International Journal of Clinical Pharmacy

, Volume 37, Issue 6, pp 1047–1056 | Cite as

Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials

Risk of sorafenib-associated death
  • Xiongwen Yang
  • Xiong Pan
  • Xiaoshu Cheng
  • Yingzhang ChengEmail author
  • Yukang KuangEmail author
Research Article


Background Sorafenib is a relatively new multi-kinase inhibitor used to treat a wide range of cancers. As fatal adverse events from sorafenib therapy are rare, their investigation requires a meta-analysis. Aim of the review To provide a meta-analysis of sorafenib-associated fatal adverse events with the most expansive and current data. Method We searched Medline, EMBASE, Web of Science and Cochrane Library databases. We also searched abstracts from a number of conferences. Twenty trials of sorafenib were found in 9434 cancer patients, tested against placebos and against other drugs. We calculated relative risks and incidences for sorafenib-associated mortality. Results Overall incidence of sorafenib-associated mortality was 3.3 %. Patients with renal cell carcinoma (RCC) and thyroid cancer had treatment-related mortality ≥5 %. Patients treated with sorafenib had a significantly greater risk of mortality than those in placebo/control groups, with an RR of 1.75. Subgroup analyses also showed significant differences in sorafenib versus placebo (RR 1.87, 95 % CI 1.23–2.86; I 2 = 0.0 %, P = 0.865); and sorafenib + platinum-based chemotherapy (RR 2.03, 95 % CI 1.15–3.59; I 2 = 0.0 %, P = 0.654). However, sorafenib had lower risk than other multi-targeted antiangiogenic tyrosine kinase inhibitors. Patients with RCC and non-small-cell lung carcinoma were significantly more vulnerable. Conclusion Sorafenib presents a significant risk of fatal adverse events (FAEs) in patients with cancer, especially for RCC or non-small-cell lung carcinoma, and in patients treated with sorafenib + platinum-based chemotherapy. However, compared with other multi-targeted antiangiogenic tyrosine kinase inhibitors, sorafenib has a lower risk of FAEs.


Adverse events Meta-analysis Mortality Relative risk Sorafenib Tyrosine kinase inhibitors 



We thank Edanz for its linguistic assistance during the preparation of this manuscript.


No special funding was received for this review.

Conflicts of interest

The authors have no conflict of interest.


  1. 1.
    Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Carlomagno F, Anaganti S, Guida T, Salvatore G, Troncone G, Wilhelm SM, et al. BAY 43-9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006;98(5):326–34.CrossRefPubMedGoogle Scholar
  3. 3.
    de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA. 1998;95(15):8847–51.PubMedCentralCrossRefGoogle Scholar
  4. 4.
    Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–44.CrossRefPubMedGoogle Scholar
  5. 5.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009;27(17):2823–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304(19):2154–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(11):1835–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Spigel DR, Burris HA 3rd, Greco FA, Shipley DL, Friedman EK, Waterhouse DM, et al. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(18):2582–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang Y, Wang L, Liu Y, Yu S, Zhang X, Shi Y, et al. Randomize trial of cisplatin plus gemcitabine with either sorafenib or placebo as first-line therapy for non-small cell lung cancer. Chin J Lung Cancer. 2011;14(3):239–44.Google Scholar
  11. 11.
    Baselga J, Segalla JG, Roche H, Del Giglio A, Pinczowski H, Ciruelos EM, et al. Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer. J Clin Oncol. 2012;30(13):1484–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, et al. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012;30(25):3084–92.CrossRefPubMedGoogle Scholar
  13. 13.
    Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31(32):4067–75.CrossRefPubMedGoogle Scholar
  14. 14.
    Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, et al. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. 2013;49(2):312–22.CrossRefPubMedGoogle Scholar
  15. 15.
    Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013;31(3):373–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14(13):1287–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol. 2013;31(30):3791–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Schwartzberg LS, Tauer KW, Hermann RC, Makari-Judson G, Isaacs C, Beck JT, et al. Sorafenib or placebo with either gemcitabine or capecitabine in patients with HER-2-negative advanced breast cancer that progressed during or after bevacizumab. Clin Cancer Res. 2013;19(10):2745–54.CrossRefPubMedGoogle Scholar
  20. 20.
    Tabernero J, Garcia-Carbonero R, Cassidy J, Sobrero A, Van Cutsem E, Kohne CH, et al. Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial. Clin Cancer Res. 2013;19(9):2541–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–28.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(8):760–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Krege S, Rexer H, vom Dorp F, de Geeter P, Klotz T, Retz M, et al. Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05). BJU Int. 2014;113(3):429–36.CrossRefPubMedGoogle Scholar
  24. 24.
    Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(3):286–96.CrossRefPubMedGoogle Scholar
  25. 25.
    Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 2013;61(4):1–117.PubMedGoogle Scholar
  26. 26.
    Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol. 2012;30(8):871–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Sivendran S, Liu Z, Portas LJ Jr, Yu M, Hahn N, Sonpavde G, et al. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat Rev. 2012;38(7):919–25.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang X-J, Zhang T-Y, Yu F-F, Wei X, Li Y-S, Xu F, et al. Risk of treatment-related mortality with sorafenib in patients with cancer. Asian Pac J Cancer Prev. 2013;14(11):6681–6.CrossRefGoogle Scholar
  29. 29.
    Institute NC. Common terminology criteria for adverse events v3. 0 (CTCAE). Cancer Therapy Evaluation Program. 2006.
  30. 30.
    Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455–63.CrossRefPubMedGoogle Scholar
  31. 31.
    Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14(6):552–62.CrossRefPubMedGoogle Scholar
  32. 32.
    Lenihan DJ. Tyrosine kinase inhibitors: can promising new therapy associated with cardiac toxicity strengthen the concept of teamwork? J Clin Oncol. 2008;26(32):5154–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Vaklavas C, Lenihan D, Kurzrock R, Tsimberidou AM. Anti-vascular endothelial growth factor therapies and cardiovascular toxicity: what are the important clinical markers to target? Oncologist. 2010;15(2):130–41.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Bair SM, Choueiri TK, Moslehi J. Cardiovascular complications associated with novel angiogenesis inhibitors: emerging evidence and evolving perspectives. Trends Cardiovasc Med. 2013;23(4):104–13.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Kimura T, Suetomi T, Miyagawa T, Tsutsumi M. A case of fatal clinical course with reversible acute cardiac failure and glucose intolerance during sorafenib therapy for metastatic renal cell carcinoma. Hinyokika Kiyo. 2012;58(8):443–6.PubMedGoogle Scholar
  36. 36.
    Frieling T, Heise J, Wassilew SW. Multiple colon ulcerations, perforation and death during treatment of malignant melanoma with sorafenib. Dtsch Med Wochenschr. 2009;134(28–29):e1–2, 1464–6.Google Scholar

Copyright information

© Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Authors and Affiliations

  1. 1.Medical College of Nanchang UniversityNanchangChina
  2. 2.The Second Affiliated Hospital of Nanchang UniversityNanchangChina
  3. 3.Thoracic Surgery of Jiangxi Province Tumor HospitalNanchangChina

Personalised recommendations