Editorial : “ Percutaneous Ablative Treatments of Hepatocellular Carcinoma “ ( See Article HEP-14-0863.R1 : Wang C et al.) The history of percutaneous ablation of primary and secondary liver tumors dates back to the mid-1980s, when, within the space of few months , researchers in Japan and Italy published the first reports of ultrasound-guided injections

of ethanol

to

ablate

hepatocellular

carcinomas (HCCs) and liver metastases ( 1,2 ). Later other types of technology were developed to produce necrosis of the tumor tissue using radiofrequency, laser, or microwave energy — all delivered via a needle inserted into the focal liver lesion under imaging guidance or during laparoscopy ( 3,4,5 ). These methods have been used mainly to treat HCCs in patients with cirrhosis who were ineligible for surgical resection, and each has been thoroughly analyzed in the literature in terms of the outcome of treatment ( overall survival, disease-free survival, tumor progression), contraindications, risks, and complications. As far as percutaneous ethanol injections (PEI) are concerned, the 5year survival rates in patients with HCCs measuring less than 3 cm range from 47% to 65% , and in a recent study of 685 Japanese patients, the 5-, 10-, and 20-year survival rates — 49%, 18% and 7.2%, respectively — were similar to those observed in patients with cirrhosis who did not have HCC ( 6 ). For larger HCCs, however, PEI has been shown to produce incomplete necrosis of the tumor tissue owing to the heterogeneous This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27615 This article is protected by copyright. All rights reserved.

Hepatology

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consistency of these tumors, which hinders uniform intralesional distribution of the alcohol. This limitation can be overcome with radiofrequency ablation (RFA), which is based on the conversion of radiofrequency energy to heat . In the treatment of HCCs exceeding 2 cm in diameter, RFA is associated with higher rates of complete necrosis and better long-term outcomes than PEI ( 7 ). In contrast, PEI has displayed good efficacy in the treatment of tumors measuring less than 2 cm, particularly those located in “problem” areas of the liver or adjacent to blood vessels, settings in which the diffusion of heat is less advisable(8 ). Microwave ablation (MWA) creates an electromagnetic field within the tumor, which induces uniform rotation of the tissue molecules and heat production that results in necrosis (9). In some studies, MWA has been compared with RFA for the treatment of HCCs of different sizes (< 3 cm and < 5 cm), but no significant differences have been observed in either setting in terms of the completeness of tumor necrosis, disease recurrence, survival or complication rates ( 10, 11). Laser thermal ablation has also been associated with high rates of complete necrosis —an average of 95% — in HCCs measuring less than 3 cm ( 12 ), but compared with other methods, it is based on relatively sophisticated technology and requires much more substantial operator experience since it involves placement of multiple optical fibers within

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the neoplastic lesion according to a programmed spatial distribution scheme. Given their widespread use, the excellent results they produce in terms of survival (comparable to that reported after surgical resection in some studies ( 13,14 )), and their acceptable complication rates ( 15,16), tumor ablation techniques are now listed in the AASLD guidelines among the potentially “curative” treatments for HCC ( 17 ). Unfortunately, however, randomized, prospective comparisons of the various techniques (e.g., RFA versus MW) are still quite rare, and thus far no one technique has emerged as significantly more effective than the others. In this issue of Hepatology Wang C et al. report the results of a randomized,

controlled

multicenter

trial

comparing

percutaneous

cryoablation (CRYO) and RFA in patients with cirrhosis, Child-Pugh class A or B liver function, and 1-2 HCC nodules measuring ≤ 4 cm. CRYO is a relatively new method that causes intralesional ice formation, cellular dehydration and lysis, and obliteration of the newly formed blood vessels within the tumor ( 18 ). This was a well-designed study, and the clinical characteristics of the patients in the two treatment groups were similar. The primary endpoints were local tumor progression at 3 years and safety. As for the former, CRYO proved to be significantly superior to RFA in patients with larger tumors (i.e., those that were 3.1 to 4 cm in diameter). The two methods were not significantly different in terms of 3 Hepatology This article is protected by copyright. All rights reserved.

Hepatology

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complication rates, which were less than 4% in both groups, or survival (overall and tumor-free) at 1, 3, and 5 years. The main contribution of this study is the demonstration that percutaneous ablation can be effective for HCCs up to 4 cm in diameter. The superiority of CRYO over RFA in the larger tumors (3.1-4.0 cm.) in terms of local tumor progression can theoretically be attributed to its ability to necrotize larger volumes of tissue, which increases the chances of ablating microsatellite lesions that are always possible with lesions of this size. The study did not compare the costs of the two procedures, and as the authors themselves point out, this is an important factor in today’s economy. The use of ablative therapies for HCC is still surrounded by a number of other unanswered questions. For example, although the efficacy of PEI for treatment of lesions < 2 cm in diameter is now well-documented, for larger tumors it is still too early to conclude that one technique is significantly better than the others (RFA, MWA, CRYO) in terms of complete necrosis rates or actuarial survival curves, although in this field it is always best to verify actual survival instead of relying on statistical projections alone. In addition, we still don’t have reliable data on the efficacy of percutaneous ablation techniques combined with other types of treatment (e.g., intra-arterial chemoembolization + RFA), an approach that might be useful for managing larger tumors. And finally, further 4 Hepatology This article is protected by copyright. All rights reserved.

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work is needed to define the role(s) of percutaneous ablation in patients with HCC who may be eligible for liver transplantation (e.g., downstaging of the tumor to allow access to the waiting list; treatment of patients who are already on the list to avoid drop-out) ( 19 ).

Gian Ludovico Rapaccini, M.D., Ph.D. Gastroenterology Unit Department of Internal Medicine Catholic University Largo A. Gemelli 8, 00168, Rome, Italy [email protected]

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microwave ablation for hepatocellular carcinoma. PLOS ONE 2013;8 (10):1-8. 12) Christophi C, Muralidharan V. Treatment of hepatocellular carcinoma by percutaneous Laser ablation. J Gastroenterol Hepatol 2001; 16: 548-552. 13) Feng K, Yen J, Li X, Xia F, Ma K, Wang S, Bie P, Dong J. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol 2012; 57: 794:802. 14) Pompili M, Saviano A, de Matthaeis N, Cucchetti A, Nuzz G, Rapaccini GL, Giuliante F. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma < cm. 3. Results of a multicenter Italian survey. J Hepatol 2013;59:89-97. 15) Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpen EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radiofrequency ablation: complications encountered in multicentric study. Radiology 2003; 226;441451. 16) Koda M, Murawaki Y, Hirooka Y, Kitamoto M, Ono M, Sakaeda H, Joko K et al. Complications of radiofrequency ablation for hepatocellular carcinoma in a multicenter study: an analysis of 16,346 trated nodules in 13,283 patients. Hepatology Research 2012; 42: 1058-1064. 17) Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208-1236. 18) Maccini M, Sehrt D, Pompeo A, Chicoli FA,Molina WR, Kim FJ. Biophysiologic considerations in cryoablation: a practical mechanistic molecular review. Int Brazil J Urol 2011;37:693-696. 7 Hepatology This article is protected by copyright. All rights reserved.

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19) Ravaioli M, Grazi GL, Piscaglia F, Trevisani F, Cescon M,Ercolani G. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8:2547-2557.

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Percutaneous ablative treatments of hepatocellular carcinoma.

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