Transarterial therapies in HCC: Does embolization increase survival?
Authors: Alejandro Forner, Jean-Claude Trinchet
Journal: Journal of Hepatology (2009)

Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: A randomized phase III trialJournal of HepatologyVol. 51Issue 6PreviewTranscatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. Full-Text PDF Treatment of hepatocellular carcinoma (HCC) is an area of active research that has witnessed unprecedented change in recent years with the emergence of transarterial chemoembolization (TACE) and sorafenib as palliative standard of care, new potentially curative treatments such as radiofrequency, and the consolidation of an evidence-based approach to evaluate all potential treatment options [[1]Llovet J.M. Di Bisceglie A.M. Bruix J. Kramer B.S. Lencioni R. Zhu A.X. et al.Design and endpoints of clinical trials in hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 698-711Crossref PubMed Scopus (1421) Google Scholar]. The implementation of screening through biannual abdominal ultrasound [[2]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5051) Google Scholar] has led to increased diagnosis of HCC at early stages in more than 50% of correctly screened patients. However, despite the correct implementation of surveillance programs, more than half of patients with HCC are diagnosed late, when potential curative treatment cannot be applied. In addition, in a high proportion of cases the disease recurs after a radical therapy. Therefore, despite significant advancements, the development of new therapeutic approaches or the refinement of currently available treatments for non-early HCC has high priority in the field of clinical research in HCC.It is well known that HCC is a neoplasm whose progression is strongly linked to neoangiogenic activity. In contrast to the dual vascularization (portal and arterial) typical of the liver parenchyma, HCC has a vascular supply mostly dependent on the hepatic artery. This feature has constituted the pathophysiological rationale for the development of several intra-arterial procedures. In that sense, the intra-arterial administration of different drugs or devices allows its distribution almost exclusively within the tumor, and the acute arterial obstruction of the feeding arteries results in selective ischemic tumor necrosis. The techniques and agents used to treat HCC by intra-arterial means are very heterogeneous and could be schematically summarized as those that only deliver an active agent into the tumor (transarterial chemotherapy (TAI), or lipiodolization if this carrier is used aiming to increase tumor exposure to the drug), those that are only aimed at blocking the artery blood flow (transarterial embolization), and finally those that consider both procedures (TACE and, more recently, radioembolization).Despite the wide use of these procedures since the late 80s, their benefits were until recently questionable. Several randomized-controlled trials (RCTs), mainly performed in France, failed to show improvement in survival, but two RCTs published in 2002, one conducted in Barcelona [[3]Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2832) Google Scholar] and the other in Hong Kong [[4]Lo 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 (2164) Google Scholar], followed by a systematic meta-analysis [[5]Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2520) Google Scholar] showed that TACE has a significant and positive impact on survival in well-selected patients with preserved liver function. The discrepancies between these trials could result from differences in the main etiologies of chronic liver diseases (alcohol in France, virus in Spain and Japan) and subsequent alteration in liver function (higher in alcoholic than in viral diseases) [[6]Beaugrand M. Trinchet J.C. Interventional radiology as a fine art.J Hepatol. 2007; 46: 362-364Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. After these successful clinical trials, the main scientific associations with HCC as their research focus established TACE as the standard of care for intermediate HCC [[2]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5051) Google Scholar].As we have commented before, TACE is not the only locoregional, intra-arterial procedure. Some authors argue that the real impact of these treatments relies on the obstruction of the arterial blood flow, and the addition of chemotherapy not only has no benefit, but also may increase the toxicity and the rate of side-effects. Disappointingly, few trials have been conducted to evaluate this issue and the survival advantage has been only found with TACE but not with embolization alone. Nevertheless, these results should be considered with caution given the small sample size of the studies. In contrast, other authors have suggested that the real efficacy of these locoregional procedures comes from the intra-tumoral delivery of high doses of active agents, and hence the addition of embolization could not improve the efficacy, and could even potentially augment the side-effects and limit the applicability and benefits of these locoregional therapies.With the aim of evaluating the real impact of adding embolization on the overall survival of patients treated with TAI, Okusaka and collaborators conducted a multi-center, open-label trial to compare the effects of TACE and TAI and to clarify the possible benefits of treatment intensification performing embolization with gelatin-sponge particles in addition to infusion chemotherapy [[7]Okusaka T. Kasugai H. Shioyama Y. Tanaka K. Kudo M. Saisho H. et al.Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.J Hepatol. 2009; 51: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. In this study, zinostatin stimalamer (SMANCS), a lipophilic anticancer agent that dissolves in lipiodol to form a stable solution, was selected as the chemotherapeutic agent for use with both TACE and TAI. The primary endpoint was survival from randomization, and the secondary endpoints were tumor response and toxicity. A total of 161 patients were randomly allocated to the TACE group (n = 79) or the TAI group (n = 82). At the time of the final analysis, 51 patients in the TACE group and 58 patients in the TAI group had died, and the median overall survival time was 646 days and 679 days, respectively (p = 0.383). Regarding tumor response, the proportion of patients with more than 50% of tumor necrosis among the patients with measurable lesions was not significantly different between the TACE group and the TAI group (48.1% vs. 34.2%; p = 0.11). Therefore, the results of this study suggest that treatment intensification by adding embolization did not increase the survival of HCC patients over SMANCS transarterial chemotherapy alone [[7]Okusaka T. Kasugai H. Shioyama Y. Tanaka K. Kudo M. Saisho H. et al.Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.J Hepatol. 2009; 51: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar].Can it be inferred from these results that embolization after intra-arterial chemotherapy does not improve survival? The answer probably is no, and it is based on several points that we will attempt to summarize. The first concern is the high rate of screening failures (61 out of 222 patients) because of ineligibility for intra-arterial treatment based on angiographic findings. This fact could reflect ill-defined eligibility criteria, and subsequently the patients’ inclusion may be based in part on the investigator criteria. Undoubtedly, this strategy certainly allows the inclusion of a heterogeneous population and in addition, constitutes a source for selection bias. In particular, the proportion of patients with cirrhosis in each group was not reported. Second, this RCT included patients with far-advanced tumors: approximately 40% of cases are advanced HCC and serum alpha-fetoprotein was >400 ng/mL in one-third. In this population, transarterial locoregional therapies, regardless of the methodology used, have poor impact on survival. Third, there was not a pre-planned treatment schedule, and after the first procedure, the next sessions were done according to the investigator criteria, resulting again in a source of potential bias. In addition, the number of protocol repetition treatments was very low (median courses, 2.2–2.4), so we could hypothesize that the maximum anticancer potential may have not been achieved. The next issue concerns the assessment of tumor response. This was done by CT scan one month after the completion of treatment and every 3–4 months thereafter and considered lipiodol accumulation in the tumor as an indicator of tumor necrosis. Although the authors have justified the measurement of lipiodol accumulation as a surrogate of necrosis with previously published radiologic–pathologic correlation studies, a more reliable strategy would have been to use magnetic resonance imaging (MRI) that could have allowed them to measure with confidence the area of necrosis. Finally, we would like to highlight the high rate of side-effects, which may be justified by the use of SMANCS in both groups, and could impair the potential benefit of these procedures and counteract any benefit from therapy.Nonetheless, we should not lose sight of the accomplishment of the authors. RCTs in the field of HCC are difficult to perform and are always very welcome. Okusaka and collaborators should be commended for having conducted a multi-center RCT aimed at answering this relevant question that fulfills the criteria put forward by the CONSORT statement (www.consort-statement.org) [[8]Moher D. Schulz K.F. Altman D.G. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.Ann Intern Med. 2001; 134: 657-662Crossref PubMed Scopus (958) Google Scholar]. Unfortunately this trial was conducted between 1999 and 2003 and several breakthroughs in the field of intra-arterial locoregional therapies have been made in the meantime. One of the most recent advancements has been the development of the drug eluting beads (DEBs) that allow a slow release of chemotherapy while simultaneously inducing a calibrated arterial obstruction. Consequently, the use of DEBs for TACE sharply decreases the passage of drug to the systemic circulation, minimizing the appearance of side-effects associated to chemotherapy, and could induce an outstanding rate of objective responses [9Varela M. Real M.I. Burrel M. Forner A. Sala M. Brunet M. et al.Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics.J Hepatol. 2007; 46: 474-481Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar, 10Malagari K. Chatzimichael K. Alexopoulou E. Kelekis A. Hall B. Dourakis S. et al.Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients.Cardiovasc Intervent Radiol. 2008; 31: 269-280Crossref PubMed Scopus (185) Google Scholar, 11Poon R.T. Tso W.K. Pang R.W. Ng K.K. Woo R. Tai K.S. et al.A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead.Clin Gastroenterol Hepatol. 2007; 5: 1100-1108Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. With these encouraging preliminary results, the current comparison between TACE using state-of-the-art devices and TAI is unjustified from an ethical point of view, thus it is improbable that other authors could confirm (or not) the results presented by Okusaka and collaborators.Further advancements are needed in the field of locoregional therapies in HCC. As emphasized by Okusaka and collaborators, rapid evaluations of new techniques using RCTs are difficult to perform and significant improvements could result from pooling large prospective databases from different geographical areas [[6]Beaugrand M. Trinchet J.C. Interventional radiology as a fine art.J Hepatol. 2007; 46: 362-364Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Efforts should be directed to develop and evaluate new active drugs and embolization agents to determine the best criteria for treatment efficacy, to assess which therapeutic regimen is more appropriate (repeat treatment according to a fixed schedule or upon disease progression after initial response) and finally, to evaluate whether the combination of TACE with other locoregional approaches such as radiofrequency ablation [[12]Lencioni R. Crocetti L. Petruzzi P. Vignali C. Bozzi E. Della Pina C. et al.Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma: a pilot clinical study.J Hepatol. 2008; 49: 217-222Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar] or with systemic drugs may further increase the impact of TACE on overall survival. Treatment of hepatocellular carcinoma (HCC) is an area of active research that has witnessed unprecedented change in recent years with the emergence of transarterial chemoembolization (TACE) and sorafenib as palliative standard of care, new potentially curative treatments such as radiofrequency, and the consolidation of an evidence-based approach to evaluate all potential treatment options [[1]Llovet J.M. Di Bisceglie A.M. Bruix J. Kramer B.S. Lencioni R. Zhu A.X. et al.Design and endpoints of clinical trials in hepatocellular carcinoma.J Natl Cancer Inst. 2008; 100: 698-711Crossref PubMed Scopus (1421) Google Scholar]. The implementation of screening through biannual abdominal ultrasound [[2]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5051) Google Scholar] has led to increased diagnosis of HCC at early stages in more than 50% of correctly screened patients. However, despite the correct implementation of surveillance programs, more than half of patients with HCC are diagnosed late, when potential curative treatment cannot be applied. In addition, in a high proportion of cases the disease recurs after a radical therapy. Therefore, despite significant advancements, the development of new therapeutic approaches or the refinement of currently available treatments for non-early HCC has high priority in the field of clinical research in HCC. It is well known that HCC is a neoplasm whose progression is strongly linked to neoangiogenic activity. In contrast to the dual vascularization (portal and arterial) typical of the liver parenchyma, HCC has a vascular supply mostly dependent on the hepatic artery. This feature has constituted the pathophysiological rationale for the development of several intra-arterial procedures. In that sense, the intra-arterial administration of different drugs or devices allows its distribution almost exclusively within the tumor, and the acute arterial obstruction of the feeding arteries results in selective ischemic tumor necrosis. The techniques and agents used to treat HCC by intra-arterial means are very heterogeneous and could be schematically summarized as those that only deliver an active agent into the tumor (transarterial chemotherapy (TAI), or lipiodolization if this carrier is used aiming to increase tumor exposure to the drug), those that are only aimed at blocking the artery blood flow (transarterial embolization), and finally those that consider both procedures (TACE and, more recently, radioembolization). Despite the wide use of these procedures since the late 80s, their benefits were until recently questionable. Several randomized-controlled trials (RCTs), mainly performed in France, failed to show improvement in survival, but two RCTs published in 2002, one conducted in Barcelona [[3]Llovet J.M. Real M.I. Montana X. Planas R. Coll S. Aponte J. et al.Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2832) Google Scholar] and the other in Hong Kong [[4]Lo 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 (2164) Google Scholar], followed by a systematic meta-analysis [[5]Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2520) Google Scholar] showed that TACE has a significant and positive impact on survival in well-selected patients with preserved liver function. The discrepancies between these trials could result from differences in the main etiologies of chronic liver diseases (alcohol in France, virus in Spain and Japan) and subsequent alteration in liver function (higher in alcoholic than in viral diseases) [[6]Beaugrand M. Trinchet J.C. Interventional radiology as a fine art.J Hepatol. 2007; 46: 362-364Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. After these successful clinical trials, the main scientific associations with HCC as their research focus established TACE as the standard of care for intermediate HCC [[2]Bruix J. Sherman M. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5051) Google Scholar]. As we have commented before, TACE is not the only locoregional, intra-arterial procedure. Some authors argue that the real impact of these treatments relies on the obstruction of the arterial blood flow, and the addition of chemotherapy not only has no benefit, but also may increase the toxicity and the rate of side-effects. Disappointingly, few trials have been conducted to evaluate this issue and the survival advantage has been only found with TACE but not with embolization alone. Nevertheless, these results should be considered with caution given the small sample size of the studies. In contrast, other authors have suggested that the real efficacy of these locoregional procedures comes from the intra-tumoral delivery of high doses of active agents, and hence the addition of embolization could not improve the efficacy, and could even potentially augment the side-effects and limit the applicability and benefits of these locoregional therapies. With the aim of evaluating the real impact of adding embolization on the overall survival of patients treated with TAI, Okusaka and collaborators conducted a multi-center, open-label trial to compare the effects of TACE and TAI and to clarify the possible benefits of treatment intensification performing embolization with gelatin-sponge particles in addition to infusion chemotherapy [[7]Okusaka T. Kasugai H. Shioyama Y. Tanaka K. Kudo M. Saisho H. et al.Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.J Hepatol. 2009; 51: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. In this study, zinostatin stimalamer (SMANCS), a lipophilic anticancer agent that dissolves in lipiodol to form a stable solution, was selected as the chemotherapeutic agent for use with both TACE and TAI. The primary endpoint was survival from randomization, and the secondary endpoints were tumor response and toxicity. A total of 161 patients were randomly allocated to the TACE group (n = 79) or the TAI group (n = 82). At the time of the final analysis, 51 patients in the TACE group and 58 patients in the TAI group had died, and the median overall survival time was 646 days and 679 days, respectively (p = 0.383). Regarding tumor response, the proportion of patients with more than 50% of tumor necrosis among the patients with measurable lesions was not significantly different between the TACE group and the TAI group (48.1% vs. 34.2%; p = 0.11). Therefore, the results of this study suggest that treatment intensification by adding embolization did not increase the survival of HCC patients over SMANCS transarterial chemotherapy alone [[7]Okusaka T. Kasugai H. Shioyama Y. Tanaka K. Kudo M. Saisho H. et al.Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.J Hepatol. 2009; 51: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Can it be inferred from these results that embolization after intra-arterial chemotherapy does not improve survival? The answer probably is no, and it is based on several points that we will attempt to summarize. The first concern is the high rate of screening failures (61 out of 222 patients) because of ineligibility for intra-arterial treatment based on angiographic findings. This fact could reflect ill-defined eligibility criteria, and subsequently the patients’ inclusion may be based in part on the investigator criteria. Undoubtedly, this strategy certainly allows the inclusion of a heterogeneous population and in addition, constitutes a source for selection bias. In particular, the proportion of patients with cirrhosis in each group was not reported. Second, this RCT included patients with far-advanced tumors: approximately 40% of cases are advanced HCC and serum alpha-fetoprotein was >400 ng/mL in one-third. In this population, transarterial locoregional therapies, regardless of the methodology used, have poor impact on survival. Third, there was not a pre-planned treatment schedule, and after the first procedure, the next sessions were done according to the investigator criteria, resulting again in a source of potential bias. In addition, the number of protocol repetition treatments was very low (median courses, 2.2–2.4), so we could hypothesize that the maximum anticancer potential may have not been achieved. The next issue concerns the assessment of tumor response. This was done by CT scan one month after the completion of treatment and every 3–4 months thereafter and considered lipiodol accumulation in the tumor as an indicator of tumor necrosis. Although the authors have justified the measurement of lipiodol accumulation as a surrogate of necrosis with previously published radiologic–pathologic correlation studies, a more reliable strategy would have been to use magnetic resonance imaging (MRI) that could have allowed them to measure with confidence the area of necrosis. Finally, we would like to highlight the high rate of side-effects, which may be justified by the use of SMANCS in both groups, and could impair the potential benefit of these procedures and counteract any benefit from therapy. Nonetheless, we should not lose sight of the accomplishment of the authors. RCTs in the field of HCC are difficult to perform and are always very welcome. Okusaka and collaborators should be commended for having conducted a multi-center RCT aimed at answering this relevant question that fulfills the criteria put forward by the CONSORT statement (www.consort-statement.org) [[8]Moher D. Schulz K.F. Altman D.G. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.Ann Intern Med. 2001; 134: 657-662Crossref PubMed Scopus (958) Google Scholar]. Unfortunately this trial was conducted between 1999 and 2003 and several breakthroughs in the field of intra-arterial locoregional therapies have been made in the meantime. One of the most recent advancements has been the development of the drug eluting beads (DEBs) that allow a slow release of chemotherapy while simultaneously inducing a calibrated arterial obstruction. Consequently, the use of DEBs for TACE sharply decreases the passage of drug to the systemic circulation, minimizing the appearance of side-effects associated to chemotherapy, and could induce an outstanding rate of objective responses [9Varela M. Real M.I. Burrel M. Forner A. Sala M. Brunet M. et al.Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics.J Hepatol. 2007; 46: 474-481Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar, 10Malagari K. Chatzimichael K. Alexopoulou E. Kelekis A. Hall B. Dourakis S. et al.Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients.Cardiovasc Intervent Radiol. 2008; 31: 269-280Crossref PubMed Scopus (185) Google Scholar, 11Poon R.T. Tso W.K. Pang R.W. Ng K.K. Woo R. Tai K.S. et al.A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead.Clin Gastroenterol Hepatol. 2007; 5: 1100-1108Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. With these encouraging preliminary results, the current comparison between TACE using state-of-the-art devices and TAI is unjustified from an ethical point of view, thus it is improbable that other authors could confirm (or not) the results presented by Okusaka and collaborators. Further advancements are needed in the field of locoregional therapies in HCC. As emphasized by Okusaka and collaborators, rapid evaluations of new techniques using RCTs are difficult to perform and significant improvements could result from pooling large prospective databases from different geographical areas [[6]Beaugrand M. Trinchet J.C. Interventional radiology as a fine art.J Hepatol. 2007; 46: 362-364Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Efforts should be directed to develop and evaluate new active drugs and embolization agents to determine the best criteria for treatment efficacy, to assess which therapeutic regimen is more appropriate (repeat treatment according to a fixed schedule or upon disease progression after initial response) and finally, to evaluate whether the combination of TACE with other locoregional approaches such as radiofrequency ablation [[12]Lencioni R. Crocetti L. Petruzzi P. Vignali C. Bozzi E. Della Pina C. et al.Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma: a pilot clinical study.J Hepatol. 2008; 49: 217-222Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar] or with systemic drugs may further increase the impact of TACE on overall survival. Alejandro Forner is partially supported by a grant from the Instituto de Salud Carlos III ( PI 05/645 ). This work is partially supported by a grant from the Instituto de Salud Carlos III ( PI 08/146 ) and by the Transversal Cancer Action of October 2007. CIBEREHD is funded by the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation).