Purpose of This PDQ Summary
Summary of Evidence

Hepatitis B Vaccine to Prevent Hepatocellular Cancer

Significance

Incidence and Mortality Risk Factors         Hepatitis B and C         Hepatitis G         Cirrhosis and other factors

Evidence of Benefit

Prevention of Hepatitis B

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Changes to This Summary (08/26/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about hepatocellular cancer (HCC) prevention. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board ¹.

Information about the following is included in this summary:

• HCC incidence and mortality statistics and information about HCC risk factors.
• Interventions for HCC prevention.
• Benefits and harms of interventions to prevent HCC.

This summary is intended as a resource to inform clinicians and other health professionals about the currently available information on HCC prevention. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system ² in reporting the evidence of benefit and potential harms associated with specific interventions. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ³, which is written in less technical language.

Summary of Evidence

Note: Separate PDQ summaries on Liver (Hepatocellular) Cancer Screening ⁴; Adult Primary Liver Cancer Treatment ⁵; Childhood Liver Cancer Treatment ⁶; and Levels of Evidence for Cancer Screening and Prevention Studies ² are also available.

Based on solid evidence, immunizing individuals against hepatitis B would lead to a decrease in the incidence of hepatocellular cancer (HCC).

Description of the Evidence

• Study Design: Evidence obtained from cohort or case-control studies.
• Internal Validity: Fair (ecologic control; no direct comparison group).
• Consistency: Limited number of studies.
• Magnitude of Effects on Health Outcomes: Reduction of risk occurs with prevention of hepatitis B infection in one intervention study. A study of vaccination in Taiwan shows that vaccination of newborns (the vaccination program includes administration of hepatitis B immunoglobulin at birth, followed by a course of hepatitis B vaccine) of mothers infected with hepatitis B virus was associated with a reduction in the average annual incidence of HCC from 0.70 per 100,000 children between 1981 and 1986 to 0.57 and 0.36 for the time periods of 1986 to 1990 and 1990 to 1994, respectively (P < .01).[1] Although there was no direct control group, the decline in incidence of HCC over time would unlikely be explained by other causes. Failures in a vaccination program may be related to either failure to receive hepatitis B immunoglobulin or failure of the hepatitis B vaccine itself.[2]
• External Validity: Good.

References

1. Chang MH, Chen CJ, Lai MS, 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 336 (26): 1855-9, 1997.  [PUBMED Abstract]
   
   
2. Chang MH, Chen TH, Hsu HM, et al.: Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems. Clin Cancer Res 11 (21): 7953-7, 2005.  [PUBMED Abstract]
   
   

Significance

Incidence and Mortality

Hepatocellular cancer (HCC) is the fourth most common cancer in the world.[1] Age-standardized incidence rates vary from 2.1 per 100,000 population in North America [2] to 80 per 100,000 population in China.[1] In the United States, it is estimated that there will be 21,370 new cases diagnosed and 18,410 deaths due to this disease in 2008.[3] There is a distinct male preponderance among all ethnic groups in the United States, although this trend is most marked among Chinese Americans, in whom the annualized rate of HCC among men is 20.9 per 100,000 and among women 8.0 per 100,000 population.[4] The table below summarizes the incidence of hepatocellular carcinoma by geographic region.[5]

HCC is very rare in persons younger than 40 years in the United States, and a much higher risk of HCC is associated with a long duration of infection with hepatitis C (e.g., greater risk after 30 years of infection). About 80% of persons with HCC have cirrhosis.[6]

Chronic hepatitis B and chronic hepatitis C (CHC) are recognized as the major factors worldwide that increase the risk of HCC, with risk being greater in the presence of coinfection with hepatitis B virus and hepatitis C virus.[7-12] The incidence of HCC in individuals with chronic hepatitis is as high as 0.46% per year. In the United States, chronic hepatitis B and CHC account for about 30% to 40% of HCC. Long-term iron depletion in CHC patients has been studied as a modality for lowering the risk of progression to HCC.[13] Iron depletion improves serum alanine aminotransferase levels and hepatic oxidative DNA damage. In a cohort study of biopsy-proven CHC patients with moderate or severe liver fibrosis, patients were divided into two groups. Patients in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44 to 144 months (median, 107 months), and were advised to consume a low-iron diet (5–7 mg iron/day).[13] Group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. Both groups included patients who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN was contradicted. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively.[13]

Chronic hepatitis G infection is not associated with HCC in either hepatitis B surface antigen-positive carriers or noncarriers.[14]

Cirrhosis is a risk factor for HCC, irrespective of the etiology of the cirrhosis.[7,8] The annual risk of developing HCC among persons with cirrhosis is between 1% and 6%.[9] Other risk factors include hemochromatosis, alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, tyrosinemia, and Wilson disease,[2] but rarely biliary cirrhosis.[15] Aflatoxins, which are mycotoxins formed by certain Aspergillus species, are a frequent contaminant of improperly stored grains and nuts. In parts of Africa, the high incidence of HCC in humans may be related to ingestion of foods contaminated with aflatoxins. This association, however, is blurred by the frequent coexistence of hepatitis B infection in those population groups. Heavy aflatoxin exposure is associated with inactivation of the p53 tumor suppressor gene, but epidemiological evidence of a causal association is limited.[16] The likely etiology of HCC is summarized in Table 2 ⁸.[17]

References

1. Parkin DM, Whelan SL, Ferlay J, et al., eds.: Cancer Incidence in Five Continents. Volume VII. Lyon, France: International Agency for Research on Cancer, 1997. 
   
   
2. Di Bisceglie AM, Carithers RL Jr, Gores GJ: Hepatocellular carcinoma. Hepatology 28 (4): 1161-5, 1998.  [PUBMED Abstract]
   
   
3. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. ¹⁰ Last accessed October 1, 2008. 
   
   
4. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online ¹¹. Last accessed July 31, 2008. 
   
   
5. Russo MW, Jacobson IM: Hepatocellular cancer: screening, surveillance, and prevention. In: Kelsen DP, Daly JM, Kern SE, et al., eds.: Gastrointestinal Oncology: Principles and Practices. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 559-568. 
   
   
6. Okuda K, Nakashima T, Kojiro M, et al.: Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology 97 (1): 140-6, 1989.  [PUBMED Abstract]
   
   
7. Benvegnù L, Fattovich G, Noventa F, et al.: Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 74 (9): 2442-8, 1994.  [PUBMED Abstract]
   
   
8. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-7, 1999.  [PUBMED Abstract]
   
   
9. Ikeda K, Saitoh S, Koida I, et al.: A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18 (1): 47-53, 1993.  [PUBMED Abstract]
   
   
10. Beasley RP: Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 61 (10): 1942-56, 1988.  [PUBMED Abstract]
    
    
11. Bruix J, Barrera JM, Calvet X, et al.: Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2 (8670): 1004-6, 1989.  [PUBMED Abstract]
    
    
12. Tsukuma H, Hiyama T, Tanaka S, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328 (25): 1797-801, 1993.  [PUBMED Abstract]
    
    
13. Kato J, Miyanishi K, Kobune M, et al.: Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 42 (10): 830-6, 2007.  [PUBMED Abstract]
    
    
14. Yuan JM, Govindarajan S, Gao YT, et al.: Prospective evaluation of infection with hepatitis G virus in relation to hepatocellular carcinoma in Shanghai, China. J Infect Dis 182 (5): 1300-3, 2000.  [PUBMED Abstract]
    
    
15. Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994.  [PUBMED Abstract]
    
    
16. Ross RK, Yuan JM, Yu MC, et al.: Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339 (8799): 943-6, 1992.  [PUBMED Abstract]
    
    
17. Shiratori Y, Yoshida H, Omata M: Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention. Expert Rev Anticancer Ther 1 (2): 277-90, 2001.  [PUBMED Abstract]
    
    

Evidence of Benefit

Prevention of Hepatitis B

Strong evidence that hepatocellular cancer (HCC) can be prevented is provided by a study of immunization to prevent transmission of hepatitis B from infected mothers to their children, suggesting that if hepatitis can be prevented, then much HCC can be prevented. Immunization programs are justified for preventing important short-term consequences of hepatitis B infection, such as acute hepatitis, chronic hepatitis, and cirrhosis.[1]

References

1. Chang MH, Chen CJ, Lai MS, 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 336 (26): 1855-9, 1997.  [PUBMED Abstract]
   
   

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Changes to This Summary (08/26/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance ¹⁵

Added text ¹⁶ to state that long-term iron depletion for CHC patients has been studied as a modality for lowering the risk of progression to HCC (cited Kato et al. as reference 13).

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