Hepatology International

, Volume 4, Issue 1, pp 396–405 | Cite as

Tumor and liver determinants of prognosis in unresectable hepatocellular carcinoma: a large case cohort study

Original Article

Abstract

Objectives

967 patients with unresectable and untransplantable, biopsy-proven hepatocellular carcinoma (HCC) were prospectively evaluated at baseline and followed up till death. Survival was the end point.

Results

We found that male gender, ascites, cirrhosis, portal vein thrombosis (PVT), elevated AFP or bilirubin, or alkaline phosphatase, were each statistically significant adverse prognostic factors. Patients with normal AFP survived longer than those with elevated AFP, even in the presence of PVT, large or bilobar tumors or cirrhosis. We used a bivariate analysis to separate patient sub groups based on liver function and tumor characteristics and found clear discrimination in survival between subsets; in addition both cirrhosis and presence of PVT were significant factors. We also used a purely mathematical approach to derive subgroups and a prognostic model for individual patients. Interestingly, the two approaches gave similar predictive information, which opens the possibility of a more detailed mathematical analysis in the future. The results of this large dataset show that amongst non-surgical HCC patients, there are clear subsets with longer survival.

Conclusion

The data supports the concept of heterogeneity of HCC. The three factors, bilirubin, AFP, and PVT predominate in prognosis.

Abbreviations

HCC

Hepatocellular carcinoma

AFP

Alpha-fetoprotein

HCV

Hepatitis C virus

ALKP

Alkaline phosphatase

GGTP

Gamma glutamyl transpeptidase

PVT

Portal vein thrombosis

CT

Computerized axial tomography scan

HR

Hazard ratio

CI

Confidence interval

References

  1. 1.
    El–Serag KR. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557–2576CrossRefPubMedGoogle Scholar
  2. 2.
    Cho SJ, Yoon JH, Hwang SS, et al. Do young hepatocellular carcinoma patients with relatively good liver function have poorer outcomes than elderly patients? J Gastroenterol Hepatol 2007;22:1226–1231CrossRefPubMedGoogle Scholar
  3. 3.
    Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer 1985;56:918–928CrossRefPubMedGoogle Scholar
  4. 4.
    Cancer of the Liver Italian Program (CLIP) investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology 1998;28:751–755Google Scholar
  5. 5.
    Cancer of the Liver Italian Program (CLIP) Investigators. Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 2000;31:840–845Google Scholar
  6. 6.
    Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004;10:S115–S120CrossRefPubMedGoogle Scholar
  7. 7.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329–338CrossRefPubMedGoogle Scholar
  8. 8.
    Tateishi R, Yoshida H, Shiina S, et al. Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients. Gut 2005;54:419–425CrossRefPubMedGoogle Scholar
  9. 9.
    Chevret S, Trinchet JC, Mathieu D, et al. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. J Hepatol 1999;31:133–141CrossRefPubMedGoogle Scholar
  10. 10.
    Leung TW, Tang AM, Zee B, et al. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002;94:1760–1769CrossRefPubMedGoogle Scholar
  11. 11.
    Omagari K, Honda S, Kadokawa Y, et al. Preliminary analysis of a newly proposed prognostic scoring system (SLiDe score) for hepatocellular carcinoma. J Gastroenterol Hepatol 2004;19:805–811CrossRefPubMedGoogle Scholar
  12. 12.
    Levy I, Sherman M. Staging of hepatocellular carcinoma: assessment of the CLIP, Okuda, and Child-Pugh staging systems in a cohort of 257 patients in Toronto. Gut 2002;50:881–885.CrossRefPubMedGoogle Scholar
  13. 13.
    Giannini E, Risso D, Botta F, et al. Prognosis of hepatocellular carcinoma in anti-HCV positive cirrhotic patients: a single-centre comparison amongst four different staging systems. J Intern Med 2004;255:399–408CrossRefPubMedGoogle Scholar
  14. 14.
    Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 2005;41:707–716CrossRefPubMedGoogle Scholar
  15. 15.
    Huang YH, Chen CH, Chang TT, et al. Evaluation of predictive value of CLIP, Okuda, TNM and JIS staging systems for hepatocellular carcinoma patients undergoing surgery. J Gastroenterol Hepatol 2005;20:765–771CrossRefPubMedGoogle Scholar
  16. 16.
    Grieco A, Pompili M, Caminiti G, et al. Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre. Gut 2005;54:411–418CrossRefPubMedGoogle Scholar
  17. 17.
    Pascual S, Zapater P, Such J, et al. Comparison of staging systems to predict survival in hepatocellular carcinoma. Liver Int 2006;26:673–679CrossRefPubMedGoogle Scholar
  18. 18.
    Kondo K, Chijiiwa K, Nagano M, et al. Comparison of seven prognostic staging systems in patients who undergo hepatectomy for hepatocellular carcinoma. Hepatogastroenterology 2007;54:1534–1538PubMedGoogle Scholar
  19. 19.
    Huo TI, Lin HC, Hsia CY, et al. The model for end-stage liver disease based cancer staging systems are better prognostic models for hepatocellular carcinoma: a prospective sequential survey. Am J Gastroenterol 2007;102:1920–1930CrossRefPubMedGoogle Scholar
  20. 20.
    Georgiades CS, Liapi E, Frangakis C, et al. Prognostic accuracy of 12 liver staging systems in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization. J Vasc Interv Radiol 2006;17:1619–1624PubMedCrossRefGoogle Scholar
  21. 21.
    Minagawa M, Ikai I, Matsuyama Y, et al. Staging of hepatocellular carcinoma: assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13, 772 patients in Japan. Ann Surg 2007;245:909–922CrossRefPubMedGoogle Scholar
  22. 22.
    Chung H, Kudo M, Takahashi S, et al. Review of current staging systems for hepatocellular carcinoma. Hepatol Res 2007;37:S210–S215CrossRefPubMedGoogle Scholar
  23. 23.
    Guglielmi A, Ruzzenente A, Pachera S, et al. Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response. Am J Gastroenterol 2008;103(3):597–604Google Scholar
  24. 24.
    Pawarode A, Voravud N, Sriuranpong V, et al. Natural history of untreated primary hepatocellular carcinoma: a retrospective study of 157 patients. Am J Clin Oncol 1998;21:386–391CrossRefPubMedGoogle Scholar
  25. 25.
    Llado L, Virgili J, Figueras J, et al. A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after transcatheter arterial chemoembolization. Cancer 2000;88:50–57CrossRefPubMedGoogle Scholar
  26. 26.
    O’Suilleabhain CB, Poon RT, Yong JL, et al. Factors predictive of 5-year survival after transarterial chemoembolization for inoperable hepatocellular carcinoma. Br J Surg 2003;90:325–331CrossRefPubMedGoogle Scholar
  27. 27.
    Yamasaki T, Kimura T, Kurokawa F, et al. Prognostic factors in patients with advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy. J Gastroenterol 2005;40:70–78CrossRefPubMedGoogle Scholar
  28. 28.
    Kogo M, Kano A, Kiuchi Y, Mitamura K, Yoneyama K. Prognostic index for survival in patients after treatment for primary hepatocellular carcinoma. Dig Dis Sci. 2007;52(9):2444–2451Google Scholar
  29. 29.
    Couto OF, Dvorchik I, Carr BI. Causes of death in patients with unresectable hepatocellular carcinoma. Dig Dis Sci 2007;52:3285–3289CrossRefPubMedGoogle Scholar
  30. 30.
    Dvorchik I, Carr BI. A simple prognostic scoring system for patients with unresectable hepatocellular carcinoma treated by chemo-embolization. Cancer Detect Prev 2007;31:154–160CrossRefPubMedGoogle Scholar
  31. 31.
    Johnson PJ, Melia WM, Palmer MK, et al. Relationship between serum alpha-fetoprotein, cirrhosis and survival in hepatocellular carcinoma. Br J Cancer 1981;44:502–505PubMedGoogle Scholar
  32. 32.
    Wang CS, Lin CL, Lee HC, et al. Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma. World J Gastroenterol 2005;11:6115–6119PubMedGoogle Scholar
  33. 33.
    Carr BI, Kanke F, Wise M, et al. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci 2007;52:776–782CrossRefPubMedGoogle Scholar
  34. 34.
    Toyoda H, Kumada T, Osaki Y, et al. Role of tumor markers in assessment of tumor progression and prediction of outcomes in patients with hepatocellular carcinoma. Hepatol Res 2007;37:S166–S171CrossRefPubMedGoogle Scholar
  35. 35.
    Volk ML, Hernandez JC, Su GL, et al. Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3. Cancer Biomark 2007;3:79–87PubMedGoogle Scholar
  36. 36.
    Shirabe K, Itoh S, Yoshizumi T, et al. The predictors of microvascular invasion in candidates for liver transplantation with hepatocellular carcinoma-with special reference to the serum levels of des-gamma-carboxy prothrombin. J Surg Oncol 2007;95:235–240CrossRefPubMedGoogle Scholar
  37. 37.
    Capurro M, Wanless IR, Sherman M, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 2003;125:89–97CrossRefPubMedGoogle Scholar
  38. 38.
    Feng JT, Liu YK, Song HY, et al. Heat-shock protein 27: a potential biomarker for hepatocellular carcinoma identified by serum proteome analysis. Proteomics 2005;5:4581–4588CrossRefPubMedGoogle Scholar
  39. 39.
    Di Tommaso L, Franchi G, Park YN, et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 2007;45:725–734CrossRefPubMedGoogle Scholar
  40. 40.
    Kim J, Ki SS, Lee SD, et al. Elevated plasma osteopontin levels in patients with hepatocellular carcinoma. Am J Gastroenterol 2006;101:2051–2059CrossRefPubMedGoogle Scholar
  41. 41.
    Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004;40:667–676CrossRefPubMedGoogle Scholar
  42. 42.
    Sun W, Xing B, Sun Y, et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics 2007;6:1798–1808CrossRefPubMedGoogle Scholar
  43. 43.
    Jia HL, Ye QH, Qin LX, et al. Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res 2007;13:1133–1139CrossRefPubMedGoogle Scholar
  44. 44.
    Poon TC, Yip TT, Chan AT, et al. Comprehensive proteomic profiling identifies serum proteomic signatures for detection of hepatocellular carcinoma and its subtypes. Clin Chem 2003;49:752–760CrossRefPubMedGoogle Scholar
  45. 45.
    Budhu AS, Zipser B, Forgues M, et al. The molecular signature of metastases of human hepatocellular carcinoma. Oncology 2005;69(Suppl 1):23–27CrossRefPubMedGoogle Scholar
  46. 46.
    Kaposi-Novak P, Lee JS, Gomez-Quiroz L, et al. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 2006;116:1582–1595CrossRefPubMedGoogle Scholar
  47. 47.
    Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–1171CrossRefPubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2009

Authors and Affiliations

  • Brian I. Carr
    • 1
  • Petr Pancoska
    • 2
  • Robert A. Branch
    • 2
  1. 1.Liver Tumor Program, Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Center for Clinical PharmacologyUniversity of PittsburghPhiladelphiaUSA

Personalised recommendations