TACE vs. surgical resection for BCLC stage B HCC
Authors: Sasan Roayaie
Journal: Journal of Hepatology (2014)

Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: A RCTJournal of HepatologyVol. 61Issue 1PreviewThe aim of this randomized comparative trial (RCT) is to compare partial hepatectomy (PH) with transcatheter arterial chemoembolization (TACE) to treat patients with resectable multiple hepatocellular carcinoma (RMHCC) outside of Milan Criteria. Full-Text PDF This issue of the Journal of Hepatology contains a very interesting and provocative study by Yin et al. that will undoubtedly generate significant debate in the hepatocellular carcinoma (HCC) community [[1]Yin L. Li H. Li A.J. Lau W.Y. Pan Z.Y. Lai E.C. et al.Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: a RCT.J Hepatol. 2014; 61: 82-88Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. The authors have to be commended for performing a well-designed trial to determine whether resection or trans-arterial chemo-embolization (TACE) yields better outcomes in patients with BCLC stage B HCC.The current European Association for Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) guidelines recommend resection as the primary treatment for HCC in patients with a single tumor, Child class A liver function with total bilirubin ⩽1 mg/dl, no evidence of clinically significant portal hypertension, and excellent performance status [2European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4479) Google Scholar, 3Bruix J. Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar]. The criteria also require patients to have no evidence of extra-hepatic disease or invasion of the portal or hepatic veins on imaging.These guidelines are essentially based on a study from 1999 that drew its conclusions from 77 patients undergoing hepatic resection for HCC [[4]Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection vs. transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1471) Google Scholar]. In addition, the guidelines are centered on the concept of who would be "ideal" candidates for resection thus yielding the highest survival for surgery as a treatment modality. Likewise, the role of TACE for treatment of BCLC stage B patients has been established by a randomized trial as well as a meta-analysis comparing TACE to best supportive care and not to other treatment modalities such as surgery [5Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation vs. symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2834) Google Scholar, 6Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2524) Google Scholar].The guidelines do not base their recommendations on what treatment modality yields the best result in a particular individual. Thus while a patient may not be an ideal candidate for surgery, resection may still yield a better outcome than the proposed BCLC treatment. We simply did not know because there has been no data.It is clear that, despite the lack of robust evidence, many centers were already offering surgery to patients with BCLC stage B and C tumors believing that resection yielded superior outcomes to TACE and sorafenib [[7]Torzilli G. Belghiti J. Kokudo N. Takayama T. Capussotti L. Nuzzo G. et al.A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group.Ann Surg. 2013; 257: 929-937Crossref PubMed Scopus (348) Google Scholar]. While other studies have attempted to compare resection to TACE, none have been conducted in a manner that allowed for drawing robust conclusion [8Zhong J.H. Xiang B.D. Gong W.F. Ke Y. Mo Q.G. Ma L. et al.Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or transarterial chemoembolization.PLoS One. 2013; 8: e68193Crossref PubMed Scopus (126) Google Scholar, 9Choi S.H. Choi G.H. Kim S.U. Park J.Y. Joo D.J. Ju M.K. et al.Role of surgical resection for multiple hepatocellular carcinomas.World J Gastroenterol. 2013; 19: 366-374Crossref PubMed Scopus (34) Google Scholar, 10Peng Z.W. Guo R.P. Zhang Y.J. Lin X.J. Chen M.S. Lau W.Y. Hepatic resection vs. transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus.Cancer. 2012; 118: 4725-4736Crossref PubMed Scopus (131) Google Scholar].The study by Yin et al. was conducted in a randomized fashion with a well-defined study population consisting of patients with BCLC stage B tumors. They found that the patients treated with resection had a median survival of 41 months, which was significantly longer when compared to 14 months for those treated with TACE. Multivariate analysis identified the type of treatment as an independently associated with survival with a 2.3 fold higher likelihood of mortality for patients treated with TACE. The survival advantage of hepatic resection was observed in patients with two tumors as well as those with more than two cancers.While the study was well constructed in terms of patient selection and statistical methods, it will likely draw criticism for the method of TACE which was used and the outcomes that were achieved. The authors performed TACE using an emulsion of 5-fluorouracil, mitomycin C, cisplatin, and lipiodol followed by Gelfoam particles and achieved a median survival of only 14 months. Trials from a decade ago using similar techniques achieved median survivals closer to 20 months [5Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation vs. symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2834) Google Scholar, 11Lo C.M. Ngan H. Tso W.K. Liu C.L. Lam C.M. Poon R.T. et al.Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology. 2002; 35: 1164-1171Crossref PubMed Scopus (2165) Google Scholar]. In addition, many centers are currently using drug-eluting particles loaded with adriamycin with some publications reporting a median survival of up to 40 months in BCLC stage B patients [[12]Burrel M. Reig M. Forner A. Barrufet M. de Lope C.R. Tremosini S. et al.Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design.J Hepatol. 2012; 56: 1330-1335Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar]. However, readers should be reminded of the fact that the average size of the tumors treated by TACE in the study by Yin et al. was 7.4 cm, substantially larger than the average tumor size reported in other manuscripts. In fact, the Liver Cancer Study Group of Japan reported a 1.95 fold increase in mortality when treating tumors >5 cm using TACE [[13]Takayasu K. Arii S. Ikai I. Kudo M. Matsuyama Y. Kojiro M. et al.Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis.AJR Am J Roentgenol. 2010; 194: 830-837Crossref PubMed Scopus (87) Google Scholar]. Likewise, treating multiple tumors was also associated with a hazard ration of 1.3. Thus, in the context of the size and number of tumors treated, the outcomes after TACE may, in fact, be quite appropriate.In summary, the study by Yin et al. provides sorely needed data that helps to answer the question "What treatment yields the best outcome for patients with BCLC stage B HCC?" Until now, we have only known that TACE yields longer survival than best supportive care for these patients. For the first time, a well-conducted randomized trial suggests that surgery may yield better results than TACE. This study will likely generate significant debate as it challenges our current concepts regarding the relative role of surgery for patients who are not considered "ideal" candidates. However, we must remember to keep our minds open to theories and data that challenge our existing mindset and realize that guidelines are not "carved in stone" and are meant to be modified as new data comes to light.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. This issue of the Journal of Hepatology contains a very interesting and provocative study by Yin et al. that will undoubtedly generate significant debate in the hepatocellular carcinoma (HCC) community [[1]Yin L. Li H. Li A.J. Lau W.Y. Pan Z.Y. Lai E.C. et al.Partial hepatectomy vs. transcatheter arterial chemoembolization for resectable multiple hepatocellular carcinoma beyond Milan criteria: a RCT.J Hepatol. 2014; 61: 82-88Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. The authors have to be commended for performing a well-designed trial to determine whether resection or trans-arterial chemo-embolization (TACE) yields better outcomes in patients with BCLC stage B HCC. The current European Association for Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) guidelines recommend resection as the primary treatment for HCC in patients with a single tumor, Child class A liver function with total bilirubin ⩽1 mg/dl, no evidence of clinically significant portal hypertension, and excellent performance status [2European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2012; 56: 908-943Abstract Full Text Full Text PDF PubMed Scopus (4479) Google Scholar, 3Bruix J. Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5052) Google Scholar]. The criteria also require patients to have no evidence of extra-hepatic disease or invasion of the portal or hepatic veins on imaging. These guidelines are essentially based on a study from 1999 that drew its conclusions from 77 patients undergoing hepatic resection for HCC [[4]Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection vs. transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1471) Google Scholar]. In addition, the guidelines are centered on the concept of who would be "ideal" candidates for resection thus yielding the highest survival for surgery as a treatment modality. Likewise, the role of TACE for treatment of BCLC stage B patients has been established by a randomized trial as well as a meta-analysis comparing TACE to best supportive care and not to other treatment modalities such as surgery [5Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation vs. symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2834) Google Scholar, 6Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2524) Google Scholar]. The guidelines do not base their recommendations on what treatment modality yields the best result in a particular individual. Thus while a patient may not be an ideal candidate for surgery, resection may still yield a better outcome than the proposed BCLC treatment. We simply did not know because there has been no data. It is clear that, despite the lack of robust evidence, many centers were already offering surgery to patients with BCLC stage B and C tumors believing that resection yielded superior outcomes to TACE and sorafenib [[7]Torzilli G. Belghiti J. Kokudo N. Takayama T. Capussotti L. Nuzzo G. et al.A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group.Ann Surg. 2013; 257: 929-937Crossref PubMed Scopus (348) Google Scholar]. While other studies have attempted to compare resection to TACE, none have been conducted in a manner that allowed for drawing robust conclusion [8Zhong J.H. Xiang B.D. Gong W.F. Ke Y. Mo Q.G. Ma L. et al.Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or transarterial chemoembolization.PLoS One. 2013; 8: e68193Crossref PubMed Scopus (126) Google Scholar, 9Choi S.H. Choi G.H. Kim S.U. Park J.Y. Joo D.J. Ju M.K. et al.Role of surgical resection for multiple hepatocellular carcinomas.World J Gastroenterol. 2013; 19: 366-374Crossref PubMed Scopus (34) Google Scholar, 10Peng Z.W. Guo R.P. Zhang Y.J. Lin X.J. Chen M.S. Lau W.Y. Hepatic resection vs. transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus.Cancer. 2012; 118: 4725-4736Crossref PubMed Scopus (131) Google Scholar]. The study by Yin et al. was conducted in a randomized fashion with a well-defined study population consisting of patients with BCLC stage B tumors. They found that the patients treated with resection had a median survival of 41 months, which was significantly longer when compared to 14 months for those treated with TACE. Multivariate analysis identified the type of treatment as an independently associated with survival with a 2.3 fold higher likelihood of mortality for patients treated with TACE. The survival advantage of hepatic resection was observed in patients with two tumors as well as those with more than two cancers. While the study was well constructed in terms of patient selection and statistical methods, it will likely draw criticism for the method of TACE which was used and the outcomes that were achieved. The authors performed TACE using an emulsion of 5-fluorouracil, mitomycin C, cisplatin, and lipiodol followed by Gelfoam particles and achieved a median survival of only 14 months. Trials from a decade ago using similar techniques achieved median survivals closer to 20 months [5Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation vs. symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2834) Google Scholar, 11Lo C.M. Ngan H. Tso W.K. Liu C.L. Lam C.M. Poon R.T. et al.Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology. 2002; 35: 1164-1171Crossref PubMed Scopus (2165) Google Scholar]. In addition, many centers are currently using drug-eluting particles loaded with adriamycin with some publications reporting a median survival of up to 40 months in BCLC stage B patients [[12]Burrel M. Reig M. Forner A. Barrufet M. de Lope C.R. Tremosini S. et al.Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design.J Hepatol. 2012; 56: 1330-1335Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar]. However, readers should be reminded of the fact that the average size of the tumors treated by TACE in the study by Yin et al. was 7.4 cm, substantially larger than the average tumor size reported in other manuscripts. In fact, the Liver Cancer Study Group of Japan reported a 1.95 fold increase in mortality when treating tumors >5 cm using TACE [[13]Takayasu K. Arii S. Ikai I. Kudo M. Matsuyama Y. Kojiro M. et al.Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis.AJR Am J Roentgenol. 2010; 194: 830-837Crossref PubMed Scopus (87) Google Scholar]. Likewise, treating multiple tumors was also associated with a hazard ration of 1.3. Thus, in the context of the size and number of tumors treated, the outcomes after TACE may, in fact, be quite appropriate. In summary, the study by Yin et al. provides sorely needed data that helps to answer the question "What treatment yields the best outcome for patients with BCLC stage B HCC?" Until now, we have only known that TACE yields longer survival than best supportive care for these patients. For the first time, a well-conducted randomized trial suggests that surgery may yield better results than TACE. This study will likely generate significant debate as it challenges our current concepts regarding the relative role of surgery for patients who are not considered "ideal" candidates. However, we must remember to keep our minds open to theories and data that challenge our existing mindset and realize that guidelines are not "carved in stone" and are meant to be modified as new data comes to light. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.