Transarterial radioembolization versus chemoembolization for the treatment of hepatocellular carcinoma (TRACE): study protocol for a randomized controlled trial

Beatrijs A Seinstra, Luc Defreyne, Bieke Lambert, Marnix G E H Lam, Helena M Verkooijen, Karel J van Erpecum, Bart van Hoek, Arian R van Erkel, Minneke J Coenraad, Imad Al Younis, Hans van Vlierberghe, Maurice A A J van den Bosch, Beatrijs A Seinstra, Luc Defreyne, Bieke Lambert, Marnix G E H Lam, Helena M Verkooijen, Karel J van Erpecum, Bart van Hoek, Arian R van Erkel, Minneke J Coenraad, Imad Al Younis, Hans van Vlierberghe, Maurice A A J van den Bosch

Abstract

Background: Hepatocellular carcinoma is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10 to 15% of hepatocellular carcinoma patients are suitable candidates for treatment with curative intent, such as hepatic resection and liver transplantation. A majority of patients have locally advanced, liver restricted disease (Barcelona Clinic Liver Cancer (BCLC) staging system intermediate stage). Transarterial loco regional treatment modalities offer palliative treatment options for these patients; transarterial chemoembolization (TACE) is the current standard treatment. During TACE, a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. Yttrium-90 radioembolization ((90)Y-RE) involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a β-emitting isotope, delivering selective internal radiation to the tumor. (90)Y-RE is increasingly used in clinical practice for treatment of intermediate stage hepatocellular carcinoma, but its efficacy has never been prospectively compared to that of the standard treatment (TACE). In this study, we describe the protocol of a multicenter randomized controlled trial aimed at comparing the effectiveness of TACE and (90)Y-RE for treatment of patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma.

Methods/design: In this pragmatic randomized controlled trial, 140 patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma, with Eastern Cooperative Oncology Group performance status 0 to 1 and Child-Pugh A to B will be randomly assigned to either (90)Y-RE or TACE with drug eluting beads. Patients assigned to (90)Y-RE will first receive a diagnostic angiography, followed by the actual transarterial treatment, which can be divided into two sessions in case of bilobar disease. Patients assigned to TACE will receive a maximum of three consecutive transarterial treatment sessions. Patients will undergo structural follow-up for a timeframe of two years post treatment. Post procedural magnetic resonance imaging (MRI) will be performed at one and three months post trial entry and at three-monthly intervals thereafter for two years to assess tumor response. Primary outcome will be time to progression. Secondary outcomes will be overall survival, tumor response according to the modified RECIST criteria, toxicities/adverse events, treatment related effect on total liver function, quality of life, treatment-related costs and cost-effectiveness.

Trial registration: NCT01381211.

References

    1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. doi: 10.3322/canjclin.55.2.74.
    1. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:S27–S34. doi: 10.1053/j.gastro.2004.09.013.
    1. Liapi E, Geschwind JF. Transcatheter and ablative therapeutic approaches for solid malignancies. J Clin Oncol. 2007;25:978–986. doi: 10.1200/JCO.2006.09.8657.
    1. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004;10:S115–S120. doi: 10.1002/lt.20034.
    1. Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet. 2009;373:614–616. doi: 10.1016/S0140-6736(09)60381-0.
    1. Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol. 1954;30:969–977.
    1. Liapi E, Georgiades CC, Hong K, Geschwind JF. Transcatheter arterial chemoembolization: current technique and future promise. Tech Vasc Interv Radiol. 2007;10:2–11. doi: 10.1053/j.tvir.2007.08.008.
    1. Buijs M, Vossen JA, Frangakis C, Hong K, Georgiades CS, Chen Y, Liapi E, Geschwind JF. Nonresectable hepatocellular carcinoma: long-term toxicity in patients treated with transarterial chemoembolization–single-center experience. Radiology. 2008;249:346–354. doi: 10.1148/radiol.2483071902.
    1. Lewandowski RJ, Kulik LM, Riaz A, Senthilnathan S, Mulcahy MF, Ryu RK, Ibrahim SM, Sato KT, Baker T, Miller FH, Omary R, Abecassis M, Salem R. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9:1920–1928. doi: 10.1111/j.1600-6143.2009.02695.x.
    1. Lewandowski RJ, Mulcahy MF, Kulik LM, Riaz A, Ryu RK, Baker TB, Ibrahim SM, Abecassis MI, Miller FH, Sato KT, Senthilnathan S, Resnick SA, Wang E, Gupta R, Chen R, Newman SB, Chrisman HB, Nemcek AA Jr, Vogelzang RL, Omary RA, Benson AB III, Salem R. Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort. Radiology. 2010;255:955–965. doi: 10.1148/radiol.10091473.
    1. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–1739. doi: 10.1016/S0140-6736(02)08649-X.
    1. 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;35:1164–1171. doi: 10.1053/jhep.2002.33156.
    1. Camma C, Schepis F, Orlando A, Albanese M, Shahied L, Trevisani F, Andreone P, Craxi A, Cottone M. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002;224:47–54. doi: 10.1148/radiol.2241011262.
    1. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37:429–442. doi: 10.1053/jhep.2003.50047.
    1. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev. 2011;3:1–60.
    1. Grosso M, Vignali C, Quaretti P, Nicolini A, Melchiorre F, Gallarato G, Bargellini I, Petruzzi P, Massa SC, Crespi S, Sarti I. Transarterial chemoembolization for hepatocellular carcinoma with drug-eluting microspheres: preliminary results from an Italian multicentre study. Cardiovasc Intervent Radiol. 2008;31:1141–1149. doi: 10.1007/s00270-008-9409-2.
    1. Malagari K, Chatzimichael K, Alexopoulou E, Kelekis A, Hall B, Dourakis S, Delis S, Gouliamos A, Kelekis D. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol. 2008;31:269–280. doi: 10.1007/s00270-007-9226-z.
    1. Malagari K, Alexopoulou E, Chatzimichail K, Hall B, Koskinas J, Ryan S, Gallardo E, Kelekis A, Gouliamos A, Kelekis D. Transcatheter chemoembolization in the treatment of HCC in patients not eligible for curative treatments: midterm results of doxorubicin-loaded DC bead. Abdom Imaging. 2008;33:512–519. doi: 10.1007/s00261-007-9334-x.
    1. 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;5:1100–1108. doi: 10.1016/j.cgh.2007.04.021.
    1. 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;46:474–481. doi: 10.1016/j.jhep.2006.10.020.
    1. Wigmore SJ, Redhead DN, Thomson BN, Currie EJ, Parks RW, Madhavan KK, Garden OJ. Postchemoembolisation syndrome–tumour necrosis or hepatocyte injury? Br J Cancer. 2003;89:1423–1427. doi: 10.1038/sj.bjc.6601329.
    1. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, Pitton M, Sergent G, Pfammatter T, Terraz S, Benhamou Y, Avajon Y, Gruenberger T, Pomoni M, Langenberger H, Schuchmann M, Dumortier J, Mueller C, Chevallier P, Lencioni R. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33:41–52. doi: 10.1007/s00270-009-9711-7.
    1. Sangro B, Salem R, Kennedy A, Coldwell D, Wasan H. Radioembolization for hepatocellular carcinoma: a review of the evidence and treatment recommendations. Am J Clin Oncol. 2011;34:422–431. doi: 10.1097/COC.0b013e3181df0a50.
    1. Vente MA, Wondergem M, van der Tweel I, van den Bosch MA, Zonnenberg BA, Lam MG, van Het Schip AD, Nijsen JF. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol. 2009;19:951–959. doi: 10.1007/s00330-008-1211-7.
    1. Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, Atassi B, Baker T, Gates V, Miller FH, Sato KT, Wang E, Gupta R, Benson AB, Newman SB, Omary RA, Abecassis M, Kulik L. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138:52–64. doi: 10.1053/j.gastro.2009.09.006.
    1. Kooby DA, Egnatashvili V, Srinivasan S, Chamsuddin A, Delman KA, Kauh J, Staley CA III, Kim HS. Comparison of Yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2010;21:224–230. doi: 10.1016/j.jvir.2009.10.013.
    1. Carr BI, Kondragunta V, Buch SC, Branch RA. Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study. Cancer. 2010;116:1305–1314. doi: 10.1002/cncr.24884.
    1. Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, Sato KT, Gupta R, Nikolaidis P, Miller FH, Yaghmai V, Ibrahim SM, Senthilnathan S, Baker T, Gates VL, Atassi B, Newman S, Memon K, Chen R, Vogelzang RL, Nemcek AA, Resnick SA, Chrisman HB, Carr J, Omary RA, Abecassis M, Benson AB III, Mulcahy MF. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140:497–507. doi: 10.1053/j.gastro.2010.10.049.
    1. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2010;53:1020–1022.
    1. Altman DG, Bland JM. Treatment allocation by minimisation. BMJ. 2005;330:843. doi: 10.1136/bmj.330.7495.843.
    1. Barentsz MW, Vente MA, Lam MG, Smits ML, Nijsen JF, Seinstra BA, Rosenbaum CE, Verkooijen HM, Zonnenberg BA, Van den Bosch MA. Technical solutions to ensure safe yttrium-90 radioembolization in patients with initial extrahepatic deposition of (99 m)technetium-albumin macroaggregates. Cardiovasc Intervent Radiol. 2011;34:1074–1079. doi: 10.1007/s00270-010-0088-4.
    1. Lambert B, Mertens J, Sturm EJ, Stienaers S, Defreyne L, D'Asseler Y. 99mTc-labelled macroaggregated albumin (MAA) scintigraphy for planning treatment with 90Y microspheres. Eur J Nucl Med Mol Imaging. 2010;37:2328–2333. doi: 10.1007/s00259-010-1566-2.
    1. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60. doi: 10.1055/s-0030-1247132.

Source: PubMed

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