Author Affiliations: Department of Transplantation and Hepatobiliary Surgery, University Medical Center, Johannes Gutenberg-University, Mainz, Germany (Otto G)

Corresponding Author: Gerd Otto, Professor, Department of Transplantation and Hepatobiliary Surgery, University Medical Center, Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany (Tel: +49-6131-17-5310; Email: gerd.otto@unimedizin-mainz.de)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60071-1

Published online February 16, 2016.

 

 

Contributors: OG wrote the whole manuscript.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

Hepatocellular carcinoma (HCC) is one of the most frequent complications in patients with liver cirrhosis.^[1] HCC without cirrhosis is rare and obviously a different entity. Treatment depends on tumor stage, liver function and general performance. Results of locoregional treatment, resection or liver transplantation are superior to those of medical therapy. Surgical approaches are potentially curative. Underlying cirrhosis is usually the limiting factor for the extent of resection and persists after resection. Liver transplantation eliminates both cirrhosis and, potentially, the tumor. Whereas surgery (functional liver capacity provided) may be performed even in advanced tumors, liver transplantation is advocated in less advanced (T2) tumors in order to keep the rate of recurrent tumor low. Responsible use of scarce grafts requires sticking to this rule.

 

Tumor growth during waiting time with consecutive drop out from the waitlist before transplantation was the principal reason to search for approaches to preventing tumor growth. In this context, transarterial chemoembolization (TACE) was successfully introduced more than two decades ago. Very early, an exciting aspect of this pretreatment emerged:^[2] patients who experienced tumor response to TACE had a significantly prolonged disease-free survival compared to those with tumor progression during TACE. The mechanism of this selection process remains unclear. Is it just “test of time”, in other words time for metastases to demask, or is TACE really capable of separating biologically favorable from aggressive ones? Many publications favor the latter assumption.^[3] There is a considerable body of literature on liver resection with preceding TACE for HCC coming mainly from Asian countries.^[4-6] The answer, however, if recurrence rate after resection for HCC is influenced by preceding TACE, remains inconclusive.

 

In the present issue of Hepatobiliary Pancreatic Diseases International, Paik and Kim^[7] report on their experience with 106 HCC patients who underwent TACE before liver resection. Thirty-one patients suffered from HCC in non-cirrhotic livers. Tumor characteristics were obviously comparable between the included patients even though tumor stage is not reported in the publication. However, this is not a crucial question as the main issue of the analysis was whether the degree of necrosis imposed by TACE is capable of differentiating between patients with good and poor prognosis. The response to TACE was quantified by pathohistological workup of the resected specimens. The extent of necrotic tissue caused by TACE was classified into complete pathologic response (CPR: 100% necrotic tumor tissue), major response (MJR: ≥50% necrosis) and minor response (MNR: <50% necrosis) and, accordingly, the 106 patients were split into three groups (CPR: n=19; MJR: n=45 and MNR: n=42). Overall survival and disease-free survival were reported. In addition, factors affecting tumor response to TACE were analyzed. Overall survival and disease-free survival were not significantly different in the three groups. Likewise, the rates of recurrences were similar. Hepatitis B was the only predictor for a pathologic response above 50% imposed by TACE.

 

The authors compared their results with those of a recently published French study^[8] which demonstrated that the overall survival following resection with preceding TACE but not disease-free survival was significantly superior to resection alone in patients with a necrosis rate of more than 90%. By scrutinizing both studies, one may conclude that the results are not totally incongruent. In the current study, 72 patients with HCC in cirrhosis but in the French study 184 cirrhotic patients were included. The tumors in the French study were more advanced and the interval between the first TACE and resection was 3 months whereas it was 1 month in the current study. The French group identified a necrosis rate exceeding 90% as a significantly discriminating factor between poor and good prognosis. The greater number of patients, longer intervals after the first TACE, more advanced tumors and 90% but not 100% as discriminating necrosis rate could have contributed to the statistical differences between both studies.

 

Is it reasonable to argue for or against TACE in combination with liver resection? We have to consider the probable pathomechanisms for recurrent disease. After transplantation, the development of metastases requires circulating tumor cells before or during surgery. These cells may become sessile in any organ including the liver and explain recurrent disease. After resection, the situation is somewhat different. Comparable to transplantation, intrahepatic and extrahepatic tumor recurrence caused by tumor dissemination of the primary may occur. Any dissemination may prompt intrahepatic as well as extrahepatic metastases and may become apparent “early” and “late” after resection (early recurrence is usually defined as occurring up to two years after surgery^[9]). However, the majority of late recurrences occurs within the cirrhotic liver and originates from premalignant hepatocytes caused by cirrhosis. In total, intrahepatic recurrence overrides extrahepatic dissemination by far.

 

In the light of these probable pathomechanisms, the question if TACE may interfere with these mechanisms in liver resection is justified. TACE may prevent tumor dissemination as its objective is to “kill” all tumor cells within a lesion. As a result, vital tumor cells cannot be disseminated before and, first of all, during surgery. That is a rather simple explanation on the mode of action of TACE but it may be correct. The question is if achieving CPR is essential for good outcome or if good outcome is only achieved in biologically favorable tumors characterized by CPR. Is TACE really capable of differentiating between relatively benign and aggressive HCCs, i.e. does good and poor response parallel good or poor prognosis? Indeed, more “benign” tumors may feature a lower dissemination rate, both intrahepatic and extrahepatic, but not a lower de-novo tumor rate. As mentioned above, de-novo tumors arise from cirrhotic liver tissue containing premalignant clonal abnormalities which are not influenced by TACE. The crucial difference between transplantation and resection appears to arise exactly from that issue. If the second mechanism ascribed to TACE, namely “biological selection” exists, the generation of de-novo tumors after resection cannot be influenced by this procedure and late recurrences may superimpose the early effect of TACE. The results reported in this article^[7] may even provide an argument for these assumptions: 7 of 8 recurrences after CPR were late recurrences, whereas early and late recurrences were equally distributed between patients with MJR and MNR. Similarly, in a French study^[8] the lower rate of early recurrences in patients with >90% necrosis compared with those with <90% reflects that recurrences originating from premalignant lesions in cirrhosis occur late and are responsible for these figures (“flat” versus “steep” decline of the curve for disease-free survival). An effective pretreatment in transplantation has not necessarily to work in resection.

 

In view of available evidence, it appears premature to decide about TACE before liver resection. From a theoretical point of view, TACE may be capable of selecting biologically favorable tumors and, thereby, “prevent” early recurrence as tumor dissemination is supposed to be limited in these tumors. However, TACE does not have the capability to prevent de-novo tumor growth from numerous premalignant cells located in the cirrhotic liver. Therefore, response to TACE does not necessarily mean good prognosis as primaries and de-novo tumors may be totally different as to their biological behavior. In addition to the questionable preventive capability of TACE, pretreatment may have a negative impact on liver function. The tumor may proceed despite TACE and the embolization may promote tumor dissemination. Therefore, the only solution of the problem is a randomized multicenter study. Included patients must have comparable tumors, identical approaches to pretreatment and standardized pathologic assessment. This study would probably lead to a reliable answer to all pending questions. 

 

 

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