Reply to “Response to locoregional treatment and alpha-fetoprotein trend in liver transplant candidates for HCC: Dwarfs standing on the shoulders of giants”
Authors: Gerd Otto
Journal: Journal of Hepatology (2014)

How to decide about liver transplantation in patients with hepatocellular carcinoma: Size and number of lesions or response to TACE?Journal of HepatologyVol. 59Issue 2PreviewLiver transplantation is a curative treatment option for patients with hepatocellular carcinoma (HCC) and liver cirrhosis. To date, patient selection for transplantation is based on size and number of nodules as assessed by imaging before listing. We hypothesized that changes in tumour features resulting from pre-transplant transarterial chemoembolisation (TACE) is a superior criterion to predict tumour recurrence. Full-Text PDF Response to locoregional treatment and alpha-fetoprotein trend in liver transplant candidates for HCC: Dwarfs standing on the shoulders of giantsJournal of HepatologyVol. 60Issue 6PreviewWe read with great interest the correspondence on the paper published by Otto et al., [1] on the response to repeated trans-arterial chemo-embolization (TACE) as a discriminating tool for selection of liver transplant (LT) candidates with hepatocellular carcinoma (HCC). Paul et al. [2] evidenced the relative small sample size and the lack of information on the role of TACE on waiting-list dropout. Our aim is to support the results obtained by Otto et al. with the strength and the statistical power of a new recently published European study. Full-Text PDF Open Access I thank Dr. Lai for his letter stressing some important issues of our recent publication [[1]Otto G. Schuchmann M. Hoppe-Lotichius M. Heise M. Weinmann A. Hansen T. et al.How to decide about liver transplantation in patients with hepatocellular carcinoma: size and number of lesions or response to TACE?.J Hepatol. 2013; 59: 279-284Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. With great interest I have recognized that Dr. Lai's analysis of the EurHeCaLT data endorse the principles of our statements in a much greater cohort of patients [[2]Lai Q. Avolio A.W. Graziadei I. Otto G. Rossi M. Tisone G. et al.Alpha-fetoprotein and modified response evaluation criteria in solid tumors progression after locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation.Liver Transpl. 2013; 19: 1108-1118Crossref PubMed Scopus (12) Google Scholar]. We have focussed on response of hepatocellular carcinomas (HCC) to trans-arterial chemoembolization (TACE) during pre-treatment before liver transplantation. Lai et al. have, in addition, included alpha fetoprotein to assess another biological tumour characteristic. The drop-out rate (in our experience 40%) was neither in our, nor in the EurHeCaLT study an issue. As we participate in the EurHeCaLT working group, we dare to point out some differences in the clinical practice of the group members. In our patients, TACE was always repeatedly performed and other approaches to pre-treatment have not been included in our analysis. Considering all differences of the EurHeCaLT group members, the similarity of the results is remarkable: regardless if the HCC met or exceeded the Milan Criteria, putative surrogates of tumour biology are predictors for tumour recurrence. This issue deserves consideration, not only since the characterization of tumour size and number still remains a clinical problem [[3]Shah S.A. Tan J.C. McGilvray I.D. Cattral M.S. Cleary S.P. Levy G.A. et al.Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma.Transplantation. 2006; 81: 1633-1639Crossref PubMed Scopus (113) Google Scholar]. Indeed, the results corroborate that "size and number tell only a partial tale of the tumour characteristics" [[4]Mehta N. Yao F.Y. Moving past "One size (and number) fits all" in the selection of candidates with hepatocellular carcinoma for liver transplantation.Liver Transpl. 2013; 19: 1055-1058Crossref PubMed Scopus (104) Google Scholar]. Dr. Lai's sentence "…waiting for reliable preoperative predictive markers of both adverse outcome and response to pre-transplant treatment…" should not be misunderstood! In my understanding – and I suppose we share this opinion – drop-out and recurrence are two sides of the same coin: tumour biology. Although there is no final proof, biologically aggressive HCCs appear to be refractory to TACE and entail, accordingly, a higher recurrence rate after transplantation. Likewise, multifocal "recurrence" immediately following surgery or radiofrequency ablation may also reflect biological aggressiveness and the outcome is poor. What we do not know is, if one of the approaches to pre-treatment is more accurate in selecting appropriate patients than the other [[5]Gordon-Weeks A.N. Snaith A. Petrinic T. Friend P.J. Burls A. Silva M.A. Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria.Br J Surg. 2011; 98: 1201-1208Crossref PubMed Scopus (66) Google Scholar]. Is the selection process ensuing from pre-treatment just proof for an extended time axis? The number of pre-transplant TACE procedures – which parallels waiting time – did not impact recurrence in our study. Response, but not time appeared to be crucial. In a few patients, however, tumours were initially stable or exhibited even partial response and progressed later despite ongoing pre-treatment. Therefore, time may be of importance. As long as we don't have reliable markers reflecting tumour biology we should aim, at least, at reinforcing the existing data to improve the selection of HCC patients amenable to liver transplantation. Transplant centres should be invited to participate in a multicentre study seizing the principles of pre-transplant treatment of the EurHeCaLT members but pre-treatment should be uniform. Finally, allow me a brief remark that should not be taken too seriously. I would like to reverse Dr. Lai's nice picture describing the giant and the dwarf: tumour biology is the giant – and the dwarf "morphology" will hopefully start descending from the giant's shoulders. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.