Reply to “The problem of the most appropriate curative treatment for hepatocellular carcinoma. When to embolize? When to operate?”
Authors: Beom Kyung Kim, Seung Up Kim
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 The problem of the most appropriate curative treatment for hepatocellular carcinoma. When to embolize? When to operate?Journal of HepatologyVol. 63Issue 1PreviewIn the Journal of Hepatology, Kim and colleagues [1] recently published an interesting and timely observation on the prognostic significance of treatment responses following transarterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC). Full-Text PDF Open Access We appreciate the valuable comments by Guerra et al. on our recently published article [[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]. They raised some issues. We recognize that surgical resection should be considered first, provided that patients are clinically eligible for this approach when considering liver function, portal pressure, remnant liver volume after surgical resection, and performance status. 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 multicentre study.J Hepatol. 2015; 62: 617-624Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar] indicated that surgical resection can prolong survival compared with loco-regional therapy in patients with hepatocellular carcinoma (HCC), regardless of the Barcelona Clinic Liver Cancer (BCLC) stage, provided that liver dysfunction (Child-Pugh Class B or Model for End-stage Liver Disease score >9) and poor performance status (Eastern Cooperative Oncology Group >1) are absent. Indeed, it is more important to identify optimal candidates who will benefit from multi-disciplinary approaches rather than offering a formulaic treatment modality. Accordingly, nonsurgical approaches can also be considered in a patient with early stage HCC to avoid the risk of postoperative complications, including hepatic insufficiency and mortality, particularly for those with a morphologically cirrhotic liver on a preoperative radiological assessment. In this clinical setting, orthotopic liver transplantation (OLT) is a better option than surgical resection as it manages the underlying cirrhotic liver and HCC simultaneously. However, OLT is often ineligible due to the shortage of appropriate donors in South Korea. Approximately, one-third of our study participants had a tumor burden within the Milan criteria [[3]Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5670) Google Scholar], i.e., BCLC early stage, in which surgical resection or OLT may be recommended according to the degree of underlying liver disease. Surgical resection should be performed with caution in highly selected patients with BCLC early stage HCC and a morphologically cirrhotic liver, if they do not receive a suitable graft quickly. Furthermore, although patients who show BCLC early stage HCC and morphologically non-cirrhotic liver may be obviously good candidates for surgical resection, nonsurgical approaches can be considered in clinical practices for several reasons, such as patient refusal to undergo surgical resection, old age, relatively poor performance status, accompanying co-morbidities, evidence of portal hypertension, high indocyanine green retention test at 15 min, high liver stiffness value assessed using transient elastography [4Kim S.U. Ahn S.H. Park J.Y. Kim D.O.Y. CHON C.Y. CHOI J.S. et al.Prediction of postoperative hepatic insufficiency by liver stiffness measurement (FibroScan((R))) before curative resection of hepatocellular carcinoma: a pilot study.Hepatol Int. 2008; 2: 471-477Crossref PubMed Scopus (68) Google Scholar, 5Wong J.S. Wong G.L. Chan A.W. Wong V.W. Cheung Y.S. Chong C.N. et al.Liver stiffness measurement by transient elastography as a predictor on posthepatectomy outcomes.Ann Surg. 2013; 257: 922-928Crossref PubMed Scopus (80) Google Scholar], and inappropriate location for surgical resection based on the remnant liver volume. The major aim of our study was to assess the impact of achieving a complete response (CR) at an early time point among patients with HCC treated with transarterial chemoembolization (TACE), not to compare the clinical outcomes between treatment modalities. When we stratified the 298 patients without tumor invasion of the peripheral portal vein branches into three groups; patients within the Milan criteria [[3]Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5670) Google Scholar], patients beyond the Milan criteria, but within the up-to-seven criteria [[6]Mazzaferro V. Llovet J.M. Miceli R. Bhoori S. Schiavo M. Mariani L. et al.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol. 2009; 10: 35-43Abstract Full Text Full Text PDF PubMed Scopus (1415) Google Scholar], and patients beyond the up-to-seven criteria, the patients within the Milan criteria had the highest CR rate (initial response, 82.9%), followed by those beyond the Milan criteria, but within the up-to-seven criteria (59.2%) (p <0.001 vs. those within the Milan criteria), and those beyond the up-to-seven criteria (13.7%) (p <0.001 vs. those beyond the Milan criteria, but within the up-to-seven criteria). Similarly, in the view of achieving a CR as the best response, patients within the Milan Criteria had the highest CR rate of 88.6%, followed by those beyond the Milan criteria, but within the up-to-seven criteria with 74.5% (p = 0.009 vs. those within the Milan criteria) and those beyond the up-to-seven criteria with 40.0% (p <0.001 vs. those beyond the Milan, but within the up-to-seven criteria) (Table 1). We agree that better clinical outcomes are anticipated after TACE in patients with a smaller tumor burden, but the prognostic significance of achieving a CR as the initial and best response was also observed in all three subgroups. Patients who achieved a CR (both initial and best response) had a longer median overall survival than the others in the subgroup within the Milan criteria (Log-rank test, p <0.05). Similar results were obtained in the subgroup beyond the Milan criteria but within the up-to-seven criteria and the subgroup beyond the up-to-seven criteria (Log-rank test, all p <0.05). Taken together, although we demonstrated the clinical significance of the response to TACE at an early time point, further studies are required for extended applications of surgical resection in patients with BCLC B stage HCC as well as those with BCLC A stage HCC and Child-Pugh A class liver function, but a morphologically cirrhotic liver. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.