TACE treatment in hepatocellular carcinoma: What should we do now?

Chemoembolization for intermediate HCC: Is there proof of survival benefit?Journal of HepatologyVol. 56Issue 4PreviewCOMMENTARY ON: Full-Text PDF Open Access We read with much interest the comment by Forner et al. [[1]Forner A. Llovet J.M. Bruix J. Chemoembolization for intermediate HCC: is there proof of survival benefit?.J Hepatol. 2012; 56: 984-986Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar] on the recently published Cochrane review on Transcatheter Arterial (Chemo) Embolization (TACE/TAE) treatment in hepatocellular carcinoma by Oliveri et al. [[2]Oliveri R.S. Wetterslev J. Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma.Cochrane Database Syst Rev. 2011; : CD004787PubMed Google Scholar]. The debate on the effectiveness of TACE in patients with intermediate stage hepatocellular carcinoma (HCC) is still open, indeed. On the one hand, as summarized in the updated American Association for the Study of Liver Diseases (AASLD) guidelines, there is no doubt that the level of evidence on the efficacy of TACE in the treatment of intermediate stage HCC is strong (IA, according to the standard evaluation [[3]Eccles M. Rousseau N. Freemantle N. Updating evidence-based clinical guidelines.J Health Serv Res Policy. 2002; 7: 98-103Crossref PubMed Scopus (28) Google Scholar], with a consequently strong grade of recommendation [Grade A]). On the other hand, there is also no doubt that this strength lies basically on the results of two randomized prospective studies [4Llovet J.M. Real M.I. Montaña X. Planas R. Coll S. Aponte J. et al.Barcelona Liver Cancer Group. 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, 5Lo C.M. Ngan H. Tso W.K. Liu C.L. Lam C.M. Poon R.T. et al.Randomized controlled trial of transarterial lipiodol chemoembolization: a multicenter randomized trial.Hepatology. 2002; 35: 1164-1171Crossref PubMed Scopus (2226) Google Scholar] that deeply condition the two meta-analyses published on the topic [6Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2592) Google Scholar, 7Cammà C. Schepis F. Orlando A. Albanese M. Shahied L. Trevisani F. et al.Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials.Radiology. 2002; 224: 47-54Crossref PubMed Scopus (748) Google Scholar]. Nevertheless, TACE is also supported by the fact that it is used in the everyday clinical practice of every center involved in the management of HCC, a very low level (IV), but still important, evidence. Dr. Forner correctly underlines that one of the papers quoted in Olivieri’s meta-analysis, the Doffoel’s randomized prospective trial of TACE vs. tamoxifen [[8]Doffoël M. Bonnetain F. Bouché O. Vetter D. Abergel A. Fratté S. et al.Fédération Francophone de Cancérologie Digestive. Multicentre randomised phase III trial comparing tamoxifen alone or with transarterial lipiodol chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402).Eur J Cancer. 2008; 44: 528-538Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar], presents many biases and includes patients that may have been “sub-optimally staged, selected and/or treated”. In several French studies, indeed (see also the two Pelletier’s articles [9Pelletier G. Ducreux M. Gay F. Luboinski M. Hagège H. Dao T. et al.Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC.J Hepatol. 1998; 29: 129-134Abstract Full Text PDF PubMed Scopus (392) Google Scholar, 10Pelletier G. Roche A. Ink O. Anciaux M.L. Derhy S. Rougier P. et al.A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma.J Hepatol. 1990; 11: 181-184Abstract Full Text PDF PubMed Scopus (389) Google Scholar]), the survival after TACE is so short that being affected by an intermediate stage HCC in France at the end of the last century would have suggested to move to other countries for treatment. Indeed, the reported 1-year survival (ranging from 25% to 50%) was not considered acceptable elsewhere and in past years those two studies heavily conditioned the clinical evaluation of TACE as a treatment for patients with multinodular HCC. The Cochrane review in any case casts new doubts on the topic, doubts that induce to wonder what to do in patients with intermediate stage HCC, if one accepts the conclusions of the review. In our experience, based on the data (prospectively collected over 20 years) of the ITA.LI.CA database, patients with intermediate stage HCC treated by TACE present a median survival of 35 months (42 months in those treated in the last decade), with 1- and 5-year survivals of 80% and 18%, respectively. Having said this, it is worth noting that only a fraction of patients with an intermediate stage HCC were treated by TACE, while in the other cases, the treatment options vary from surgery or percutaneous treatments to best supportive care, depending on a number of factors not considered in the Barcelona Clinic Liver Cancer (BCLC) algorithm, such as age, co-morbidities, patient’s decision, and local expertise, particularly, as far as the availability of highly experienced surgical teams is concerned. Interestingly enough, patients with intermediate stage HCC who can be treated more aggressively tend to survive longer than those treated by TACE (median survival of 52 months and 5-year survival over 30%). Our, still unpublished, data clearly demonstrate that TACE should not be abandoned, remaining the standard of care, in clinical practice, for most patients with intermediate stage HCC. However, the indication to TACE should not be automatic and, if the patients are considered eligible for more aggressive treatments, in a multidisciplinary approach also including percutaneous ablation and surgery, an even better survival can be obtained. Nowadays, there is indication for a combined/sequential tailored treatment, with a strategy that involves hepatologists, interventional radiologists, and surgeons. Likely, in the near future an adjuvant treatment with sorafenib or new anti-angiogenetic molecules will be part of this strategy. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.