Neue chirurgische Ansätze beim hepatozellulären Karzinom

 

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Zusammenfassung

In den letzten Jahren hat sich die Behandlung des hepatozellulären Karzinoms (HCC) signifikant gewandelt. Die Einführung von sonografischen Screeningprogrammen für Patienten mit Leberzirrhose führt zunehmend zur Diagnose von HCC im Frühstadium. Die Leberresektion und Lebertransplantation stellen potenziell kurative Behandlungsoptionen dar. Sie können jedoch nur bei einer limitierten Anzahl von Patienten angewandt werden. Die Indikation zur Leberresektion besteht bei Patienten mit kleinem HCC und ohne Zirrhose. In Ausnahmefällen kann auch eine Resektion eines HCC in einer zirrhotischen Leber erfolgen, falls die Möglichkeit zur Lebertransplantation nicht gegeben ist. Die Lebertransplantation ist Methode der Wahl bei Patienten mit Zirrhose und einer Tumorgröße innerhalb der Milan-Kriterien. Der Mangel an Spenderorganen sowie die daraus resultierende Zeit auf der Warteliste sind prognoselimitierende Faktoren. Die transarterielle Chemoembolisation (TACE) und die Radiofrequenzablation (RFA) bieten die Möglichkeit einer lokalen Tumorkontrolle beim fortgeschrittenen HCC und werden zunehmend intraoperativ in Ergänzung zur Leberresektion eingesetzt. Das Langzeitüberleben wird signifikant durch das Auftreten von Lokalrezidiven oder Fernmetastasen eingeschränkt. Die Anwendung des Multikinase-Inhibitors Sorafenib in der (neo-)adjuvanten Situation wird gegenwärtig in prospektiven Studien untersucht.

Abstract

New advances in the treatment of HCC have emerged in recent years. The implementation of surveillance programmes has led to better diagnosis of HCC at early stages. Liver resection and liver transplantation remain the only potentially curative treatment options that can be applied in a limited number of patients resulting in 5-year survival rates as high as 75 – 80 %. Resection is indicated in patients with limited disease and absence of cirrhosis. Liver transplantation is beneficial in patients with cirrhosis and tumour size according to the Milan criteria. Organ donor shortage and the consequently long waiting time limits its applicability. TACE and radiofrequency ablation provide local tumour control in unresectable HCC and are increasingly used in addition to tumour resection. The major drawback of all treatments is the risk for local tumour recurrence or tumour progress during the waiting time for transplantation. The application of sorafenib in the (neo-)adjuvant situation is being tested in clinical trials.

Literatur

• 1 El-Serag H B. Hepatocellular carcinoma and hepatitis C in the United States.  Hepatology. 2002;  36 S74-S83
  Google Scholar
• 2 Bruix J, Sherman M, Llovet J M. 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
• 3 Llovet J M, Bruix J. Hepatocellular carcinoma.  The Lancet. 2003;  362 1907-1917
  Google Scholar
• 4 Frilling A, Fruhauf N, Sotiropoulos G C. et al . Surgical therapy of hepatocellular carcinoma.  Zentralbl Chir. 2003;  128 900-905
  Google Scholar
• 5 Llovet J M, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008.  J Hepatol. 2008;  48 (Suppl 1) S20-S37
  Google Scholar
• 6 Kojiro M. Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view.  Liver Transpl. 2004;  10 S3-S8
  Google Scholar
• 7 Bruix J, Sherman M. Management of hepatocellular carcinoma.  Hepatology. 2005;  42 1208-1236
  Google Scholar
• 8 Forner A, Vilana R, Ayuso C. et al . Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma.  Hepatology. 2008;  47 97-104
  Google Scholar
• 9 McMahon B J, Bulkow L, Harpster A. et al . Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study.  Hepatology. 2000;  32 842-846
  Google Scholar
• 10 Llovet J M, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification.  Semin Liver Dis. 1999;  19 329-338
  Google Scholar
• 11 Llovet J M, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival.  Hepatology. 2003;  37 429-442
  Google Scholar
• 12 Llovet J M, Ricci S, Mazzaferro V. et al . Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a phase III randomized placebocontrolled trial.  J Clin Oncol. 2007;  25 LBA1
  Google Scholar
• 13 Llovet J M, Ricci S, Mazzaferro V. et al . Sorafenib in advanced hepatocellular carcinoma.  N Engl J Med. 2008;  359 378-390
  Google Scholar
• 14 Llovet J M, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma.  Semin Liver Dis. 2005;  25 181-200
  Google Scholar
• 15 Belghiti J, Hiramatsu K, Benoist S. et al . Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection.  J Am Coll Surg. 2000;  191 38-46
  Google Scholar
• 16 Bismuth H, Majno P E. Hepatobiliary surgery.  J Hepatol. 2000;  32 208-224
  Google Scholar
• 17 Marin-Hargreaves G, Azoulay D, Bismuth H. Hepatocellular carcinoma: surgical indications and results.  Crit Rev Oncol Hematol. 2003;  47 13-27
  Google Scholar
• 18 Makuuchi M, Sano K. The surgical approach to HCC: our progress and results in Japan.  Liver Transpl. 2004;  10 S46-S52
  Google Scholar
• 19 Makuuchi M, Sano K. The surgical approach to HCC: our progress and results in Japan.  Liver Transpl. 2004;  10 S46-S52
  Google Scholar
• 20 Ikai I, Arii S, Kojiro M. et al . Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey.  Cancer. 2004;  101 796-802
  Google Scholar
• 21 Hoshida Y, Villanueva A, Kobayashi M. et al . Gene expression in fixed tissues and outcome in hepatocellular carcinoma.  N Engl J Med. 2008;  359 1995-2004
  Google Scholar
• 22 Matikainen S, Sareneva T, Ronni T. et al . Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells.  Blood. 1999;  93 1980-1991
  Google Scholar
• 23 Torzilli G, Olivari N, Moroni E. et al . Contrast-enhanced intraoperative ultrasonography in surgery for hepatocellular carcinoma in cirrhosis.  Liver Transpl. 2004;  10 S34-S38
  Google Scholar
• 24 Murakami T, Mochizuki K, Nakamura H. Imaging evaluation of the cirrhotic liver.  Semin Liver Dis. 2001;  21 213-224
  Google Scholar
• 25 Bruix J, Castells A, Bosch J. et al . Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure.  Gastroenterology. 1996;  111 1018-1022
  Google Scholar
• 26 Zhou X D, Tang Z Y, Yang B H. et al . Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma.  Cancer. 2001;  91 1479-1486
  Google Scholar
• 27 Poon R T, Fan S T, Lo C M. et al . Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation.  Ann Surg. 2002;  235 373-382
  Google Scholar
• 28 Belghiti J, Panis Y, Farges O. et al . Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis.  Ann Surg. 1991;  214 114-117
  Google Scholar
• 29 Imamura H, Matsuyama Y, Tanaka E. et al . Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.  J Hepatol. 2003;  38 200-207
  Google Scholar
• 30 Kumada T, Nakano S, Takeda I. et al . Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma.  Hepatology. 1997;  25 87-92
  Google Scholar
• 31 Yamamoto M, Arii S, Sugahara K. et al . Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma.  Br J Surg. 1996;  83 336-340
  Google Scholar
• 32 Yamasaki S, Hasegawa H, Kinoshita H. et al . A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma.  Jpn J Cancer Res. 1996;  87 206-211
  Google Scholar
• 33 Mazzaferro V, Romito R, Schiavo M. et al . Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis.  Hepatology. 2006;  44 1543-1554
  Google Scholar
• 34 Lau W Y, Leung T W, Ho S K. et al . Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial.  Lancet. 1999;  353 797-801
  Google Scholar
• 35 Llovet J M, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.  Hepatology. 1999;  30 1434-1440
  Google Scholar
• 36 Mazzaferro V, Regalia E, Dogia R. et al . Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.  N Engl J Med. 1996;  334 693-699
  Google Scholar
• 37 Sala M, Llovet J M, Vilana R. et al . Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.  Hepatology. 2004;  40 1352-1360
  Google Scholar
• 38 Figueras J, Ibanez L, Ramos E. et al . Selection criteria for liver transplantation in early-stage hepatocellular carcinoma with cirrhosis: results of a multicenter study.  Liver Transpl. 2001;  7 877-883
  Google Scholar
• 39 Mazzaferro V, Battiston C, Perrone S. et al . Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study.  Ann Surg. 2004;  240 900-909
  Google Scholar
• 40 Graziadei I W, Sandmueller H, Waldenberger P. et al . Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome.  Liver Transplantation. 2003;  9 557-563
  Google Scholar
• 41 Maddala Y K, Stadheim L, Andrews J C. et al . Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization.  Liver Transpl. 2004;  10 449-455
  Google Scholar
• 42 Otto G, Heise M, Moench C. et al . Transarterial chemoembolization before liver transplantation in 60 patients with hepatocellular carcinoma.  Transplant Proc. 2007;  39 537-539
  Google Scholar
• 43 Majno P E, Adam R, Bismuth H. et al . Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis.  Annals of Surgery. 1997;  226 688-701
  Google Scholar
• 44 Decaens T, Roudot-Thoraval F, Bresson-Hadni S. et al . Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.  Liver Transpl. 2005;  11 767-775
  Google Scholar
• 45 Porrett P M, Peterman H, Rosen M. et al . Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular cancer in the current MELD era.  Liver Transpl. 2006;  12 665-673
  Google Scholar
• 46 Yao F Y, Hirose R, LaBerge J M. et al . A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation.  Liver Transpl. 2005;  11 1505-1514
  Google Scholar
• 47 Yao F Y, Ferrell L, Bass N M. et al . Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.  Hepatology. 2001;  33 1394-1403
  Google Scholar
• 48 Hoffmann K, Glimm H, Radeleff B. et al . Prospective, randomized, double-blind, multi-center, Phase III clinical study on transarterial chemoembolization (TACE) combined with Sorafenib® versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation – HeiLivCa (ISRCTN24081794).  BMC Cancer. 2008;  8 349
  Google Scholar
• 49 Kaihara S, Kiuchi T, Ueda M. et al . Living-donor liver transplantation for hepatocellular carcinoma.  Transplantation. 2003;  75 S37-S40
  Google Scholar
• 50 Kaihara S, Kiuchi T, Ueda M. et al . Living-donor liver transplantation for hepatocellular carcinoma.  Transplantation. 2003;  75 S37-S40
  Google Scholar
• 51 Lo C M, Fan S T, Liu C L. et al . The role and limitation of living donor liver transplantation for hepatocellular carcinoma.  Liver Transpl. 2004;  10 440-447
  Google Scholar
• 52 Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan.  Ann Surg. 2004;  240 451-459
  Google Scholar
• 53 Sotiropoulos G C, Lang H, Sgourakis G. et al . Liberal Policy in Living Donor Liver Transplantation for Hepatocellular Carcinoma: Lessons Learned.  Dig Dis Sci. 2008;  epub ahead of print
  Google Scholar
• 54 Mehrabi A, Fonouni H, Müller S A. et al . Current concepts in transplant surgery: liver transplantation today.  Langenbecks Arch Surg. 2008;  393 245-260
  Google Scholar
• 55 Schmied B M, Mehrabi A, Schallert C. et al . Evolution of liver transplantation at the University of Heidelberg:interventions influencing the patient referal.  Transplantation. 2005;  80 147-150
  Google Scholar
• 56 Choi D, Lim H K, Joh J W. et al . Combined hepatectomy and radiofrequency ablation for multifocal hepatocellular carcinomas: long-term follow-up results and prognostic factors.  Ann Surg Oncol. 2007;  14 3510-3518
  Google Scholar
• 57 Livraghi T, Meloni F, Stasi di M. et al . Sustained complete response and complication rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still treatment of choice.  Hepatology. 2008;  47 82-89
  Google Scholar
• 58 Scaife C L, Ng C S, Ellis L M. et al . Accuracy of preoperative imaging of hepatic tumors with helical computed tomography.  Ann Surg Oncol. 2006;  13 542-546
  Google Scholar
• 59 Kim Y S, Rhim H, Lim H K. et al . Intraoperative radiofrequency ablation for hepatocellular carcinoma: long-term results in a large series.  Ann Surg Oncol. 2008;  15 1862-1870
  Google Scholar
• 60 Philip P A, Mahoney M R, Allmer C. et al . Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer.  J Clin Oncol. 2005;  23 6657-6663
  Google Scholar
• 61 Wilhelm S M, Carter C, Tang L. et al . BAY 43 – 9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.  Cancer Res. 2004;  64 7099-7109
  Google Scholar

Prof. Dr. J. Schmidt

Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Ruprecht-Karls-Universität

Im Neuenheimer Feld 110

69120 Heidelberg

Email: jan.schmidt@med.uni-heidelberg.de