Lipiodol transarterial chemoembolization for hepatocellular carcinoma: Where are we now?
Authors: Franco Trevisani, Rita Golfieri
Journal: Hepatology (2016)

Potential conflict of interest: Prof. Trevisani consults, advises, is on the speakers' bureau for, and received grants from Bayer. Dr. Golfieri advises and is on the speakers' bureau for Sirtex and Boston. She is on the speakers' bureau for Bayer. See Article on Page 106 Transarterial chemoembolization (TACE) is one of the leading treatments for hepatocellular carcinoma (HCC), with nearly half of all HCC patients undergoing the procedure at some point during their clinical history.1 The most common technique relies on the arterial infusion of an anticancer drug emulsified with Lipiodol, followed by the occlusion of the tumor‐feeding artery with an occluding agent. However, several alternatives to Lipiodol‐TACE have emerged in recent years, with a growing number of Western centers adopting a procedure based on the injection of embolizing microspheres loaded with a chemotherapeutic agent (drug‐eluting beads; DEB), usually doxorubicin. Although DEB‐TACE is considered to be less toxic and better standardized than the conventional Lipiodol‐TACE,2 a recent multicenter, randomized, controlled trial (RCT) comparing Lipiodol‐ and DEB‐TACE reported no differences in patient survival or safety outcomes between the two treatments, thus renewing interest in conventional TACE.3 In this background, the systematic review of Lipiodol‐TACE studies published in the current issue of Hepatology4 is particularly timely. The review's aim was to provide comprehensive information on the efficacy and safety of the "conventional" TACE procedure, thus enabling care providers to calibrate their outcomes against benchmarks obtained by a comprehensive analysis of the literature. Indeed, incessant technical improvements and the evolving patient selection criteria for transarterial procedures make it increasingly difficult to compare results of conventional TACE among different studies and its efficiency versus that of alternatives, such as DEB‐TACE or internal radiation with yttrium90 microspheres. In their analysis, Lencioni et al. analyzed 101 studies (10,108 patients) to assess Lipiodol‐TACE efficacy and 217 studies (15,351 patients, 27,497 sessions) to scrutinize its safety. The researchers reviewed studies (prevalently single‐arm or multiple‐arm nonrandomized) published between 1980 and 2013 in the English literature. Their analysis demonstrated that Lipiodol‐TACE leads to an objective (complete+partial) radiological response in 52.5% of cases, with a median overall survival of 19.4 months, a 3‐year survival rate of 40.4%, and a progression‐free survival at 3 years of 15.6%. Procedure‐related deaths occurred in 0.6% of cases, mainly attributable to acute liver failure, followed by bleeding and infections. Liver enzyme elevation was the most frequent adverse event (52%), followed by postembolization syndrome (48%). Overall, this study provides a comprehensive analysis of patient outcomes with Lipiodol‐TACE, both worldwide and outside the controlled conditions of randomized studies. It is also reassuring that the survival figures and the safety profile were consistent with data from RTCs that allowed us to include TACE among the evidence‐based therapeutic options for HCC. A remaining key question from this analysis then is, what is next? Should we pursue alternative TACE strategies or continue to develop this old, but likely not yet outdated, treatment? The data provided by the review are less helpful to answer this question, for several reasons. First, a dilutional bias may have affected the results, given that the studies included in the analysis spanned 33 years. Poorer survival obtained with technically obsolete procedures may have diluted higher survival rates achieved with modern procedures. Indeed, the median overall survival of 19.4 months is similar to that reported in a meta‐analysis published 11 years ago and is much lower than the best figures achieved in recent years. To circumvent this drawback, the researchers assessed the results according to their publication period (i.e., before and after 2002). However, median survival in the two periods was similar (18.5 vs. 19.8 months), and a clinically relevant difference was only evident at 3‐year follow‐up, that is, among long‐term survivors (27.8 vs. 43.4 months). One might question whether this subanalysis sufficiently accounted for a possible dilutional bias effect. Indeed, a more articulated analysis of Lipiodol‐TACE results with respect to time and focusing on the highest‐quality studies shows a clear trend of progressively improving outcomes over the last 15 years (Fig. 1A; Supporting Table S1). A similar trend was noted analyzing the results coming from clinical practice of ITA.LI.CA centers, where survival of patients undergoing Lipiodol‐TACE improved after 2002, attributable to technical improvements in procedure and more appropriated patient selection criteria.5Figure 1: Median survival (A) and objective radiological response rate (B) of patients undergoing Lipiodol‐TACE according to the calendar period. Triangles indicate survivals of patients with a very early/early HCC, according to the BCLC staging system (for more details, see Supporting Table S1). Dashed lines indicate the median values reported by Lencioni et al.4Another point that deserves a comment is the wide range of TACE outcomes reported by the analyzed studies. Approximately one third of patients were either dead within 1 year or alive 5 years after the procedure. Factors explaining this confounding heterogeneity may be inherent to both patient‐ and tumor‐related characteristics. Indeed, approximately half the patient series did not exclude cases with vascular invasion, many studies included Child‐Pugh B patients, and 25 series even Child‐Pugh C cases. The researchers acknowledged that the initial sharp decline in survival was likely generated by the presence of individuals with poor liver function and/or portal vein invasion, thus raising questions about the generalizability of their presented survival estimates. Subanalyses focusing on candidates with well‐preserved liver function (Child‐Pugh A) and without vascular invasion would have revealed the results achievable with Lipiodol‐TACE in an optimal setting. On the other hand, because TACE is also used in patients with early HCCs (not amenable to curative approaches) or in those with limited peripheral vascular invasion, specific analysis of these cases is warranted. Indeed, considering the great heterogeneity of potential candidates to TACE, several groups have proposed new selection criteria aimed at optimizing the patient enrollment for the first and subsequent TACE sessions.6 Although robust external validation is still needed before accepting such criteria in clinical practice, these attempts indicate that the strategy for improving TACE appropriateness and outcome relies on a proper selection of potential candidates, making results deriving from heterogeneous populations with "unresectable" HCC obsolete and useless. Future systematic reviews on this topic should include, whenever possible, metaregression analysis evaluating the influence of parameters that vary between studies, and presenting survival estimates according to baseline characteristics of patients. The radiological response to Lipiodol‐TACE is an important surrogate endpoint in assessing treatment effect. The 52.5% overall objective (complete+partial) response reported by the systematic review should be interpreted cautiously. This estimate was, in fact, obtained using different criteria (World Health Organization, Response Evaluation Criteria in Solid Tumors [RECIST], modified RECIST [mRECIST], European Association for the Study of the Liver, and Japanese criteria) across studies and is remarkably lower than figures reported by several recent series in which the more appropriate mRECIST criteria were used (Fig. 1B). Last, several problems inherent to Lipiodol‐TACE remain unresolved: Can its outcome be optimized using a certain anticancer drug (or a given combination)? What is the optimal drug dose? What is the preferable therapeutic schedule: "on demand" or according to a predefined interval? At present, what is the actual efficacy of Lipiodol‐TACE? If it is realistic to envision that future RCTs will give us an answer to most of these questions, the true efficacy of this treatment may never be known because it would require an unethical trial where some patients would receive no intervention. Therefore, efforts should be devoted to achieve TACE outcomes better than the present ones. In this respect, the Lencioni et al. review is a valuable guidepost, describing the world‐wide scenario we should progress from and highlighting issues for future studies aimed at improving the efficiency of transarterial therapy: identification of optimal anticancer drugs and treatment schedule; definition of evidence‐based stopping rules for this therapy; and refinement of patient selection criteria. Moreover, in order to optimize the use of TACE, future studies should be designed to assess its results, rather than in patients with an intermediate Barcelona Clinic Liver Cancer (BCLC) stage HCC or "unresectable" tumors, in more homogenous subsets of patients. Treatment outcomes need to be stratified according to the baseline characteristics of candidates, including performance status, Child‐Pugh class, tumor size and number, and peripheral portal invasion. Overcoming a "one‐size‐fits‐all" mindset in analyzing available data and designing future trials is the first step in moving toward a future of personalized medicine for HCC.