Digestive Diseases and Sciences

, Volume 56, Issue 10, pp 3086–3100 | Cite as

Tumor Marker Levels Before and After Curative Treatment of Hepatocellular Carcinoma as Predictors of Patient Survival

  • Atsushi Nanashima
  • Naota Taura
  • Takafumi Abo
  • Tatsuki Ichikawa
  • Ichiro Sakamoto
  • Takeshi Nagayasu
  • Kazuhiko Nakao
Original Article



α-fetoprotein (AFP) is used as a marker for hepatocellular carcinoma (HCC), which is influenced by hepatitis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is a sensitive diagnostic marker. Changes in these markers after treatment may reflect curability and predict outcome.


We conducted an analysis of prognosis in 470 HCC patients who received curative treatments, and examined the relationship between changes in AFP and PIVKA-II levels after 1 month of treatment in 156 patients. Subjects were divided into three groups according to changes in both levels: (1) normal (L) group before treatment, (2) normalization (N) or (3) decreased but still above normal level or unchanged (ANU) group after treatment.


High AFP and PIVKA-II levels were significantly associated with poor tumor-free and overall survival. The presence of large size and advanced stage were significantly associated with prevalence of DU group. Overall survival in the AFP-L group was significantly better than that of other groups and overall survival in PIVKA-II-L and N groups were significantly better than that of the PIVKA-II-ANU groups. The combination of changes in the AFP- ANU and PIVKA-II- ANU groups showed the worst tumor-free and overall survivals. Multivariate analysis identified high pre-treatment levels of AFP and PIVKA-II and combination of AFP- ANU and PIVKA-II- ANU as significant determinants of poor tumor-free and overall survival, particularly in patients who underwent hepatectomy.


We conclude that high levels of AFP or PIVKA-II after treatment for HCC did not sufficiently reflect curative efficacy of treatment and reflected a poor predictor of prognosis in HCC patients.


Hepatocellular carcinoma PIVKA-II AFP Post-curative treatment change Survival 


  1. 1.
    Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010;42:S206–S214.PubMedCrossRefGoogle Scholar
  2. 2.
    Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–S50.PubMedCrossRefGoogle Scholar
  3. 3.
    Nakano M, Ando E, Kuromatsu R, et al. Recent progress in the management of hepatocellular carcinoma detected during a surveillance program in Japan. Hepatol Res. 2010;40:989–996.PubMedCrossRefGoogle Scholar
  4. 4.
    Guiu B, Minello A, Cottet V, et al. A 30-year, population-based study shows improved management and prognosis of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2010;8:986–991.PubMedCrossRefGoogle Scholar
  5. 5.
    Di Bisceglie AM. Issues in screening and surveillance for hepatocellular carcinoma. Gastroenterology. 2004;127:S104–S107.PubMedCrossRefGoogle Scholar
  6. 6.
    Pang RW, Joh JW, Johnson PJ, et al. Biology of hepatocellular carcinoma. Ann Surg Oncol. 2008;15:962–971.PubMedCrossRefGoogle Scholar
  7. 7.
    Okuda H, Nakanishi T, Takatsu K, et al. Clinicopathologic features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein-L3 and seronegative for des-gamma-carboxy prothrombin in comparison with those seropositive for des-gamma-carboxy prothrombin alone. J Gastroenterol Hepatol. 2002;17:772–778.PubMedCrossRefGoogle Scholar
  8. 8.
    Inoue S, Nakao A, Harada A, et al. Clinical significance of abnormal prothrombin (DCP) in relation to postoperative survival and prognosis in patients with hepatocellular carcinoma. Am J Gastroenterol. 1994;89:2222–2226.PubMedGoogle Scholar
  9. 9.
    Nakagawa T, Seki T, Shiro T, et al. Clinicopathologic significance of protein induced vitamin K absence or antagonist II and alpha-fetoprotein in hepatocellular carcinoma. Int J Oncol. 1999;14:281–286.PubMedGoogle Scholar
  10. 10.
    Tamano M, Sugaya H, Oguma M, et al. Serum and tissue PIVKA-II expression reflect the biological malignant potential of small hepatocellular carcinoma. Hepatol Res. 2002;22:261–269.PubMedCrossRefGoogle Scholar
  11. 11.
    Yamashita F, Tanaka M, Satomura S, et al. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas. Gastroenterology. 1996;111:996–1001.PubMedCrossRefGoogle Scholar
  12. 12.
    Kokudo N, Makuuchi M. Evidence-based clinical practice guidelines for hepatocellular carcinoma in Japan: The J-HCC guidelines. J Gastroenterol. 2009;44:119–121.PubMedCrossRefGoogle Scholar
  13. 13.
    Nanashima A, Morino S, Yamaguchi H, et al. Modified CLIP using PIVKA-II for evaluating prognosis after hepatectomy for hepatocellular carcinoma. Eur J Surg Oncol. 2003;29:735–742.PubMedCrossRefGoogle Scholar
  14. 14.
    Nanashima A, Sumida Y, Tobinaga S, et al. Postoperative changes in protein-induced vitamin K absence or antagonist II levels after hepatectomy in patients with hepatocellular carcinoma: Relationship to prognosis. HPB (Oxford). 2006;8:137–141.Google Scholar
  15. 15.
    Iwadou S, Nouso K, Kuwaki K, et al. Time-dependent analysis of predisposing factors for the recurrence of hepatocellular carcinoma. Liver Int. 2010;30:1027–1032.PubMedCrossRefGoogle Scholar
  16. 16.
    Kishi K, Sonomura T, Mitsuzane K, et al. Time courses of PIVKA-II and AFP levels after hepatic artery embolization and hepatic artery infusion against hepatocellular carcinoma: relation between the time course and tumor necrosis. Radiat Med. 1992;10:189–195.PubMedGoogle Scholar
  17. 17.
    Nobuoka D, Kato Y, Gotohda N, et al. Postoperative serum alpha-fetoprotein level is a useful predictor of recurrence after hepatectomy for hepatocellular carcinoma. Oncol Rep. 2010;24:521–528.PubMedGoogle Scholar
  18. 18.
    Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology. 2009;137:110–118.PubMedCrossRefGoogle Scholar
  19. 19.
    Liver Cancer Study Group of Japan. Stage. In: Makuuchi M, ed. The general rules for the clinical and pathological study of primary liver cancer (in Japanese). 4th ed. Tokyo: Kanehara & Co. Ltd.; 2000:19.Google Scholar
  20. 20.
    Donati M, Brancato G, Donati A. Clinical biomarkers in hepatocellular carcinoma (HCC). Front Biosci (Schol Ed). 2010;2:571–577.CrossRefGoogle Scholar
  21. 21.
    Malaguarnera G, Giordano M, Paladina I, et al. Serum markers of hepatocellular carcinoma. Dig Dis Sci. 2010;55:2744–2755.PubMedCrossRefGoogle Scholar
  22. 22.
    Yamamoto K, Imamura H, Matsuyama Y, et al. Significance of alpha-fetoprotein and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy. Ann Surg Oncol. 2009;16:2795–2804.PubMedCrossRefGoogle Scholar
  23. 23.
    Nanashima A, Sumida Y, Abo T, et al. Modified Japan Integrated Staging is currently the best available staging system for hepatocellular carcinoma patients who have undergone hepatectomy. J Gastroenterol. 2006;41:250–256.PubMedCrossRefGoogle Scholar
  24. 24.
    Koh T, Taniguchi H, Katoh H, et al. Are both PIVKA-II and alpha-fetoprotein necessary in follow-up management after hepatic resection for hepatocellular carcinoma? Hepatogastroenterology. 2002;49:1615–1618.PubMedGoogle Scholar
  25. 25.
    Kanazumi N, Takeda S, Inoue S, et al. PIVKA-II during perioperative period in patients with hepato-biliary-pancreatic diseases. Hepatogastroenterology. 2000;47:1695–1699.PubMedGoogle Scholar
  26. 26.
    Wang CS, Lin CL, Lee HC, et al. Usefulness of serum des-gamma-carboxy prothrombin in detection of hepatocellular carcinoma. World J Gastroenterol. 2005;11:6115–6159.PubMedGoogle Scholar
  27. 27.
    Kim HS, Park JW, Jang JS, et al. Prognostic values of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in hepatitis B virus-related hepatocellular carcinoma: a prospective study. J Clin Gastroenterol. 2009;43:482–488.PubMedCrossRefGoogle Scholar
  28. 28.
    Ogawa C, Kudo M, Minami Y, et al. Tumor markers after radiofrequency ablation therapy for hepatocellular carcinoma. Hepatogastroenterology. 2008;55:1454–1457.PubMedGoogle Scholar
  29. 29.
    Taketomi A, Sanefuji K, Soejima Y, et al. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation. Transplantation. 2009;87:531–537.PubMedCrossRefGoogle Scholar
  30. 30.
    Lu LG, Zeng MD, Wan MB, et al. Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters. World J Gastroenterol. 2003;9:2574–2578.PubMedGoogle Scholar
  31. 31.
    Abdel-Wahab M, El-Husseiny TS, El Hanafy E, et al. Prognostic factors affecting survival and recurrence after hepatic resection for hepatocellular carcinoma in cirrhotic liver. Langenbecks Arch Surg. 2010;395:625–632.PubMedCrossRefGoogle Scholar
  32. 32.
    Strople J, Lovell G, Heubi J. Prevalence of subclinical vitamin K deficiency in cholestatic liver disease. J Pediatr Gastroenterol Nutr. 2009;49:78–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Lin CT, Hsu KF, Chen TW, et al. Comparing hepatic resection and transarterial chemoembolization for Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma: change for treatment of choice? World J Surg. 2010;34:2155–2161.PubMedCrossRefGoogle Scholar
  34. 34.
    Nobuoka D, Kato Y, Gotohda N, et al. Postoperative serum alpha-fetoprotein level is a useful predictor of recurrence after hepatectomy for hepatocellular carcinoma. Oncol Rep. 2010;24:521–528.PubMedGoogle Scholar
  35. 35.
    Tamura Y, Igarashi M, Suda T, et al. Fucosylated fraction of alpha-fetoprotein as a predictor of prognosis in patients with hepatocellular carcinoma after curative treatment. Dig Dis Sci. 2010;55:2095–2101.PubMedCrossRefGoogle Scholar
  36. 36.
    Yamamoto K, Imamura H, Matsuyama Y, et al. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC. J Gastroenterol. 2010;45:1272–1282.PubMedCrossRefGoogle Scholar
  37. 37.
    Abrams P, Marsh JW. Current approach to hepatocellular carcinoma. Surg Clin North Am. 2010;90:803–816.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Atsushi Nanashima
    • 1
  • Naota Taura
    • 2
  • Takafumi Abo
    • 1
  • Tatsuki Ichikawa
    • 2
  • Ichiro Sakamoto
    • 3
  • Takeshi Nagayasu
    • 1
  • Kazuhiko Nakao
    • 2
  1. 1.Division of Surgical Oncology and Department of SurgeryNagasaki University HospitalNagasakiJapan
  2. 2.Department of Gastroenterology and HepatologyNagasaki University HospitalNagasakiJapan
  3. 3.Department of RadiologyNagasaki University HospitalNagasakiJapan

Personalised recommendations