Targeted Oncology

, Volume 12, Issue 6, pp 795–803 | Cite as

Validation of a Simple Scoring System to Predict Sorafenib Effectiveness in Patients with Hepatocellular Carcinoma

  • Giovan Giuseppe Di Costanzo
  • Andrea Casadei Gardini
  • Giorgia Marisi
  • Francesco Giuseppe Foschi
  • Mario Scartozzi
  • Rocco Granata
  • Luca Faloppi
  • Stefano Cascinu
  • Nicola Silvestris
  • Oronzo Brunetti
  • Vincenzo Ostilio Palmieri
  • Giorgio Ercolani
  • Raffaella Tortora
Original Research Article



Sorafenib is recommended for the treatment of advanced-stage hepatocellular carcinoma (HCC). Nonetheless, it is expensive, effective in few patients, and may cause significant adverse effects. Therefore, accurate selection of patients is needed. In a previous study, we constructed a simple scoring system to predict patients’ outcomes based on the occurrence of sorafenib adverse effects.


The present study aimed to validate this scoring system in a real-life cohort of HCC patients.

Patients and Methods

Clinical records of 279 outpatients treated with sorafenib in eight Italian centers were retrospectively analyzed. Adverse effects considered to calculate the score were skin toxicity, diarrhea, and arterial hypertension, occurring during the first month of therapy. For each adverse effect, 1 point was assigned if present; and 0 points if absent (resulting in a total score between 0 and 3).


Median overall survival (OS) was 10.8 months and median time to progression (TTP) was 5.1 months. At multivariate analysis, performance status, α-fetoprotein (AFP), and Child-Pugh score were independently associated with TTP and OS. A progressive increase of OS and TTP was observed in patients with scores from 0 to 3 (p < 0.001). Six-, 12-, and 24-month survival probabilities were 55.1, 24.5, and 7.9% in score 0 patients, and 100, 80.9, and 46.2% in score 3 patients, respectively. Complete response was observed in one patient (0.4%), partial responses in 41 (15.2%), and stable disease in 117 (43.5%). The disease control rate in patients with scores of 0, 1, 2, and 3 was 34.3, 51.6, 80.9, and 96.3%, respectively (p < 0.001). Complete or partial responses were not observed in score 0 patients.


We have validated a useful scoring system to predict outcomes in sorafenib-treated HCC patients. This score is easy to calculate and suitable for implementation in daily clinical practice.


Author’s Contribution

G.G.D. and R.T. designed the study’s concept. R.T, A.C.G., G.M., F.G.F., L.P., S.C., N.S., V.O.P, G.E., and O.B. contributed to the data collection and analysis. G.G.D. drafted the manuscript. G.G.D. and R.G. revised the manuscript.

Compliance with Ethical Standards


No funding was received for the preparation of this article.

Conflicts of Interest

The authors declare no conflicts of interest.


  1. 1.
    Ferlay J, Soerjomataram II, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014;136:E359–86.Google Scholar
  2. 2.
    Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9:191–211.CrossRefPubMedGoogle Scholar
  3. 3.
    Goh GB, Chang P, Tan C. Changing epidemiology of hepatocellular carcinoma in Asia. Best Pract Res Clin Gastroenterol. 2015;29:919–28.CrossRefPubMedGoogle Scholar
  4. 4.
    Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: Translating knowledge into practice. Clin Gastroenterol Hepatol. 2015;13:2140–51.Google Scholar
  5. 5.
    European Association for the Study of the Liver. EASL–EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.Google Scholar
  6. 6.
    Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An update. Hepatology. 2011;53:1020–2.Google Scholar
  7. 7.
    Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the Study of the liver consensus. Hepatol Int. 2010;4:439–74.Google Scholar
  8. 8.
    Nishida N, Kitano M, Sakurai T, et al. Molecular mechanism and prediction of sorafenib chemoresistance in human hepatocellular carcinoma. Dig Dis. 2015;33:771–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Berretta M, Rinaldi L, Di Benedetto F, et al. Angiogenesis inhibitors for the treatment of hepatocellular carcinoma. Front Pharmacol. 2016;7:428.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Cao G, Li X, Qin C, Li J. Prognostic value of VEGF in hepatocellular carcinoma patients treated with Sorafenib: A meta-analysis. Med Sci Monit. 2015;21:3144–51.Google Scholar
  11. 11.
    Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial. J Hepatol. 2012;57:821–9.Google Scholar
  12. 12.
    Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.Google Scholar
  13. 13.
    Lencioni R, Kudo M, Ye SL, et al. GIDEON (global investigation of therapeutic DEcisions in hepatocellular carcinoma and of its treatment with sorafeNib): Second interim analysis. Int J Clin Pract. 2014;68:609–17.Google Scholar
  14. 14.
    Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia–Pacific trial. Eur J Cancer. 2012;48:1452–65.Google Scholar
  15. 15.
    Song T, Zhang W, Wu Q, et al. A single center experience of sorafenib in advanced hepatocellular carcinoma patients: Evaluation of prognostic factors. Eur J Gastroenterol Hepatol. 2011;23:1233–8.Google Scholar
  16. 16.
    Pinter M, Sieghart W, Hucke F, et al. Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib. Aliment Pharmacol Ther. 2011;34:949–59.CrossRefPubMedGoogle Scholar
  17. 17.
    Wörns MA, Koch S, Niederle IM, et al. The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib. Dig Liver Dis. 2013;45:408–13.CrossRefPubMedGoogle Scholar
  18. 18.
    Cho JY, Paik YH, Lim HY, et al. Clinical parameters predictive of outcomes in sorafenib-treated patients with advanced hepatocellular carcinoma. Liver Int. 2013;33:950–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Llovet JM, Pena CE, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2290–300.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang Z, Zhou X, Shen H, et al. Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: Evidence from an in vitro study. BMC Med. 2009;7:41.Google Scholar
  21. 21.
    Vincenzi B, Santini D, Russo A, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist. 2010;15:85–92.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Di Fiore F, Rigal O, Ménager C, Michel P, Pfister C. Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib. Br J Cancer. 2011;105:1811–3.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Di Costanzo GG, De Stefano G, Tortora R, et al. Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma. Future Oncol. 2015;11:943–51.CrossRefPubMedGoogle Scholar
  24. 24.
    Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang X, Yang XR, Huang XW, Wang WM, Shi RY, et al. Sorafenib in treatment of patients with advanced hepatocellular carcinoma: A systematic review. Hepatobiliary Pancreat Dis Int. 2012;11:458–66.Google Scholar
  26. 26.
    Wang Z, Wu XL, Zeng WZ, Xu GS, Xu H, et al. Meta-analysis of the efficacy of sorafenib for hepatocellular carcinoma. Asian Pac J Cancer Prev. 2013;14:691–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Peng S, Zhao Y, Xu F, Jia C, Xu Y, et al. An updated meta-analysis of randomized controlled trials assessing the effect of sorafenib in advanced hepatocellular carcinoma. PLoS One. 2014;9:e112530.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Shao YY, Shau WY, Chan SY, Lu LC, Hsu CH, Cheng AL. Treatment efficacy differences of sorafenib for advanced hepatocellular carcinoma: A meta-analysis of randomized clinical trials. Oncology. 2015;88:345–52.Google Scholar
  29. 29.
    Zhu AX, Kang YK, Rosmorduc O, Evans TJ, Santoro A, Ross P, et al. Biomarker analyses of clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib with or without erlotinib in the SEARCH trial. Clin Cancer Res. 2016;22:4870–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Takeda H, Nishikawa H, Osaki Y, Tsuchiya K, Joko K, Japanese Red Cross Liver Study Group, et al. Proposal of Japan red cross score for sorafenib therapy in hepatocellular carcinoma. Hepatol Res. 2015;45(10):E130–40.Google Scholar
  31. 31.
    Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: A systematic review and meta-analysis. Acta Oncol. 2008;47:176–86.Google Scholar
  32. 32.
    Zhang L, Zhou Q, Ma L, Wu Z, Wang Y. Meta-analysis of dermatological toxicities associated with sorafenib. Clin Exp Dermatol. 2011;36:344–50.CrossRefPubMedGoogle Scholar
  33. 33.
    Yada M, Masumoto A, Motomura K, Tajiri H, Morita Y, Suzuki H. Indicators of sorafenib efficacy in patients with advanced hepatocellular carcinoma. World J Gastroenterol. 2014;20:12581–7.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Shomura M, Kagawa T, Shiraishi K, Hirose S, Arase Y, Koizumi J, et al. Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma. World J Hepatol. 2014;6:670–6.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Otsuka T, Eguchi Y, Kawazoe S, Yanagita K, Ario K, Kitahara K. Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib. Hepatol Res. 2012;42:879–86.CrossRefPubMedGoogle Scholar
  36. 36.
    Reig M, Torres F, Rodriguez-Lope C, Forner A, LLarch N, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61:318–24.CrossRefPubMedGoogle Scholar
  37. 37.
    Li Y, Li S, Zhu Y, Liang X, Meng H, Chen J, et al. Incidence and risk of sorafenib-induced hypertension: A systematic review and meta-analysis. J Clin Hypertens. 2014;16:177–85.Google Scholar
  38. 38.
    Funakoshi T, Latif A, Galsky MD. Risk of hypertension in cancer patients treated with sorafenib: An updated systematic review and meta-analysis. J Hum Hypertens. 2013;27:601–11.Google Scholar
  39. 39.
    Hamnvik O, Choueiri T, Turchin A, et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer. 2015;121:311–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: Hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol. 2013;36:319–24.Google Scholar
  41. 41.
    Akutsu N, Sasaki S, Takagi H, et al. Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy. Int J Clin Oncol. 2015;20:105–10.CrossRefPubMedGoogle Scholar
  42. 42.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.CrossRefPubMedGoogle Scholar
  43. 43.
    Sica DA. Angiogenesis inhibitors and hypertension: An emerging issue. J Clin Oncol. 2006;24:1329–31.Google Scholar
  44. 44.
    Levy BI. Blood pressure as a potential biomarker of the efficacy angiogenesis inhibitor. Ann Oncol. 2009;20:200–3.CrossRefPubMedGoogle Scholar
  45. 45.
    Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol. 2009;20:227–30.CrossRefPubMedGoogle Scholar
  46. 46.
    Rudin CM, Liu W, Desai A, et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol. 2008;26:1119–27.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Koschny R, Gotthardt D, Koehler C, et al. Diarrhea is a positive outcome predictor for sorafenib treatment of advanced hepatocellular carcinoma. Oncology. 2013;84:6–13.CrossRefPubMedGoogle Scholar
  48. 48.
    Bettinger D, Schultheiß M, Knuppel E, et al. Diarrhoea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2012;56:789.CrossRefPubMedGoogle Scholar
  49. 49.
    Doyle A, Marsh P, Gill R, Rodov M, Mohsen W, Varma P, et al. Sorafenib in the treatment of hepatocellular carcinoma: A multi-centre real-world study. Scand J Gastroenterol. 2016;51:979–85.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Giovan Giuseppe Di Costanzo
    • 1
  • Andrea Casadei Gardini
    • 2
  • Giorgia Marisi
    • 3
  • Francesco Giuseppe Foschi
    • 4
  • Mario Scartozzi
    • 5
  • Rocco Granata
    • 1
  • Luca Faloppi
    • 5
  • Stefano Cascinu
    • 6
  • Nicola Silvestris
    • 7
  • Oronzo Brunetti
    • 7
  • Vincenzo Ostilio Palmieri
    • 8
  • Giorgio Ercolani
    • 9
  • Raffaella Tortora
    • 1
  1. 1.Department of Transplantation – Liver UnitCardarelli HospitalNaplesItaly
  2. 2.Department of Medical OncologyIstituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCSMeldolaItaly
  3. 3.Biosciences Laboratory, IRST IRCCSMeldolaItaly
  4. 4.DPT Internal MedicineFaenza HospitalFaenzaItaly
  5. 5.Department of Medical OncologyUniversity Hospital CagliariCagliariItaly
  6. 6.Department of Hematology and OncologyUniversity Hospital, University of Modena and Reggio EmiliaModenaItaly
  7. 7.Medical Oncology UnitCancer Institute “Giovanni Paolo II”BariItaly
  8. 8.Biomedical Sciences and Human OncologyUniversity of BariBariItaly
  9. 9.Surgical OncologyGeneral Hospital Morgagni-PierantoniForlìItaly

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