Abstract
Tyrosine kinase inhibitors (TKIs) are widely used for systemic chemotherapy of hepatocellular carcinoma (HCC). Arterial thromboembolism (ATE) has been reported to be an adverse event associated with TKI therapy, but its incidence is rare. Here, we report a case of an HCC patient who developed a thrombus in the superior mesenteric artery (SMA) while on TKI therapy. The patient was a 78-year-old Japanese man with hepatitis C virus-associated HCC with multiple nodules. Several sessions of transarterial chemoembolization therapy caused him to become refractory to the treatment. Sorafenib and regorafenib therapy had also been previously performed, but his disease continued to progress gradually. Therefore, we started lenvatinib therapy. When a contrast-enhanced computed tomography (CT) examination was performed 2 months later, we found a thrombus in the SMA. Retrospective analysis of the CT images revealed that the thrombus formed during the sorafenib–regorafenib sequential therapy and it developed rapidly, especially during the lenvatinib therapy. An HCC patient developed a thrombus in the SMA during TKI therapy. The incidence of ATE is rare in TKI treatment; however, long-term or sequential TKI therapy may increase the frequency of ATE. Further study is needed.
Similar content being viewed by others
References
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73.
Finn RS, Merle P, Granito A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial. J Hepatol. 2018;69:353–8.
Iavarone M, Cabibbo G, Piscaglia F, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology. 2011;54:2055–63.
Katayama K, Kiyota R, Imai T, et al. Factors affecting therapeutic effects in 17 patients with advanced hepatocellular carcinoma who were treated with sorafenib for more than 12 months. Case Rep Oncol. 2018;11:711–20.
Ren Z, Zhu K, Kang H, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:894–900.
Izzedine H, Ederhy S, Goldwasser F, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol. 2009;20:807–15.
Ranpura V, Hapani S, Chuang J, et al. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010;49:287–97.
Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28:2280–5.
Hiraoka A, Kumada T, Kudo M, et al. Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions: multicenter analysis. Cancer Med. 2019;8:137–46.
Winnik S, Lohmann C, Siciliani G, et al. Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis–implications for cardiovascular safety. Int J Cardiol. 2013;168:2453–61.
Touyz RM, Hermann SMS, Hermann J. Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. J Am Soc Hypertens. 2018;12:409–25.
Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378:615–24.
Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014:638747.
Yamamoto Y, Imamura H, Matsuyama Y, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6:18.
Okamoto K, Ikemori-Kawada M, Jestel A, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2015;6:89–94.
Oshima Y, Tanimoto T, Yuji K, et al. Association between aortic dissection and systemic exposure of vascular endothelial growth factor pathway inhibitors in the Japanese adverse drug event report database. Circulation. 2017;135:815–7.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Human rights
All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Informed consent
Informed consent was obtained from the patient who is the subject of this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Nawa, T., Katayama, K., Kiyota, R. et al. Development of a thrombus in the superior mesenteric artery associated with sequential therapy with tyrosine kinase inhibitors for hepatocellular carcinoma. Clin J Gastroenterol 13, 247–251 (2020). https://doi.org/10.1007/s12328-019-01021-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12328-019-01021-6