastases using glass microspheres: safety and survival outcomes from a 531-patient multicenter study. J Nucl Med. 2016 doi: 10.2967/jnumed.115.166082.
    1. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008 doi: 10.1002/hep.21980.
    1. Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol. 2012 doi: 10.1016/j.jhep.2011.07.012.
    1. Lahti SJ, Xing M, Zhang D, Lee JJ, Magnetta MJ, Kim HS. KRAS status as an independent prognostic factor for survival after yttrium-90 radioembolization therapy for unresectable colorectal cancer liver metastases. J Vasc Interv Radiol. 2015 doi: 10.1016/j.jvir.2015.05.032.
    1. Ziv E, Bergen M, Yarmohammadi H, et al. PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases. Oncotarget. 2017 doi: 10.18632/oncotarget.15278.
    1. van den Hoven A, Rosenbaum C, Elias S, et al. Insights into the dose-response relationship of hepatic radioembolization with resin yttrium-90 microspheres: a prospective cohort study in patients with colorectal cancer liver metastases. J Vasc Interv Radiol. 2016 doi: 10.1016/j.jvir.2015.12.031.
    1. Hermann A-L, Dieudonné A, Ronot M, et al. Relationship of tumor radiation–absorbed dose to survival and response in hepatocellular carcinoma treated with transarterial radioembolization with 90 Y in the SARAH study. Radiology. 2020 doi: 10.1148/radiol.2020191606.
    1. Sofocleous CT, Vasiniotis Kamarinos N. Tumor-absolbed dose: the missing link in radioembolization. Radiology. 2020 doi: 10.1148/radiol.2020202354.
    1. Adam A, De Baère T, Bilbao JI, et al. Standards of quality assurance in interventional oncology, First Edition. CIRSE–Cardiovascular and Interventional Radiological Society of Europe. 2018. ISBN 978-3-9502501-5-2

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren