Transarterial Embolization Alone Versus Drug-Eluting Beads Chemoembolization for Hepatocellular Carcinoma

NCT04803019 | Unknown Phase 3

• 1 other identifier: RAD-18-TAcE
• Study Type: interventional
• Target: 154
• Locations: 1 country
• Sites: 1

Brief Summary

Developed in Japan in the 1980s, TACE became the most frequent treatment for unresectable hepatocellular carcinoma (HCC) in patients with preserved hepatic function after 2002, when two radiochemotherapies (RCTs) showed survival benefits for HCC patients who underwent conventional Lipiodol-based TACE (cTACE). Nowadays, nearly half of HCC patients undergo this procedure during their clinical history. In the last ten years, cTACE has been challenged by an alternative procedure, drug-eluting beads-TACE (DEB-TACE), after the introduction of calibrated embolizing microspheres loaded with a chemotherapeutic agent. DEB-TACE is considered to be less toxic and better standardized than cTACE, with reported no differences in patient survival. Since 2006, DEB-TACE has become the standard in many centers worldwide. Though, the need of adding doxorubicin to small beads embolization alone (TAE) remains unsettled. Though cTACE/DEB-TACE and TAE have been compared in several RCTs, no study demonstrated a clear survival benefit associated with the former. Our study aims to compare first-line DEB-TACE and TAE on a random sample of HCC with the hypothesis that the addition of drug to embolization with small size beads is not associated with a survival benefit when compared to embolization alone performed with tiny calibrated microspheres. HCC is considered a chemo-resistant tumor and to date there is no clear evidence of benefits in associating anticancer agents to TAE. On the other hand, the optimal size of embolic agents has still to be defined. A comparative evaluation of TACE and TAE is essential for two additional reasons: a) it is still unclear whether side effects following embolization procedures are related to the embolization itself, to drug addition or both; b) DEB-TACE procedure is more expensive than TAE and, given the current attention on cancer-related health care cost control, identification of opportunities for cost savings in HCC treatments of an increasingly common cancer would be valuable.

Conditions

Carcinoma, Hepatocellular

Outcome Measures

Primary Outcomes (1)

• Time to progression

  TTP since randomization, as recommended from expert panel opinion, after TAE and DEB-TACE

  The TTP considered as the reference value is 9 months

Study Arms (2)

DEB-TACE or chemoembolization with microspheres

ACTIVE COMPARATOR

The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM® (Boston Scientific) microspheres. TANDEM® embozene microspheres are made of non-resorbable, biocompatible, hydrogel microspheres, subjected to precision calibration and coated with an inorganic perfluorate polymer (Polyzene®-F)

Combination Product: DEB-TACE

TAE or embolization with microspheres

ACTIVE COMPARATOR

The TAE will be performed with Embozene microspheres (Boston Scientific). Embozene microspheres are spherical particles of hydrogel, precisely calibrated, biocompatible, non-absorbable and coated with a perfluorinated inorganic polymer (Polyzene®-F)

Device: TAE

Interventions

DEB-TACE COMBINATION_PRODUCT

The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM® (Boston Scientific) microspheres. TANDEM® embozene microspheres are made of non-resorbable, biocompatible, hydrogel microspheres, subjected to precision calibration and coated with an inorganic perfluorate polymer (Polyzene®-F). TANDEM® embozene microspheres are available in three different sizes, in 2 ml and 3 ml volumes of product and are supplied in preloaded vials and syringes.The maximum loadable amount on the hydrospheres 50 mg of Doxorubicina for ml. The maximum injectable dose of Doxorubicin for each treatment is 150 mg and therefore the maximum amount of microspheres that can be used for each treatment is 3 ml. The size of microspheres that will be used in this study is up to 100 ± 25 μm.

Also known as: Chemoembolization with microspheres

DEB-TACE or chemoembolization with microspheres

TAE DEVICE

The TAE will be performed with Embozene microspheres (Boston Scientific). Embozene microspheres are spherical particles of hydrogel, precisely calibrated, biocompatible, non-absorbable and coated with a perfluorinated inorganic polymer (Polyzene®-F). This medical device is available in various sizes; in this study, to avoid that the particle size exceeds the one used for the treatment of arm A, it will be possible to use microspheres with dimensions up to 100 μm (range 75 ± 125 μm). Embozene microspheres are offered in vials containing 1 ml of suspended product in physiological saline solution for apyrogenic sterile transport. The total volume of the Embozene microspheres, including the transport solution, is about 7 ml. To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy.

Also known as: Embolization with microspheres

TAE or embolization with microspheres

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- First level eligibility criteria include
• HCC diagnosis according to the AASLD criteria \[26\];
• patients ≥18 years;
• HCC unsuitable for curative treatment or had failed/recurred after resection/ablation diagnosed according to the AASLD criteria;
• no previous treatment in target lesions (prior treatments including resection on non-target lesions will be accepted);
• Child-Pugh class A or B (max score 7);
• ECOG Performance Status (PS) \<2;
• target lesion measurable according to mRECIST.
• Second level eligibility criteria include:
• The modified hepatoma arterial-embolization prognostic score (m-HAP-II), based on bilirubin, albumin, serum alpha fetoprotein, tumor number and tumor size, divides patients in 4 classes (A, B, C, D) with different survivals and is useful for prognosis stratification. The first selection criteria will be m-HAP-II classes B or C fulfilment.
• The UNOS/TNM stage: only patients with T1, T2, T3 and T4 tumors will be included.
• These two main criteria will be used for stratification of patients prior to randomization in order to obtain identical prevalence of m-HAP-II classes B/C and of UNOS/TNM stages from T1 to T4a
• obtaining of the informed consent.

You may not qualify if:

• infiltrative HCC;
• neoplastic branch or main portal vein invasion;
• equivocal hepatic lesion;
• advanced liver disease (bilirubin levels \>2.5 mg dl-1, albumin \<30 g l-1, platelets \<50 x 109/L, INR \>1.5);
• ascites and/or F3 oesophageal varices;
• other tumors in the previous 5 years;
• technical contraindications to arteriography or TACE.

Sponsors & Collaborators

• IRCCS Azienda Ospedaliero-Universitaria di Bologna: lead

Study Sites (1)

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, Italy

RECRUITING

Related Publications (28)

• Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1734-9. doi: 10.1016/S0140-6736(02)08649-X.

  PMID: 12049862 BACKGROUND

• Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002 May;35(5):1164-71. doi: 10.1053/jhep.2002.33156.

  PMID: 11981766 BACKGROUND

• Geschwind JF, Kudo M, Marrero JA, Venook AP, Chen XP, Bronowicki JP, Dagher L, Furuse J, Ladron de Guevara L, Papandreou C, Sanyal AJ, Takayama T, Ye SL, Yoon SK, Nakajima K, Lehr R, Heldner S, Lencioni R. TACE Treatment in Patients with Sorafenib-treated Unresectable Hepatocellular Carcinoma in Clinical Practice: Final Analysis of GIDEON. Radiology. 2016 May;279(2):630-40. doi: 10.1148/radiol.2015150667. Epub 2016 Jan 8.

  PMID: 26744927 BACKGROUND

• Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, Sherman M. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015 Sep;35(9):2155-66. doi: 10.1111/liv.12818. Epub 2015 Mar 25.

  PMID: 25752327 BACKGROUND

• Golfieri R, Giampalma E, Renzulli M, Cioni R, Bargellini I, Bartolozzi C, Breatta AD, Gandini G, Nani R, Gasparini D, Cucchetti A, Bolondi L, Trevisani F; PRECISION ITALIA STUDY GROUP. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer. 2014 Jul 15;111(2):255-64. doi: 10.1038/bjc.2014.199. Epub 2014 Jun 17.

  PMID: 24937669 BACKGROUND

• Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, Girardi L, Cillo U, Burra P, Giacomin A, Farinati F. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol. 2008 Apr;103(4):914-21. doi: 10.1111/j.1572-0241.2007.01712.x. Epub 2008 Jan 2.

  PMID: 18177453 BACKGROUND

• Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, Choi JI, Kim HB, Lee WJ, Kim CM. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci. 2008 Oct;99(10):2037-44. doi: 10.1111/j.1349-7006.2008.00909.x.

  PMID: 19016764 BACKGROUND

• Brown KS. Chemotherapy and other systemic therapies for hepatocellular carcinoma and liver metastases. Semin Intervent Radiol. 2006 Mar;23(1):99-108. doi: 10.1055/s-2006-939845.

  PMID: 21326724 BACKGROUND

• Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, Ayuso C, Castells L, Montana X, Llovet JM, Bruix J. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007 Mar;46(3):474-81. doi: 10.1016/j.jhep.2006.10.020. Epub 2006 Nov 29.

  PMID: 17239480 BACKGROUND

• Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, Tibballs J, Meyer T, Patch DW, Burroughs AK. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol. 2007 Jan-Feb;30(1):6-25. doi: 10.1007/s00270-006-0062-3.

  PMID: 17103105 BACKGROUND

• Tsochatzis EA, Meyer T, Burroughs AK. Hepatocellular carcinoma. N Engl J Med. 2012 Jan 5;366(1):92; author reply 92-3. doi: 10.1056/NEJMc1112501. No abstract available.

  PMID: 22216857 BACKGROUND

• Poon RT, Tso WK, Pang RW, Ng KK, Woo R, Tai KS, Fan ST. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol. 2007 Sep;5(9):1100-8. doi: 10.1016/j.cgh.2007.04.021. Epub 2007 Jul 12.

  PMID: 17627902 BACKGROUND

• Cucchetti A, Trevisani F, Cappelli A, Mosconi C, Renzulli M, Pinna AD, Golfieri R. Cost-effectiveness of doxorubicin-eluting beads versus conventional trans-arterial chemo-embolization for hepatocellular carcinoma. Dig Liver Dis. 2016 Jul;48(7):798-805. doi: 10.1016/j.dld.2016.03.031. Epub 2016 May 20.

  PMID: 27263056 BACKGROUND

• Malagari K, Pomoni M, Kelekis A, Pomoni A, Dourakis S, Spyridopoulos T, Moschouris H, Emmanouil E, Rizos S, Kelekis D. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2010 Jun;33(3):541-51. doi: 10.1007/s00270-009-9750-0. Epub 2009 Nov 24.

  PMID: 19937027 BACKGROUND

• Meyer T, Kirkwood A, Roughton M, Beare S, Tsochatzis E, Yu D, Davies N, Williams E, Pereira SP, Hochhauser D, Mayer A, Gillmore R, O'Beirne J, Patch D, Burroughs AK. A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma. Br J Cancer. 2013 Apr 2;108(6):1252-9. doi: 10.1038/bjc.2013.85. Epub 2013 Feb 28.

  PMID: 23449352 BACKGROUND

• Brown KT, Do RK, Gonen M, Covey AM, Getrajdman GI, Sofocleous CT, Jarnagin WR, D'Angelica MI, Allen PJ, Erinjeri JP, Brody LA, O'Neill GP, Johnson KN, Garcia AR, Beattie C, Zhao B, Solomon SB, Schwartz LH, DeMatteo R, Abou-Alfa GK. Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-Eluting Microspheres Compared With Embolization With Microspheres Alone. J Clin Oncol. 2016 Jun 10;34(17):2046-53. doi: 10.1200/JCO.2015.64.0821. Epub 2016 Feb 1.

  PMID: 26834067 BACKGROUND

• Massarweh NN, Davila JA, El-Serag HB, Duan Z, Temple S, May S, Sada YH, Anaya DA. Transarterial bland versus chemoembolization for hepatocellular carcinoma: rethinking a gold standard. J Surg Res. 2016 Feb;200(2):552-9. doi: 10.1016/j.jss.2015.09.034. Epub 2015 Oct 3.

  PMID: 26507276 BACKGROUND

• Osuga K, Hori S, Hiraishi K, Sugiura T, Hata Y, Higashihara H, Maeda N, Tomoda K, Nakamura H. Bland embolization of hepatocellular carcinoma using superabsorbent polymer microspheres. Cardiovasc Intervent Radiol. 2008 Nov-Dec;31(6):1108-16. doi: 10.1007/s00270-008-9369-6. Epub 2008 Jun 10.

  PMID: 18543028 BACKGROUND

• Takayasu K, Arii S, Ikai I, Omata M, Okita K, Ichida T, Matsuyama Y, Nakanuma Y, Kojiro M, Makuuchi M, Yamaoka Y; Liver Cancer Study Group of Japan. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology. 2006 Aug;131(2):461-9. doi: 10.1053/j.gastro.2006.05.021.

  PMID: 16890600 BACKGROUND

• Tsochatzis E, Meyer T, Marelli L, Burroughs AK. Which transarterial therapy is best for hepatocellular carcinoma?--the evidence to date. J Hepatol. 2010 Sep;53(3):588. doi: 10.1016/j.jhep.2010.01.031. Epub 2010 Mar 24. No abstract available.

  PMID: 20472319 BACKGROUND

• Tsochatzis E, Meyer T, O'Beirne J, Burroughs AK. Transarterial chemoembolisation is not superior to embolisation alone: the recent European Association for the Study of the Liver (EASL) - European Organisation for Research and Treatment of Cancer (EORTC) guidelines. Eur J Cancer. 2013 Apr;49(6):1509-10. doi: 10.1016/j.ejca.2012.11.012. Epub 2012 Dec 8. No abstract available.

  PMID: 23231982 BACKGROUND

• Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008 May 21;100(10):698-711. doi: 10.1093/jnci/djn134. Epub 2008 May 13.

  PMID: 18477802 BACKGROUND

• Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60. doi: 10.1055/s-0030-1247132. Epub 2010 Feb 19.

  PMID: 20175033 BACKGROUND

• Julious SA. Sample sizes for clinical trials with normal data. Stat Med. 2004 Jun 30;23(12):1921-86. doi: 10.1002/sim.1783.

  PMID: 15195324 BACKGROUND

• Bruix J, Reig M, Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. Gastroenterology. 2016 Apr;150(4):835-53. doi: 10.1053/j.gastro.2015.12.041. Epub 2016 Jan 12.

  PMID: 26795574 BACKGROUND

• Park Y, Kim SU, Kim BK, Park JY, Kim DY, Ahn SH, Park YE, Park JH, Lee YI, Yun HR, Han KH. Addition of tumor multiplicity improves the prognostic performance of the hepatoma arterial-embolization prognostic score. Liver Int. 2016 Jan;36(1):100-7. doi: 10.1111/liv.12878. Epub 2015 Jun 22.

  PMID: 26013186 BACKGROUND

• Cappelli A, Cucchetti A, Cabibbo G, Mosconi C, Maida M, Attardo S, Pettinari I, Pinna AD, Golfieri R. Refining prognosis after trans-arterial chemo-embolization for hepatocellular carcinoma. Liver Int. 2016 May;36(5):729-36. doi: 10.1111/liv.13029. Epub 2015 Dec 23.

  PMID: 26604044 BACKGROUND

• Italian Association for the Study of the Liver (AISF); AISF Expert Panel; AISF Coordinating Committee; Bolondi L, Cillo U, Colombo M, Craxi A, Farinati F, Giannini EG, Golfieri R, Levrero M, Pinna AD, Piscaglia F, Raimondo G, Trevisani F, Bruno R, Caraceni P, Ciancio A, Coco B, Fraquelli M, Rendina M, Squadrito G, Toniutto P. Position paper of the Italian Association for the Study of the Liver (AISF): the multidisciplinary clinical approach to hepatocellular carcinoma. Dig Liver Dis. 2013 Sep;45(9):712-23. doi: 10.1016/j.dld.2013.01.012. Epub 2013 Feb 23.

  PMID: 23769756 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Microspheres; Embolization, Therapeutic

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Equipment and Supplies; Hemostatic Techniques; Therapeutics; Therapeutic Occlusion

Study Officials

• Rita Golfieri, Professor

  IRCCS Azienda Ospedaliero-Universitaria di Bologna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rita Golfieri, Professor

CONTACT

051 214 2311; rita.golfieri@aosp.bo.it

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 15, 2021
• First Posted: March 17, 2021
• Study Start: December 4, 2019
• Primary Completion: April 30, 2022
• Study Completion: April 30, 2022
• Last Updated: March 19, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)