Skip to main content

Advertisement

SpringerLink
Log in

Antiplatelet Therapy is Associated with a Better Prognosis for Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma after Liver Resection

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Recurrence of hepatocellular carcinoma (HCC) with unsatisfactory survival is common after surgical resection. Antiplatelet therapy with aspirin or clopidogrel was recently shown to prevent hepatic carcinogenesis in a murine model, but its effect in humans had not been clarified. This study aimed to investigate the association between antiplatelet therapy and the outcomes for patients with hepatitis B virus (HBV)-related HCC after liver resection.

Methods

By analyzing data from the Taiwan National Health Insurance Research Database, 9461 HBV-related HCC patients who had undergone liver resection between January 1997 and December 2011 were identified. After one-to-four matching by sex, age, and propensity score, 442 patients with antiplatelet therapy and 1768 patients without antiplatelet therapy were enrolled for the analysis. The Kaplan–Meier method and modified Cox proportional hazards models were used for survival and multivariable, stratified analyses.

Results

Recurrence-free survival and overall survival after resection surgery were significantly better after 5 years in the treated cohort than in the untreated cohort (52.8 vs 47.9 %; p = 0.021 and 80.3 vs 65.4 %; p < 0.001, respectively). Besides, antiplatelet therapy reduced the risk of HCC recurrence (hazard ratio [HR] 0.73; p < 0.001) and overall mortality (HR 0.57; p < 0.001) in the multivariable analysis. However, antiplatelet use significantly increased the risk of upper gastrointestinal bleeding (odds ratio [OR] 1.91; p < 0.001).

Conclusions

Use of aspirin or clopidogrel was associated with better recurrence-free survival and overall survival among patients with HBV-related HCC after liver resection. However, these agents should be used with caution due to the adverse effects of upper gastrointestinal bleeding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.

    Article  PubMed  Google Scholar 

  2. Altekruse SF, McGlynn KA, Dickie LA, Kleiner DE. Hepatocellular carcinoma confirmation, treatment, and survival in surveillance, epidemiology, and end results registries, 1992–2008. Hepatology. 2012;55:476–82.

    Article  PubMed  Google Scholar 

  3. Marquardt JU, Galle PR, Teufel A. Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies. J Hepatol. 2012;56:267–75.

    Article  PubMed  Google Scholar 

  4. Hsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology. 2013;58:150–7.

    Article  CAS  PubMed  Google Scholar 

  5. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73e1.

    Article  PubMed  PubMed Central  Google Scholar 

  6. de Lope CR, Tremosini S, Forner A, Reig M, Bruix J. Management of HCC. J Hepatol. 2012;56(Suppl 1):S75–87.

    Article  PubMed  Google Scholar 

  7. Fuks D, Dokmak S, Paradis V, Diouf M, Durand F, Belghiti J. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology. 2012;55:132–40.

    Article  PubMed  Google Scholar 

  8. 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;244:771–80.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cho YK, Rhim H, Noh S. Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review. J Gastroenterol Hepatol. 2011;26:1354–60.

    PubMed  Google Scholar 

  10. 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;39:215–21.

    Article  CAS  PubMed  Google Scholar 

  11. 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;38:200–7.

    Article  PubMed  Google Scholar 

  12. McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis. 2011;15:223–43, vii–x.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Singh S, Singh PP, Roberts LR, Sanchez W. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2013;11(1):45–54.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sitia G, Aiolfi R, Di Lucia P, et al. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci USA. 2012;109:E2165–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA. 2012;308:1906–14.

    Article  CAS  PubMed  Google Scholar 

  16. Lee PC, Hu YW, Hung MH, et al. The risk of cancer in patients with benign anal lesions: a nationwide population-based study. Am J Med. 2013;126:1143 e9–18.

    Google Scholar 

  17. Wang YP, Chen YT, Tsai CF, et al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014;171:54–61.

    Article  PubMed  Google Scholar 

  18. D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a nonrandomized control group. Stat Med. 1998;17:2265–81.

    Article  PubMed  Google Scholar 

  19. Hung HH, Chiou YY, Hsia CY, et al. Survival rates are comparable after radiofrequency ablation or surgery in patients with small hepatocellular carcinomas. Clin Gastroenterol Hepatol. 2011;9:79–86.

    Article  PubMed  Google Scholar 

  20. Lori S, Parsons ORG, Seattle WA. Reducing bias in a propensity-score-matched-pair sample using greedy matching techniques. 2014. http://www2.sas.com/proceedings/sugi26/p214-26.pdf. Retrieved 18 Nov 2014.

  21. Poon D, Anderson BO, Chen LT, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 2009;10:1111–8.

    Article  PubMed  Google Scholar 

  22. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol. 2009;51:890–7.

    Article  PubMed  Google Scholar 

  24. Fan ST, Mau Lo C, Poon RT, et al. Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: a 20-year experience. Ann Surg. 2011;253:745–58.

    Article  PubMed  Google Scholar 

  25. Roayaie S, Obeidat K, Sposito C, et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology. 2013;57:1426–35.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cucchetti A, Piscaglia F, Grigioni AD, et al. Preoperative prediction of hepatocellular carcinoma tumour grade and micro-vascular invasion by means of artificial neural network: a pilot study. J Hepatol. 2010;52:880–8.

    Article  PubMed  Google Scholar 

  27. Swann JB, Vesely MD, Silva A, et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA. 2008;105:652–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Calvisi DF. Inhibition of hepatitis B virus-associated liver cancer by antiplatelet therapy: a revolution in hepatocellular carcinoma prevention? Hepatology. 2013;57:848–50.

    Article  PubMed  Google Scholar 

  30. Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am J Gastroenterol. 2008;103:1663–73.

    Article  PubMed  Google Scholar 

  31. Wong JS, Wong GL, Tsoi KK, et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther. 2011;33:1104–12.

    Article  PubMed  Google Scholar 

  32. Yin J, Li N, Han Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol. 2013;31:3647–55.

    Article  CAS  PubMed  Google Scholar 

  33. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  CAS  PubMed  Google Scholar 

  34. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol. 2006;1:23–61.

    Article  CAS  PubMed  Google Scholar 

  35. Semple JW, Italiano JE Jr, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11:264–74.

    Article  CAS  PubMed  Google Scholar 

  36. Iannacone M, Sitia G, Narvaiza I, Ruggeri ZM, Guidotti LG. Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus. Clin Vaccine Immunol. 2007;14:1532–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maini MK, Schurich A. Platelets harness the immune response to drive liver cancer. Proc Natl Acad Sci USA. 2012;109:12840–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Nonsteroidal antiinflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst. 2012;104:1808–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jankowska H, Hooper P, Jankowski JA. Aspirin chemoprevention of gastrointestinal cancer in the next decade: a review of the evidence. Pol Arch Med Wewn. 2010;120:407–12.

    CAS  PubMed  Google Scholar 

  40. Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T. Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology. 2003;38:756–68.

    Article  CAS  PubMed  Google Scholar 

  41. Cervello M, Foderaa D, Florena AM, et al. Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: possible role in tumor promotion and angiogenesis. World J Gastroenterol. 2005;11:4638–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med. 2006;119:624–38.

    Article  CAS  PubMed  Google Scholar 

  43. Jaben EA, Mulay SB, Stubbs JR. Reversing the effects of antiplatelet agents in the setting of intracranial hemorrhage: a look at the literature. J Intensiv Care Med. 2015;30:3–7.

    Article  PubMed  Google Scholar 

  44. Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med. 2005;352:287–9.

    Article  CAS  PubMed  Google Scholar 

  45. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation. 2002;106:1893–900.

    Article  PubMed  Google Scholar 

  46. Su CW, Chiou YW, Tsai YH, et al. The influence of hepatitis B viral load and pre-S deletion mutations on postoperative recurrence of hepatocellular carcinoma and the tertiary preventive effects by antiviral therapy. PLoS One. 2013;8:e66457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

Grants were received from the Center of Excellence for Cancer Research at Taipei Veterans General Hospital (MOHW105-TDU-B-211-124-001) in Taipei, Taiwan.

Disclosure

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

    Pei-Chang Lee MD & Teh-Ia Huo MD

  2. Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan

    Pei-Chang Lee MD, Yu-Wen Hu MD, Chun-Chia Chen MD, Chia-Jen Liu MD, PhD, Chien-Wei Su MD, PhD, Yee Chao MD, Tzeng-Ji Chen MD, PhD & Han-Chieh Lin MD

  3. Division of Gastroenterology and Hepatology, Department of Medicine, Yuanshan Branch, Taipei Veterans General Hospital, Yilan, Taiwan

    Pei-Chang Lee MD

  4. Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chiu-Mei Yeh MS

  5. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Yu-Wen Hu MD & Yee Chao MD

  6. Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

    Yu-Wen Hu MD & Chia-Jen Liu MD, PhD

  7. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chun-Chia Chen MD, Chien-Wei Su MD, PhD, Teh-Ia Huo MD, Yi-Hsiang Huang MD, PhD & Han-Chieh Lin MD

  8. Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chia-Jen Liu MD, PhD

  9. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Yi-Hsiang Huang MD, PhD & Jaw-Ching Wu MD, PhD

  10. Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan

    Tzeng-Ji Chen MD, PhD

  11. Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

    Jaw-Ching Wu MD, PhD

Authors
  1. Pei-Chang Lee MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chiu-Mei Yeh MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Wen Hu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Chia Chen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chia-Jen Liu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chien-Wei Su MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teh-Ia Huo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi-Hsiang Huang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yee Chao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tzeng-Ji Chen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Han-Chieh Lin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jaw-Ching Wu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chia-Jen Liu MD, PhD or Chien-Wei Su MD, PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 24 kb)

10434_2016_5520_MOESM2_ESM.tif

Supplementary material 2 (TIFF 14328 kb). Selection of Study Cohort. HCC, hepatocellular carcinoma; HBV, hepatitis B virus.

10434_2016_5520_MOESM3_ESM.tif

Supplementary material 3 (TIFF 3935 kb). Recurrence-free Survival and Overall Survival of HCC After Surgical Resection in Aspirin-treated Patients. HCC, hepatocellular carcinoma.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, PC., Yeh, CM., Hu, YW. et al. Antiplatelet Therapy is Associated with a Better Prognosis for Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma after Liver Resection. Ann Surg Oncol 23 (Suppl 5), 874–883 (2016). https://doi.org/10.1245/s10434-016-5520-9

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-016-5520-9

Keywords

Search

Navigation