Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials
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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.
KeywordsAdverse 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.
- 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
- 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.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
- 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
- 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
- 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.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
- 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
- 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
- 29.Institute NC. Common terminology criteria for adverse events v3. 0 (CTCAE). Cancer Therapy Evaluation Program. 2006. http://ctep.cancer.gov/reporting/ctc_archive.html.
- 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
- 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