Fatal Liver Failure in a Patient Treated With Sunitinib for Renal Cell Carcinoma Willmosh Mermershtain, Irena Lazarev, Noa Shani-Shrem, Samuel Ariad Introduction Sunitinib (sunitinib malate, SU11248, SUTENT; Pfizer, New York, NY) is a novel small molecule receptor tyrosine kinase inhibi- tor with direct antitumor as well as antiangiogenic activity via target- ing the vascular endothelial growth factor, platelet-derived growth factor, KIT, and FLT3 receptor tyrosine kinases. 1 The drug is ap- proved multinationally for the treatment of renal cell carcinoma (RCC), gastrointestinal stromal tumor, and pancreatic neuroendo- crine tumor. 2 The safety of sunitinib has been studied in patients with RCC with only a relatively small proportion of patients with grade 2/3 liver toxicity and no grade 4 toxicity. 2,3 A few case reports described serious liver toxicity, including fatal outcome ascribed to the treatment with sunitinib. 4-6 Here we report a case of a patient with RCC and chronic obstructive lung disease accompanied by severe pulmonary arterial hypertension that developed fulminant he- patic failure during the first cycle of treatment with sunitinib. A possible mechanism of toxicity in this case and review of the literature are presented in this report. Case Report In July 2011, a 62-year-old man presented with progressive weak- ness and anorexia that followed a new treatment with sunitinib. Jaundice, fever, and vomiting developed during the 2 days before his presentation. The patient’s medical history included chronic ob- structive lung disease for which he received inhalations with tiotro- pium and was accompanied by severe pulmonary arterial hyperten- sion. Tamsulosin 0.4 mg daily and dutasteride 0.5 mg daily were given for benign prostatic hypertrophy. The patient was not taking any over-the counter or herbal medicines. The patient had been a heavy smoker, with an estimate of more than 100 pack-years of consumption of cigarettes. He had no personal history of liver dis- ease, nor of drug abuse, and reported rare consumption of alcohol only. In December 2010, the patient was studied for worsening of symptoms related to chronic obstructive lung disease. His FEV 1 was 32%, and free-air, arterial blood saturation was 89%. Despite treat- ment with oral steroids and inhaled bronchodilators, lung functions did not improve. A computed tomography of the chest showed ad- vanced emphysematous changes accompanied by widening of the pulmonary arteries to a maximal diameter of 27 mm. In addition, a 5-cm mass was found in the left kidney, typical of RCC. Steroids were gradually tapered off, and inhalations with tiotropium were prescribed. An echocardiogram confirmed the diagnosis of pulmo- nary arterial hypertension with mild tricuspid regurgitation. Because of his poor lung function, the pulmonologist recommended that the Departments of Oncology, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva, Israel Submitted: Dec 3, 2011; Revised: Aug 26, 2012; Accepted: Sep 13, 2012; Epub: Oct 12, 2012 Address for correspondence: Samuel Ariad, Department of Oncology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, PO Box 151, Israel 84101 E-mail contact: ariads@clalit.org.il Clinical Practice Points ● Sunitinib is a novel small molecule receptor tyrosine kinase inhibitor with direct antitumor as well as anti- angiogenic activity via targeting the vascular endothe- lial growth factor (VEGF), platelet-derived growth fac- tor (PDGF), KIT, and FLT3 receptor tyrosine kinases. ● It is widely used for the treatment of renal cell carci- noma (RCC), gastrointestinal stromal tumor (GIST), and pancreatic neuroendocrine tumor (pNET). ● We report a case of fatal hepatic failure in a patient with RCC treated with sunitinib during the first cycle of treatment. ● The patient had pre-existing advanced emphysema accompanied by severe pulmonary arterial hyperten- sion. He was not receiving any other drugs that are known to cause liver damage or to potentiate sunitinib toxicity. ● We suggest that fulminant hepatic failure during treat- ment with sunitinib in this case was related to pulmo- nary arterial hypertension. Clinical Genitourinary Cancer, Vol. 11, No. 1, 70-2 © 2013 Elsevier Inc. All rights reserved. Keywords: Adverse reaction, Hepatotoxicity, Pulmonary arterial hypertension, Sunitinib, Tyrosine kinase Case Report 70 Clinical Genitourinary Cancer March 2013 1558-7673/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2012.09.005