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Effect of early adverse events resulting in sorafenib dose adjustments on survival outcomes of advanced hepatocellular carcinoma patients



Sorafenib is a current first-line treatment option for advanced hepatocellular carcinoma (HCC). This study aimed to evaluate the impact of early adverse events (AEs) requiring sorafenib dose adjustment on survival outcomes of patients with advanced HCC.


The study was a secondary analysis of the phase III clinical trial NCT00699374. A landmark Cox proportional hazard analysis was used to evaluate the association between early AEs requiring sorafenib dose adjustment with survival outcomes. The primary outcome was overall survival (OS) with progression-free survival (PFS) as secondary.


AEs requiring sorafenib dose adjustment within the first 28 days of therapy were significantly associated with OS (HR [95% CI]; dose interruption = 0.9 [0.7–1.2]; dose reduction = 0.6 [0.5–0.9]; discontinuation = 1.7 [0.9–3.4]; P = 0.005). No statistically significant association with PFS was identified (P = 0.148).


Sorafenib dose interruptions and reduction due to AEs did not compromise the survival outcomes of patient with advanced HCC. Patients who required a sorafenib dose reduction were observed to have more favourable OS compared to those who did not experience an AE which required a dose adjustment.

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  1. World Health Organization: Cancer fact sheets. (2018).

  2. Vogel A, Cervantes A, Chau I et al (2018) Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 29(Supplement_4):238–255

    Article  Google Scholar 

  3. Cheng AL, Kang YK, Chen Z et al (2009) 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 10(1):25–34

    CAS  Article  Google Scholar 

  4. Abou-Alfa GK, Schwartz L, Ricci S et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(26):4293–4300

    CAS  Article  Google Scholar 

  5. Trotti A, Colevas AD, Setser A et al (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13(3):176–181

    Article  Google Scholar 

  6. Marrero JA, Kudo M, Venook AP et al (2016) Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol 65(6):1140–1147

    CAS  Article  Google Scholar 

  7. Vincenzi B, Santini D, Russo A et al (2010) Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 15(1):85–92

    CAS  Article  Google Scholar 

  8. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390

    CAS  Article  Google Scholar 

  9. Otsuka T, Eguchi Y, Kawazoe S et al (2012) Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib. Hepatol Res 42(9):879–886

    CAS  Article  Google Scholar 

  10. Shomura M, Kagawa T, Shiraishi K et al (2014) Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma. World J Hepatol 6(9):670–676

    Article  Google Scholar 

  11. Cheng AL, Kang YK, Lin DY et al (2013) Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31(32):4067–4075

    CAS  Article  Google Scholar 

  12. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    CAS  Article  Google Scholar 

  13. Kawashima A, Takayama H, Arai Y et al (2011) One-month relative dose intensity of not less than 50% predicts favourable progression-free survival in sorafenib therapy for advanced renal cell carcinoma in Japanese patients. Eur J Cancer 47(10):1521–1526

    CAS  Article  Google Scholar 

  14. Wildiers H, Reiser M (2011) Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol 77(3):221–240

    Article  Google Scholar 

  15. Reiss KA, Yu S, Mamtani R et al (2017) Starting dose of sorafenib for the treatment of hepatocellular carcinoma: a retrospective, multi-institutional study. J Clin Oncol 35(31):3575–3581

    CAS  Article  Google Scholar 

  16. Gore ME, Jones RJ, Ravaud A et al (2017) Sorafenib dose escalation in treatment-naive patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study. BJU Int 119(6):846–853

    CAS  Article  Google Scholar 

  17. Hopkins AM, Van Dyk M, Rowland A et al (2019) Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: a pooled analysis of clinical trial data. Pigment Cell Melanoma Res 32(4):576–583

    CAS  Article  Google Scholar 

  18. Tang E, Rowland A, McKinnon RA et al (2019) Effect of early adverse events resulting in ado-trastuzumab emtansine dose adjustments on survival outcomes of HER2+ advanced breast cancer patients. Breast Cancer Res Treat 178(2):473–477

    CAS  Article  Google Scholar 

  19. Halmos B, Tan E-H, Soo RA et al (2019) Impact of afatinib dose modification on safety and effectiveness in patients with EGFR mutation-positive advanced NSCLC: results from a global real-world study (RealGiDo). Lung Cancer 127:103–111

    Article  Google Scholar 

  20. Coriat R, Nicco C, Chereau C et al (2012) Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol Cancer Ther 11(10):2284–2293

    CAS  Article  Google Scholar 

  21. Ogawa C, Morita M, Omura A et al (2017) Hand-foot syndrome and post-progression treatment are the good predictors of better survival in advanced hepatocellular carcinoma treated with sorafenib: a multicenter study. Oncology 93(suppl 1):113–119

    Article  Google Scholar 

  22. Koschny R, Gotthardt D, Koehler C et al (2013) Diarrhea is a positive outcome predictor for sorafenib treatment of advanced hepatocellular carcinoma. Oncology 84(1):6–13

    CAS  Article  Google Scholar 

  23. Hotte SJ, Bjarnason GA, Heng DYC et al (2011) Progression-free survival as a clinical trial endpoint in advanced renal cell carcinoma. Curr Oncol (Toronto, Ont.) 18(Suppl 2):S11–S19

    Google Scholar 

  24. Pazdur R (2008) Endpoints for assessing drug activity in clinical trials. Oncologist 13(Suppl 2):19–21

    Article  Google Scholar 

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Ashley Hopkins is an early career researcher funded by a Fellowship from the National Breast Cancer Foundation, Australia. Warit Ruanglertboon was supported by the Royal Thai Government Scholarship, Thailand. Andrew Rowland (mid-career) and Michael Sorich (principal) are funded by a Beat Cancer Fellowships from Cancer Council of South Australia, Australia. Research undertaken with the financial support of Cancer Council South Australia’s Beat Cancer Project on behalf of its donors and the State Government through the Department of Health (Grant ID: 1159924 and 1127220).

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All authors contributed to study design, interpretation, and preparation the manuscript.

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Correspondence to Warit Ruanglertboon.

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M. J. S. and A. R. report investigator-initiated project grants from Pfizer, outside the scope of the submitted work. A. M. H. and W. R. have no conflicts of interest to disclose.

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Ruanglertboon, W., Sorich, M.J., Rowland, A. et al. Effect of early adverse events resulting in sorafenib dose adjustments on survival outcomes of advanced hepatocellular carcinoma patients. Int J Clin Oncol 25, 1672–1677 (2020).

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  • Sorafenib
  • Adverse events
  • Dose adjustment
  • Prediction
  • Survival
  • Response