Behandlungsstrategien bei Intermediate-Stage-HCC

Einleitung

Das HCC (Leberzellkarzinom) ist die 6.-häufigste Krebsart und die 3.-häufigste Ursache der durch eine Krebserkrankung bedingten Sterblichkeit in der Welt [1]. Trotz der weit verbreiteten Screening-Programme wird mehr als die Hälfte der HCC erst in späten Stadien diagnostiziert, wenn eine potenziell kurative Therapie (Resektion oder Lebertransplantation) nicht mehr angeboten werden kann [2]. Für Patienten mit einem inoperablen, nicht durch Transplantation therapierbaren HCC und einer relativ gut erhaltenen Leberfunktion (intermediäres HCC) stellen die lokoregionären, transarteriellen Behandlungsmethoden die wichtigsten therapeutischen Optionen dar. Die beiden bedeutendsten europäischen Leitlinien zum HCC, die EASL-EORTC- (European Association for the Study of the Liver und European Organisation for Research and Treatment of Cancer) und die ESMO-ESDO-Leitlinie (European Society for medical Oncology und European Society of digestive Oncology), empfehlen für intermediäre HCC gemäß der Klassifikation der BCLC (Barcelona Clinic of Liver Cancer) die TACE (transarterielle Chemoembolisation; Abb. [1]). Auch die AASLD (American Association for the Study of Liver Diseases) empfiehlt bei BCLC-B-Patienten mit einem Performance-Status 0 und einer multinodulären Erkrankung ein transarterielles Vorgehen.

Abb. 1 Therapieempfehlungen bei HCC in Abhängigkeit vom Tumorstadium. Schematische Darstellung. a EASL-EORTC-Leitlinie [3]. b ESMO-Leitlinie [4]. BSC = Best supportive Care; OS = Overall Survival; PEI = Percutaneous Ethanol Injection; PS = Performance Status; RFA = Radiofrequency Ablation; TACE = Transarterial Chemoembolization.

Die besondere Gefäßversorgung der Leber (A. hepatica und V. porta) und die in den meisten Fällen ausgeprägte Neoangiogenese des HCC während seiner Progression ergeben die Rationale aller katheterbasierten, transarteriellen Therapien. Am häufigsten verwendete Embolisationstechniken bei der HCC-Behandlung:

• TACE: Es werden 2 Formen unterschieden: ohne (TACE) oder mit chemotherapeutikabindenden bzw. -freisetzenden Sphären (DEB-TACE). Bei der TACE wird eine selektive Medikamentengabe mit einer blutflussreduzierenden Embolisation der tumorversorgenden Gefäße kombiniert.

• ⁹⁰Y-RE (⁹⁰Yttrium-Radioembolisation): Diese Technik stellt dagegen eine Form der Brachytherapie dar. Die mit ⁹⁰Y beladenen Mikrosphären ermöglichen nach arterieller Applikation eine interne Bestrahlung des Tumors.

Die folgende Übersicht versucht, den aktuellen Stand der transarteriellen Verfahren und ihre Rolle bei der Behandlung von Patienten mit einem intermediären HCC darzustellen.

• Literatur

• 1 Bosch FX, Ribes J, Diaz M et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127: 5-S16
• 2 Kim WR, Gores GJ, Benson JT et al. Mortality and hospital utilization for hepatocellular carcinoma in the United States. Gastroenterology 2005; 129: 486-493
• 3 EASL-EORTC. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56: 908-943
• 4 Verslype C, Rosmorduc O, Rougier P et al. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23: vii41-48
• 5 Marelli L, Stigliano R, Triantos C et al. Transarterial therapy for hepatocellular carcinoma: Which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007; 30: 6-25
• 6 Nakamura H, Hashimoto T, Oi H et al. Transcatheter oily chemoembolization of hepatocellular carcinoma. Radiology 1989; 170: 783-786
• 7 Raoul JL, Heresbach D, Bretagne JF et al. Chemoembolization of hepatocellular carcinomas. A study of the biodistribution and pharmacokinetics of doxorubicin. Cancer 1992; 70: 585-590
• 8 Kan Z, McCuskey PA, Wright KC et al. Role of Kupffer cells in iodized oil embolization. Invest Radiol 1994; 29: 990-993
• 9 Bouvier A, Ozenne V, Aube C et al. Transarterial chemoembolisation: effect of selectivity on tolerance, tumour response and survival. Eur Radiol 2011; 21: 1719-1726
• 10 Kim HC, Chung JW, Lee W et al. Recognizing extrahepatic collateral vessels that supply hepatocellular carcinoma to avoid complications of transcatheter arterial chemoembolization. Radiographics 2005; 25: 25-S39
• 11 Camma C, Schepis F, Orlando A et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002; 224: 47-54
• 12 Llovet JM, Real MI, Montana X et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734-1739
• 13 Lo CM, Ngan H, Tso WK et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164-1171
• 14 Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: 1020-1022
• 15 Hu HT, Kim JH, Lee LS et al. Chemoembolization for hepatocellular carcinoma: multivariate analysis of predicting factors for tumor response and survival in a 362-patient cohort. J Vasc Interv Radiol 2011; 22: 917-923
• 16 Kim KM, Kim JH, Park IS et al. Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion. J Gastroenterol Hepatol 2009; 24: 806-814
• 17 Luo J, Guo RP, Lai EC et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. Ann Surg Oncol 2011; 18: 413-420
• 18 Raoul JL, Sangro B, Forner A et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 2011; 37: 212-220
• 19 Hong K, Khwaja A, Liapi E et al. New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 2006; 12: 2563-2567
• 20 Poon RT, Tso WK, Pang RW 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: 1100-1108
• 21 Varela M, Real MI, Burrel M et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46: 474-481
• 22 Reyes DK, Vossen JA, Kamel IR et al. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J 2009; 15: 526-532
• 23 Lammer J, Malagari K, Vogl T et al. Prospective randomized study of doxorubicin-eluting bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33: 41-52
• 24 Grosso M, Vignali C, Quaretti P et al. Transarterial chemoembolization for hepatocellular carcinoma with drug-eluting microspheres: preliminary results from an Italian multicentre study. Cardiovasc Intervent Radiol 2008; 31: 1141-1149
• 25 Malagari K, Pomoni M, Moschouris H et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Intervent Radiol 2012; 35: 1119-1128
• 26 Malagari K, Pomoni M, Kelekis A et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2010; 33: 541-551
• 27 Burrel M, Reig M, Forner A 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: 1330-1335
• 28 Sergio A, Cristofori C, Cardin R et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008; 103: 914-921
• 29 Strebel BM, Dufour JF. Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease. Expert Rev Anticancer Ther 2008; 8: 1743-1749
• 30 Kudo M, Imanaka K, Chida N et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47: 2117-2127
• 31 Kennedy A, Nag S, Salem R et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007; 68: 13-23
• 32 Hilgard P, Hamami M, Fouly AE et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010; 52: 1741-1749
• 33 Inarrairaegui M, Martinez-Cuesta A, Rodriguez M et al. Analysis of prognostic factors after yttrium-90 radioembolization of advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2010; 77: 1441-1448
• 34 Mazzaferro V, Sposito C, Bhoori S et al. Yttrium(90) radioembolization for intermediate-advanced hepatocarcinoma: A phase II study. Hepatology 2012; [Epub ahead of print]
• 35 Sangro B, Carpanese L, Cianni R et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011; 54: 868-878
• 36 Riaz A, Lewandowski RJ, Kulik L et al. Radiologic-pathologic correlation of hepatocellular carcinoma treated with chemoembolization. Cardiovasc Intervent Radiol 2010; 33: 1143-1152
• 37 Salem R, Lewandowski RJ, Kulik L et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011; 140: 497-507
• 38 Lewandowski RJ, Kulik LM, Riaz A et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009; 9: 1920-1928
• 39 Inarrairaegui M, Pardo F, Bilbao JI et al. Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma. Eur J Surg Oncol 2012; 38: 594-601
• 40 Bruix J, Raoul JL, Sherman M et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012; 57: 821-829
• 41 Inarrairaegui M, Thurston KG, Bilbao JI et al. Radioembolization with use of yttrium-90 resin microspheres in patients with hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2010; 21: 1205-1212
• 42 Sangro B, Gil-Alzugaray B, Rodriguez J et al. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer 2008; 112: 1538-1546
• 43 Gil-Alzugaray B, Chopitea A, Inarrairaegui M et al. Prognostic factors and prevention of radioembolization-induced liver disease. Hepatology 2012; 57: 1078-1087