Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
Preoperative AFP levels are not useful for predicting recurrence or survival endpoints following curative hepatectomy for HCC.
Reference
Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.
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.
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.
Pang RW, Joh JW, Johnson PJ, Monden M, Pawlik TM, Pooon RT. Biology of hepatocellular carcinoma. Ann Surg Oncol. 2008;15:962–71.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001;5:145–59.
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.
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.
Ball D, Rose E, Alpert E. Alpha-fetoprotein levels in normal adults. Am J Med Sci. 1992;303:157–9.
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.
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.
Debruyne EN, Delanghe JR. Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications. Clin Chim Acta. 2008;395:19–26.
Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11:550–60.
Ridgeway G, McCaffrey D, Morral A. 2010. twang: Toolkit for Weighting and Analysis of Nonequivalent Groups. R package version 1.0-2. http://CRAN.R-project.org/package=twang.
Ho DE, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat. Software. 2011;42:1–28. http://www.jstatsoft.org/v42/i08/.
Kalbfleisch JD, Prentice L. The Statistical Analysis of Failure Time Data. Hoboken, NJ: John Wiley & Sons, 2002.
Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
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.
Pepe MS. The Statistical Evaluation of Medical Tests for Classification and Prediction. Oxford University Press: Oxford Statistical Science Series, 2003.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol. 2009;170:244–56.
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.
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.
Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997;127:757–63.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Ju Hyun Shim and Da-Lim Yoon contributed equally to this study and share first authorship.
Electronic supplementary material
Below is the link to the electronic supplementary material.
10434_2012_2416_MOESM3_ESM.tif
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)
Rights and permissions
About this article
Cite this article
Shim, J.H., Yoon, DL., Han, S. et al. 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. Ann Surg Oncol 19, 3687–3696 (2012). https://doi.org/10.1245/s10434-012-2416-1
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-012-2416-1