Acute hepatic failure following monotherapy with sunitinib for ovarian cancer

Taran, A; Ignatov, Atanas; Smith, Bobbie; Costa, Serban Dan; Bischoff, Joachim

doi:10.1007/s00280-008-0814-7

Cited by 19 publications

(8 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The frequency of severe adverse events occurring in these studies suggests a potentially better tolerability of the lower dose of 37.5 mg given in a 4 weeks on and 2 weeks off schedule. Whether sunitinib could induce life-threatening hepatic toxicity with liver failure, as has been reported previously in ovarian cancer, 41 should be carefully evaluated in larger HCC populations in the future.…”

Section: Early Clinical Experience In Hccmentioning

confidence: 83%

Development of Sunitinib in Hepatocellular Carcinoma: Rationale, Early Clinical Experience, and Correlative Studies

Duda¹,

Sahani²,

Jain³

2009

The Cancer Journal

View full text Add to dashboard Cite

The approval of a multitargeted receptor tyrosine kinase inhibitor, sorafenib, with activity against vascular endothelial growth factor receptor-2 and -3, Raf-1 and B-Raf, platelet-derived growth factor receptor-α and -β, and other kinases, has ushered in the era of molecular targeted agents in advanced hepatocellular carcinoma (HCC). Sunitinib malate is an oral, multitargeted inhibitor of vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-α and -β, and other kinases implicated in tumor growth, angiogenesis, and metastasis. Sunitinib has been approved in metastatic renal cell carcinoma and gastrointestinal stromal tumor and is undergoing active clinical development in HCC. Early evidence of antitumor activity and a promising safety profile for this agent have emerged from single arm phase II trials in United States, European, and Asian patients with advanced HCC. Correlative studies of imaging and circulating biomarkers have provided insights into the potential mechanism of action of sunitinib. Additional phase II studies using either single agent or in combination with chemotherapeutic agents are ongoing, and a phase III trial comparing sunitinib and sorafenib in advanced HCC is actively accruing patients. Here, we review the current progress and future directions for the development of sunitinib in advanced HCC.

show abstract

Section: Early Clinical Experience In Hccmentioning

confidence: 83%

Development of Sunitinib in Hepatocellular Carcinoma: Rationale, Early Clinical Experience, and Correlative Studies

Duda¹,

Sahani²,

Jain³

2009

The Cancer Journal

View full text Add to dashboard Cite

show abstract

“…Sunitinib can cause hepatotoxicity, including acute hepatitis and fatal fulminant hepatic failure, and it should be discontinued after grades 3 and 4 hepatic adverse events [23][24][25] . However, sunitinib has also been shown to be protective of the liver.…”

Section: Toxicities Of Folfox and Sunitinibmentioning

confidence: 99%

Medullary Thyroid Cancer and Pseudocirrhosis: Case Report and Literature Review

et al. 2012

View full text Add to dashboard Cite

and spindle-cell morphologies, and a diagnosis of medullary thyroid carcinoma (mtc) was made.On baseline positron-emission tomography (pet)/ ct imaging, hypodensities corresponding to hypermetabolic foci in both hepatic lobes were observed [ Figure 1 , and cytokeratin 7, but negative for thyroglobulin, cytokeratin 20, and alpha-fetoprotein, which is consistent with mtc metastatic to the liver. At the time of diagnosis, the patient was not taking medications, and she had an unremarkable personal medical history and no family history of thyroid disease, endocrine disorders, or neoplasm.In March 2008, the patient enrolled in a phase i clinical trial (NCT00599924) of 5-fluorouracil (5fu), leucovorin, and oxaliplatin (folfox) in combination with sunitinib, a tyrosine kinase inhibitor with multiple targets, including the vascular endothelial growth factor receptor and the rearranged during transfection (RET) proto-oncogene, which is often upregulated in neuroendocrine tumors such as mtc 1 . The patient received folfox (leucovorin 400 mg/m 2 ; 5-fluorouracil 400 mg/m 2 intravenous bolus, followed by 2400 mg/m 2 infusion over 46 hours; oxaliplatin 85 mg/m 2 ) every 2 weeks and sunitinib 37.5 g daily for 4 weeks, followed by a 2-week rest period. In July 2008, after 4 months of folfox-sunitinib, the patient showed measureable tumor regression in the liver [Figure 1(D)] that qualified as a partial response according to the Response Evaluation Criteria in Solid Tumors. The folfox was discontinued, and the patient was maintained on single-agent sunitinib, which she tolerated well for 15 months with stable liver metastases. The patient underwent serial pet/ ct imaging without intravenous contrast to monitor her disease.In November 2009 (21 months after diagnosis), the patient developed abdominal bloating, early satiety, and right upper quadrant pain that increased with inspiration. Pulmonary exam demonstrated dullness ABSTRACT Pseudocirrhosis is a rare form of liver disease that can cause clinical symptoms and radiographic signs of cirrhosis; however, its histologic features suggest a distinct pathologic process. In the setting of cancer, hepatic metastases and systemic chemotherapy are suspected causes of pseudocirrhosis. Here, we present a patient with medullary thyroid carcinoma metastatic to the liver who developed pseudocirrhosis while on maintenance sunitinib after receiving 5-fluorouracil, leucovorin, and oxaliplatin (folfox) in combination with sunitinib. Cirrhotic change in liver morphology was accompanied by diffusely infiltrative carcinomatous disease resembling the primary tumor. We discuss the diagnosis of pseudocirrhosis in this case and review the literature regarding pseudocirrhosis in cancer. KEY WORDSMedullary thyroid cancer, pseudocirrhosis, carcinomatous cirrhosis CASE DESCRIPTIONA 49-year-old white woman presented in January 2008 with a left-sided cervical mass without associated complaints of neck pain, stridor, dysphonia, dysphagia, malaise, fever, or chills. Physical examination was remarkable for a f...

show abstract

“…Although the clinical dose of sunitinib (50–150 mg·day −1 ) is not too high, sunitinib is given to patients continuously for several months, which might cause accumulation of sunitinib and its reactive metabolites. This might explain why sunitinib does not induce liver injury after the first round of use, with liver injury typically occuring during later cycles of sunitinib (Guillen et al, ; Mermershtain et al, ; Mueller et al, ; Taran et al, ; Weise et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…A population‐based cohort study also found that severe liver injury occurred infrequently during exposure to sunitinib: 7.4–9.3% patients had doubled alanine transaminase (ALT) elevation; 8.6–18.1% patients had elevated bilirubin (Shantakumar et al, ). Furthermore, many clinical cases were reported on liver failure following sunitinib administration (Guillen, Meijer, & de Jongh, ; Mermershtain, Lazarev, Shani‐Shrem, & Ariad, ; Mueller, Rockey, & Rashkin, ; Taran, Ignatov, Smith, Costa, & Bischoff, ; Weise, Liu, & Shields, ). Recent studies reported that mitochondrial damage, inhibition of glycolysis, and metabolic activation contributed to sunitinib hepatotoxicity (Amaya et al, ; Paech, Bouitbir, & Krahenbuhl, ).…”

Section: Introductionmentioning

confidence: 99%

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Zhao

Zhang

Xiao

et al. 2019

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose Sunitinib is a small‐molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. Experimental Approach In the present study, mice were treated with 60, 150, and 450 mg·kg−1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra‐performance LC electrospray ionization quadrupole time‐of‐flight MS‐based metabolomics. Key Results Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib‐induced hepatotoxicity. Using a non‐targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid β‐oxidation (β‐FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. Conclusions and Implications These studies identified significant alterations in mitochondrial β‐FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

show abstract

Acute hepatic failure following monotherapy with sunitinib for ovarian cancer

Cited by 19 publications

References 6 publications

Development of Sunitinib in Hepatocellular Carcinoma: Rationale, Early Clinical Experience, and Correlative Studies

Development of Sunitinib in Hepatocellular Carcinoma: Rationale, Early Clinical Experience, and Correlative Studies

Medullary Thyroid Cancer and Pseudocirrhosis: Case Report and Literature Review

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Contact Info

Product

Resources

About