Response to locoregional treatment and alpha-fetoprotein trend in liver transplant candidates for HCC: Dwarfs standing on the shoulders of giants
Authors: Quirino Lai, Alfonso W. Avolio, Ivo Graziadei, Jan Lerut
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 Reply to "Response to locoregional treatment and alpha-fetoprotein trend in liver transplant candidates for HCC: Dwarfs standing on the shoulders of giants"Journal of HepatologyVol. 60Issue 6PreviewI thank Dr. Lai for his letter stressing some important issues of our recent publication [1]. 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]. 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. Full-Text PDF Open Access We read with great interest the correspondence on the paper published by Otto et al., [[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 (92) Google Scholar] 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]Paul A. Sotiropoulos G. Gerken G. Saner F.H. How to decide about liver transplantation in patients with hepatocellular carcinoma: size and number of lesions or response to TACE?.J Hepatol. 2014; 60: 463-464Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] 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. Using prospectively recorded data from 6 Centers with different allocation systems, we have confirmed the role of the response to locoregional treatments (LRT) as predictor of survival and HCC recurrence [[3]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 (5) Google Scholar]. mRECIST progression after LRT and alpha-fetoprotein (AFP) slope >15 ng/ml/month resulted independent predictors not only in 116 Milan-criteria (MC)-OUT, but also in 306 MC-IN patients. Moreover, no TACE alone but also different LRTs were performed in the routine pre-LT workout, demonstrating that response to LRT works well independently from the stage. We agree on the Zurich Conference recommendations [[4]Clavien P.A. Lesurtel M. Bossuyt P.M. Gores G.J. Langer B. Perrier A. OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.Lancet Oncol. 2012; 13: e11-e22Abstract Full Text Full Text PDF PubMed Scopus (761) Google Scholar]: The preoperative assessment of the size of largest tumor or total diameter remains crucial. However, pre-operative radiological staging for MC-IN and MC-OUT patients may differ in both directions in up to 25% of cases when compared to post-transplant histopathology [[5]Bargellini I. Bozzi E. Campani D. Carrai P. De Simone P. Pollina L. et al.Modified RECIST to assess tumor response after transarterial chemoembolization of hepatocellular carcinoma: CT-pathologic correlation in 178 liver explants.Eur J Radiol. 2013; 82: e212-e218Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. Although response to LRTs has already been shown in the beginning of the nineties as a useful tool for the selection of HCC patients as the seminal paper by Majno et al. clearly shows [[6]Majno P.E. Adam R. Bismuth H. Castaing D. Ariche A. Krissat J. et al.Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis.Ann Surg. 1997; 226: 688-701Crossref PubMed Scopus (472) Google Scholar], the delayed introduction in clinical practice of standardized and effective LRT techniques (TACE, radiofrequency ablation, radio-embolization) has hampered their routine use in the pre-LT management of HCC. As a consequence, the evaluation of the prognostic role of response after LRT has only recently been implemented. Mehta and Yao synthesized that there is "growing evidence that size and number tell only a partial tale of the tumor characteristics that predict post-transplant recurrence" [[7]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 (108) Google Scholar]. It is not known yet if LRTs represent per se a surrogate of tumor biology or if LRT works only through the proof of time. On this scope, we recently demonstrated that "fast track" LT does not allow to time the selection patients according to tumor aggressiveness [[8]Lai Q. Avolio A.W. Lerut J. Singh G. Chan S.C. Berloco P.B. et al.Recurrence of hepatocellular cancer after liver transplantation: the role of primary resection and salvage transplantation in East and West.J Hepatol. 2012; 57: 974-979Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. We recognize some limitations. Both the studies by Otto et al. and Lai et al. did not investigate the effect of LRT on the dropout during waiting-time. However, an ongoing analysis performed on 821 patients coming from the EurHeCaLT study group further confirmed the role of radiological progression as selection tool in terms of drop-out rate [[9]Lai Q. Graziadei I. Otto G. Goffette P. Berloco P. Tisone G. et al.Alpha-fetoprotein increase and radiological progression as more refined clinical tools for a justified selection of HCC liver recipients.Liver Transpl. 2013; 19: S118Crossref PubMed Scopus (12) Google Scholar]. Secondarily, CT scans older than 5 years are not always well evaluated by mRECIST criteria. In conclusion, waiting for reliable preoperative predictive markers of both adverse outcome and response to pretransplant treatment [[10]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 (69) Google Scholar], morphologic criteria remain the giants in the evaluation of LT candidates. Biological criteria still are the dwarfs. However, when dwarfs climb the shoulders of giants, they have the chance to see far, allowing longer survivals. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.