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

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Abstract

Background

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.

Objective

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).

Results

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.

Conclusions

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.

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References

  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.

  2. Bosch FX, Ribes J, Cleries R, et al. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9:191–211.

    Article  PubMed  Google Scholar 

  3. Goh GB, Chang P, Tan C. Changing epidemiology of hepatocellular carcinoma in Asia. Best Pract Res Clin Gastroenterol. 2015;29:919–28.

    Article  PubMed  Google Scholar 

  4. Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: Translating knowledge into practice. Clin Gastroenterol Hepatol. 2015;13:2140–51.

  5. European Association for the Study of the Liver. EASL–EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

  6. Bruix J, Sherman M. Management of Hepatocellular Carcinoma: An update. Hepatology. 2011;53:1020–2.

  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.

  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.

    Article  PubMed  Google Scholar 

  9. Berretta M, Rinaldi L, Di Benedetto F, et al. Angiogenesis inhibitors for the treatment of hepatocellular carcinoma. Front Pharmacol. 2016;7:428.

    PubMed  PubMed Central  CAS  Google Scholar 

  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.

  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.

  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.

  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.

  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.

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  24. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  43. Sica DA. Angiogenesis inhibitors and hypertension: An emerging issue. J Clin Oncol. 2006;24:1329–31.

  44. Levy BI. Blood pressure as a potential biomarker of the efficacy angiogenesis inhibitor. Ann Oncol. 2009;20:200–3.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  46. Rudin CM, Liu W, Desai A, et al. Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. J Clin Oncol. 2008;26:1119–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

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Authors and Affiliations

  1. Department of Transplantation – Liver Unit, Cardarelli Hospital, via A. Cardarelli 9, 80131, Naples, Italy

    Giovan Giuseppe Di Costanzo, Rocco Granata & Raffaella Tortora

  2. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Andrea Casadei Gardini

  3. Biosciences Laboratory, IRST IRCCS, Meldola, Italy

    Giorgia Marisi

  4. DPT Internal Medicine, Faenza Hospital, AUSL Romagna, Forli, Faenza, Italy

    Francesco Giuseppe Foschi

  5. Department of Medical Oncology, University Hospital Cagliari, Cagliari, Italy

    Mario Scartozzi & Luca Faloppi

  6. Department of Hematology and Oncology, University Hospital, University of Modena and Reggio Emilia, Modena, Italy

    Stefano Cascinu

  7. Medical Oncology Unit, Cancer Institute “Giovanni Paolo II”, Bari, Italy

    Nicola Silvestris & Oronzo Brunetti

  8. Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy

    Vincenzo Ostilio Palmieri

  9. Surgical Oncology, General Hospital Morgagni-Pierantoni, Forlì, Italy

    Giorgio Ercolani

Authors
  1. Giovan Giuseppe Di Costanzo
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  2. Andrea Casadei Gardini
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Contributions

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.

Corresponding author

Correspondence to Giovan Giuseppe Di Costanzo.

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No funding was received for the preparation of this article.

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The authors declare no conflicts of interest.

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Di Costanzo, G.G., Casadei Gardini, A., Marisi, G. et al. Validation of a Simple Scoring System to Predict Sorafenib Effectiveness in Patients with Hepatocellular Carcinoma. Targ Oncol 12, 795–803 (2017). https://doi.org/10.1007/s11523-017-0522-5

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