Which transarterial therapy is best for hepatocellular carcinoma? – The evidence to date
Authors: Emmanuel Tsochatzis, Tim Meyer, Laura Marelli, Andrew K. Burroughs
Journal: Journal of Hepatology (2010)

We read with interest the recently published randomised control trial (RCT) of transarterial chemoembolization (TACE) vs. transarterial chemotherapy (TAI) [[1]Okusaka T. Kasugai H. Shioyama Y. Tanaka K. Kudo M. Saisho H. et al.Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.J Hepatol. 2009; 51: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar] for hepatocellular carcinoma (HCC), and the accompanying editorial [[2]Forner A. Trinchet J.C. Transarterial therapies in HCC: does embolization increase survival?.J Hepatol. 2009; 51: 981-983Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. The authors addressed a long-standing debate on whether the combination of chemotherapy and embolization is more effective than either therapy alone. They found no difference between TACE and TAI with regards to patients' survival. We agree with the editorial that the results are confounded by the low number of protocol treatments and the high percentage of patients with advanced tumours who are unlikely to respond. However, there are further issues not raised in the editorial, which also confound the interpretation of this randomised study, and transarterial therapy for HCC in general. Firstly, TACE is not a standardised procedure [[3]Marelli L. Stigliano R. Triantos C. Senzolo M. Cholongitas E. Davies N. et al.Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.Cardiovasc Intervent Radiol. 2007; 30: 6-25Crossref PubMed Scopus (699) Google Scholar] with different embolic and chemotherapeutic agents, different arterial selectivity before embolisation, and different schedules and indications for repeat sessions. Indeed, gelatine sponge particles, the most common embolizing agent used in previous RCTS, only provides short-term artery occlusion that lasts at most for 2 weeks, whereas polyvinyl alcohol particles (PVA), now used in many centres, result in permanent artery occlusion [[3]Marelli L. Stigliano R. Triantos C. Senzolo M. Cholongitas E. Davies N. et al.Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.Cardiovasc Intervent Radiol. 2007; 30: 6-25Crossref PubMed Scopus (699) Google Scholar]. Apart from the duration and effectiveness of the embolisation, the value of the current chemotherapeutic agents has little evidence to support their use. Firstly, these same agents are not effective if given systematically with similar systemic concentrations when given intra-arterially [[4]Burroughs A. Hochhauser D. Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum.Lancet Oncol. 2004; 5: 409-418Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar]. Secondly, there are now three published RCTs of transarterial embolisation alone (TAE) versus TACE, all using the sub-optimal gelatine sponge in both arms [5Chang J.M. Tzeng W.S. Pan H.B. Yang C.F. Lai K.H. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. A randomized controlled study.Cancer. 1994; 74: 2449-2453Crossref PubMed Scopus (139) Google Scholar, 6Kawai S. Okamura J. Ogawa M. Ohashi Y. Tani M. Inoue J. et al.Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma – a comparison of lipiodol-transcatheter arterial embolization with and without adriamycin (first cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan.Cancer Chemother Pharmacol. 1992; 31: S1-S6Crossref PubMed Scopus (116) Google Scholar, 7Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2911) Google Scholar]; a metanalysis shows no difference in survival [[3]Marelli L. Stigliano R. Triantos C. Senzolo M. Cholongitas E. Davies N. et al.Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.Cardiovasc Intervent Radiol. 2007; 30: 6-25Crossref PubMed Scopus (699) Google Scholar]. Given the side effects of the chemotherapeutic agents, their use must be questioned. Lastly, we have shown in our meta-analysis that TAI has no effect [[3]Marelli L. Stigliano R. Triantos C. Senzolo M. Cholongitas E. Davies N. et al.Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.Cardiovasc Intervent Radiol. 2007; 30: 6-25Crossref PubMed Scopus (699) Google Scholar]. The new drug eluting beads (DEBs) favoured in the editorial as the optimal transarterial approach, undoubtedly limit the systemic side effects of TACE but are not more effective as shown in a recent randomised study [[8]Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol, 2009. doi: .Google Scholar]. In addition, there is no randomised study in patients, of bland beads alone, and neither versus PVA particles in TAE. PVA particles could represent the optimal embolizing agent due to the permanence of arterial occlusion [[3]Marelli L. Stigliano R. Triantos C. Senzolo M. Cholongitas E. Davies N. et al.Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.Cardiovasc Intervent Radiol. 2007; 30: 6-25Crossref PubMed Scopus (699) Google Scholar] and could be considered the reference embolizing agent to use as a comparator. We are conducting a randomised trial of TAE vs. TACE with PVA particles in both arms (http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=1495), scheduling 3-week embolisations to fit into the oncological principles of the use of chemotherapy and cell cycle [[4]Burroughs A. Hochhauser D. Meyer T. Systemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum.Lancet Oncol. 2004; 5: 409-418Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar]. We believe optimal TAE or TACE should be evaluated fully, before "jumping" to the much more expensive DEB as a standard transarterial therapy. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.