The problem of the most appropriate curative treatment for hepatocellular carcinoma. When to embolize? When to operate?
Authors: Francesco Guerra, Giovanni Battista Levi Sandri
Journal: Journal of Hepatology (2015)

Complete response at first chemoembolization is still the most robust predictor for favorable outcome in hepatocellular carcinomaJournal of HepatologyVol. 62Issue 6PreviewThe aim of this study is to evaluate the prognostic significances of not only the initial and the best response during repeated transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), but if eligible, also the time point of achieving treatment responses. Full-Text PDF Reply to “The problem of the most appropriate curative treatment for hepatocellular carcinoma. When to embolize? When to operate?”Journal of HepatologyVol. 63Issue 1PreviewWe appreciate the valuable comments by Guerra et al. on our recently published article [1]. They raised some issues. Full-Text PDF Open Access In the Journal of Hepatology, Kim and colleagues [[1]Kim B.K. Kim S.U. Kim K.A. Chung Y.E. Kim M.J. Park M.S. et al.Complete response at first chemoembolization is still the most robust predictor for favorable outcome in hepatocellular carcinoma.J Hepatol. 2015; 62: 1304-1310Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar] recently published an interesting and timely observation on the prognostic significance of treatment responses following transarterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC). We congratulate the authors for their paper, which was read with great interest because of the special need of published, specific analyses on this matter. Actually, the implications of their findings can be of significant value in clinical practice, especially considering potential predictive applications. However, with regard to methodology, some aspects require further consideration as we are concerned that the selection criteria used may impair the power of the analysis and the possibility to draw definitive conclusions from their outcomes. As exclusion criteria the authors considered five thorough features: inadequate target lesion (infiltrative pattern or largest lesion being smaller than one centimetre), other primary or secondary malignancies, presence of extrahepatic tumour lesions and/or invasion to main portal vein, Child-Pugh class different from A and presence of uncontrolled functional or metabolic disease. Some perplexities arise. The clinical and radiological conditions evaluated by the inclusion protocol are likely to admit a number of patients which may represent optimal candidates to surgical resection. In this regard, it would be extremely interesting to know how many included patients had very early (0), early (A) and intermediate (B) stage according to the Barcelona Clinic Liver Cancer (BCLC) classification at preprocedural assessment. Likewise, it would be interesting to know on the basis of which criteria unresectability was assessed, by considering that the median tumour size was reported to be 3.1 centimetres, with the number of lesions being <4 for the largest majority of cases. Of note, large and multiple tumours were finally independently associated with failure to achieve complete response after the initial TACE treatment. Thus, better responses were observed in patients with small, single or few intrahepatic lesions, preserved liver function and, potentially, low co-morbidity. In fact, the outcomes should be more appropriately analysed in comparison with those of surgical resection given that the subgroup of patients who experienced better results was likely to include a number of excellent candidates to liver resection. In this regard, in a recent, extremely interesting multicentric study published by Vitale et al. [[2]Vitale A. Burra P. Frigo A.C. Trevisani F. Farinati F. Spolverato G. et al.Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages: a multicenter study.J Hepatol. 2015; 62: 617-624Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar], including more than 2000 patients with HCC and preserved liver function, resection was confirmed to be associated with significant survival benefit over loco-regional therapies, regardless of BCLC stages. Furthermore, it has been demonstrated that radical therapies such as surgical resection and liver transplantation achieve better results and are increasingly employed even in HCC patients with intermediate and advanced diseases [3Vitale A. Morales R.R. Zanus G. Farinati F. et al.Barcelona Clinic Liver Cancer staging and transplant survival benefit for patients with hepatocellular carcinoma: a multicentre, cohort study.Lancet Oncol. 2011; 12: 654-662Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 4Torzilli G. Belghiti J. Kokudo N. Takayama T. Capussotti L. Nuzzo G. et al.A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations? An observational study of the HCC East-West study group.Ann Surg. 2013; 257: 929-937Crossref PubMed Scopus (365) Google Scholar]. The problem of offering HCC patients the most appropriate therapy is not new. Indeed, although it is largely known that in patients with preserved hepatic function and resectable malignancies, the best chance for a cure is surgical extirpation [2Vitale A. Burra P. Frigo A.C. Trevisani F. Farinati F. Spolverato G. et al.Survival benefit of liver resection for patients with hepatocellular carcinoma across different Barcelona Clinic Liver Cancer stages: a multicenter study.J Hepatol. 2015; 62: 617-624Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 5Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3685) Google Scholar]. It has already been demonstrated that the recommendation whether to receive surgery is largely influenced by the type of specialist by whom patients are seen initially [[6]Nathan H. Bridges J.F. Schulick R.D. et al.Understanding surgical decision making in early hepatocellular carcinoma.J Clin Oncol. 2011; 29: 619-625Crossref PubMed Scopus (52) Google Scholar]. In this regard, what several authors lately observed [6Nathan H. Bridges J.F. Schulick R.D. et al.Understanding surgical decision making in early hepatocellular carcinoma.J Clin Oncol. 2011; 29: 619-625Crossref PubMed Scopus (52) Google Scholar, 7Ulahannan S.V. Duffy A.G. McNeel T.S. Kish J.K. Dickie L.A. Rahma O.E. et al.Earlier presentation and application of curative treatments in hepatocellular carcinoma.Hepatology. 2014; 60: 1637-1644Crossref PubMed Scopus (68) Google Scholar] sharply indicates the need for further evidence on treatment strategies and stronger collaboration among specialists, especially considering how much has changed through the last decades in the rapidly maturing field of hepatic surgery. First, liver resection indications for HCC have been implemented with new surgical treatments: the Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) procedure may increase the rate of curative resections for tumours previously considered unresectable for major vascular invasion or tumour thrombosis [[8]Levi Sandri G.B. Lai Q. Rayar M. Sulpice L. ALPPS procedure for hepatocellular carcinoma with macrovascular thrombosis: a new opportunity?.J Hepatol. 2015; 62: 241-242Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Second, it must be considered that with the diffusion of modern technologies, the significant rate of morbidity and mortality historically associated with hepatic surgery has decreased dramatically. Advanced laparoscopy as well as robotics now permit oncologically adequate and safe surgery with the advantages of the minimally invasive method and respected principles of parenchyma-sparing surgery [9Giulianotti P.C. Coratti A. Sbrana F. et al.Robotic liver surgery: results for 70 resections.Surgery. 2011; 149: 29-39Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 10Gaillard M. Tranchart H. Dagher I. Laparoscopic liver resections for hepatocellular carcinoma: current role and limitations.World J Gastroenterol. 2014; 7: 4892-4899Crossref Scopus (35) Google Scholar]. Given the significant rise in prevalence of predisposing conditions, in coming years hepatologists will be increasingly confronted with the question of the most appropriate therapy for HCC patients. Currently, a substantive mismatch exists between the possibility of receiving curative surgery and its application [[7]Ulahannan S.V. Duffy A.G. McNeel T.S. Kish J.K. Dickie L.A. Rahma O.E. et al.Earlier presentation and application of curative treatments in hepatocellular carcinoma.Hepatology. 2014; 60: 1637-1644Crossref PubMed Scopus (68) Google Scholar]. While we agree with the successful nonoperative management of HCC patients with TACE, we further commend that all patients with potentially resectable HCC should be routinely evaluated in dedicated centres with large experience of liver surgery, possibly where the technological progress is part of daily surgical practice. Otherwise, we are possibly missing a valuable opportunity to significantly improve the patients’ survival and quality of life. Francesco Guerra and Giovanni Battista Levi Sandri have no conflict of interests related to the present paper and declare no financial relationships with any pharmaceutical or device company.