American Journal of Therapeutics 23, e583–e587 (2016)
A Rare Case of Sunitinib-Induced Hyperammonemic Encephalopathy and Hypothyroidism in Metastatic Renal Cell Carcinoma Kezban Nur Pilancı, MD,1* Filiz Elbüken, MD,2 Çetin Ordu, MD,¹ Gülistan Köksal, MD,3 Mehmet Hakan Tekelio glu, MD,4 Kerem Okutur, MD,¹ Süha Göksel, MD,5 Ülkühan Köksal, MD,¹ Tarık Akçal, MD,4 and Cosxkun Tecimer, MD¹
Sunitinib has become a standard treatment agent for metastatic renal cell carcinoma (RCC) for several years. However, various adverse events have been reported. We present a rare adverse effect of hyperammonemic encephalopathy induced by sunitinib. A 66-year-old woman with metastatic RCC referred to the emergency department with confusion that developed 14 days after the initiation of 50 mg/d of sunitinib. Her serum ammonia and thyroid-stimulating hormone levels were markedly elevated (146 mg/ dL and 27.27 mIU/mL, respectively). Sunitinib was discontinued, and an enema with lactulose and L-thyroxine were administered. Her mental status and neurologic symptoms were normalized 7 days after the treatment. Serum ammonia level decreased to 61 mg/dL and thyroid stimulating hormone level decreased 22.34 mIU/mL. The incidence of sunitinib-induced hyperammonemia is rarely reported. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. Sunitinib-induced hyperammonemia is very rare, and to the best of our knowledge, this is fourth case hyperammonemia and first case hyperammonemic encephalopathy with hypothyroidism as an adverse effect. Therefore, it is important for clinicians to be aware of hyperammonemia that can occur in several days after the initiation of sunitinib treatment in metastatic RCC. Keywords: hyperammonemic encephalopathy, sunitinib, renal cell carcinoma, hypothyroidism
INTRODUCTION Sunitinib malate is an oral multitarget tyrosine kinase inhibitor, which has shown antiangiogenic and antitumor activities in several in vitro and in vivo tumor models.1–6 Sunitinib selectively inhibits class III, V, 1
Department of Medical Oncology, Faculty of Medicine, Bilim University, Istanbul, Turkey; Departments of 2Radiology, 3Medical Oncology, and 4General Surgery, Gayrettepe Florence Nightingale Hospital, Besiktas, Turkey; and 5Department of Pathology, Acıbadem Hospital, Istanbul, Turkey. The authors have no conflicts of interest to declare. *Address for correspondence: Avrupa Florence Nightingale Hastanesi, Bilim Universitesi, S xisxhane, Beyoglu, No: 1, Istanbul 34440, Turkey. E-mail: [email protected]
and XII split kinase domain receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR 1, VEGFR 2, and VEGFR 3), platelet-derived growth factor receptors (PDGFR-a and PDGFR-h), stem cell factor receptor, and FMS-like tyrosine kinase-3 receptor, as well as the glial cell line–derived neurotrophic factor receptor.2,3,5,7,8 Sunitinib is used worldwide for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumors.9,10 The management of adverse effects is essential for treatment continuance. Various adverse effects have been reported, including diarrhea, nausea, hypertension, and thyroid dysfunction.9,10 We report a case of hyperammonemic encephalopathy and hypothyroidism induced by sunitinib after metastasectomy of isolated multicentric pancreatic lesions due to RCC.
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e584
Pilancı et al
CASE REPORT A 66-year-old woman referred to our hospital with confusion in February 2013. Twelve years ago, in 2001, she had undergone right radical nephrectomy for RCC. The pathologic stage revealed T3N0M0. She had indigestion, nausea, and bloating in November 2012. Physical examination on admission revealed no abnormalities. Laboratory studies indicated hyperglycemia (213 mg/dL), but the levels of the tumor markers (CEA and CA19-9) and bilirubin, liver function tests, serum amylase were all in normal limits. Magnetic resonance imaging (MRI) showed hypervascular medullary masses on head, tail, and corpus in the pancreas (Figure 1). Positron emission tomography with F-18 fluorodeoxyglucose indicated an increased uptake of F-18 fluorodeoxyglucose within the lesion of the pancreatic uncinate processes (SUV[max]: 4.8). No extrapancreatic uptake was seen. A computerized tomography of the thorax and MRI of the brain were performed for the detection of metastasis. Both of them were negative. A biopsy was performed under computerized tomography guidance. Head and uncinate process of pancreatic gland were chosen as a target for fine needle aspiration biopsy. The result of pathology was metastasis of RCC. Vimentin, PAN-CK, RCC, and CD10 were significantly positive. Complete pancreatectomy, splenectomy, and cholecystectomy were performed in January 22, 2013 (Figure 2). These pathologic findings were consistent with pancreatic metastases from RCC (Figure 3). The postoperative course was uneventful, and the patient was discharged 2 weeks after the surgery, and sunitinib treatment was initiated. She was presented to the emergency department with confusion
FIGURE 1. MRI image. American Journal of Therapeutics (2016) 23(2)
FIGURE 2. Pathologic gross appearance of resected pancreas.
developed 14 days after sunitinib (50 mg/d) therapy. MRI of the brain showed no evidence of brain metastasis. She had no risk factors like medications for viral hepatitis and alcoholic liver disease. Laboratory tests showed AST (34 IU/L) and ALT (25 IU/L), normal total bilirubin (0.58 mg/dL), INR (1.10), and markedly elevated ammonia (146 mg/dL; normal range, 11–51 mg/dL) and thyroid-stimulating hormone (TSH) (27.27mIU/mL; normal range, 0.27–4.20). There were no signs of hemorrhage, infection, or renal insufficiency. Sunitinib was discontinued. Under the clinical diagnosis of sunitinib-induced hyperammonemic encephalopathy and hypothyroidism, an enema with lactulose was administered every hour, and L-thyroxine
FIGURE 3. Histology of the resected pancreatic specimen showing clear cells of RCC, capsule, and normal pancreas. www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A Very Rare Sunitinib-Induced Adverse Effect
was given for hypothyroidism. Her mental status and neurologic symptoms were normalized in 7 days after the treatment. Also, serum ammonia level decreased to 61 mg/dL.
DISCUSSION Sunitinib is a small molecule and an inhibitor of certain receptor tyrosine kinases, including VEGFR types 1 and 2 (FLT-1 and FLK-1/KDR), PDGFR-a and PDGFR-b, stem cell factor receptor (c-KIT), and the FLT-3 and RET kinases.11 Clear cell RCC is characterized by frequent loss of the von Hippel–Lindau tumor suppressor gene, resulting in an increased transcription of several proteins, including vascular endothelial growth factor and platelet-derived growth factor.12 Tumor angiogenesis is stimulated in part by VEGF binding to its receptor. Preclinical data suggest that sunitinib has antitumor activity that might result predominantly from the inhibition of tumor angiogenesis, although it also has direct antiproliferative and apoptotic effects on certain tumor types (metastatic RCC, imatinib resistant gastrointestinal stromal tumors).3 The recommended dose for sunitinib for patients with advanced RCC is one 50-mg oral dose daily, with or without food, for 4 consecutive weeks, followed by a 2-week period without treatment, comprising a 6-week cycle.7 Treatment is continued until progression of the disease, occurrence of unacceptable toxic effects, or the refusal of the therapy.7 The most common (.15%) adverse effects are fatigue, diarrhea, nausea, anorexia, dysgeusia, vomiting, yellow skin, mucosal inflammation, hypertension (.140/90 mm Hg), rash, stomatitis, dyspepsia, headache, hand–foot syndrome, asthenia, hair color changes, anemia, neutropenia, and thrombocytopenia.13 Rare but serious ones are venous thromboembolism, hepatic failure (22–435 days after the initiation of treatment), prolonged QT interval, hypothyroidism, and reversible posterior leukoencephalopathy syndrome.14–17 Hyperammonemic encephalopathy is rare adverse effect after sunitinib treatment. Ammonia, the major nitrogenous product of protein catabolism, is a highly toxic compound, particularly to the brain. Hyperammonemic encephalopathy is an uncommon potentially fatal complication of chemotherapy that is characterized by abrupt alteration in mental status with a markedly elevated serum ammonium level in the absence of obvious liver disease.18 Hypothyroidism has been reported in patients as early as 1–2 weeks after the initiation of sunitinib treatment, and the incidence increases progressively with www.americantherapeutics.com
e585
the duration of therapy.19 In 85% RCC cases, patients treated with sunitinib had abnormal results including elevation of TSH levels, decreased T3 levels, and, less commonly, decreased T4 or free-thyroxine index levels.19 An abnormal serum TSH concentration and mild symptoms are consistent with hypothyroidism, such as fatigue, anorexia, edema, fluid retention, or cold intolerance, and may precede the onset of overt hypothyroidism, which may rapidly progress from mild to profound.20 Patients with subclinical hypothyroidism should also be considered for the treatment; typical doses of L-thyroxine should normalize TSH levels and resolve symptoms.21 Pancreatic metastasis of RCC is rare and usually present themselves many years after the primary diagnosis.22–24 They are accompanied by metastatic lesions in the brain, lungs, or bones. Solitary tumors in the pancreas are extremely rare (0.3% of all pancreatic tumors).25 In the absence of widespread disease, pancreatic resection can provide long-term survival in metastatic RCC, although a few cases have been reported with long-term follow-up.23 The prognosis is better than pancreatic adenocarcinoma. Surgical resection of primary RCC and metastatic deposits remain the most effective treatment because chemotherapy, radiotherapy, and hormonal therapy are generally ineffective.26 Five-year survival ranges from 29% to 81%.27,28 Matsumoto et al29 investigated the clinical efficacy and safety of sunitinib in patients with imatinibresistant gastrointestinal stromal tumor. The common adverse events were hand–foot syndrome, liver dysfunction, fatigue, anorexia, and hypertension. Hyperammonemia was observed in 1 patient, who was given 7 courses of sunitinib. The patient was asymptomatic. This adverse event may in part be caused by a vascular disorder related to the antiangiogenic properties of sunitinib. Lee et al30 report 2 cases of hyperammonemic encephalopathy induced by sunitinib with metastatic gastrointestinal stromal tumour (GIST). Sunitinib was the probable cause of hyperammonemic encephalopathy in both cases. Neurologic symptoms were resolved within 24 hours after the withdrawal of the drug (combined with supportive care). Hyperammonemia occurs when ammonia is either overproduced or insufficiently eliminated from the blood. The metabolism of ammonia occurs primarily through the urea cycle, where it is a by-product of the conversion of amino acids to a-ketoacids.18 The association between sunitinib and 6 enzymes involved in the urea cycle has not been studied.31 In this case study, we seek to present an isolated multicentric metastatic disease of the pancreas of a patient who has undergone right radical nephrectomy American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e586
for RCC. Initially, the patient was referred to the surgery department for radical pancreatectomy for having the benefit of increasing the survival and hence, she had no other systemic metastases. Three weeks after the surgery, sunitinib was administered to the patient. Her medical treatment was complicated with hyperammonemic encephalopathy and hypothyroidism on the 14th day. Supportive medical care and L-thyroxine were sufficient to overcome these complications of treatment. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. It is important that clinicians be aware that hyperammonemia and hypothyroidism can occur several days after the start of sunitinib in patients with metastatic RCC.
Pilancı et al
10.
11. 12.
13.
14.
15.
REFERENCES 16. 1. Osusky KL, Hallahan DE, Fu A, et al. The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels. Angiogenesis. 2004;7:225–233. 2. Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471–478. 3. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9: 327–337. 4. Murray LJ, Abrams TJ, Long KR, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis. 2003;20:757–766. 5. O’Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605. 6. Schueneman AJ, Himmelfarb E, Geng L, et al. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003;63:4009–4016. 7. Product information. Sunitinib Malate (Sutent). Available at: http://www.pfizer.com/files/products/uspi_ sutent. pdf. Accessed July 12, 2010. 8. Kim DW, Jo YS, Jung HS, et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab. 2006;91: 4070–4076. 9. Rock EP, Goodman V, Jiang JX, et al. Food and Drug Administration drug approval summary: sunitinib malate fort he treatment of gastrointestinal stromal tumor American Journal of Therapeutics (2016) 23(2)
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and advanced renal cell carcinoma. Oncologist. 2007;12: 107–113. Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expandedaccess trial. Lancet Oncol. 2009;10:757–763. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884–896. Patel PH, Chadalavada RS, Chaganti RS, et al. Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res. 2006;12:7215–7220. Blay JY. Pharmacological management of gastrointestinal stromal tumours: an update on the role of sunitinib. Ann Oncol. 2010;21:208–215. 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;28:2280–2285. Taran A, Ignatov A, Smith B, et al. Acute hepatic failure following monotherapy with sunitinib for ovarian cancer. Cancer Chemother Pharmacol. 2009;63:971–972. Mueller EW, Rockey ML, Rashkin MC. Sunitinib-related fulminant hepatic failure: case report and review of the literature. Pharmacotherapy. 2008;28:1066–1070. Cumurciuc R, Martinez-Almoyna L, Henry C, et al. Posterior reversible encephalopathy syndrome during sunitinib therapy. Rev Neurol (Paris). 2008;164:605–607. Nott L, Price TJ, Pittman K, et al. Hyperammonemia encephalopathy: an important cause of neurological deterioration following chemotherapy. Leuk Lymphoma. 2007;48:1702–1711. Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2007;99:81–83. Kollmannsberger C, Soulieres D, Wong R, et al. Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. Can Urol Assoc J. 2007;1:S41–S54. Wu S, Chen JJ, Kudelka A, et al. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008;9:117–123. Thompson LD, Heffess CS. Renal cell carcinoma to the pancreas in surgical pathology material: a clinicopathologic study of 21 cases with a review of the literature. Cancer. 2000;89:1076–1088. Sohn TA, Yeo CJ, Cameron JL, et al. Renal cell carcinoma metastatic to the pancreas: results of surgical management. J Gastrointest Surg. 2001;5:346–351. Crippa S, Angelini C, Mussi C, et al. Surgical treatment of metastatic tumors to the pancreas: a single center experience and review of the literature. World J Surg. 2006;30:1536–1542. Robbins EG, Franceschi D, Barkin JS. Solitary metastatic tumors to the pancreas: a case report and review of the literature. Am J Gastroenterol. 1996;91:2414–2417. Cooperman AM. Pancreatic cancer: the bigger picture. Surg Clin North Am. 2001;81:557–574. www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A Very Rare Sunitinib-Induced Adverse Effect 27. Tuech JJ, Pessaux P, Chautard D, et al. Results of duedenopancreatectomy for solitary pancreatic metastasis from renal cell carcinoma. J Hepatobiliary Pancreatic Surg. 1999;6:396–398. 28. Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998;16: 2261–2266. 29. Matsumoto K, Sawaki A, Mizuno N, et al. Clinical efficacy and safety of sunitinib after imatinib failure in
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e587 Japanese patients with gastrointestinal stromal tumor. Jpn J Clin Oncol. 2011;41:57–62. 30. Lee NR, Yhim HY, Yim CY, et al. Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors. Ann Pharmacother. 2011;45:e56. 31. Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab. 2009;11:823–835.
American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A Rare Case of Sunitinib-Induced Hyperammonemic Encephalopathy and Hypothyroidism in Metastatic Renal Cell Carcinoma Kezban Nur Pilancı, MD,1* Filiz Elbüken, MD,2 Çetin Ordu, MD,¹ Gülistan Köksal, MD,3 Mehmet Hakan Tekelio glu, MD,4 Kerem Okutur, MD,¹ Süha Göksel, MD,5 Ülkühan Köksal, MD,¹ Tarık Akçal, MD,4 and Cosxkun Tecimer, MD¹
Sunitinib has become a standard treatment agent for metastatic renal cell carcinoma (RCC) for several years. However, various adverse events have been reported. We present a rare adverse effect of hyperammonemic encephalopathy induced by sunitinib. A 66-year-old woman with metastatic RCC referred to the emergency department with confusion that developed 14 days after the initiation of 50 mg/d of sunitinib. Her serum ammonia and thyroid-stimulating hormone levels were markedly elevated (146 mg/ dL and 27.27 mIU/mL, respectively). Sunitinib was discontinued, and an enema with lactulose and L-thyroxine were administered. Her mental status and neurologic symptoms were normalized 7 days after the treatment. Serum ammonia level decreased to 61 mg/dL and thyroid stimulating hormone level decreased 22.34 mIU/mL. The incidence of sunitinib-induced hyperammonemia is rarely reported. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. Sunitinib-induced hyperammonemia is very rare, and to the best of our knowledge, this is fourth case hyperammonemia and first case hyperammonemic encephalopathy with hypothyroidism as an adverse effect. Therefore, it is important for clinicians to be aware of hyperammonemia that can occur in several days after the initiation of sunitinib treatment in metastatic RCC. Keywords: hyperammonemic encephalopathy, sunitinib, renal cell carcinoma, hypothyroidism
INTRODUCTION Sunitinib malate is an oral multitarget tyrosine kinase inhibitor, which has shown antiangiogenic and antitumor activities in several in vitro and in vivo tumor models.1–6 Sunitinib selectively inhibits class III, V, 1
Department of Medical Oncology, Faculty of Medicine, Bilim University, Istanbul, Turkey; Departments of 2Radiology, 3Medical Oncology, and 4General Surgery, Gayrettepe Florence Nightingale Hospital, Besiktas, Turkey; and 5Department of Pathology, Acıbadem Hospital, Istanbul, Turkey. The authors have no conflicts of interest to declare. *Address for correspondence: Avrupa Florence Nightingale Hastanesi, Bilim Universitesi, S xisxhane, Beyoglu, No: 1, Istanbul 34440, Turkey. E-mail: [email protected]
and XII split kinase domain receptor tyrosine kinases, including vascular endothelial growth factor receptors (VEGFR 1, VEGFR 2, and VEGFR 3), platelet-derived growth factor receptors (PDGFR-a and PDGFR-h), stem cell factor receptor, and FMS-like tyrosine kinase-3 receptor, as well as the glial cell line–derived neurotrophic factor receptor.2,3,5,7,8 Sunitinib is used worldwide for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumors.9,10 The management of adverse effects is essential for treatment continuance. Various adverse effects have been reported, including diarrhea, nausea, hypertension, and thyroid dysfunction.9,10 We report a case of hyperammonemic encephalopathy and hypothyroidism induced by sunitinib after metastasectomy of isolated multicentric pancreatic lesions due to RCC.
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e584
Pilancı et al
CASE REPORT A 66-year-old woman referred to our hospital with confusion in February 2013. Twelve years ago, in 2001, she had undergone right radical nephrectomy for RCC. The pathologic stage revealed T3N0M0. She had indigestion, nausea, and bloating in November 2012. Physical examination on admission revealed no abnormalities. Laboratory studies indicated hyperglycemia (213 mg/dL), but the levels of the tumor markers (CEA and CA19-9) and bilirubin, liver function tests, serum amylase were all in normal limits. Magnetic resonance imaging (MRI) showed hypervascular medullary masses on head, tail, and corpus in the pancreas (Figure 1). Positron emission tomography with F-18 fluorodeoxyglucose indicated an increased uptake of F-18 fluorodeoxyglucose within the lesion of the pancreatic uncinate processes (SUV[max]: 4.8). No extrapancreatic uptake was seen. A computerized tomography of the thorax and MRI of the brain were performed for the detection of metastasis. Both of them were negative. A biopsy was performed under computerized tomography guidance. Head and uncinate process of pancreatic gland were chosen as a target for fine needle aspiration biopsy. The result of pathology was metastasis of RCC. Vimentin, PAN-CK, RCC, and CD10 were significantly positive. Complete pancreatectomy, splenectomy, and cholecystectomy were performed in January 22, 2013 (Figure 2). These pathologic findings were consistent with pancreatic metastases from RCC (Figure 3). The postoperative course was uneventful, and the patient was discharged 2 weeks after the surgery, and sunitinib treatment was initiated. She was presented to the emergency department with confusion
FIGURE 1. MRI image. American Journal of Therapeutics (2016) 23(2)
FIGURE 2. Pathologic gross appearance of resected pancreas.
developed 14 days after sunitinib (50 mg/d) therapy. MRI of the brain showed no evidence of brain metastasis. She had no risk factors like medications for viral hepatitis and alcoholic liver disease. Laboratory tests showed AST (34 IU/L) and ALT (25 IU/L), normal total bilirubin (0.58 mg/dL), INR (1.10), and markedly elevated ammonia (146 mg/dL; normal range, 11–51 mg/dL) and thyroid-stimulating hormone (TSH) (27.27mIU/mL; normal range, 0.27–4.20). There were no signs of hemorrhage, infection, or renal insufficiency. Sunitinib was discontinued. Under the clinical diagnosis of sunitinib-induced hyperammonemic encephalopathy and hypothyroidism, an enema with lactulose was administered every hour, and L-thyroxine
FIGURE 3. Histology of the resected pancreatic specimen showing clear cells of RCC, capsule, and normal pancreas. www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A Very Rare Sunitinib-Induced Adverse Effect
was given for hypothyroidism. Her mental status and neurologic symptoms were normalized in 7 days after the treatment. Also, serum ammonia level decreased to 61 mg/dL.
DISCUSSION Sunitinib is a small molecule and an inhibitor of certain receptor tyrosine kinases, including VEGFR types 1 and 2 (FLT-1 and FLK-1/KDR), PDGFR-a and PDGFR-b, stem cell factor receptor (c-KIT), and the FLT-3 and RET kinases.11 Clear cell RCC is characterized by frequent loss of the von Hippel–Lindau tumor suppressor gene, resulting in an increased transcription of several proteins, including vascular endothelial growth factor and platelet-derived growth factor.12 Tumor angiogenesis is stimulated in part by VEGF binding to its receptor. Preclinical data suggest that sunitinib has antitumor activity that might result predominantly from the inhibition of tumor angiogenesis, although it also has direct antiproliferative and apoptotic effects on certain tumor types (metastatic RCC, imatinib resistant gastrointestinal stromal tumors).3 The recommended dose for sunitinib for patients with advanced RCC is one 50-mg oral dose daily, with or without food, for 4 consecutive weeks, followed by a 2-week period without treatment, comprising a 6-week cycle.7 Treatment is continued until progression of the disease, occurrence of unacceptable toxic effects, or the refusal of the therapy.7 The most common (.15%) adverse effects are fatigue, diarrhea, nausea, anorexia, dysgeusia, vomiting, yellow skin, mucosal inflammation, hypertension (.140/90 mm Hg), rash, stomatitis, dyspepsia, headache, hand–foot syndrome, asthenia, hair color changes, anemia, neutropenia, and thrombocytopenia.13 Rare but serious ones are venous thromboembolism, hepatic failure (22–435 days after the initiation of treatment), prolonged QT interval, hypothyroidism, and reversible posterior leukoencephalopathy syndrome.14–17 Hyperammonemic encephalopathy is rare adverse effect after sunitinib treatment. Ammonia, the major nitrogenous product of protein catabolism, is a highly toxic compound, particularly to the brain. Hyperammonemic encephalopathy is an uncommon potentially fatal complication of chemotherapy that is characterized by abrupt alteration in mental status with a markedly elevated serum ammonium level in the absence of obvious liver disease.18 Hypothyroidism has been reported in patients as early as 1–2 weeks after the initiation of sunitinib treatment, and the incidence increases progressively with www.americantherapeutics.com
e585
the duration of therapy.19 In 85% RCC cases, patients treated with sunitinib had abnormal results including elevation of TSH levels, decreased T3 levels, and, less commonly, decreased T4 or free-thyroxine index levels.19 An abnormal serum TSH concentration and mild symptoms are consistent with hypothyroidism, such as fatigue, anorexia, edema, fluid retention, or cold intolerance, and may precede the onset of overt hypothyroidism, which may rapidly progress from mild to profound.20 Patients with subclinical hypothyroidism should also be considered for the treatment; typical doses of L-thyroxine should normalize TSH levels and resolve symptoms.21 Pancreatic metastasis of RCC is rare and usually present themselves many years after the primary diagnosis.22–24 They are accompanied by metastatic lesions in the brain, lungs, or bones. Solitary tumors in the pancreas are extremely rare (0.3% of all pancreatic tumors).25 In the absence of widespread disease, pancreatic resection can provide long-term survival in metastatic RCC, although a few cases have been reported with long-term follow-up.23 The prognosis is better than pancreatic adenocarcinoma. Surgical resection of primary RCC and metastatic deposits remain the most effective treatment because chemotherapy, radiotherapy, and hormonal therapy are generally ineffective.26 Five-year survival ranges from 29% to 81%.27,28 Matsumoto et al29 investigated the clinical efficacy and safety of sunitinib in patients with imatinibresistant gastrointestinal stromal tumor. The common adverse events were hand–foot syndrome, liver dysfunction, fatigue, anorexia, and hypertension. Hyperammonemia was observed in 1 patient, who was given 7 courses of sunitinib. The patient was asymptomatic. This adverse event may in part be caused by a vascular disorder related to the antiangiogenic properties of sunitinib. Lee et al30 report 2 cases of hyperammonemic encephalopathy induced by sunitinib with metastatic gastrointestinal stromal tumour (GIST). Sunitinib was the probable cause of hyperammonemic encephalopathy in both cases. Neurologic symptoms were resolved within 24 hours after the withdrawal of the drug (combined with supportive care). Hyperammonemia occurs when ammonia is either overproduced or insufficiently eliminated from the blood. The metabolism of ammonia occurs primarily through the urea cycle, where it is a by-product of the conversion of amino acids to a-ketoacids.18 The association between sunitinib and 6 enzymes involved in the urea cycle has not been studied.31 In this case study, we seek to present an isolated multicentric metastatic disease of the pancreas of a patient who has undergone right radical nephrectomy American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e586
for RCC. Initially, the patient was referred to the surgery department for radical pancreatectomy for having the benefit of increasing the survival and hence, she had no other systemic metastases. Three weeks after the surgery, sunitinib was administered to the patient. Her medical treatment was complicated with hyperammonemic encephalopathy and hypothyroidism on the 14th day. Supportive medical care and L-thyroxine were sufficient to overcome these complications of treatment. The relationship between sunitinib and the development of hyperammonemia is not well understood, and the mechanism is unclear. It is important that clinicians be aware that hyperammonemia and hypothyroidism can occur several days after the start of sunitinib in patients with metastatic RCC.
Pilancı et al
10.
11. 12.
13.
14.
15.
REFERENCES 16. 1. Osusky KL, Hallahan DE, Fu A, et al. The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels. Angiogenesis. 2004;7:225–233. 2. Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471–478. 3. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9: 327–337. 4. Murray LJ, Abrams TJ, Long KR, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis. 2003;20:757–766. 5. O’Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605. 6. Schueneman AJ, Himmelfarb E, Geng L, et al. SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res. 2003;63:4009–4016. 7. Product information. Sunitinib Malate (Sutent). Available at: http://www.pfizer.com/files/products/uspi_ sutent. pdf. Accessed July 12, 2010. 8. Kim DW, Jo YS, Jung HS, et al. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab. 2006;91: 4070–4076. 9. Rock EP, Goodman V, Jiang JX, et al. Food and Drug Administration drug approval summary: sunitinib malate fort he treatment of gastrointestinal stromal tumor American Journal of Therapeutics (2016) 23(2)
17.
18.
19.
20.
21.
22.
23.
24.
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