Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 446–448
doi: 10.1111/jcpt.12160
Case Report
Regorafenib-induced hyperammonemic encephalopathy J. C. Kuo* BMedSc MBBS, S. Parakh* MBChB and D. Yip*† MBBS FRACP *Department of Medical Oncology, The Canberra Hospital, Garran, ACT, and †ANU Medical School, Australian National University, Acton, ACT, Australia
Received 2 March 2014, Accepted 6 March 2014
Keywords: adverse drug reactions, biological therapy, gastrointestinal stromal tumours, hepatic encephalopathy
trial, despite the incidence of grade three or four hepatotoxicity not being higher than placebo. In the CORRECT trial,4 a study explored the use of regorafenib in refractory metastatic colorectal cancer, a significantly higher incidence of grade three or four hepatotoxicity was observed, but none had grade five hepatotoxicity. Hyperammonemic encephalopathy related to regorafenib use has not been previously reported in the literature.
SUMMARY What is known and objective: Regorafenib improves progression-free survival as a late-line treatment for patients with metastatic gastrointestinal stromal tumour (GIST). As a multitargeted tyrosine kinase inhibitor (TKI), the expected adverse events of regorafenib are similar to those reported with imatinib, sunitinib or sorafenib. We report the first case of hyperammonemic encephalopathy related to regorafenib in a patient with metastatic GIST. Case summary: A 61-year-old man maintained on regorafenib for metastatic GIST presented with acute confusion. Discontinuation of regorafenib led to complete resolution of confusion, which later recurred with hyperammonemia on recommencing regorafenib. Cessation of regorafenib and normalization of hyperammonemia then resulted in resolution of confusion. What is new and conclusions: Regorafenib withdrawal and recommencement had influenced the confusional state and hyperammonemia in this patient. There is a probable relationship between regorafenib and metabolic encephalopathy. There are case reports of similar encephalopathy thought to be induced by other multitargeted TKI, and, as such, a class effect could be postulated.
CASE REPORT A 61-year-old Caucasian man with metastatic GIST that progressed despite multiple lines of treatments, both systemic and livertargeted, was commenced on regorafenib in August 2012. He was otherwise well with no medical co-morbidities or other regular medications. Thirteen months later, he was admitted to The Canberra Hospital, Canberra, Australia, in September 2013, with an episode of acute confusion. He was afebrile on presentation but had a marked neutrophilia with a neutrophil count of 34 9 109/L [five times upper limit of normal (ULN)] and an elevated C-reactive protein (CRP) of 111 mg/L (20 times ULN). Due to the possibility of sepsis, he was commenced on broad-spectrum intravenous antibiotics with meropenem and linezolid. Liver function tests (LFT) on admission remained stable in comparison with his baseline LFT and were consistent with a mild cholestatic derangement with a total bilirubin of 47 lmol/L (NR 2–20 lmol/L), alkaline phosphatase (ALP) of 306 U/L (NR 20–110 U/L) and gamma-glutamate aminotransferase (GGT) of 169 U/L (NR 12– 64 U/L). The alanine aminotransferase was normal at 36 U/L (NR < 55 U/L). A computed tomography scan of the brain did not reveal any intracranial pathology. An abdominal ultrasound revealed moderate ascites. A septic screen including blood culture, urine culture and chest X-ray was unremarkable. In terms of the history of metastatic GIST, he was first diagnosed with a solitary liver metastasis in 2007, 1 year after a gastrectomy for a primary GIST resection. This was treated by liver metastasectomy and imatinib was commenced. In August 2008, he was noted to have another hepatic recurrence and underwent further liver metastasectomy. His treatment was switched to sunitinib, which he continued until October 2011 when disease progression with new peritoneal metastases was confirmed. He was treated with nilotinib for 3 months, but in the setting of further disease progression, was commenced on sorafenib, which stabilized the disease. Three months later in April 2012, he had further disease progression with intra-abdominal recurrence. Sorafenib was subsequently changed to pazopanib, after a partial hepatectomy, duodenectomy and right nephrectomy were performed in June 2012. Despite this, further disease progression was noted on a positron-emitting tomography scan in August
WHAT IS KNOWN AND OBJECTIVE There have been recent advances in the management of metastatic gastrointestinal stromal tumour (GIST) with the recently published GRID trial1 demonstrating a 5-fold increase in progression-free survival with regorafenib as a late-line treatment in comparison with placebo. The expected adverse events of regorafenib are similar to those reported with other multitargeted tyrosine kinase inhibitor (TKI): imatinib, sunitinib or sorafenib. Hypertension, hand-foot skin reaction and diarrhoea are amongst the most common grade three or higher adverse events according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE; version 3.0).2 Other rarer adverse events include hepatotoxicity, haemorrhage, myocardial ischaemia and infarction, gastrointestinal perforation or fistula formation, reversible posterior leukoencephalopathy syndrome and impaired wound healing.3 Pre-existing mild-to-moderate hepatic impairment is not a contraindication in commencing regorafenib.3 However, there was one case of fatal hepatotoxicity in the GRID Correspondence: Associate Professor Desmond Yip, Department of Medical Oncology, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Australia. Tel.: +612 6244 2220; fax: +612 6244 4266; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
446
J. C. Kuo et al.
Regorafenib-induced encephalopathy
of advanced hepatocellular carcinoma, has been debated by Giovanni et al.,9 who reported two cases of metabolic encephalopathy possibly precipitated by the use of sorafenib in a 62-patient, single-institutional case series. Discontinuation of sorafenib led to complete resolution of confusional state, and re-administration in one patient resulted in recurrence of encephalopathy.9 The authors of the case series suspected that sorafenib may have direct neuronal action, which could have triggered the onset of metabolic encephalopathy.9 Marks et al.10 reported another isolated case of sorafenib-induced encephalopathy in a patient with advanced hepatocellular carcinoma. The encephalopathy resolved when sorafenib was withheld but then recurred when the drug was recommenced.10 The underlying mechanism of encephalopathy remained unclear, but in light of similar presentation, it was reasonably suspected to be a result of a class effect of these TKIs.11 Cases of encephalopathy where serum ammonia was reported are summarized in Table 1. The treatment for encephalopathy is dictated by its underlying cause, and in the setting of hyperammonemia, commonly used treatments aim to reduce ammonia production and absorption. This can be achieved by administration of non-absorbable disaccharides such as lactulose and non-absorbable antibiotics such as rifaximin.12 Other agents such as oral ornithine-aspartate,13 which enhances metabolism of ammonia to glutamine, and sodium benzoate,14 which enhances renal excretion of ammonia, were similarly effective. The timing between the recommencement of regorafenib and the onset of recurrent confusional episodes in our case suggests that there may be a causal relationship. The subsequently discovered hyperammonemia in the setting of stable liver function supports the diagnosis of drug-induced metabolic encephalopathy. In addition to the cessation of regorafenib, lactulose was commenced, reducing the serum ammonia level effectively with a clinical improvement in the patient’s confusion. This is consistent with the finding of a prospective evaluation that serum ammonia levels correlate with the severity of hepatic encephalopathy.15 It appears that hepatic encephalopathy is an uncommon occurrence in patients with hepatic malignant infiltration, except in primary hepatocellular carcinoma or neuroendocrine tumour with hepatic metastases.11 Our patient had a predisposition to hepatic failure with a pre-existing reduction of liver function due to prior liver resection, the presence of liver metastases and probable radiation-induced liver disease from radio-embolization and stereotactic external beam radiotherapy administered within the preceding 5 months. Nevertheless, applying the Naranjo probability scale, calculated at 8, the role of regorafenib in inducing the metabolic encephalopathy is probable.16
2012. Regorafenib was thereafter commenced, at a dose of 160 mg daily every 3 weeks of 4 weeks. In the interim, he underwent liver-targeted therapy with yttrium-90 resin microsphere radioembolization (with a total dose of 02 Giga-becquerel) in April 2013 and also stereotactic radio surgery (with 36 Grey in 6 fractions) in June 2013 to a chest wall lesion. Despite receiving a relatively low dose of radiation, his subsequent LFT 2 months later demonstrated a cholestatic derangement consistent with radiationinduced liver disease. This derangement remained static prior to his hospital admission. During his hospital admission, regorafenib was discontinued, and within 72 h, he had a complete resolution of the confusional state with improvement also in the inflammatory markers. After a 12-day hospital admission, he was discharged with oral antibiotics and was recommenced on regorafenib. Unfortunately, 10 days following the hospital discharge, he represented with a 24-h history of acute confusion. Physical examination at the time of readmission was unremarkable apart from a mildly reduced Glasgow Coma Score of 13. Repeated septic screens were negative. The total white cell count was within normal limit; however, CRP remained elevated at 55 mg/L (eleven times ULN). His LFTs were stable. There was no new change on a repeat abdominal ultrasound. He was recommenced on broadspectrum intravenous antibiotics, and regorafenib was withheld. Magnetic resonance imaging of the brain excluded posterior reversible encephalopathy syndrome. Within 72 h of ceasing regorafenib, there was a considerable improvement in his mental state. The patient then recommenced regorafenib on his own accord 2 days later. Within 10 days of recommencing regorafenib, he became acutely confused again. Antibiotics were continued during this period of time, and his LFT had remained stable. Further work-up this time revealed an elevated serum ammonia level of 105 lmol/L (twice the ULN with the NR of 10–50 lmol/L). He was commenced on lactulose with discontinuation of regorafenib. The serum ammonia level fell within 48 h to 67 lmol/L, with clinical improvement in his cognition. During the next 4 days, his serum ammonia level returned to within normal range at 49 lmol/L with complete resolution of his confusional state. CASE DISCUSSION Cases of metabolic encephalopathy have been reported with various multitargeted TKIs. There are two case reports of imatinibinduced hepatic encephalopathy5,6 and three cases of sunitinibinduced encephalopathy.7,8 In patients with pre-existing hepatic cirrhosis, the safety of initiating sorafenib, the standard treatment
Table 1. Case reports of hyperammonemic encephalopathy induced by multitargeted TKI Case report
Age/sex
Lee et al7 Lee et al7 Shea et al8 Brandi et al9
58/Male 68/Female 61/Male 75/Male
Diagnosis
GIST with liver metastases GIST, no known hepatic compromise Pancreatic NET with liver metastases HCC with hepatic cirrhosis
Drug
Sunitinib Sunitinib Sunitinib Sorafenib
Serum ammonia (lmol/L)
150 278 147 657
Managementa
Lactulose Lactulose Lactulose None
Time to recovery
24 h 24 h 24 h 2 weeks
NET, neuroendocrine tumour; HCC, hepatocellular carcinoma. a In addition to withdrawal of causative medication.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 446–448 447
J. C. Kuo et al.
Regorafenib-induced encephalopathy
metabolic encephalopathy in the setting of pre-existing liver function derangement needs to be considered. Discontinuation of regorafenib, as well as ammonia-lowering therapy, is essential to the management of this adverse effect, and recommencement of regorafenib should be discouraged.
WHAT IS NEW AND CONCLUSION We report the first case of a probable regorafenib-induced hyperammonemic encephalopathy in a man with metastatic GIST. Having had prior heavily treated hepatic metastases may have been contributory, but the role of regorafenib is not to be discounted. Regorafenib, as a last-line treatment, is likely to become more widely utilized not only in metastatic GIST but also in metastatic colorectal cancer, and the possibility of inducing
CONFLICT OF INTEREST None.
REFERENCES 1. Demetri GD, Reichardt P, Kang YK et al. 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, 2013;381:295–302. 2. Trotti A, Colevas AD, Setser A et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol, 2003;13:176–181. 3. Crona DJ, Keisler MD, Walko CM. Regorafenib: a novel multitargeted tyrosine kinase inhibitor for colorectal cancer and gastrointestinal stromal tumors. Ann Pharmacother, 2013;47:1685–1696. 4. Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 2013;381:303–312. 5. Ridruejo E, Cacchione R, Villamil AG, Marciano S, Gadano AC, Mando OG. Imati-
6.
7.
8.
9.
10.
11.
nib-induced fatal acute liver failure. World J Gastroenterol, 2007;13:6608–6611. Tonyali O, Coskun U, Yildiz R et al. Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors. Med Oncol, 2010;27:768–773. Lee NR, Yhim HY, Yim CY, Kwak JY, Song EK. Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors. Ann Pharmacother, 2011;45:e56. Shea YF, Chiu WY, Mok MY, Hung IF, Yau CC. Sunitinib-induced hyperammonaemia in a patient with pancreatic neuroendocrine tumour. J Clin Pharm Ther, 2013;38:327–329. Brandi G, de Rosa F, Calza L et al. Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients? Liver Int, 2013;33:488–493. Marks AB, Gerard R, Fournier P, Coupe P, Gautier S. Sorafenib-induced hepatic encephalopathy. Annals Pharmacother, 2009;43:2121. Willson KJ, Nott LM, Broadbridge VT, Price T. Hepatic encephalopathy associated with cancer or anticancer therapy. Gastrointest Cancer Res, 2013;6:11–16.
© 2014 John Wiley & Sons Ltd
12. Conn HO, Leevy CM, Vlahcevic ZR et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology, 1977;72:573–583. 13. Kircheis G, Nilius R, Held C et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology, 1997;25:1351–1360. 14. Sushma S, Dasarathy S, Tandon RK, Jain S, Gupta S, Bhist MS. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology, 1992;16:138–144. 15. Ong JP, Aggarwal A, Krieger D et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med, 2003;114:188–193. 16. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther, 1981;30:239–245.
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 446–448 448
doi: 10.1111/jcpt.12160
Case Report
Regorafenib-induced hyperammonemic encephalopathy J. C. Kuo* BMedSc MBBS, S. Parakh* MBChB and D. Yip*† MBBS FRACP *Department of Medical Oncology, The Canberra Hospital, Garran, ACT, and †ANU Medical School, Australian National University, Acton, ACT, Australia
Received 2 March 2014, Accepted 6 March 2014
Keywords: adverse drug reactions, biological therapy, gastrointestinal stromal tumours, hepatic encephalopathy
trial, despite the incidence of grade three or four hepatotoxicity not being higher than placebo. In the CORRECT trial,4 a study explored the use of regorafenib in refractory metastatic colorectal cancer, a significantly higher incidence of grade three or four hepatotoxicity was observed, but none had grade five hepatotoxicity. Hyperammonemic encephalopathy related to regorafenib use has not been previously reported in the literature.
SUMMARY What is known and objective: Regorafenib improves progression-free survival as a late-line treatment for patients with metastatic gastrointestinal stromal tumour (GIST). As a multitargeted tyrosine kinase inhibitor (TKI), the expected adverse events of regorafenib are similar to those reported with imatinib, sunitinib or sorafenib. We report the first case of hyperammonemic encephalopathy related to regorafenib in a patient with metastatic GIST. Case summary: A 61-year-old man maintained on regorafenib for metastatic GIST presented with acute confusion. Discontinuation of regorafenib led to complete resolution of confusion, which later recurred with hyperammonemia on recommencing regorafenib. Cessation of regorafenib and normalization of hyperammonemia then resulted in resolution of confusion. What is new and conclusions: Regorafenib withdrawal and recommencement had influenced the confusional state and hyperammonemia in this patient. There is a probable relationship between regorafenib and metabolic encephalopathy. There are case reports of similar encephalopathy thought to be induced by other multitargeted TKI, and, as such, a class effect could be postulated.
CASE REPORT A 61-year-old Caucasian man with metastatic GIST that progressed despite multiple lines of treatments, both systemic and livertargeted, was commenced on regorafenib in August 2012. He was otherwise well with no medical co-morbidities or other regular medications. Thirteen months later, he was admitted to The Canberra Hospital, Canberra, Australia, in September 2013, with an episode of acute confusion. He was afebrile on presentation but had a marked neutrophilia with a neutrophil count of 34 9 109/L [five times upper limit of normal (ULN)] and an elevated C-reactive protein (CRP) of 111 mg/L (20 times ULN). Due to the possibility of sepsis, he was commenced on broad-spectrum intravenous antibiotics with meropenem and linezolid. Liver function tests (LFT) on admission remained stable in comparison with his baseline LFT and were consistent with a mild cholestatic derangement with a total bilirubin of 47 lmol/L (NR 2–20 lmol/L), alkaline phosphatase (ALP) of 306 U/L (NR 20–110 U/L) and gamma-glutamate aminotransferase (GGT) of 169 U/L (NR 12– 64 U/L). The alanine aminotransferase was normal at 36 U/L (NR < 55 U/L). A computed tomography scan of the brain did not reveal any intracranial pathology. An abdominal ultrasound revealed moderate ascites. A septic screen including blood culture, urine culture and chest X-ray was unremarkable. In terms of the history of metastatic GIST, he was first diagnosed with a solitary liver metastasis in 2007, 1 year after a gastrectomy for a primary GIST resection. This was treated by liver metastasectomy and imatinib was commenced. In August 2008, he was noted to have another hepatic recurrence and underwent further liver metastasectomy. His treatment was switched to sunitinib, which he continued until October 2011 when disease progression with new peritoneal metastases was confirmed. He was treated with nilotinib for 3 months, but in the setting of further disease progression, was commenced on sorafenib, which stabilized the disease. Three months later in April 2012, he had further disease progression with intra-abdominal recurrence. Sorafenib was subsequently changed to pazopanib, after a partial hepatectomy, duodenectomy and right nephrectomy were performed in June 2012. Despite this, further disease progression was noted on a positron-emitting tomography scan in August
WHAT IS KNOWN AND OBJECTIVE There have been recent advances in the management of metastatic gastrointestinal stromal tumour (GIST) with the recently published GRID trial1 demonstrating a 5-fold increase in progression-free survival with regorafenib as a late-line treatment in comparison with placebo. The expected adverse events of regorafenib are similar to those reported with other multitargeted tyrosine kinase inhibitor (TKI): imatinib, sunitinib or sorafenib. Hypertension, hand-foot skin reaction and diarrhoea are amongst the most common grade three or higher adverse events according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE; version 3.0).2 Other rarer adverse events include hepatotoxicity, haemorrhage, myocardial ischaemia and infarction, gastrointestinal perforation or fistula formation, reversible posterior leukoencephalopathy syndrome and impaired wound healing.3 Pre-existing mild-to-moderate hepatic impairment is not a contraindication in commencing regorafenib.3 However, there was one case of fatal hepatotoxicity in the GRID Correspondence: Associate Professor Desmond Yip, Department of Medical Oncology, The Canberra Hospital, Yamba Drive, Garran, ACT 2605, Australia. Tel.: +612 6244 2220; fax: +612 6244 4266; e-mail: [email protected]
© 2014 John Wiley & Sons Ltd
446
J. C. Kuo et al.
Regorafenib-induced encephalopathy
of advanced hepatocellular carcinoma, has been debated by Giovanni et al.,9 who reported two cases of metabolic encephalopathy possibly precipitated by the use of sorafenib in a 62-patient, single-institutional case series. Discontinuation of sorafenib led to complete resolution of confusional state, and re-administration in one patient resulted in recurrence of encephalopathy.9 The authors of the case series suspected that sorafenib may have direct neuronal action, which could have triggered the onset of metabolic encephalopathy.9 Marks et al.10 reported another isolated case of sorafenib-induced encephalopathy in a patient with advanced hepatocellular carcinoma. The encephalopathy resolved when sorafenib was withheld but then recurred when the drug was recommenced.10 The underlying mechanism of encephalopathy remained unclear, but in light of similar presentation, it was reasonably suspected to be a result of a class effect of these TKIs.11 Cases of encephalopathy where serum ammonia was reported are summarized in Table 1. The treatment for encephalopathy is dictated by its underlying cause, and in the setting of hyperammonemia, commonly used treatments aim to reduce ammonia production and absorption. This can be achieved by administration of non-absorbable disaccharides such as lactulose and non-absorbable antibiotics such as rifaximin.12 Other agents such as oral ornithine-aspartate,13 which enhances metabolism of ammonia to glutamine, and sodium benzoate,14 which enhances renal excretion of ammonia, were similarly effective. The timing between the recommencement of regorafenib and the onset of recurrent confusional episodes in our case suggests that there may be a causal relationship. The subsequently discovered hyperammonemia in the setting of stable liver function supports the diagnosis of drug-induced metabolic encephalopathy. In addition to the cessation of regorafenib, lactulose was commenced, reducing the serum ammonia level effectively with a clinical improvement in the patient’s confusion. This is consistent with the finding of a prospective evaluation that serum ammonia levels correlate with the severity of hepatic encephalopathy.15 It appears that hepatic encephalopathy is an uncommon occurrence in patients with hepatic malignant infiltration, except in primary hepatocellular carcinoma or neuroendocrine tumour with hepatic metastases.11 Our patient had a predisposition to hepatic failure with a pre-existing reduction of liver function due to prior liver resection, the presence of liver metastases and probable radiation-induced liver disease from radio-embolization and stereotactic external beam radiotherapy administered within the preceding 5 months. Nevertheless, applying the Naranjo probability scale, calculated at 8, the role of regorafenib in inducing the metabolic encephalopathy is probable.16
2012. Regorafenib was thereafter commenced, at a dose of 160 mg daily every 3 weeks of 4 weeks. In the interim, he underwent liver-targeted therapy with yttrium-90 resin microsphere radioembolization (with a total dose of 02 Giga-becquerel) in April 2013 and also stereotactic radio surgery (with 36 Grey in 6 fractions) in June 2013 to a chest wall lesion. Despite receiving a relatively low dose of radiation, his subsequent LFT 2 months later demonstrated a cholestatic derangement consistent with radiationinduced liver disease. This derangement remained static prior to his hospital admission. During his hospital admission, regorafenib was discontinued, and within 72 h, he had a complete resolution of the confusional state with improvement also in the inflammatory markers. After a 12-day hospital admission, he was discharged with oral antibiotics and was recommenced on regorafenib. Unfortunately, 10 days following the hospital discharge, he represented with a 24-h history of acute confusion. Physical examination at the time of readmission was unremarkable apart from a mildly reduced Glasgow Coma Score of 13. Repeated septic screens were negative. The total white cell count was within normal limit; however, CRP remained elevated at 55 mg/L (eleven times ULN). His LFTs were stable. There was no new change on a repeat abdominal ultrasound. He was recommenced on broadspectrum intravenous antibiotics, and regorafenib was withheld. Magnetic resonance imaging of the brain excluded posterior reversible encephalopathy syndrome. Within 72 h of ceasing regorafenib, there was a considerable improvement in his mental state. The patient then recommenced regorafenib on his own accord 2 days later. Within 10 days of recommencing regorafenib, he became acutely confused again. Antibiotics were continued during this period of time, and his LFT had remained stable. Further work-up this time revealed an elevated serum ammonia level of 105 lmol/L (twice the ULN with the NR of 10–50 lmol/L). He was commenced on lactulose with discontinuation of regorafenib. The serum ammonia level fell within 48 h to 67 lmol/L, with clinical improvement in his cognition. During the next 4 days, his serum ammonia level returned to within normal range at 49 lmol/L with complete resolution of his confusional state. CASE DISCUSSION Cases of metabolic encephalopathy have been reported with various multitargeted TKIs. There are two case reports of imatinibinduced hepatic encephalopathy5,6 and three cases of sunitinibinduced encephalopathy.7,8 In patients with pre-existing hepatic cirrhosis, the safety of initiating sorafenib, the standard treatment
Table 1. Case reports of hyperammonemic encephalopathy induced by multitargeted TKI Case report
Age/sex
Lee et al7 Lee et al7 Shea et al8 Brandi et al9
58/Male 68/Female 61/Male 75/Male
Diagnosis
GIST with liver metastases GIST, no known hepatic compromise Pancreatic NET with liver metastases HCC with hepatic cirrhosis
Drug
Sunitinib Sunitinib Sunitinib Sorafenib
Serum ammonia (lmol/L)
150 278 147 657
Managementa
Lactulose Lactulose Lactulose None
Time to recovery
24 h 24 h 24 h 2 weeks
NET, neuroendocrine tumour; HCC, hepatocellular carcinoma. a In addition to withdrawal of causative medication.
© 2014 John Wiley & Sons Ltd
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 446–448 447
J. C. Kuo et al.
Regorafenib-induced encephalopathy
metabolic encephalopathy in the setting of pre-existing liver function derangement needs to be considered. Discontinuation of regorafenib, as well as ammonia-lowering therapy, is essential to the management of this adverse effect, and recommencement of regorafenib should be discouraged.
WHAT IS NEW AND CONCLUSION We report the first case of a probable regorafenib-induced hyperammonemic encephalopathy in a man with metastatic GIST. Having had prior heavily treated hepatic metastases may have been contributory, but the role of regorafenib is not to be discounted. Regorafenib, as a last-line treatment, is likely to become more widely utilized not only in metastatic GIST but also in metastatic colorectal cancer, and the possibility of inducing
CONFLICT OF INTEREST None.
REFERENCES 1. Demetri GD, Reichardt P, Kang YK et al. 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, 2013;381:295–302. 2. Trotti A, Colevas AD, Setser A et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol, 2003;13:176–181. 3. Crona DJ, Keisler MD, Walko CM. Regorafenib: a novel multitargeted tyrosine kinase inhibitor for colorectal cancer and gastrointestinal stromal tumors. Ann Pharmacother, 2013;47:1685–1696. 4. Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 2013;381:303–312. 5. Ridruejo E, Cacchione R, Villamil AG, Marciano S, Gadano AC, Mando OG. Imati-
6.
7.
8.
9.
10.
11.
nib-induced fatal acute liver failure. World J Gastroenterol, 2007;13:6608–6611. Tonyali O, Coskun U, Yildiz R et al. Imatinib mesylate-induced acute liver failure in a patient with gastrointestinal stromal tumors. Med Oncol, 2010;27:768–773. Lee NR, Yhim HY, Yim CY, Kwak JY, Song EK. Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors. Ann Pharmacother, 2011;45:e56. Shea YF, Chiu WY, Mok MY, Hung IF, Yau CC. Sunitinib-induced hyperammonaemia in a patient with pancreatic neuroendocrine tumour. J Clin Pharm Ther, 2013;38:327–329. Brandi G, de Rosa F, Calza L et al. Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients? Liver Int, 2013;33:488–493. Marks AB, Gerard R, Fournier P, Coupe P, Gautier S. Sorafenib-induced hepatic encephalopathy. Annals Pharmacother, 2009;43:2121. Willson KJ, Nott LM, Broadbridge VT, Price T. Hepatic encephalopathy associated with cancer or anticancer therapy. Gastrointest Cancer Res, 2013;6:11–16.
© 2014 John Wiley & Sons Ltd
12. Conn HO, Leevy CM, Vlahcevic ZR et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology, 1977;72:573–583. 13. Kircheis G, Nilius R, Held C et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology, 1997;25:1351–1360. 14. Sushma S, Dasarathy S, Tandon RK, Jain S, Gupta S, Bhist MS. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology, 1992;16:138–144. 15. Ong JP, Aggarwal A, Krieger D et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med, 2003;114:188–193. 16. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther, 1981;30:239–245.
Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 446–448 448
![[Hyperammonemic encephalopathy in multiple myeloma].](/assets/img/hold.png)
