Strategien zur Prävention des hepatozellulären  Karzinoms bei der Hepatitis-Virus-Infektion

Zusammenfassung

Die durch die Hepatitis-Viren B (HBV) und C (HCV) induzierte Leberzirrhose stellt den Hauptrisikofaktor für die Entwicklung eines hepatozellulären Karzinoms (HCC) dar. Die Prävention der chronischen Hepatitis-Virus-Infektion bzw. der Entstehung einer Leberzirrhose hat daher zentrale Bedeutung für die Primärprävention des HCC. Durch eine konsequente Impfung gegen HBV kann die Rate der HBV-Infektionen signifikant reduziert und die HCC-assoziierte Mortalität gesenkt werden. Wegen des Fehlens eines Impfstoffes gegen HCV müssen sich die Bemühungen zur Primärprävention der HCV-Infektion auf die Reduktion risikoreicher Verhaltensweisen und die Verbesserung hygienischer Bedingungen beschränken. Im präzirrhotischen Stadium einer chronischen HBV- oder HCV-Infektion kann durch eine effektive antivirale Therapie mit dem Ziel eines dauerhaften virologischen Ansprechens die Entwicklung einer Zirrhose bzw. eines HCC wirkungsvoll verhindert werden. Bei Patienten mit bereits bestehender Zirrhose bleibt jedoch selbst bei anhaltender virologischer Remission nach antiviraler Therapie das Risiko für die HCC-Entwicklung erhöht und erfordert weiterhin ein regelmäßiges Screening zur HCC-Früherkennung. Inwiefern virologische Nonresponder hinsichtlich der HCC-Entwicklung von einer antiviralen Dauertherapie profitieren, kann noch nicht sicher beurteilt werden. Die Frühdiagnose der chronischen HBV- und HCV-Infektion stellt daher den entscheidenden Faktor bei der Prävention des HCC dar. Eine Sekundärprävention nach kurativer Resektion bzw. lokal ablativer Therapie durch eine antivirale Therapie scheint die Rate später Rezidive zu senken. Die Lebertransplantation stellt heutzutage die wirksamste sekundär präventive Strategie für ausgewählte Patienten mit HCC dar. Im Anschluss an eine Lebertransplantation spielt das Immunsuppressivum Sirolimus aufgrund seiner zusätzlichen antiproliferativen Eigenschaften möglicherweise eine Rolle in der Sekundärprävention des HCC.

Abstract

Liver cirrhosis induced by HBV and HCV infections is the main risk factor for the development of hepatocellular carcinoma (HCC). Therefore, prevention of chronic infection with hepatitis viruses and prevention of the development of cirrhosis are essential for the primary prevention of HCC. A consequent vaccination program for HBV is suitable to reduce the rate of infections and the HCC-associated mortality. Since no vaccine is available for HCV, the reduction of risky behaviour and the improvement of hygiene standards are the mainstays for prevention of HCV. An efficient antiviral therapy aimed at the durable suppression of the viral load reduces the risk of progression to cirrhosis and development of HCC in precirrhotic stages of chronic HBV or HCV infections. In cirrhotic patients, the risk of developing HCC remains elevated even if a sustained virological response is achieved, thus requiring further screening with the intention of the early detection of HCC. It is too early to judge whether virological nonresponders profit from continued antiviral therapy. Therefore, the early diagnosis of chronic HBV or HCV infection is the single most important factor for the prevention of HCC. Secondary prevention after surgical resection or local ablative therapy may reduce the frequency of late recurrence. Liver transplantation is today the most effective measure of secondary prevention for selected patients with HCC. Due to its antiproliferative effects, the immunosuppressive drug sirolimus may play a role for secondary prevention of HCC following transplantation.

Schlüsselwörter

Leber - Virushepatitis - Hepatitis B - Hepatitis C

Key words

liver - viral hepatitis - hepatitis B - hepatitis C

Literatur

• 1 Bosch F X, Ribes J, Diaz M. et al . Primary liver cancer: worldwide incidence and trends.  Gastroenterology. 2004;  127 (5 Suppl 1) S5-S16
• 2 Kubicka S, Rudolph K L, Hanke M. et al . Hepatocellular carcinoma in Germany: a retrospective epidemiological study from a low-endemic area.  Liver. 2000;  20 (4) 312-318
• 3 Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.  J Viral Hepat. 2004;  11 (2) 97-107
• 4 Yang H I, Lu S N, Liaw Y F. et al . Hepatitis B e antigen and the risk of hepatocellular carcinoma.  N Engl J Med. 2002;  347 (3) 168-174
• 5 Chan H L, Hui A Y, Wong M L. et al . Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma.  Gut. 2004;  53 (10) 1494-1498
• 6 Livingston S E, Simonetti J P, McMahon B J. et al . Hepatitis B virus genotypes in alaska native people with hepatocellular carcinoma: preponderance of genotype f.  J Infect Dis. 2007;  195 (1) 5-11
• 7 Tanaka Y, Mukaide M, Orito E. et al . Specific mutations in enhancer II/core promoter of hepatitis B virus subgenotypes C1 / C2 increase the risk of hepatocellular carcinoma.  J Hepatol. 2006;  45 (5) 646-653
• 8 Chen C J, Yang H I, Su J. et al . Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.  Jama. 2006;  295 (1) 65-73
• 9 Pollicino T, Squadrito G, Cerenzia G. et al . Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection.  Gastroenterology. 2004;  126 (1) 102-110
• 10 Fattovich G, Giustina G, Christensen E. et al . Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep).  Gut. 2000;  46 (3) 420-426
• 11 Bruno S, Silini E, Crosignani A. et al . Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study.  Hepatology. 1997;  25 (3) 754-758
• 12 Squadrito G, Pollicino T, Cacciola I. et al . Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients.  Cancer. 2006;  106 (6) 1326-1230
• 13 Colombo M, Kuo G, Choo Q L. et al . Prevalence of antibodies to hepatitis C virus in Italian patients with hepatocellular carcinoma.  Lancet. 1989;  2 (8670) 1006-1008
• 14 Fattovich G, Stroffolini T, Zagni I. et al . Hepatocellular carcinoma in cirrhosis: incidence and risk factors.  Gastroenterology. 2004;  127 (5 Suppl 1) S35-50
• 15 Wang L Y, Hatch M, Chen C J. et al . Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan.  Int J Cancer. 1996;  67 (5) 620-625
• 16 Bressac B, Kew M, Wands J. et al . Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.  Nature. 1991;  350 (6317) 429-431
• 17 Hsu I C, Metcalf R A, Sun T. et al . Mutational hotspot in the p53 gene in human hepatocellular carcinomas.  Nature. 1991;  350 (6317) 427-428
• 18 Chang M H, Chen C J, Lai M S. et al . Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group.  N Engl J Med. 1997;  336 (26) 1855-1859
• 19 RKI . Epidemiologisches Bulletin Nr. 32.  2003; 
• 20 RKI . Epidemiologisches Bulletin Nr. 46.  2005; 
• 21 GAVI . Global alliance for vaccines and immunization.  , www.gavialliance.org
• 22 Bronowicki J P, Venard V, Botte C. et al . Patient-to-patient transmission of hepatitis C virus during colonoscopy.  N Engl J Med. 1997;  337 (4) 237-240
• 23 Kaufmann M, Bode J C. Risk of hepatitis C virus infection in medical occupations.  Versicherungsmedizin. 1997;  49 (4) 132-134
• 24 Terrault N A. Sexual activity as a risk factor for hepatitis C.  Hepatology. 2002;  36 (5 Suppl 1) S99-105
• 25 Wild C P, Hall A J. Primary prevention of hepatocellular carcinoma in developing countries.  Mutat Res. 2000;  462 (2 - 3) 381-393
• 26 Mommeja-Marin H, Mondou E, Blum M R. et al . Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature.  Hepatology. 2003;  37 (6) 1309-1319
• 27 Lin S M, Sheen I S, Chien R N. et al . Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.  Hepatology. 1999;  29 (3) 971-975
• 28 Fattovich G, Giustina G, Realdi G. et al . Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP).  Hepatology. 1997;  26 (5) 1338-1342
• 29 Zonneveld van M, Honkoop P, Hansen B E. et al . Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.  Hepatology. 2004;  39 (3) 804-810
• 30 Lin S M, Yu M L, Lee C M. et al . Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma.  J Hepatol. 2007;  46 (1) 45-52
• 31 Papatheodoridis G V, Manesis E, Hadziyannis S J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.  J Hepatol. 2001;  34 (2) 306-313
• 32 Lampertico P, Del Ninno E, Vigano M. et al . Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy.  Hepatology. 2003;  37 (4) 756-763
• 33 Camma C, Giunta M, Andreone P. et al . Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach.  J Hepatol. 2001;  34 (4) 593-602
• 34 Colonno R J, Genovesi E V, Medina I. et al . Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection.  J Infect Dis. 2001;  184 (10) 1236-1245
• 35 Liaw Y F, Sung J J, Chow W C. et al . Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;  351 (15) 1521-1431
• 36 Jaeckel E, Cornberg M, Wedemeyer H. et al . Treatment of acute hepatitis C with interferon alfa-2b.  N Engl J Med. 2001;  345 (20) 1452-1457
• 37 Manns M P, McHutchison J G, Gordon S C. et al . Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet. 2001;  358 (9286) 958-965
• 38 Fried M W, Shiffman M L, Reddy K R. et al . Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med. 2002;  347 (13) 975-982
• 39 Poynard T, McHutchison J, Manns M. et al . Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C.  Gastroenterology. 2002;  122 (5) 1303-1313
• 40 Hayashi N, Kasahara A. Interferon for decreasing the incidence of hepatocellular carcinoma in patients with chronic hepatitis C.  Oncology. 2002;  62 (Suppl 1) 87-93
• 41 Ikeda K, Saitoh S, Arase Y. et al . Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis.  Hepatology. 1999;  29 (4) 1124-1130
• 42 Ikeda K, Arase Y, Saitoh S. et al . Anticarcinogenic impact of interferon on patients with chronic hepatitis C: a large-scale long-term study in a single center.  Intervirology. 2006;  49 (1 - 2) 82-90
• 43 Bruno S, Stroffolini T, Colombo M. et al . Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.  Hepatology. 2007;  45 (3) 579-587
• 44 Nishiguchi S, Shiomi S, Nakatani S. et al . Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis.  Lancet. 2001;  357 (9251) 196-197
• 45 Papatheodoridis G V, Papadimitropoulos V C, Hadziyannis S J. Effect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a meta-analysis.  Aliment Pharmacol Ther. 2001;  15 (5) 689-698
• 46 Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases.  Drugs. 2001;  61 (14) 2035-2063
• 47 Windmeier C, Gressner A M. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis.  Gen Pharmacol. 1997;  29 (2) 181-196
• 48 Rambaldi A, Gluud C. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis.  Cochrane Database Syst Rev. 2005;  CD002148
• 49 Orlent H, Hansen B E, Willems M. et al . Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial.  J Hepatol. 2006;  45 (4) 539-546
• 50 Arase Y, Ikeda K, Murashima N. et al . The long term efficacy of glycyrrhizin in chronic hepatitis C patients.  Cancer. 1997;  79 (8) 1494-1500
• 51 Habu D, Shiomi S, Tamori A. et al . Role of vitamin K 2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver.  Jama. 2004;  292 (3) 358-361
• 52 Wang J S, Shen X, He X. et al . Protective alterations in phase 1 and 2 metabolism of aflatoxin B 1 by oltipraz in residents of Qidong, People’s Republic of China.  J Natl Cancer Inst. 1999;  91 (4) 347-354
• 53 Luo H, Tang L, Tang M. et al . Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine.  Carcinogenesis. 2006;  27 (2) 262-268
• 54 Gelatti U, Covolo L, Franceschini M. et al . Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study.  J Hepatol. 2005;  42 (4) 528-534
• 55 Tanaka K, Hara M, Sakamoto T. et al . Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.  Cancer Sci. 2006;  8 8
• 56 Montella M, Polesel J, La Vecchia C. et al . Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.  Int J Cancer. 2007;  120 (7) 1555-1559
• 57 Larsson S C, Wolk A. Coffee consumption and risk of liver cancer: a meta-analysis.  Gastroenterology. 2007;  132 (5) 1740-1745
• 58 Greten T F, Blum H E, Manns M P. et al . Treatment of hepatocellular carcinoma.  Z Gastroenterol. 2006;  44 (1) 43-49
• 59 Morimoto O, Nagano H, Sakon M. et al . Diagnosis of intrahepatic metastasis and multicentric carcinogenesis by microsatellite loss of heterozygosity in patients with multiple and recurrent hepatocellular carcinomas.  J Hepatol. 2003;  39 (2) 215-221
• 60 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 (2) 200-207
• 61 Sasaki Y, Yamada T, Tanaka H. et al . Risk of recurrence in a long-term follow-up after surgery in 417 patients with hepatitis B- or hepatitis C-related hepatocellular carcinoma.  Ann Surg. 2006;  244 (5) 771-780
• 62 Schwartz J D, Schwartz M, Mandeli J. et al . Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials.  Lancet Oncol. 2002;  3 (10) 593-603
• 63 Lai E C, Lo C M, Fan S T. et al . Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial.  Arch Surg. 1998;  133 (2) 183-188
• 64 Piao C Y, Fujioka S, Iwasaki Y. et al . Lamivudine treatment in patients with HBV-related hepatocellular carcinoma - using an untreated, matched control cohort.  Acta Med Okayama. 2005;  59 (5) 217-224
• 65 Kubo S, Tanaka H, Takemura S. et al . Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus.  Hepatol Res. 2007;  37 (2) 94-100
• 66 Sun H C, Tang Z Y, Wang L. et al . Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial.  J Cancer Res Clin Oncol. 2006;  132 (7) 458-465
• 67 Lin S M, Lin C J, Hsu C W. et al . Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors.  Cancer. 2004;  100 (2) 376-382
• 68 Kubo S, Nishiguchi S, Hirohashi K. et al . Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial.  Ann Intern Med. 2001;  134 (10) 963-967
• 69 Uenishi T, Nishiguchi S, Tamori A. et al . Influence of interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma.  Hepatol Res. 2006;  36 (3) 195-200
• 70 Kubo S, Hirohashi K, Tanaka H. et al . Risk factors for recurrence after resection of hepatitis C virus-related hepatocellular carcinoma.  World J Surg. 2000;  24 (12) 1559-1565
• 71 Shiratori Y, Shiina S, Teratani T. et al . Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus.  Ann Intern Med. 2003;  138 (4) 299-306
• 72 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 (6) 1543-1554
• 73 Cornberg M, Protzer U, Dollinger M M. et al . Prophylaxis, Diagnosis and Therapy of Hepatitis-B-Virus- (HBV-)Infection: upgrade of the guideline, AWMF-Register 021 / 011.  Z Gastroenterol. 2007;  45 (6) 525-574
• 74 Muto Y, Moriwaki H, Ninomiya M. et al . 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 (24) 1561-1567
• 75 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 (13) 1046-1047
• 76 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 (9155) 797-801
• 77 Boucher E, Corbinais S, Rolland Y. et al . Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma.  Hepatology. 2003;  38 (5) 1237-1241
• 78 Partensky C, Sassolas G, Henry L. et al . Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study.  Arch Surg. 2000;  135 (11) 1298-1300
• 79 Takayama T, Sekine T, Makuuchi M. et al . Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial.  Lancet. 2000;  356 (9232) 802-807
• 80 Abou-Alfa G K, Schwartz L, Ricci S. et al . Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.  J Clin Oncol. 2006;  24 (26) 4293-4300
• 81 Kawata S, Yamasaki E, Nagase T. et al . Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial.  Br J Cancer. 2001;  84 (7) 886-891
• 82 Lersch C, Schmelz R, Erdmann J. et al . Treatment of HCC with pravastatin, octreotide, or gemcitabine - a critical evaluation.  Hepatogastroenterology. 2004;  51 (58) 1099-1103
• 83 Jonas S, Bechstein W O, Steinmuller T. et al . Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis.  Hepatology. 2001;  33 (5) 1080-1086
• 84 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 (6) 1394-1403
• 85 Bismuth H, Majno P E, Adam R. Liver transplantation for hepatocellular carcinoma.  Semin Liver Dis. 1999;  19 (3) 311-322
• 86 Bernal E, Montero J L, Delgado M. et al . Adjuvant chemotherapy for prevention of recurrence of invasive hepatocellular carcinoma after orthotopic liver transplantation.  Transplant Proc. 2006;  38 (8) 2495-2498
• 87 Otto G, Heise M, Moench C. et al . Transarterial chemoembolization before liver transplantation in 60 patients with hepatocellular carcinoma.  Transplant Proc. 2007;  39 (2) 537-539
• 88 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 (7) 767-775
• 89 Leckel K, Beecken W D, Jonas D. et al . The immunosuppressive drug mycophenolate mofetil impairs the adhesion capacity of gastrointestinal tumour cells.  Clin Exp Immunol. 2003;  134 (2) 238-245
• 90 Schumacher G, Oidtmann M, Rosewicz S. et al . Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus which promotes cell growth.  Transplant Proc. 2002;  34 (5) 1392-1393
• 91 Guba M, von Breitenbuch P, Steinbauer M. et al . Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.  Nat Med. 2002;  8 (2) 128-135
• 92 Koehl G E, Andrassy J, Guba M. et al . Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice.  Transplantation. 2004;  77 (9) 1319-1326
• 93 Kneteman N M, Oberholzer J, Al Saghier M. et al . Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.  Liver Transpl. 2004;  10 (10) 1301-1311
• 94 Hojo M, Morimoto T, Maluccio M. et al . Cyclosporine induces cancer progression by a cell-autonomous mechanism.  Nature. 1999;  397 (6719) 530-534
• 95 Donckier V, Troisi R, Toungouz M. et al . Donor stem cell infusion after non-myeloablative conditioning for tolerance induction to HLA mismatched adult living-donor liver graft.  Transpl Immunol. 2004;  13 (2) 139-146
• 96 DKFZ . Krebsatlas.  2006;  , www.dkfz.de/epi/Home_d/Programm/AG/Praevent/Krebshom/main/deutsch/frame5.html
• 97 Llovet J M, Burroughs A, Bruix J. Hepatocellular carcinoma.  Lancet. 2003;  362 (9399) 1907-1917
• 98 Oon C J. Long-term survival following treatment of hepatocellular carcinoma in Singapore: evaluation of Wellferon in the prophylaxis of high-risk pre-cancerous conditions.  Cancer Chemother Pharmacol. 1992;  31 (Suppl) S137-142
• 99 Mazzella G, Accogli E, Sottili S. et al . Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis.  J Hepatol. 1996;  24 (2) 141-147
• 100 International Interferon-alpha Hepatocellular Carcinoma Study Group . Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study.  Lancet. 1998;  351 (9115) 1535-1539
• 101 Yuen M F, Hui C K, Cheng C C. et al . Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.  Hepatology. 2001;  34 (1) 139-145
• 102 Nishiguchi S, Kuroki T, Nakatani S. et al . Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis.  Lancet. 1995;  346 (8982) 1051-1055
• 103 Fattovich G, Giustina G, Degos F. et al . Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP).  J Hepatol. 1997;  27 (1) 201-205
• 104 Valla D C, Chevallier M, Marcellin P. et al . Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment.  Hepatology. 1999;  29 (6) 1870-1875
• 105 Shiratori Y, Ito Y, Yokosuka O. et al . Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival.  Ann Intern Med. 2005;  142 (2) 105-114
• 106 Someya T, Ikeda K, Saitoh S. et al . Interferon lowers tumor recurrence rate after surgical resection or ablation of hepatocellular carcinoma: a pilot study of patients with hepatitis B virus-related cirrhosis.  J Gastroenterol. 2006;  41 (12) 1206-1213
• 107 El-Serag H B. Hepatocellular carcinoma: recent trends in the United States.  Gastroenterology. 2004;  127 (5 Suppl 1) S27-34
• 108 Perz J F, Armstrong G L, Farrington L A. et al . The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.  J Hepatol. 2006;  45 (4) 529-538
• 109 Chang M H, Shau W Y, Chen C J. et al . Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls.  Jama. 2000;  284 (23) 3040-3042
• 110 Ni Y H, Chang M H, Huang L M. et al . Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination.  Ann Intern Med. 2001;  135 (9) 796-800