Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Meta-Analysis of Randomized Controlled Trials

PURPOSE: To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC).

MATERIALS AND METHODS: Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 were supplemented with manual searches, with the keywords “hepatocellular carcinoma,” “liver cell carcinoma,” “randomized controlled trial [RCT],” and “chemoembolization.” Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta–regression analysis.

RESULTS: Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; P = .015) compared with nonactive treatment. Analysis of comparative RCTs helped to predict that overall mortality was significantly lower in patients treated with transarterial embolization (TAE) than in those treated with transarterial chemotherapy (odds ratio, 0.72; 95% CI: 0.53, 0.98; P = .039) and that there is no evidence that transarterial chemoembolization is more effective than TAE (odds ratio, 1.007; 95% CI: 0.79, 1.27; P = .95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit.

CONCLUSION: In patients with unresectable HCC, chemoembolization significantly improved the overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.

© RSNA, 2002

References

  • 1 El-Serang HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:745-750. Crossref, MedlineGoogle Scholar
  • 2 Yuen MF, Cheng CC, Lauder IJ, Lam SK, Ooi CG, Lai Cl. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience. Hepatology 2000; 31:330-335. Crossref, MedlineGoogle Scholar
  • 3 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30:1434-1440. Crossref, MedlineGoogle Scholar
  • 4 Mathurin P, Rixe O, Carbonell N, et al. Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta-analysis? Aliment Pharmacol Ther 1998; 12:111-126. CrossrefGoogle Scholar
  • 5 Koda M, Murawaki Y, Kawasaki H. The combination therapy of transcatheter arterial embolization and percutaneous ethanol injection for small hepatocellular carcinoma: randomized controlled study (abstr). J Hepatol 2000; 32:164. Crossref, MedlineGoogle Scholar
  • 6 Lai E, Choi TK, Tong SW, Ong GB, Wong J. Treatment on unresectable hepatocellular carcinoma: results of a randomized controlled trial. World J Surg 1986; 10:501-509. Crossref, MedlineGoogle Scholar
  • 7 Lin DY, Liaw YF, Lee TY, Lai CM. Hepatic arterial embolization in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Gastroenterology 1988; 94:453-456. Crossref, MedlineGoogle Scholar
  • 8 Pelletier G, Roche A, Ink O, et al. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatol 1990; 11:181-184. Crossref, MedlineGoogle Scholar
  • 9 Madden MV, Krige JEJ, Bailey S, et al. Randomised trial of targeted chemotherapy with lipiodol and 5-epidoxorubicin compared with symptomatic treatment for hepatoma. Gut 1993; 34:1598-1600. Crossref, MedlineGoogle Scholar
  • 10 Raoul JL, Guyader D, Bretagne JF, et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med 1994; 35:1782-1787. MedlineGoogle Scholar
  • 11 Lu C, Qi Y, Peng S. Lipiodolization with or without gelatin sponge in hepatic chemoembolization for hepatocellular carcinoma. Chin Med J (Engl) 1994; 107:209-215. MedlineGoogle Scholar
  • 12 Groupe d’Étude et de Traitment du Carcinome Hépatocellulaire. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 1995; 332:1256-1261. Crossref, MedlineGoogle Scholar
  • 13 Pelletier G, Ducreux M, Gay F, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. J Hepatol 1998; 29:129-134. Crossref, MedlineGoogle Scholar
  • 14 Bruix J, Llovet JM, Castells A, et al. 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- 1583. Crossref, MedlineGoogle Scholar
  • 15 Kasugai H, Kojima J, Tatsuta M, et al. Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil. Gastroenterology 1989; 97:965-971. Crossref, MedlineGoogle Scholar
  • 16 Osaka Study Group on Hepatocellular Carcinoma. Studies on the chemotherapy with 5-fluorouracil in transcatheter chemoembolization (TAE) treated patients with resectable on non-resectable hepatocellular carcinoma. Cancer Chemother Pharmacol 1989; 23(suppl):S29-S32. Crossref, MedlineGoogle Scholar
  • 17 Kawai S, Okamura J, Ogawa M, et al. 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(suppl 1):S1-S6. Crossref, MedlineGoogle Scholar
  • 18 Okamura J, Kawai S, Ogawa M, et al. 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(suppl 1):S20-S24. Crossref, MedlineGoogle Scholar
  • 19 Ikeda K, Inoue H, Yano T, Kobayashi H, Nakajo M. Comparison of the anticancer effect ADMOS alone and ADMOS with CDDP in the treatment of hepatocellular carcinoma by intra-arterial injection. Cancer Chemother Pharmacol 1992; 31(suppl 1):S65-S68. Crossref, MedlineGoogle Scholar
  • 20 Yoshikawa M, Saisho H, Ebara M, et al. 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(suppl):S149-S152. Crossref, MedlineGoogle Scholar
  • 21 Kawai S, Tani M, Okamura J, et al. Prospective 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(suppl):S97-S102. Crossref, MedlineGoogle Scholar
  • 22 Watanabe S, Nishioka M, Ohta Y, Ogawa N, Ito S, Yamamoto Y. Prospective and randomized controlled study of chemoembolization therapy in patients with advanced hepatocellular carcinoma. Cooperative Study Group for Liver Cancer Treatment in Shikoku area. Cancer Chemother Pharmacol 1994; 33(suppl):S93-S96. Google Scholar
  • 23 Chang JM, Tzeng WS, Pan HB, Yang FC, Lai KH. Transcatheter arterial embolization with or without Cisplatin treatment of hepatocellular carcinoma. Cancer 1994; 74:2449-2453. Crossref, MedlineGoogle Scholar
  • 24 Ikeda K, Saitoh S, Koida I, et al. A prospective randomized evaluation of a compound of Tegafur and Uracil as an adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Am J Clin Oncol 1995; 18:204-210. Crossref, MedlineGoogle Scholar
  • 25 Hatanaka Y, Yamashita Y, Takahashi M, et al. Unresectable hepatocellular carcinoma: analysis of prognostic factors in transcatheter management. Radiology 1995; 195:747-752. LinkGoogle Scholar
  • 26 Bhattacharya S, Novell JR, Dusheiko GM, Hilson AJ, Dick R, Hobbs KE. Epirubicin-lipiodol chemotherapy versus 131iodine-lipiodol radiotherapy in the treatment of unresectable hepatocellular carcinoma. Cancer 1995; 76:2202-2210. Crossref, MedlineGoogle Scholar
  • 27 Bartolozzi C, Lencioni R, Caramella D, et al. Treatment of large HCC: transcatheter arterial chemoembolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization. Radiology 1995; 197:812- 818. LinkGoogle Scholar
  • 28 Kawai S, Tani M, Okamura J, et al. Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a comparison of epirubicin and doxorubicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan. Semin Oncol 1997; 24(suppl 6):38-45. Google Scholar
  • 29 Raoul JL, Guyader D, Bretagne JF, et al. Prospective randomized trial of chemoembolization versus intraarterial injection of 131I-labeled-iodized oil in the treatment of hepatocellular carcinoma. Hepatology 1997; 26:1156-1161. MedlineGoogle Scholar
  • 30 Ikeda K, Saitoh S, Suzuki Y, et al. 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; 20:202-208. Crossref, MedlineGoogle Scholar
  • 31 Kwok PC, Lam TW, Chan SC, et al. A randomized clinical trial comparing autologous blood clot and gelfoam in transarterial chemoembolization for inoperable hepatocellular carcinoma. J Hepatol 2000; 32:955-964. Crossref, MedlineGoogle Scholar
  • 32 Izumi R, Shimizu K, Iyobe T, et al. Postoperative adjuvant hepatic arterial infusion of lipiodol containing anticancer drugs in patients with hepatocellular carcinoma. Hepatology 1994; 20:295-301. Crossref, MedlineGoogle Scholar
  • 33 Wu CC, Ho YZ, Ho WL, Wu TC, Liu TJ, P’eng FK. Preoperative transcatheter arterial chemoembolization for resectable large hepatocellular carcinoma: a reappraisal. Br J Surg 1995; 82:122-126. Crossref, MedlineGoogle Scholar
  • 34 Lygidakis NJ, Potoulakis J, Konstantinidou AE, Spanos H. Hepatocellular carcinoma: surgical resection versus surgical resection combined with pre and post operative locoregional immunotherapy-chemotherapy—a prospective randomized study. Anticancer Res 1995; 15:543-550. MedlineGoogle Scholar
  • 35 Kawata A, Une Y, Hosokawa M, et al. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients: adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. Am J Clin Oncol 1995; 18:257-262. Crossref, MedlineGoogle Scholar
  • 36 Matsuda Y, Kawata S, Nagase T, et al. Interleukin-6 in transcatheter embolization for patients with hepatocellular carcinoma. Cancer 1994; 73:53-57. Crossref, MedlineGoogle Scholar
  • 37 Kajanti M, Pyrhonen S, Mantyla M, Rissanen P. Intra-arterial and intravenous use of 4′ epidoxorubicin combined with 5-fluorouracil in primary hepatocellular carcinoma: a randomized comparison. Am J Clin Oncol 1992; 15:37-40. Crossref, MedlineGoogle Scholar
  • 38 Yamashita Y, Takahashi M, Koga Y, et al. Prognostic factors in the treatment of hepatocellular carcinoma with transcatheter arterial embolization and arterial infusion. Cancer 1991; 67:385-391. Crossref, MedlineGoogle Scholar
  • 39 Rougier P, Pelletier G, Ducreux M, et al. Unresectable hepatocellular carcinoma: lack of efficacy of lipiodol chemoembolization—final results of a multicenter randomized trial (abstr). Proc Am Soc Clin Oncol 1997; 16:279A. Google Scholar
  • 40 Pelletier G, Ducreux M, Broseta V, et al. Essai randomisé de la chimioembolisation lipiodolée dans le traitement du carcinome hépatocellulaire (CHC) non résectable (abstr). Gastroenterol Clin Biol 1996; 20:182A. Google Scholar
  • 41 Bourguet P, Raoul JL, Guyader D. Randomised controlled trial of chemo-embolization vs intra-arterial injection of 131 I-labelled iodized oil (Lipiocis) in the treatment of hepatocellular carcinoma (abstr). Eur J Nucl Med 1994; 21:S52. Google Scholar
  • 42 Bruix J, Llovet JM, Castells A, et al. Treatment of hepatocellular carcinoma by transarterial embolization (TAE): a prospective placebo controlled trial (abstr). Hepatology 1997; 26:249A. Google Scholar
  • 43 Llovet JM, Real MI, Vilana R, et al. Chemoembolization improves survival in patients with unresectable hepatocellular carcinoma (abstr). J Hepatol 2001; 34:11A. Crossref, MedlineGoogle Scholar
  • 44 Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35:421-430. Google Scholar
  • 45 Lau J, Ioannidis JPA, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127:820-826. Crossref, MedlineGoogle Scholar
  • 46 Nicolucci A, Grilli R, Alexanian AA, Apolone G, Torri W, Liberati A. Quality evolution and clinical implications of randomized, controlled trials on the treatment of lung cancer: a lost opportunity for meta-analysis. JAMA 1989; 262:2101-2107. Crossref, MedlineGoogle Scholar
  • 47 Jüni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999; 282:1054-1060. Crossref, MedlineGoogle Scholar
  • 48 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177-188. Crossref, MedlineGoogle Scholar
  • 49 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22:719-748. MedlineGoogle Scholar
  • 50 Normand SL. Tutorial in biostatistics meta-analysis: formulating, evaluating, combining, and reporting. Stat Med 1999; 18:321-359. Crossref, MedlineGoogle Scholar
  • 51 Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999; 18:2693-2708. Crossref, MedlineGoogle Scholar
  • 52 Yamashita Y, Torashima M, Oguni T, et al. Liver parenchymal changes after transcatheter arterial embolization therapy for hepatoma: CT evaluation. Abdom Imaging 1993; 18:352-356. Crossref, MedlineGoogle Scholar
  • 53 Stuart K, Stokes K, Jenkins R, Trey C, Clouse M. Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oil/gelatin powder chemoembolization. Cancer 1993; 72:3202-3209. Crossref, MedlineGoogle Scholar
  • 54 Ernst O, Sergent G, Mizrahi D, Delemazure O, Paris JC, L’Hermine C. Treatment of hepatocellular carcinoma by transcatheter arterial chemoembolization: comparison of planned periodic chemoembolization and chemoembolization based on tumor response. AJR Am J Roentgenol 1999; 172:59-64. Crossref, MedlineGoogle Scholar

Article History

Published in print: July 2002