Abstract
Primary Objective
Recently, selective internal radiation therapy using yttrium-90 (Y90) glass microspheres (TheraSphere™) was approved for reimbursement by health authorities in France. The PROACTIF study aims to gather data on effectiveness, patient quality of life, and safety with use of Y90 glass microspheres in real-world clinical settings in France.
Inclusion Criteria
Patient with a diagnosis of hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCC), and/or metastatic colorectal cancer (mCRC) who was treated with a dose of Y90 glass microspheres that has been reimbursed in France and who do not oppose use of their personal medical data.
Exclusion Criteria
If data collection is opposed, treatment is reimbursed but not administered, or treatment is administered but not reimbursed.
Outcome Measures
Primary outcome measures include overall survival from time of Y90 glass microsphere treatment and quality of life, as assessed using the Functional Assessment of Cancer Therapy- Hepatobiliary questionnaire.
Estimated Number of Patients to Be Included
This is an open study and there is no set number of patients; 115 have already been enrolled.
Planned Subgroup Analyses
Analyses will be stratified by disease state (HCC, iCC, or mCRC). Subgroups to be analyzed include age group, unilobar/bilobar disease at baseline, Eastern Cooperative Oncology Group (ECOG) status at baseline, liver tumor burden at baseline, target lesion size, and standard versus multi-compartment personalized dosimetry treatment.
Planned Recruitment and Observation Period
Recruitment includes patients who are prescribed and treated with a commercial vial of Y90 glass microspheres between 01 January 2019 and 31 December 2024.
Trial registration
ClinicalTrials.gov Identifier: NCT04069468.
Similar content being viewed by others
Abbreviations
- HCC:
-
Hepatocellular carcinoma
- iCC:
-
Intrahepatic cholangiocarcinoma
- mCRC:
-
Metastatic colorectal cancer
- SIRT:
-
Selective internal radiation therapy
- BCLC:
-
Barcelona clinic liver cancer
- Y90:
-
Yttrium-90
- PROACTIF:
-
A prospective, post approval, multiple centre, open-label, non- interventional, registry study to evaluate effectiveness of therasphere in clinical practice in France
- QoL:
-
Quality of life
- RIHP3:
-
Recherche impliquant la personne humaine de categorie 3
- FACT-Hep:
-
Functional assessment of cancer therapy – hepatobiliary cancer
- Bq:
-
Becquerel
- EDC:
-
Electronic data capture
- PIS:
-
Patient information sheet
- GDPR:
-
General data protection regulation
- eCRF:
-
Electronic case report form
- PVT:
-
Portal vein thrombosis
- 99mTc-MAA:
-
Technetium albumin aggregated
- SPECT:
-
Single-photon emission computed tomography
- CT:
-
Computed tomography
- IFU:
-
Instructions for use
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- INR:
-
International normalized ratio
- AFP:
-
Alpha-fetoprotein
- CA19-9:
-
Carbohydrate antigen 19-9
- CEA:
-
Carcinoembryonic antigen
- MRI:
-
Magnetic resonance imaging
- RECIST 1.1:
-
Response evaluation criteria in solid tumors
- mRECIST:
-
Modified response evaluation criteria in solid tumors
- MCD:
-
Multi-compartment dosimetry
- PET:
-
Positron emission tomography
- OS:
-
Overall survival
- SAEs:
-
Serious adverse events
- AEs:
-
Adverse events
- NCI-CTCAE:
-
National cancer institute common terminology criteria for adverse events
- CR:
-
Complete response
- PR:
-
Partial response
- SD:
-
Stable disease
- PD:
-
Progressive disease
- DVH:
-
Dose volume histogram
- ECOG:
-
Eastern cooperative oncology group
- ALBI:
-
Albumin-bilirubin
- CI:
-
Confidence interval
- FOLFOX:
-
Folinic acid, fluorouracil, and oxaliplatin
References
Llovet J, Ducreux M, Lencioni R, Di Bisceglie AM, Galle PR, Dufour JF. European association for the study of the L, European organisation for R, treatment of C EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.
European Association for the Study of the Liver. Corrigendum to “EASL clinical practice guidelines: management of hepatocellular carcinoma” J Hepatol 69 (2018) 182–236]. J Hepatol. 2019;70(4):817.
European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14.
Benson AB, D’Angelica MI, Abbott DE, et al. Hepatobiliary cancers, version 2. 2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(5):541–65.
Benson AB, Venook AP, Al-Hawary MM, et al. Colon cancer, version 2 2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(3):329–59.
Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150(4):835–53.
Gabr A, Kulik L, Mouli S, et al. Liver transplantation following Yttrium-90 radioembolization: 15-year experience in 207-patient cohort. Hepatology. 2020;73:998.
Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9(8):1920–8.
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: Off J Am Soc Clin Oncol. 2018;36(19):1913–21.
Salem R, Gilbertsen M, Butt Z, et al. Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin Gastroenterol Hepatol. 2013;11(10):1358–65.
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;18(12):1624–36.
Abbott AM, Kim R, Hoffe SE, et al. Outcomes of therasphere radioembolization for colorectal metastases. Clin Colorectal Cancer. 2015;14(3):146–53.
Lance C, McLennan G, Obuchowski N, et al. Comparative analysis of the safety and efficacy of transcatheter arterial chemoembolization and yttrium-90 radioembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2011;22(12):1697–705.
Salem R, Lewandowski RJ, Kulik L, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140(2):497–507.
Venerito M, Pech M, Canbay A, et al. NEMESIS: non-inferiority, individual patient meta-analysis of selective internal radiation therapy with Yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma. J Nucl Med Off Publ, Soc Nucl Med. 2020;37:e15604.
Chauhan N, Bukovcan J, Boucher E, et al. Intra-arterial TheraSphere yttrium-90 glass microspheres in the treatment of patients with unresectable hepatocellular carcinoma: Protocol for the STOP-HCC phase 3 randomized controlled trial. JMIR Res Protoc. 2018;7(8):e11234.
Kappadath SC, Mikell J, Balagopal A, Baladandayuthapani V, Kaseb A, Mahvash A. Hepatocellular carcinoma tumor dose response after (90)Y-radioembolization with glass microspheres using (90)Y-SPECT/CT-based voxel dosimetry. Int J Radiat Oncol Biol Phys. 2018;102(2):451–61.
Kokabi N, Camacho JC, Xing M, 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;121(13):2164–74.
Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol. 2006;94(7):572–86.
Lewandowski RJ, Gabr A, Abouchaleh N, et al. Radiation segmentectomy: potential curative therapy for early hepatocellular carcinoma. Radiology. 2018;287(3):1050–8.
Lewandowski RJ, Salem R. Yttrium-90 radioembolization of hepatocellular carcinoma and metastatic disease to the liver. Semin Intervent Radiol. 2006;23(1):64–72.
Moreno-Luna LE, Yang JD, Sanchez W, et al. Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2013;36(3):714–23.
Salem R, Gabr A, Riaz A, et al. Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience. Hepatology. 2018;68(4):1429–40.
Salem R, Johnson GE, Kim E, et al. Yttrium-90 radioembolization for the treatment of solitary unresectable HCC: the LEGACY study. Hepatology. 2021;74:2342.
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. JMIR Res Protoc. 2019;8(1):e11545.
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 Off Publ Soc Nucl Med. 2016;57(5):665–71.
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;18(1):8–18.
Kurilova I, Bendet A, Fung EK, et al. Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres. Abdom Radiol (NY). 2021;46(7):3428–36.
Mulcahy MF, Mahvash A, Pracht M, et al. Radioembolization with chemotherapy for colorectal liver metastases: a randomized, open-label, international, multicenter phase III trial. Ann Oncol. 2021;32:S1295.
Padia SA, Johnson GE, Agopian VG, et al. Yttrium-90 radiation segmentectomy for hepatic metastases: a multi-institutional study of safety and efficacy. J Surg Oncol. 2021;123(1):172–8.
Chiesa C, Mira M, Bhoori S, et al. Radioembolization of hepatocarcinoma with (90)Y glass microspheres: treatment optimization using the dose-toxicity relationship. Eur J Nucl Med Mol Imaging. 2020;47(13):3018–32.
Garin E, Palard X, Rolland Y. Personalised dosimetry in radioembolisation for HCC: impact on clinical outcome and on trial design. Cancers (Basel). 2020;12(6):1557.
Garin E, Rolland Y, Edeline J. (90)Y-loaded microsphere SIRT of HCC patients with portal vein thrombosis: high clinical impact of 99mTc-MAA SPECT/CT-based dosimetry. Semin Nucl Med. 2019;49(3):218–26.
Garin E, Tselikas L, Guiu B, 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.
Gulec SA, Mesoloras G, Stabin M. Dosimetric techniques in 90Y-microsphere therapy of liver cancer: the MIRD equations for dose calculations. J Nucl Med Off Publ Soc Nucl Med. 2006;47(7):1209–11.
Cella D, Butt Z, Kindler HL, et al. Validity of the FACT hepatobiliary (FACT-Hep) questionnaire for assessing disease-related symptoms and health-related quality of life in patients with metastatic pancreatic cancer. Qual Life Res. 2013;22(5):1105–12.
Institute NC Common terminology criteria for adverse events (CTCAE) version 5. US Department of Health and Human Services, (2018) Bethesda, MD,
Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244(2):254–9.
Acknowledgements
The authors wish to acknowledge Carole Allimant, MD, for performing blinded centralized dosimetric assessments, and Alexandra Greenberg-Worisek, PhD, MPH (Boston Scientific Corporation) for medical writing assistance.
Funding
The PROACTIF Registry study is funded by Biocompatibles/Boston Scientific Corporation. The funding body provided support in the analysis of data and in providing medical writing support for the manuscript.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Conflict of interest
E.G.: Received fees and a grant from BTG Ltd./Boston Scientific Corporation. J.P.: Nothing to disclose. C.B.: Nothing to disclose. C.S.: Nothing to disclose. D.M-G.: Nothing to disclose. J.E.: Received fees and support for research from Boston Scientific; consultant for Roche, AstraZeneca, MSD, BMS, Eisai, Bayer, and Ipsen. J-F.B: Consultant for Bayer, Astra-Zeneca, IPSEN, ESAI, Roche, and BMS. A.B.: Nothing to disclose. J.T.: Nothing to disclose. A.R: Nothing to disclose. S.B.: Nothing to disclose. D.S.: Nothing to disclose. T. de B.: Consultant for Boston Scientific Corporation, Guerbet, GE-Healthcare, HD Technologies, Terumo, Astra-Zeneca, and Eisai; speaker for Boston Scientific Corporation, Guerbet, GE-Healthcare, HD Technologies, and Terumo. C. S-D: Nothing to disclose. C.M.: Nothing to disclose. J.G.: Nothing to disclose. P.C.: Nothing to disclose. H.R.: Consultant for Boston Scientific Corporation. E.V.: Received fees for methodological consulting from Biocompatibles UK Ltd. S.M.: Nothing to disclose. E.V.: Receives fees from Bayer, BMS, Johnson & Johnson, and Boston Scientific Corporation; serves as consultant for Nanobiotix; academic collaboration with EchoSens, Fluoptics, and IntraSence. B.P.: Employee of Biocompatibles/Boston Scientific Corporation. E.B.: Employee of Biocompatibles/Boston Scientific Corporation. B.G.: Consultant for Boston Scientific, Quantum Surgical, Terumo. Received research grant from Roche, Guerbet.
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. This study was classified in France as Recherche Impliquant la Personne Humaine de Catégorie 3 (RIHP 3) by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) due to its observational, non-interventional design. The protocol was approved by a randomly assigned to one of the 39 Independent Ethics Committees in France prior to the study’s initiation (assigned to French Ethics Committee « Ile de France VII»); assignments are made by the French National Commission for Research Involving Human Persons (CNRIPH).
Informed Consent
Patients will receive a Patient Information Sheet (PIS), which they will be able to review prior to treatment and about which patients will be given the opportunity to ask questions of the investigator or delegate. As detailed by the General Data Protection Regulation (GDPR) and requested by the ethics committee, this PIS will inform the patient about the purpose and aim of the registry and how their personal medical data will be used. After reviewing this sheet, clinicians will document whether the patient expresses verbal non-opposition to data collection in the patient’s record (“non-opposition to data collection”).
Consent for Publication
Consent for publication was obtained for every individual person’s data included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
*All members of PROACTIF Registry Group listed in Supplementary Material A.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Garin, E., Pinaquy, JB., Bailly, C. et al. Evaluating the Effectiveness of Yttrium-90 Glass Microspheres in the Treatment of Hepatocellular Carcinoma, Intrahepatic Cholangiocarcinoma, and Metastatic Colorectal Cancer in Practice: Protocol for the Prospective PROACTIF Phase IV Registry Study in France. Cardiovasc Intervent Radiol 45, 1–11 (2022). https://doi.org/10.1007/s00270-021-03002-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00270-021-03002-0