Medikamentöse Therapie des hepatozellulären Karzinoms

H. C. Spangenberg; I. Zuber-Jerger; R. Thimme; H. E. Blum; F. von Weizsäcker

doi:10.1055/s-2003-44797

Zentralblatt für Chirurgie, Table of Contents

Zentralbl Chir 2003; 128(11): 906-910
DOI: 10.1055/s-2003-44797

Originalarbeiten und Übersichten

Medikamentöse Therapie des hepatozellulären Karzinoms

Systemic Treatment for Hepatocellular CarcinomaH. C. Spangenberg¹ , I. Zuber-Jerger¹ , R. Thimme¹ , H. E. Blum¹ , F. von Weizsäcker¹

¹Abteilung Innere Medizin II, Medizinische Universitätsklinik Albert-Ludwigs-Universität Freiburg(Ärztlicher Direktor: Prof. Dr. Drs. h. c. H. E. Blum)

Abstract

Zusammenfassung

Das hepatozelluläre Karzinom (HCC) ist einer der häufigsten malignen Tumoren weltweit. Für die medikamentöse Therapie des HCC wurden bzw. werden verschiedene Strategien evaluiert: konventionelle Chemotherapie, Tamoxifen, Octreotid, Thymostimulin bzw. α₁-Thymophysin, Pravastatin, ¹³¹J-Lipiodol sowie die transarterielle Chemoperfusion (TAC) bzw. Chemoembolisation (TACE). Lediglich für die TACE (als Monotherapie oder kombiniert mit Pravastatin) ließ sich bisher ein Überlebensvorteil bei selektionierten Patienten nachweisen. Neue, viel versprechende Therapiestrategien wie Immun- bzw. Gentherapie, Antiangiogenese und Cyclooxygenaseinhibition werden zur Zeit in präklinischen und klinischen Studien evaluiert. Für die Primärprävention des HCC existieren wirksame Strategien und auch in der Sekundärprävention sind erste Erfolge berichtet worden.

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies worldwide. A variety of pharmacological strategies has been evaluated in the treatment of HCC: classical chemotherapy, tamoxifen, octreotide, thymostimulin, pravastatin, ¹³¹I-lipiodol as well as transarterial chemoperfusion (TAC) and chemoembolisation (TACE). TACE monotherapy or TACE combined with pravastatin resulted in a survival benefit of selected HCC patients. New strategies such as immunotherapy, antiangiogenic agents or cyclooxygenase inhibitors are under clinical investigation and might play a role in future therapies for HCC. Efficient strategies for the primary prevention of HCC are available and promising concepts in the secondary prevention have been reported.

Schlüsselwörter

Hepatozelluläres Karzinom - medikamentöse Therapie - transarterielle Chemoembolisation - Antihormontherapie

Key words

Hepatocellular carcinoma - systemic therapy - transarterial chemoembolisation - tamoxifen - octreotide

Full Text

References

Literatur

1 Allgaier H P. Das hepatozelluläre Karzinom. UNI-MED, Bremen 2002
2 Biederer C, Ries S, Brandts C H, McCormick F. Replication-selective viruses for cancer therapy. J Mol Med. 2002; 80 163-175
3 Block A, Chen S H, Kosai K, Finegold M, Woo S L. Adenoviral-mediated herpes simplex virus thymidine kinase gene transfer: regression of hepatic metastasis of pancreatic tumors. Pancreas. 1997; 15 25-34
4 Blum H E, Linhart H. Gene therapy for hepatocellular carcinoma. Viral Hepatitis. 1999; 5 147-157
5 Camma C, Schepis F, Orlando A, Albanese M, Shahied L, Trevisani F, Andreone P, Craxi A, Cottone M. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002; 224 47-54
6 Cantz T, Ott M, Kubicka S, Manns M P. Gen- und Immuntherapie von Lebererkrankungen. Internist. 2001; 42 1357-1365
7 Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases. Nature. 2000; 407 249-257
8 Caruso M, Panis Y, Gagandeep S, Houssin D, Salzman J L, Klatzmann D. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc Natl Acad Sci USA. 1993; 90 7024-7028
9 Castells A, Bruix J, Bru C, Ayuso C, Roca M, Boix L, Vilana R, Rodes J. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology. 1995; 109 917-922
10 Chan E S, Chow P K, Tai B C, Machin D, Sook C. Neoadjuvant and adjuvant therapy for operable hepatocellular carcinoma. Update Software. The Cochrane Library, Oxford 2002; 4
11 Chen C J, Yu M W, Liaw Y F. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997; 12 294-308
12 Cheng A L, Yeh K H, Fine R L, Chuang S E, Yang C H, Wang L H, Chen D S. Biochemical modulation of doxorubicin by high-dose tamoxifen in the treatment of advanced hepatocellular carcinoma. Hepatogastroenterology. 1998; 45 1955-1960
13 Chenivesse X, Franco D, Brechot C. MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis. J Hepatol. 1993; 18 168-172
14 Chow P K, Tai B C, Tan C K, Machin D, Win K M, Johnson P J, Soo K C. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology. 2002; 36 1221-1226
15 CLIP Group (Cancer of the Liver Italian Programme) . Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet. 1998; 352 17-20
16 Deuffic S, Buffat L, Poynard T, Valleron A J. Modeling the hepatitis C virus epidemic in France. Hepatology. 1999; 29 1596-1601
17 Elba S, Giannuzzi V, Misciagna G, Manghisi O G. Randomized controlled trial of tamoxifen versus placebo in inoperable hepatocellular carcinoma. Ital J Gastroenterol. 1994; 26 66-68
18 El-Serag H B, Mason A C. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999; 340 745-750
19 Engstrom P F, Levin B, Moertel C G, Schutt A. A phase II trial of tamoxifen in hepatocellular carcinoma. Cancer. 1990; 65 2641-2643
20 Farinati F, Salvagnini M, de Maria N, Fornasiero A, Chiaramonte M, Rossaro L, Naccarato R. Unresectable hepatocellular carcinoma: a prospective controlled trial with tamoxifen. J Hepatol. 1990; 11 297-301
21 Friedl J, Stift A, Paolini P, Roth E, Steger G G, Mader R, Jakesz R, Gnant M F. Tumor antigen pulsed dendritic cells enhance the cytolytic activity of tumor infiltrating lymphocytes in human hepatocellular cancer. Cancer Biother Radiopharm. 2000; 15 477-486
22 Fuchs C S, Clark J W, Ryan D P, Kulke M H, Kim H, Earle C C, Vincitore M, Mayer R J, Stuart K E. A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2002; 94 3186-3191
23 Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, Chayama K, Murashima N, Kumada H. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor. A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000; 32 228-232
24 Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001; 84 886-891
25 Khuri F R, Nemunaitis J, Ganly I, Arseneau J, Tannock I F, Romel L, Gore M, Ironside J, MacDougall R H, Heise C, Randlev B, Gillenwater A M, Bruso P, Kaye S B, Hong W K, Kirn D H. A controlled trial of intratumoral Onyx-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med. 2000; 6 879-885
26 Kin M, Torimura T, Ueno T, Nakamura T, Ogata R, Sakamoto M, Tamaki S, Sata M. Angiogenesis inhibitor TNP-470 suppresses the progression of experimentally-induced hepatocellular carcinoma in rats. Int J Oncol. 2000; 16 375-382
27 Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos O N. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut. 1998; 42 442-447
28 Kubicka S, Rudolph K L, Tietze M K, Lorenz M, Manns M. Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology. 2001; 48 783-789
29 Ladhams A, Schmidt C, Sing G, Butterworth L, Fielding G, Tesar P, Strong R, Leggett B, Powell L, Maddern G, Ellem K, Cooksley G. Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells. J Gastroenterol Hepatol. 2002; 17 889-896
30 Lau W Y, Leung T W, Ho S K, Chan M, Machin D, Lau J, Chan A T, Yeo W, Mok T S, Yu S C, Leung N W, Johnson P J. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet. 1999; 353 797-801
31 Lin D Y, Lin S M, Liaw Y F. Non-surgical treatment of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997; 12 319-328
32 Lisker-Melman M, Martin P, Hoofnagle J H. Conditions associated with hepatocellular carcinoma. Med Clin North Am. 1989; 73 999-1009
33 Llovet J M, Real M I, Montana X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Sola R, Rodes J, Bruix J. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002; 359 1734-1739
34 Lo 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 1164-1171
35 Lozano R D, Patt T Z, Hassan M M. Oral capecatibine for the treatment of hepatobiliary cancers. Proc Am Soc Clin Oncol. 2000; 19 264
36 Martinez Cerezo F J, Tomas A, Donoso L, Enriquez J, Guarner C, Balanzo J, Martinez Nogueras A, Vilardell F. Controlled trial of tamoxifen in patients with advanced hepatocellular carcinoma. J Hepatol. 1994; 20 702-706
37 Mathurin P, Rixe O, Carbonell N, Bernard B, Cluzel P, Bellin M F, Khayat D, Opolon P, Poynard T. Review article: Overview of medical treatments in unresectable hepatocellular carcinoma - an impossible meta-analysis?. Aliment Pharmacol Ther. 1998; 12 111-126
38 Murray C J, Lopez A D. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997; 349 1269-1276
39 Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki K T, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996; 334 1561-1567
40 Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999; 340 1046-1047
41 Neuhaus P, Jonas S. Lebertransplantation beim hepatozellulären Karzinom: neue Entwicklungen. Schweiz Rundsch Med Prax. 2002; 91 1396-1400
42 Palmieri G, Biondi E, Morabito A, Rea A, Gravina A, Bianco A R. Thymostimulin treatment of hepatocellular carcinoma on liver cirrhosis. Int J Canc. 1996; 8 827-832
43 Patt Y Z, Hassan M M, Lozano R D, Ellis L M, Peterson J A, Waugh K A. Durable clinical response of refractory hepatocellular carcinoma to orally administered thalidomide. Am J Clin Oncol. 2000; 23 319-321
44 Patt Y Z, Hassan M M, Lozano R D, Waugh K A, Hoque A M, Frome A I, Lahoti S, Ellis L, Vauthey J N, Curley S A, Schnirer I I, Raijman I. Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer. Clin Cancer Res. 2001; 7 3375-3380
45 Perrone F, Gallo C, Daniele B, Gaeta G B, Izzo F, Capuano G, Adinolfi L E, Mazzanti R, Farinati F, Elba S, Piai G, Calandra M, Stanzione M, Mattera D, Aiello A, De Sio I, Castiglione F, Russo M, Persico M, Felder M, Manghisi O G, De Maio E, Di Maio M, Pignata S. Tamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomised controlled trial. Curr Pharm Des. 2002; 8 1013-1019
46 Rabe C, Pilz T, Allgaier H P, Halm U, Strasser C, Wettstein M, Sauerbruch T, Caselmann W H. Klinische Resultate einer Octreotidbehandlung bei 63 Patienten mit hepatozellulärem Karzinom. Z Gastroenterol. 2002; 40 395-400
47 Reubi J C, Zimmermann A, Jonas S, Waser B, Neuhaus P, Laderach U, Wiedenmann B. Regulatory peptide receptors in human hepatocellular carcinomas. Gut. 1999; 45 766-774
48 Riestra S, Rodriguez M, Delgado M, Suarez A, Gonzalez N, de la Mata M, Diaz G, Mino-Fugarolas G, Rodrigo L. Tamoxifen does not improve survival of patients with advanced hepatocellular carcinoma. J Clin Gastroenterol. 1998; 26 200-203
49 Schachschal G, Lochs H, Plauth M. Controlled clinical trial of doxorubicin and tamoxifen versus tamoxifen monotherapy in hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2000; 12 281-284
50 Schwartz J D, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol. 2002; 3 593-603
51 Simonetti R G, Liberati A, Angiolini C, Pagliaro L. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials. Ann Oncol. 1997; 8 117-136
52 Soini Y, Virkajarvi N, Raunio H, Paakko P. Expression of P-glycoprotein in hepatocellular carcinoma: a potential marker of prognosis. J Clin Pathol. 1996; 49 470-473
53 Stefanini G F, Foschi F G, Castelli E, Marsigli L, Biselli M, Mucci F, Bernardi M, Van Thiel D H, Gasbarrini G. Alpha-1-thymosin and transcatheter arterial chemoembolization in hepatocellular carcinoma patients: a preliminary experience. Hepatogastroenterology. 1998; 45 209-215
54 Takahashi M, Sato T, Sagawa T, Lu Y, Sato Y, Iyama S, Yamada Y, Fukaura J, Takahashi S, Miyanishi K, Yamashita T, Sasaki K, Kogawa K, Hamada H, Kato J, Niitsu Y. E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor. Mol Ther. 2002; 5 627-634
55 Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000; 356 802-807
56 Urbich C, Dernbach E, Zeiher A M, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002; 90 737-744
57 Villa E, Moles A, Ferretti I, Buttafoco P, Grottola A, Del Buono M, De Santis M, Manenti F. Natural history of inoperable hepatocellular carcinoma: estrogen receptors' status in the tumor is the strongest prognostic factor for survival. Hepatology. 2000; 32 233-238
58 Villa E, Grottola A, Buttafaco P, Buono M G, Giannini F, Manno M, Bertani H, Dugani A, Manenti F. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors. Br J Cancer. 2001; 85 1606-1608
59 Vincent L, Soria C, Mirshahi F, Opolon P, Mishal Z, Vannier J P, Soria J, Hong L. Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, inhibits endothelial cell proliferation induced by angiogenic factors in vitro and angiogenesis in in vivo models. Arterioscler Thromb Vasc Biol. 2002; 22 623-629
60 von Weizsacker F, Allgaier H P, Blum H E. Prävention des hepatozellulären Karzinoms. Schweiz Rundsch Med Prax. 2002; 91 1393-1395
61 Weis M, Heeschen C, Glassford A J, Cooke J P. Statins have biphasic effects on angiogenesis. Circulation. 2002; 105 739-745
62 Yang T S, Lin Y C, Chen J S, Wan H M, Wang C H. Phase-II-study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2000; 89 750-756
63 Yang T S, Wang C H, Hsieh R K, Chen J S, Fung M C. Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma: a phase I-II trial. Ann Oncol. 2002; 13 1771-1778
64 Yuen M F, Poon R T, Lai C L, Fan S T, Lo C M, Wong K W, Wong W M, Wong B C. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology. 2002; 36 687-691

Prof. Dr. F. von Weizsäcker

Abteilung Innere Medizin II

Medizinische Universitätsklinik

Albert-Ludwigs-Universität Freiburg

Hugstetter Straße 55

79106 Freiburg

Email: weiz@ukl.uni-freiburg.de