Abstract
Background
Regorafenib is a novel multikinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). Hypertension is one of the major adverse events of this agent, but to date the incidence and risk of hypertension with regorafenib have not been systematically investigated. We have conducted a systematic review and meta-analysis of published clinical trials to determine its overall incidence and risk.
Methods
PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies published up to September 9, 2013. Eligible studies were prospective phase II or III clinical trials using regorafenib in cancer patients with data on hypertension available. The incidence and relative risk (RR) of hypertension were calculated using a random-effects model.
Results
Data from a total of 1,069 patients (regorafenib n = 750; controls n = 319) from five clinical trials were included for analysis. The overall incidence of all-grade and high-grade hypertension were 44.4 % [95 % confidence interval (CI) 30.8–59.0 %) and 12.5 % (95 % CI 5.2–27.1 %), respectively. The use of regorafenib in cancer patients was associated with a significantly increased risk of all-grade (RR 3.76, 95 % CI 2.35–5.99) and high-grade (RR, 8.39, 95 % CI 3.10–22.71) hypertension. The risk might vary with tumor types (P = 0.000).
Conclusions
Patients with cancer receiving regorafenib have a significantly higher risk of developing hypertension. Close monitoring and appropriate management of this hypertension are strongly recommended.
Similar content being viewed by others
References
Davis SL, Eckhardt SG, Messersmith WA et al (2013) The development of regorafenib and its current and potential future role in cancer therapy. Drugs Today 49(2):105–115
Strumberg D, Schultheis B (2012) Regorafenib for cancer. Expert Opin Investig Drugs 21(6):879–889
Wilhelm SM, Dumas J, Adnane L et al (2011) Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 129(1):245–255
Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):303–312
George S, Wang Q, Heinrich MC et al (2012) Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 30(19):2401–2407
Demetri GD, Reichardt P, Kang YK et al (2013) Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863):295–302
ClinicalTrials.gov [Internet] Regorafenib. National Library of Medicine (US), Bethesda. Available at: http://www.clinicaltrials.gov/ct2/results/map?term=regorafenib. Accessed 10 Sep 2013
Belum VR, Wu S, Lacouture ME (2013) Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Investig New Drugs 31(4):1078–1086
Funakoshi T, Latif A, Galsky MD (2013) Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. J Hum Hypertens 7(10):601–611
Qi WX, He AN, Shen Z et al (2013) Incidence and risk of hypertension with a novel multitargeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol 76(3):348–357
Qi WX, Lin F, Sun YJ et al (2013) Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis. Cancer Chemother Pharmacol 71(2):431–439
Qi WX, Shen Z, Lin F et al (2013) Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials. Br J Clin Pharmacol 75(4):919–930
Zhu X, Stergiopoulos K, Wu S (2009) Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 48(1):9–17
Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134
Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124
Chu TF, Rupnick MA, Kerkela R et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370(9604):2011–2019
Bruix J, Tak WY, Gasbarrini A et al (2013) Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study. Eur J Cancer 9(16):3412–3419
Eisen T, Joensuu H, Nathan PD et al (2012) Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol 13(10):1055–1062
Weisstuch JM, Dworkin LD (1992) Does essential hypertension cause end-stage renal disease? Kidney Int Suppl 36(7):S33–S37
Aronow WS (2013) Optimal blood pressure goals in patients with hypertension at high risk for cardiovascular events. Am J Ther. doi:10.1097/MJT.0b013e31827c5372
Rixe O, Billemont B, Izzedine H (2007) Hypertension as a predictive factor of Sunitinib activity. Ann Ocol 8:1117
Rini BI, Cohen DP, Lu DR et al (2011) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103(9):763–773
Estfan B, Byrne M, Kim R (2013) Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol 36(4):319–324
Wu S, Chen JJ, Kudelka A et al (2008) Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 9(2):117–123
Kappers MH, de Beer VJ, Zhou Z et al (2012) Sunitinib-induced systemic vasoconstriction in swine is endothelin mediated and does not involve nitric oxide or oxidative stress. Hypertension 59(1):151–157
Banfor PN, Franklin PA, Segreti JA et al (2009) ETA receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor ABT-869 in telemetry-instrumented rats. J Cardiovasc Pharmacol 53(2):173–178
Lankhorst S, Kappers MH, van Esch JH et al (2013) Hypertension during vascular endothelial growth factor inhibition: focus on nitric oxide, endothelin-1, and oxidative stress. Antioxid Redox Signal. doi:10.1089/ars.2013.5244.:3
Kappers MH, Smedts FM, Horn T et al (2011) The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. Hypertension 58(2):295–302
Shirasaki Y, Tsushima T, Nasu Y et al (2004) Long-term consequence of renal function following nephrectomy for renal cell cancer. Int J Urol 11(9):704–708
Melman A, Grim CE, Weinberger MH (1977) Increased incidence of renal cell carcinoma with hypertension. J Urol 118(4):531–532
Izzedine H, Ederhy S, Goldwasser F et al (2009) Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol 20(5):807–815
Langenberg M, Van Herpen C, De Bono J et al (2008) Optimal management of emergent hypertension during treatment with a VEGF signaling inhibitor: a randomized phase II study of cediranib. J Clin Oncol 26[Suppl]:(abstr 3555)
Acknowledgments
This project is supported by grants from National Natural Science Foundation of China (81272252), Natural Science Foundation of Jiangsu Province (BK2011656).
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Zexing Wang and Jing Xu contributed equally to this work.
Rights and permissions
About this article
Cite this article
Wang, Z., Xu, J., Nie, W. et al. Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. Eur J Clin Pharmacol 70, 225–231 (2014). https://doi.org/10.1007/s00228-013-1598-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-013-1598-1