Chemoembolization for hepatocellular carcinoma

Curative therapies for hepatocellular carcinoma (HCC), such as resection, liver transplantation, and percutaneous ablation, can be applied in selected patients with early tumors; this includes approximately 30%–40% of all cases. More advanced stages require local or systemic therapies. Data on the efficacy of these treatments are derived from small randomized controlled trials (RCT) and meta-analysis. Chemoembolization, a technique combining intra-arterial chemotherapy and selected ischemia, has produced modest survival advantages in 2 RCTs and a meta-analysis, and is currently the mainstay of treatment for these stages. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion, who constitute less than 15% of the HCC population. In these cases, the benefits derived by achieving objective responses (30%–50% of cases) are not offset by the deterioration of the liver function. Treatment-related mortality is less than 4%. No survival advantages have yet been shown with embolization or intra-arterial chemotherapy alone. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal retreatment schedule. The analysis of efficacy in these trials should be adjusted for prognostic factors, such as the presence of symptoms, Child-Pugh class, and segmental vascular invasion. Curative therapies for hepatocellular carcinoma (HCC), such as resection, liver transplantation, and percutaneous ablation, can be applied in selected patients with early tumors; this includes approximately 30%–40% of all cases. More advanced stages require local or systemic therapies. Data on the efficacy of these treatments are derived from small randomized controlled trials (RCT) and meta-analysis. Chemoembolization, a technique combining intra-arterial chemotherapy and selected ischemia, has produced modest survival advantages in 2 RCTs and a meta-analysis, and is currently the mainstay of treatment for these stages. The ideal candidates for this option are patients with well-preserved liver function (Child-Pugh class A) and multinodular asymptomatic tumors without vascular invasion, who constitute less than 15% of the HCC population. In these cases, the benefits derived by achieving objective responses (30%–50% of cases) are not offset by the deterioration of the liver function. Treatment-related mortality is less than 4%. No survival advantages have yet been shown with embolization or intra-arterial chemotherapy alone. Further RCTs are needed to assess the best chemotherapeutic agent and the ideal retreatment schedule. The analysis of efficacy in these trials should be adjusted for prognostic factors, such as the presence of symptoms, Child-Pugh class, and segmental vascular invasion. Hepatocellular carcinoma (HCC) is a major health problem worldwide, involving more than 500,000 new cases yearly, with an age-adjusted incidence of 5.5–14.9 per 105 population.1Parkin D.M. Bray F. Ferlay J. Pisani P. Estimating the world cancer burden Globocan 2000.Int J Cancer. 2001; 94: 153-156Crossref PubMed Scopus (3311) Google Scholar In some areas of Asia and the Middle East, HCC ranks as the first cause of death caused by cancer. The incidence of HCC is increasing in Europe and the United States,2El Serag H.B. Mason A.C. Rising incidence of hepatocellular carcinoma in the United States.N Engl J Med. 1999; 340: 745-750Crossref PubMed Scopus (2716) Google Scholar and HCC is currently the leading cause of death among cirrhotic patients.3Sangiovanni A. Del Ninno E. Fasani P. De Fazio C. Ronchi G. Romeo R. Morabito A. de Franchis R. Colombo M. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance.Gastroenterology. 2004; 126: 1005-1014Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar There is no agreement on a common treatment strategy for patients with HCC worldwide, and several proposals have been published.4Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholar, 5Mor E. Kaspa R.T. Sheiner P. Schwartz M. Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation.Ann Intern Med. 1998; 129: 643-653Crossref PubMed Scopus (196) Google Scholar, 6Poon R.T. Fan S.T. Tsang F.H. Wong J. Locoregional therapies for hepatocellular carcinoma a critical review from the surgeon's perspective.Ann Surg. 2002; 235: 466-486Crossref PubMed Scopus (384) Google Scholar, 7Yamamoto J. Okada S. Shimada K. Okusaka T. Yamasaki S. Ueno H. Kosuge T. Treatment strategy for small hepatocellular carcinoma comparison of long-term results after percutaneous ethanol injection therapy and surgical resection.Hepatology. 2001; 34: 707-713Crossref PubMed Scopus (214) Google Scholar In Western countries, surveillance programs have led to an increase in the applicability of radical therapies that nowadays are indicated in 30%–40% of patients.4Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholar These effective options that may allow long-term cure include resection, transplantation, and percutaneous ablation. Numerous noncontrolled studies provide indirect evidence that these treatments enhance survival. Resection and transplantation achieve the best outcomes in well-selected candidates (5-year survival of 60%–70%), and compete as the first option in patients with early tumors from an intention-to-treat perspective.4Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholar, 8Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. Montalto F. Ammatuna M. Morabito A. Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5693) Google Scholar, 9Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma resection versus transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1488) Google Scholar Resection yields good results in the small percentage of candidates who present with single tumors and excellent liver functional reserve. Transplantation is the first choice for patients with small multinodular tumors (3 nodules ≤3 cm) or those with advanced liver dysfunction.8Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. Montalto F. Ammatuna M. Morabito A. Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5693) Google Scholar, 9Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma resection versus transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1488) Google Scholar If surgery is precluded, locoregional therapies are applied. Percutaneous treatments provide good results (5-year survival of 40%–50%), but are unable to achieve response rates and outcomes comparable with those of surgical treatments, even when applied as the first option.4Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholar, 10Arii S. Yamaoka Y. Futagawa S. Inoue K. Kobayashi K. Kojiro M. Makuuchi M. Nakamura Y. Okita K. Yamada R. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas a retrospective and nationwide survey in Japan.Hepatology. 2000; 32: 1224-1229Crossref PubMed Scopus (698) Google Scholar Several therapies have been proposed for patients who cannot benefit from a radical approach. Some of them have been assessed through randomized controlled trials (RCT), but only approximately 70 such robust investigations have been conducted during the last 25 years.11Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2566) Google Scholar In these studies, only chemoembolization has been shown to improve survival in well-selected candidates,12Lin D.Y. Liaw Y.F. Lee T.Y. Lai C.M. Hepatic arterial embolization in patients with unresectable hepatocellular carcinoma—a randomized controlled trial.Gastroenterology. 1988; 94: 453-456Abstract PubMed Google Scholar, 13Pelletier G. Roche A. Ink O. Anciaux M.L. Derhy S. Rougier P. Lenoir C. Attali P. Etienne J.P. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma.J Hepatol. 1990; 11: 181-184Abstract Full Text PDF PubMed Scopus (388) Google Scholar, 14GETCHA comparison of lipiodol chemoembolization in European patients with unresectable hepatocellular carcinoma.N Engl J Med. 1995; 332: 1256-1261Crossref PubMed Scopus (856) Google Scholar, 15Bruix J. Llovet J.M. Castells A. Montana X. Bru C. Ayuso M.C. Vilana R. Rodes J. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma results of a randomized, controlled trial in a single institution.Hepatology. 1998; 27: 1578-1583Crossref PubMed Scopus (510) Google Scholar, 16Pelletier G. Ducreux M. Gay F. Luboinski M. Hagege H. Dao T. Van Steenbergen W. Buffet C. Rougier P. Adler M. Pignon J.P. Roche A. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization a multicenter randomized trial.J Hepatol. 1998; 29: 129-134Abstract Full Text PDF PubMed Scopus (391) Google Scholar, 17Lo C.M. Ngan H. Tso W.K. Liu C.L. Lam C.M. Poon R.T. Fan S.T. Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology. 2002; 35: 1164-1171Crossref PubMed Scopus (2205) Google Scholar, 18Llovet J.M. Real M.I. Montanya X. Planas R. Coll S. Aponte A.J. Ayuso C. Sala M. Muchart J. Solă R. Rodés J. Bruix J. Barcelona-Clínic-Liver Cancer GroupArterial embolization, chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma a randomized controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2878) Google Scholar, 19Kasugai H. Kojima J. Tatsuta M. Okuda S. Sasaki Y. Imaoka S. Fujita M. Ishiguro S. Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intra-arterial infusion of a mixture of cisplatin and ethiodized oil.Gastroenterology. 1989; 97: 965-971PubMed Google Scholar, 20Kawai S. Okamura J. Ogawa M. Ohashi Y. Tani M. Inoue J. Kawarada Y. Kusano M. Kubo Y. Kuroda C. The Cooperative Study Group for Liver Cancer Treatment of Japan. Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison of lipiodol-transcatheter arterial embolization with and without Adriamycin (first cooperative study).Cancer Chemother Pharmacol. 1992; 31: S1-S6Crossref PubMed Scopus (117) Google Scholar, 21Okamura J. Kawai S. Ogawa M. Ohashi Y. Tani M. Inoue J. Kawarada Y. Kusano M. Kubo Y. Kuroda C. The Cooperative Study Group for Liver Cancer Treatment of Japan. Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison of L-TAE with Farmorubicin and L-TAE with Adriamycin (second cooperative study).Cancer Chemother Pharmacol. 1992; 31: S20-S24Crossref PubMed Scopus (20) Google Scholar, 22Kawai S. Tani M. Okamura J. Ogawa M. Ohashi Y. Monden M. Hayashi S. Inoue J. Kawarada Y. Kusano M. Cooperative Study Group for Liver Cancer Treatment of JapanProspective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison between L-TAE with Farmorubicin and L-TAE with Adriamycin preliminary results (second cooperative study).Cancer Chemother Pharmacol. 1994; 33: S97-S102Crossref PubMed Scopus (25) Google Scholar, 23Chang J.M. Tzeng W.S. Pan H.B. Yang C.F. Lai K.H. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. A randomized controlled study.Cancer. 1994; 74 ([published erratum appears in Cancer 1995;75:1218]): 2449-2453Crossref PubMed Scopus (139) Google Scholar, 24Hatanaka Y. Yamashita Y. Takahashi M. Koga Y. Saito R. Nakashima K. Urata J. Miyao M. Unresectable hepatocellular carcinoma analysis of prognostic factors in transcatheter management.Radiology. 1995; 195: 747-752Crossref PubMed Scopus (103) Google Scholar, 25Ikeda K. Saitoh S. Suzuki Y. Koida I. Tsubota A. Kobayashi M. Arase Y. Chayama K. Murashima N. Kumada H. A prospective randomized administration of 5′-deoxy-5-fluorouridine as adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization.Am J Clin Oncol. 1997; 20: 202-208Crossref PubMed Scopus (20) Google Scholar, 26Chen M.S. Li J.Q. Zhang Y.Q. Lu L.X. Zhang W.Z. Yuan Y.F. Guo Y.P. Lin X.J. Li G.H. High-dose iodized oil transcatheter arterial chemoembolization for patients with large hepatocellular carcinoma.World J Gastroenterol. 2002; 8: 74-78PubMed Google Scholar but a recent European RCT showed that only 112 of 903 consecutively evaluated HCC patients were suitable for these treatments, representing 12% of the whole HCC population18Llovet J.M. Real M.I. Montanya X. Planas R. Coll S. Aponte A.J. Ayuso C. Sala M. Muchart J. Solă R. Rodés J. Bruix J. Barcelona-Clínic-Liver Cancer GroupArterial embolization, chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma a randomized controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2878) Google Scholar (Table 1). Other locoregional treatments, such as internal radiation27Raoul J.L. Guyader D. Bretagne J.F. Heautot J.F. Duvauferrier R. Bourguet P. Bekhechi D. Deugnier Y.M. Gosselin M. Prospective randomized trial of chemoembolization versus intra-arterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma.Hepatology. 1997; 26: 1156-1161PubMed Google Scholar and intra-arterial chemotherapy, provide promising results,28Watanabe S. Nishioka M. Ohta Y. Ogawa N. Ito S. Yamamoto Y. Cooperative Study Group for Liver Cancer Treatment in Shikoku areaProspective and randomized controlled study of chemoembolization therapy in patients with advanced hepatocellular carcinoma.Cancer Chemother Pharmacol. 1994; 33: S93-S96PubMed Google Scholar, 29Yoshikawa M. Saisho H. Ebara M. Iijima T. Iwama S. Endo F. Kimura M. Shimamura Y. Suzuki Y. Nakano T. A randomized trial of intrahepatic arterial infusion of 4′-epidoxorubicin with Lipiodol versus 4′-epidoxorubicin alone in the treatment of hepatocellular carcinoma.Cancer Chemother Pharmacol. 1994; 33: S149-S152Crossref PubMed Scopus (64) Google Scholar, 30Kawai S. Tani M. Okamura J. Ogawa M. Ohashi Y. Monden M. Hayashi S. Inoue J. Kawarada Y. Kusano M. Kubo Y. Kuroda C. Sakata Y. Shimamura Y. Jinno K. Takahashi A. Takayasu K. Tamura K. Nagasue N. Nakanishi Y. Makino M. Masuzawa M. Yumoto Y. Mori T. Oda T. The Cooperative Study Group for Liver Cancer Treatment of JapanProspective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma a comparison of epirubicin and doxorubicin (second cooperative study).Semin Oncol. 1997; 24: S6Google Scholar, 31Chung Y.H. Song I.H. Song B.C. Lee G.C. Koh M.S. Yoon H.K. Lee Y.S. Sung K.B. Suh D.J. Combined therapy consisting of intra-arterial cisplatin infusion and systemic interferon-alpha for hepatocellular carcinoma patients with major portal vein thrombosis or distant metastasis.Cancer. 2000; 88: 1986-1991Crossref PubMed Scopus (140) Google Scholar but without any proven impact on survival. Tamoxifen is an ineffective treatment for HCC.11Llovet J.M. Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma chemoembolization improves survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2566) Google Scholar Clinical data assessing new generations of drugs, such as cytostatic agents, new cytotoxic compounds, immunomodulators, or gene therapies, are still scarce.Table 1Patients With HCC Evaluated in a Randomized Controlled Trial Assessing Chemoembolization Versus Embolization Versus Control, July 1996–July 2000All patients N = 903 (%)Patients with early HCC treated by curative therapies310 (34.3) Surgical treatments: resection or liver transplantationaIncluding both cadaveric and living donor liver transplantation.154 Percutaneous treatmentsbIncluding percutaneous ethanol injection and radiofrequency thermal ablation.156Patients at intermediate-advanced stage394 (43.7) Patients included in the study112 (12.4) Patients with exclusion criteria282 Age >75 y68 Advanced liver disease46 Contraindication for embolization/doxorubicin29 Vascular invasion or extrahepatic spread97 Patient's refusal to participate in the study42End-stage tumor disease199 (22)Modified and reprinted with permission.4Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholara Including both cadaveric and living donor liver transplantation.b Including percutaneous ethanol injection and radiofrequency thermal ablation. Open table in a new tab Modified and reprinted with permission.4Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3788) Google Scholar The present review will focus on the analysis of the data assessing arterial embolization and intra-arterial treatments for HCC. This includes 27 RCTs and numerous noncontrolled studies assessing transarterial embolization (TAE), chemoembolization (TACE), lipiodolization, and intra-arterial chemotherapy as a primary treatment of HCC. Progression of HCC is closely linked to neoangiogenic activity.32Nakashima T. Kojiro M. Pathologic characteristics of hepatocellular carcinoma.Semin Liver Dis. 1986; 6: 259-266Crossref PubMed Scopus (122) Google Scholar At very early stages, the tumor is not highly vascularized and receives its blood supply from both the portal vein and the hepatic artery. However, when the neoplasm grows into a more advanced stage (usually measuring more than 2 cm in diameter), the blood supply is mostly dependent on the hepatic artery.32Nakashima T. Kojiro M. Pathologic characteristics of hepatocellular carcinoma.Semin Liver Dis. 1986; 6: 259-266Crossref PubMed Scopus (122) Google Scholar Large HCCs receive their main blood supply almost entirely through the hepatic artery. This specific arterial vascular profile provides the basis for the development of arterial obstruction as an effective therapy. Acute arterial obstruction results in ischemic tumor necrosis with a high rate of objective responses. The techniques and agents used to treat HCC by intra-arterial means are very heterogeneous. This hinders adequate analyses and interpretation of the results of clinical trials as well as the ability to conduct meta-analyses, highlighting the need for a common definition of the procedures performed. At least 3 groups of procedures should be considered. These are first, procedures aimed at achieving arterial occlusion, such as arterial embolization or chemoembolization; second, procedures aimed at delivering nonocclusive antitumoral substances, such as arterial chemotherapy or lipiodolization (Table 2); and finally, procedures aimed at delivering internal radiation (iodine131, yttrium90), which should be considered separately.Table 2Intra-arterial Treatments for Hepatocellular Carcinoma Assessed in the Setting of 27 Randomized Controlled Trials (1978–2002)Vascular occlusion (agents used)Chemotherapy (agents used)Objective response rateRCTArterial embolization/chemoembolization15%–55%17 (7)aRCT comparing active treatment versus conservative management or suboptimal therapies.Arterial embolizationYes Gelatin spongeNo Polyvinyl alcohol Coils Blood clotChemoembolizationYes Gelatin spongeYes—Lipiodol + doxorubicin, cisplatin, epirubicin Polyvinyl alcoholArterial chemotherapy12%–42%10 (1)aRCT comparing active treatment versus conservative management or suboptimal therapies.LipiodolizationNoYes—Lipiodol + doxorubicin, cisplatin, epirubicin ADMOS + cisplatin, epidoxorubicin Epirubicin + mitomycinIntra-arterial chemotherapyNoYes—Cisplatin Epidoxorubicin + 5FU Doxorubicin, cisplatinADMOS, Adriamycin/mitomycin C oil suspension.a RCT comparing active treatment versus conservative management or suboptimal therapies. Open table in a new tab ADMOS, Adriamycin/mitomycin C oil suspension. Arterial embolization, which leads to the occlusion of arterial flow, is also referred to as TAE, transcatheter arterial embolization, hepatic arterial embolization, hepatic arterial obstruction, or intra-arterial embolization. The hepatic artery blood flow may be obstructed by compressing the vessel from the outside or by placing an obstructing agent inside the vascular lumen. The first approach, surgical ligation of the hepatic artery, was performed years ago but was abandoned because of the high rate of severe side effects, including death.33Balasegaram M. Complete hepatic dearterialization for primary carcinoma of the liver. Report of twenty-four patients.Am J Surg. 1972; 124: 340-345Abstract Full Text PDF PubMed Scopus (64) Google Scholar In fact, surgical ligation was frequently performed to control peritoneal bleeding caused by rupture of the HCC, but the same therapeutic effect might be achieved by TAE.34Sato Y. Fujiwara K. Furui S. Ogata I. Oka Y. Hayashi S. Ohta Y. Iio M. Oka H. Benefit of transcatheter arterial embolization for ruptured hepatocellular carcinoma complicating liver cirrhosis.Gastroenterology. 1985; 89: 157-159PubMed Google Scholar The internal obstruction of the hepatic artery may be achieved by the injection or intra-arterial placement of several agents: metallic coils, Gelfoam (cubes or powder), polyvinyl alcohol, starch microspheres, or even autologous blood clots.12Lin D.Y. Liaw Y.F. Lee T.Y. Lai C.M. Hepatic arterial embolization in patients with unresectable hepatocellular carcinoma—a randomized controlled trial.Gastroenterology. 1988; 94: 453-456Abstract PubMed Google Scholar, 13Pelletier G. Roche A. Ink O. Anciaux M.L. Derhy S. Rougier P. Lenoir C. Attali P. Etienne J.P. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma.J Hepatol. 1990; 11: 181-184Abstract Full Text PDF PubMed Scopus (388) Google Scholar, 14GETCHA comparison of lipiodol chemoembolization in European patients with unresectable hepatocellular carcinoma.N Engl J Med. 1995; 332: 1256-1261Crossref PubMed Scopus (856) Google Scholar, 15Bruix J. Llovet J.M. Castells A. Montana X. Bru C. Ayuso M.C. Vilana R. Rodes J. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma results of a randomized, controlled trial in a single institution.Hepatology. 1998; 27: 1578-1583Crossref PubMed Scopus (510) Google Scholar, 16Pelletier G. Ducreux M. Gay F. Luboinski M. Hagege H. Dao T. Van Steenbergen W. Buffet C. Rougier P. Adler M. Pignon J.P. Roche A. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization a multicenter randomized trial.J Hepatol. 1998; 29: 129-134Abstract Full Text PDF PubMed Scopus (391) Google Scholar, 17Lo C.M. Ngan H. Tso W.K. Liu C.L. Lam C.M. Poon R.T. Fan S.T. Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma.Hepatology. 2002; 35: 1164-1171Crossref PubMed Scopus (2205) Google Scholar, 18Llovet J.M. Real M.I. Montanya X. Planas R. Coll S. Aponte A.J. Ayuso C. Sala M. Muchart J. Solă R. Rodés J. Bruix J. Barcelona-Clínic-Liver Cancer GroupArterial embolization, chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma a randomized controlled trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2878) Google Scholar, 19Kasugai H. Kojima J. Tatsuta M. Okuda S. Sasaki Y. Imaoka S. Fujita M. Ishiguro S. Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intra-arterial infusion of a mixture of cisplatin and ethiodized oil.Gastroenterology. 1989; 97: 965-971PubMed Google Scholar, 20Kawai S. Okamura J. Ogawa M. Ohashi Y. Tani M. Inoue J. Kawarada Y. Kusano M. Kubo Y. Kuroda C. The Cooperative Study Group for Liver Cancer Treatment of Japan. Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison of lipiodol-transcatheter arterial embolization with and without Adriamycin (first cooperative study).Cancer Chemother Pharmacol. 1992; 31: S1-S6Crossref PubMed Scopus (117) Google Scholar, 21Okamura J. Kawai S. Ogawa M. Ohashi Y. Tani M. Inoue J. Kawarada Y. Kusano M. Kubo Y. Kuroda C. The Cooperative Study Group for Liver Cancer Treatment of Japan. Prospective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison of L-TAE with Farmorubicin and L-TAE with Adriamycin (second cooperative study).Cancer Chemother Pharmacol. 1992; 31: S20-S24Crossref PubMed Scopus (20) Google Scholar, 22Kawai S. Tani M. Okamura J. Ogawa M. Ohashi Y. Monden M. Hayashi S. Inoue J. Kawarada Y. Kusano M. Cooperative Study Group for Liver Cancer Treatment of JapanProspective and randomized clinical trial for the treatment of hepatocellular carcinoma—a comparison between L-TAE with Farmorubicin and L-TAE with Adriamycin preliminary results (second cooperative study).Cancer Chemother Pharmacol. 1994; 33: S97-S102Crossref PubMed Scopus (25) Google Scholar, 23Chang J.M. Tzeng W.S. Pan H.B. Yang C.F. Lai K.H. Transcatheter arterial embolization with or without cisplatin treatment of hepatocellular carcinoma. A randomized controlled study.Cancer. 1994; 74 ([published erratum appears in Cancer 1995;75:1218]): 2449-2453Crossref PubMed Scopus (139) Google Scholar, 24Hatanaka Y. Yamashita Y. Takahashi M. Koga Y. Saito R. Nakashima K. Urata J. Miyao M. Unresectable hepatocellular carcinoma analysis of prognostic factors in transcatheter management.Radiology. 1995; 195: 747-752Crossref PubMed Scopus (103) Google Scholar, 25Ikeda K. Saitoh S. Suzuki Y. Koida I. Tsubota A. Kobayashi M. Arase Y. Chayama K. Murashima N. Kumada H. A prospective randomized administration of 5′-deoxy-5-fluorouridine as adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization.Am J Clin Oncol. 1997; 20: 202-208Crossref PubMed Scopus (20) Google Scholar, 26Chen M.S. Li J.Q. Zhang Y.Q. Lu L.X. Zhang W.Z. Yuan Y.F. Guo Y.P. Lin X.J. Li G.H. High-dose iodized oil transcatheter arterial chemoembolization for patients with large hepatocellular carcinoma.World J Gastroenterol. 2002; 8: 74-78PubMed Google Scholar, 36Chuang V.P. Wallace S. Soo C.S. Charnsangavej C. Bowers T. Therapeutic Ivalon embolization of hepatic tumors.AJR Am J Roentgenol. 1982; 138: 289-294Crossref PubMed Scopus (64) Google Scholar, 37Ito K. Kusunoki H. Okamoto E. Ozawa M. Ishikawa A. Matsuura M. Nakajima N. Intra-arterial alcoholization of advanced hepatocellular carcinoma.Cancer Chemother Pharmacol. 1994; 33: 42-47Crossref Scopus (22) Google Scholar, 38Carr B.I. Zajko A. Bron K. Orons P. Sammon J. Baron R. Phase II study of Spherex (degradable starch microspheres) injected into the hepatic artery in conjunction with doxorubicin and cisplatin in the treatment of advanced-stage hepatocellular carcinoma interim analysis.Semin Oncol. 1997; 24: S6PubMed Google Scholar, 39Bruix J. Castells A. Montanya X. Calvet X. Bru C. Ayuso C. Jover L. Garcia L. Vilana R. Boix L. Phase II study of transarterial embolization in European patients with hepatocellular carcinoma need for controlled trials.Hepatology. 1994; 20: 643-650Crossref PubMed Scopus (88) Google Scholar Most investigators use gelatin sponge prepared as 1-mm cubes. Gelfoam powder was used to achieve a more distal embolization, but this has been associated with biliary strictures, and thus should be avoided.35Makuuchi M. Sukigara M. Mori T. Kobayashi J. Yamazaki S. Hasegawa H. Moriyama N. Takayasu K. Hirohashi S. Bile duct necrosis complication of transcatheter hepatic arterial embolization.Radiology. 1985; 156: 331-334PubMed Google Scholar Polyvinyl alcohol (Ivalon) achieves a more distal obstruction and may be used to embolize small vessels or even collaterals that have been formed after repeated embolization with other agents. Starch microspheres induce a transient obstruction of the hepatic artery branches because they are degraded in a short period of time. However, their antitumoral effect is less intense. Nowadays, the use of metallic coils has been almost abandoned. The injection of autologous blood clots has been scarcely used, but it has been reported to achieve almost the same effects as with a gelatin sponge. Chemoembolization refers to the same process preceded by the administration of chemotherapeutic agents, usually mixed with lipiodol as a vehicle. This procedure refers to those named TACE or intra-arterial chemoembolization. Chemotherapy agents must be injected before arterial obstruction. Attempting to increase the selective delivery of chemotherapy into the tumor, it is very common to suspend the antineoplastic agent in lipiodol, an oily contrast agent used for lymphographic studies. This contrast is selectively retained within the tumor,