Annals of Surgical Oncology

, Volume 19, Issue 12, pp 3687–3696 | Cite as

Is Serum Alpha-Fetoprotein Useful for Predicting Recurrence and Mortality Specific to Hepatocellular Carcinoma After Hepatectomy? A Test Based on Propensity Scores and Competing Risks Analysis

  • Ju Hyun Shim
  • Da-Lim Yoon
  • Seungbong Han
  • Young-Joo Lee
  • Sung-Gyu Lee
  • Kang Mo Kim
  • Young-Suk Lim
  • Han Chu Lee
  • Young-Hwa Chung
  • Yung Sang Lee
Hepatobiliary Tumors



Serum alpha-fetoprotein (AFP) is frequently used to predict posthepatectomy outcomes in patients with hepatocellular carcinoma (HCC), but its predictive value is still not established. Therefore, we assessed the prognostic significance of AFP status.


Of 525 patients undergoing curative hepatectomy for HCC, 290 had preoperative AFP levels of ≥20 ng/mL (AFP-positive group) and 235 had AFP levels of <20 ng/mL (AFP-negative group). We compared the 2 groups with respect to time-to-recurrence, using the inverse probability of treatment weighted (IPTW) for the entire cohort and propensity score matching, and the cumulative incidence of HCC-specific mortality using competing risks regression.


During follow-up (median duration 64 months, range 2–137 months), HCC recurred in 54.9 % of the AFP-negative group and 52.4 % of the AFP-positive group; there was no death without recurrence. After IPTW adjustment, time-to-recurrence did not differ in the 2 groups (hazard ratio [HR] 0.86, 95 % confidence interval [95 % CI] 0.66–1.12; P = 0.28). In a propensity-score matched cohort (152 pairs), time-to-recurrence data were similar to those obtained by IPTW adjustment (HR 0.91, 95 % CI 0.65–1.25; P = 0.55). There was no difference in recurrence pattern (site and stage) or treatment between the 2 groups even after propensity-score matching. The adjusted HR evaluating the impact of AFP positivity on the risk of HCC-specific mortality was 0.77 (95 % CI 0.54–1.08; P = 0.13) A multivariable competing risks analysis also failed to reveal a significant correlation between baseline AFP level and HCC-specific mortality in the AFP-positive group.


Preoperative AFP levels are not useful for predicting recurrence or survival endpoints following curative hepatectomy for HCC.

Supplementary material

10434_2012_2416_MOESM1_ESM.doc (112 kb)
Supplementary material 1 (DOC 112 kb)
10434_2012_2416_MOESM2_ESM.tif (1.5 mb)
Supplementary Fig. 1. Allocation scheme of patients based on serum AFP status before hepatic resection (TIFF 1526 kb)
10434_2012_2416_MOESM3_ESM.tif (1.3 mb)
Supplementary Fig. 2. ROC curves of serum AFP for predicting a recurrence and b death specific to HCC after hepatic resection at various time-points. The AUROCs of serum AFP were 0.53, 0.49, and 0.46, respectively, for predicting 1-, 3-, and 5-year recurrence and 0.51, 0.48, and 0.47, respectively, for predicting 3-, 5-, and 8-year mortality: the corresponding best cut-off values were 13.1 (circle), 12.1 (square), and 422,000 ng/mL (triangle), respectively, and 14.7 (circle), 2.8 (square), and 11.9 ng/mL (triangle), respectively. (TIFF 1305 kb)


  1. 1.
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.PubMedCrossRefGoogle Scholar
  2. 2.
    Poon RT, Fan ST, Ng IO, Wong J. Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal. Ann Surg. 2000;231:544–51.PubMedCrossRefGoogle Scholar
  3. 3.
    Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243:229–35.PubMedCrossRefGoogle Scholar
  4. 4.
    Pang RW, Joh JW, Johnson PJ, Monden M, Pawlik TM, Pooon RT. Biology of hepatocellular carcinoma. Ann Surg Oncol. 2008;15:962–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Nanashima A, Taura N, Abo T, Ichikawa T, Sakamoto I, Nagayasu T, et al. Tumor marker levels before and after curative treatment of hepatocellular carcinoma as predictors of patient survival. Dig Dis Sci. 2011;56:3086–100.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhang XF, Qi X, Meng B, Liu C, Yu L, Wang B, et al. Prognosis evaluation in alpha-fetoprotein negative hepatocellular carcinoma after hepatectomy: comparison of five staging systems. Eur J Surg Oncol. 2010;36:718–24.PubMedCrossRefGoogle Scholar
  7. 7.
    Tangkijvanich P, Anukulkarnkusol N, Suwangool P, Lertmaharit S, Hanvivatvong O, Kullavanijaya P, et al. Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol. 2000;31:302–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Tyson GL, Duan Z, Kramer JR, Davila JA, Richardson PA, El-Serag HB. Level of alpha-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:989–94.PubMedCrossRefGoogle Scholar
  9. 9.
    Santambrogio R, Opocher E, Costa M, Barabino M, Zuin M, Bertolini E, et al. Hepatic resection for “BCLC Stage A” hepatocellular carcinoma. The prognostic role of alpha-fetoprotein. Ann Surg Oncol. 2012;19:426–34.PubMedCrossRefGoogle Scholar
  10. 10.
    Lerose R, Molinari R, Rocchi E, Manenti F, Villa E. Prognostic features and survival of hepatocellular carcinoma in Italy: impact of stage of disease. Eur J Cancer. 2001;37:239–45.PubMedCrossRefGoogle Scholar
  11. 11.
    Yamamoto K, Imamura H, Matsuyama Y, Hasegawa K, Beck Y, Sugawara Y, et al. Significance of alpha-fetoprotein and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy. Ann Surg Oncol. 2009;16:2795–804.PubMedCrossRefGoogle Scholar
  12. 12.
    Yeh CN, Lee WC, Chen MF. Hepatic resection and prognosis for patients with hepatocellular carcinoma larger than 10 cm: two decades of experience at Chang Gung memorial hospital. Ann Surg Oncol. 2003;10:1070–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Toyoda H, Kumada T, Kaneoka Y, Osaki Y, Kimura T, Arimoto A, et al. Prognostic value of pretreatment levels of tumor markers for hepatocellular carcinoma on survival after curative treatment of patients with HCC. J Hepatol. 2008;49:223–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim HS, Park JW, Jang JS, Kim HJ, Shin WG, Kim KH, 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;43:482–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Kiriyama S, Uchiyama K, Ueno M, Ozawa S, Hayami S, Tani M, et al. Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival. Ann Surg. 2011;254:984–91.PubMedCrossRefGoogle Scholar
  16. 16.
    Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145–59.PubMedCrossRefGoogle Scholar
  17. 17.
    Lee SG, Hwang S. How I do it: assessment of hepatic functional reserve for indication of hepatic resection. J Hepatobiliary Pancreat Surg. 2005;12:38–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Hepatology. 2003;37:1114–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Ball D, Rose E, Alpert E. Alpha-fetoprotein levels in normal adults. Am J Med Sci. 1992;303:157–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Sizaret P, Martel N, Tuyns A, Reynaud S. Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups. Digestion. 1977;15:97–103.PubMedCrossRefGoogle Scholar
  21. 21.
    Ruoslahti E, Seppala M. Studies of carcino-fetal proteins. 3. Development of a radioimmunoassay for -fetoprotein. Demonstration of -fetoprotein in serum of healthy human adults. Int J Cancer. 1971;8:374–83.PubMedCrossRefGoogle Scholar
  22. 22.
    Debruyne EN, Delanghe JR. Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications. Clin Chim Acta. 2008;395:19–26.PubMedCrossRefGoogle Scholar
  23. 23.
    Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11:550–60.PubMedCrossRefGoogle Scholar
  24. 24.
    Ridgeway G, McCaffrey D, Morral A. 2010. twang: Toolkit for Weighting and Analysis of Nonequivalent Groups. R package version 1.0-2.
  25. 25.
    Ho DE, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat. Software. 2011;42:1–28.
  26. 26.
    Kalbfleisch JD, Prentice L. The Statistical Analysis of Failure Time Data. Hoboken, NJ: John Wiley & Sons, 2002.CrossRefGoogle Scholar
  27. 27.
    Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.CrossRefGoogle Scholar
  28. 28.
    Hosmer DW, Hosmer T, Le Cessie S, Lemeshow S. A comparison of goodness-of-fit tests for the logistic regression model. Stat Med. 1997;16:965–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Pepe MS. The Statistical Evaluation of Medical Tests for Classification and Prediction. Oxford University Press: Oxford Statistical Science Series, 2003.Google Scholar
  30. 30.
    Tateishi R, Shiina S, Yoshida H, Teratani T, Obi S, Yamashiki N, et al. Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers. Hepatology. 2006;44:1518–27.PubMedCrossRefGoogle Scholar
  31. 31.
    Okusaka T, Okada S, Ueno H, Ikeda M, Yoshimori M, Shimada K, et al. Evaluation of the therapeutic effect of transcatheter arterial embolization for hepatocellular carcinoma. Oncology. 2000;58:293–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Mailey B, Artinyan A, Khalili J, Denitz J, Sanchez-Luege N, Sun CL, et al. Evaluation of absolute serum alpha-fetoprotein levels in liver transplant for hepatocellular cancer. Arch Surg. 2011;146:26–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, 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;94:1760–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Koda M, Murawaki Y, Mitsuda A, Ohyama K, Horie Y, Suou T, et al. Predictive factors for intrahepatic recurrence after percutaneous ethanol injection therapy for small hepatocellular carcinoma. Cancer. 2000;88:529–37.PubMedCrossRefGoogle Scholar
  35. 35.
    Chevret S, Trinchet JC, Mathieu D, Rached AA, Beaugrand M, Chastang C, et al. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. J Hepatol. 1999;31:133–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Prospective validation of the CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. The Cancer of the Liver Italian Program (CLIP) Investigators. Hepatology. 2000;31:840–5.CrossRefGoogle Scholar
  37. 37.
    Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y, et al. Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2006;4:111–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology. 1995;22:432–8.PubMedGoogle Scholar
  39. 39.
    Trevisani F, D’Intino PE, Caraceni P, Pizzo M, Stefanini GF, Mazziotti A, et al. Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer. 1995;75:2220–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Trevisani F, D’Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol. 2001;34:570–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Kurth T, Walker AM, Glynn RJ, Chan KA, Gaziano JM, Berger K, et al. Results of multivariable logistic regression, propensity matching, propensity adjustment, and propensity-based weighting under conditions of nonuniform effect. Am J Epidemiol. 2006;163:262–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Alberti C, Metivier F, Landais P, Thervet E, Legendre C, Chevret S. Improving estimates of event incidence over time in populations exposed to other events: application to three large databases. J Clin Epidemiol. 2003;56:536–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol. 2009;170:244–56.PubMedCrossRefGoogle Scholar
  44. 44.
    Fujiyama S, Tanaka M, Maeda S, Ashihara H, Hirata R, Tomita K. Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma. Oncology 2002; 62 Suppl 1:57–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.Google Scholar
  46. 46.
    Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997;127:757–63.PubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Ju Hyun Shim
    • 1
  • Da-Lim Yoon
    • 1
  • Seungbong Han
    • 2
  • Young-Joo Lee
    • 3
  • Sung-Gyu Lee
    • 3
  • Kang Mo Kim
    • 1
  • Young-Suk Lim
    • 1
  • Han Chu Lee
    • 1
  • Young-Hwa Chung
    • 1
  • Yung Sang Lee
    • 1
  1. 1.Department of Gastroenterology, Asan Liver Center, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  2. 2.Department of Biostatistics, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  3. 3.Department of Surgery, Asan Liver Center, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea

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