Reply to: ‘‘Repeated transarterial chemoembolization: An overfitting effort?’’
Authors: Xavier Adhoute, Guillaume Penaranda, Jean Luc Raoul, Marc Bourlière
Journal: Journal of Hepatology (2015)

Retreatment with TACE: The ABCR SCORE, an aid to the decision-making processJournal of HepatologyVol. 62Issue 4PreviewTransarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC) and it is the most commonly used treatment for HCC worldwide. However, no prognostic indices, designed to select appropriate candidates for repeat conventional TACE, have been incorporated in the guidelines. Full-Text PDF Repeated transarterial chemoembolization: An overfitting effort?Journal of HepatologyVol. 62Issue 6PreviewWe read with great interest the article by Adhoute et al. published in Journal of Hepatology [1]. The authors developed a point score system, the ABCR [standing for Alpha-fetoprotein (AFP), Barcelona Clinic Liver Cancer (BCLC), Child-Pugh and Response], to assist in the decision making on whether to retreat hepatocellular carcinoma (HCC) patients with multiple transarterial chemoembolization (TACE) sessions. The study population consisted of HCC patients treated with repeated consecutive TACE sessions and the resulting significant parameters from regression analysis were used to build the score. Full-Text PDF Open Access We would like to thank Facciorusso et al. for their commentaries on our article and for applying our ABCR score to their important cohort of patients. Transarterial chemoembolization (TACE) is recommended for intermediate stage hepatocellular carcinoma (HCC) based on the algorithm of the Barcelona–Clinic Liver Cancer (BCLC) system [1Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3821) Google Scholar, 2Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.Hepatology. 2003; 37 (Review): 429-442Crossref PubMed Scopus (2651) Google Scholar], and is the most widely used treatment for HCC [[3]Park J.W. Sherman M. Colombo M. Roberts L.R. Schwartz M. Degos F. et al.Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: first characterization of the full study population.J Clin Oncol. 2012; 30 (Abstract): Abstr 4033Google Scholar]. No consensus exists for treatment methods, number of courses to be administered, objectives (complete or partial response, disease stabilization), and retreatment schedule but performing TACE guided by the radiologic response and individual tolerance appears to be the most logical option. Moreover, as suggested by Bolondi et al., intermediate stage represents a heterogeneous group of patients [[4]Bolondi L. Burroughs A. Dufour J.F. Galle P.R. Mazzaferro V. Piscaglia F. et al.Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions.Semin Liver Dis. 2012; 32: 348-359PubMed Google Scholar] and, in our group, as in some other groups, a segmental portal vein thrombosis, corresponding to BCLC C patients was not considered as an absolute contra-indication for TACE. This can certainly impact on the efficacy and tolerance, and is therefore of crucial importance to know relatively early, at least before severe toxicities, which patients will benefit from additional sessions. ABCR score can be used as an aid to the decision making process before retreatment with the second and/or the third TACE, but it must be validated in a prospective study. It consists of parameters already used by clinicians to guide their decision, including a worsening of liver function after TACE and radiological response (by EASL criteria) [[5]Gillmore R. Stuart S. Kirkwood A. Hameeduddin A. Woodward N. Burroughs A.K. et al.EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization.J Hepatol. 2011; 55: 1309-1316Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar], which is assigned with the highest coefficient (−3 points), whether partial or complete. In our HCC cohorts, representative of common practice including mostly BCLC B HCC and BCLC A HCC that are not suitable for curative treatment and less frequently stage C HCC due to segmental portal vein thrombosis (less than 10% in our validation cohorts), the calculated score before the second TACE is clearly correlated with the overall survival (OS). In our experience, we distinguished three groups with significantly different survival. One can suppose that the cut-off values described in our paper can differ from one team to another depending on inclusion criteria. In our experience, patients with ABCR score ⩾4 do not benefit from an additional course. The Milan team found close results (median OS of ABCR ⩽0 and [1Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3821) Google Scholar, 2Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.Hepatology. 2003; 37 (Review): 429-442Crossref PubMed Scopus (2651) Google Scholar, 3Park J.W. Sherman M. Colombo M. Roberts L.R. Schwartz M. Degos F. et al.Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: first characterization of the full study population.J Clin Oncol. 2012; 30 (Abstract): Abstr 4033Google Scholar] groups, 39 and 40 months respectively vs. ABCR ⩾4, 13 months). The non-significance (p = 0.19) is probably related to the low number of patients in the ABCR ⩾4 group (n = 7). It would be of interest to know if in their experience, of clearly excellent candidates for TACE, there exist also a linear relationship between score and OS. Since the publication, we tested the ABCR score in a merged cohort of 186 patients, median age 69 [66–70] years, with BCLC A HCC 17%, BCLC B HCC 66% and BCLC C HCC 17%, Child-Pugh A cirrhosis 86%, mostly related to alcohol (42%) and viral disease (32%). Consistently, we found a correlation between score and survival (Table 1). Logistic regression analysis on each score threshold shows that several thresholds are possible, but the threshold ⩾3 seems the best compromise (AUC [CI 95%] 0.785 [0.728; 0.844], likelihood ratio (LR) 33.04, p <0.0001, Akaike information criterion (AIC) 167.175) relative to a value threshold ⩾2 (AUC [CI 95%] 0.715 [0.657; 0.769], (LR) 32.03, p <0.0001, AIC 222. 808).Table 1Evolution of median overall survival following ABCR score with different thresholds in a merged cohort of 186 patients treated by TACE. Open table in a new tab The difference between the ABCR ⩽0 and ABCR [1Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3821) Google Scholar, 2Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.Hepatology. 2003; 37 (Review): 429-442Crossref PubMed Scopus (2651) Google Scholar, 3Park J.W. Sherman M. Colombo M. Roberts L.R. Schwartz M. Degos F. et al.Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: first characterization of the full study population.J Clin Oncol. 2012; 30 (Abstract): Abstr 4033Google Scholar] groups mainly involves the presence of a radiological response (−3 points); for example 94% of patients in the group ABCR ⩽0 against 2% for the ABCR group [1Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3821) Google Scholar, 2Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.Hepatology. 2003; 37 (Review): 429-442Crossref PubMed Scopus (2651) Google Scholar, 3Park J.W. Sherman M. Colombo M. Roberts L.R. Schwartz M. Degos F. et al.Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: first characterization of the full study population.J Clin Oncol. 2012; 30 (Abstract): Abstr 4033Google Scholar] had a radiological response in this new analysis. The Milan team did not find any difference in survival between the two groups in their cohort, likely because a radiological response was observed later, after the second TACE in the ABCR [1Forner A. Llovet J.M. Bruix J. Hepatocellular carcinoma.Lancet. 2012; 379: 1245-1255Abstract Full Text Full Text PDF PubMed Scopus (3821) Google Scholar, 2Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.Hepatology. 2003; 37 (Review): 429-442Crossref PubMed Scopus (2651) Google Scholar, 3Park J.W. Sherman M. Colombo M. Roberts L.R. Schwartz M. Degos F. et al.Observations of hepatocellular carcinoma (HCC) management patterns from the global HCC bridge study: first characterization of the full study population.J Clin Oncol. 2012; 30 (Abstract): Abstr 4033Google Scholar] group. The optimal time point for assessment to TACE response is not specified, several algorithms have been proposed [6Raoul J.L. Sangro B. Forner A. Mazzaferro V. Piscaglia F. Bolondi L. et al.Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization.Cancer Treat Rev. 2011; 37: 212-220Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar, 7Bruix J. Reig M. Rimola J. Forner A. Burrel M. Vilana R. et al.Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques.Hepatology. 2011; 54: 2238-2244Crossref PubMed Scopus (98) Google Scholar]. Taking into account the fact that some of our patients were not considered in the BCLC guidelines as good candidates for TACE, we considered that an early evaluation will be crucial in order to stop an early detrimental effect. We share the comment about the possible over-fitting and that is why sharing experience from other groups is of major interest and we thank the Milan team for their help. Experiences utilizing our ABCR score in other institutes would be interesting and most welcome. The bootstrap sampling as proposed by Facciorusso et al. seems to be attractive and needs to be applied in new cohorts. Finally, we fully agree with this letter to the Editor that it is of paramount importance now to improve prognostication and indication to retreatment, but perhaps in a more extended cohort of patients in order to know if it is possible to extend indication of TACE towards some more advanced HCC cases. Adhoute Xavier: Board member (Bayer). Penaranda Guillaume: grant from Bayer. Raoul Jean-Luc: Board member (Bayer, BMS, Daichi). Bourliere Marc: Board member (Merck-Schering Plough, Giléad, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, GSK), speaker (Merck-Schering Plough – Giléad, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, Novartis, GSK). XA, MB, JLR are MD in charge of the patients; XA, MB collected the data and GP proceed to statistical analysis; XA, GP wrote the letter; JLR and MB revised the manuscript.