Reactions 1462, p31 - 27 Jul 2013

STemozolomide

Liver injury: 4 case reportsFour patients aged 47–70 years developed liver injury during

treatment with temozolomide. Three of the patients were alsoreceiving levetiracetam and one patient had also received theantibiotics cefalexin and ciprofloxacin [not all routes, dosages,indications, or durations of treatment to reaction onset stated].

A 70-year-old man developed anorexia, confusion, andjaundice, 8 weeks after starting treatment with oraltemozolomide 150mg daily for 6 weeks for malignantanaplastic astrocytoma. The time to onset of his liver injurywas 54 days. His other medication included levetiracetam.Tests revealed elevated ALT, AST, ALP, and bilirubin. A liverbiopsy revealed prominent zone 3 cholestasis, interfacehepatitis, mild portal inflammation, and bile duct paucity. Histemozolomide and levetiracetam were withdrawn. He hadclinically improved 6 weeks after presentation but was stilljaundiced. His ALT, ALP, and bilirubin levels had improved. Helater died of tumour progression.

A 47-year-old man, who had a history of hepatitis C,developed pruritus and dark urine 7 months after starting oraltemozolomide 170mg daily for metastatic melanoma. Thetime to onset of his liver injury was 168 days. Physicalexamination revealed jaundice. Tests revealed elevated ALT,AST, ALP, and bilirubin. A CT scan showed diffuse fattyinfiltration of his liver. A liver biopsy showed changes of acutehepatitis with portal infiltrates, widespread duct injury, andinterface hepatitis. His temozolomide was withdrawn and hisliver test abnormalities had resolved 3 months afterpresentation. He later died of a haemorrhage from a rupturedcerebral aneurysm.

A 58-year-old woman who had a history of anoligoastrocytoma, had received temozolomide 200–250mgdaily for 13 months in 2004. Temozolomide 200mg daily wasrestarted 3 years later and continued for 21 days. Shedeveloped elevated liver enzyme levels. The time to onset ofher liver injury was 25 days. Her temozolomide wasdiscontinued. Her other medication included levetiracetamwhich she had taken for 7 years for seizures. A liver biopsyrevealed moderate intrahepatic cholestasis, minimalinflammation, and probable bile duct paucity. Hertemozolomide and levetiracetam were withdrawn. Herenzyme levels improved over the following months althoughher ALP level was mildly elevated at her 6-month visit. She diedof tumour progression.

A 65-year-old man received oral temozolomide 200mg dailyfor glioblastoma multiforme. He started levetiracetam at thesame time for seizure prophylaxis. He presented with a 3-dayhistory of nausea and jaundice approximately 10 weeks later.The time to onset of his liver injury was 74 days. His othermedications had included a 10-day course of cefalexin 3 weeksprior to presentation for cellulitis and a 5-day course ofciprofloxacin 6 days prior to presentation for the sameinfection. Tests revealed elevated ALT, AST, ALP, and bilirubin.A CT scan revealed fatty infiltration of the liver. A liver biopsyshowed canalicular cholestasis, mild ductopenia, and mildperivenular fibrosis. His temozolomide was discontinued. Hisserum ALT levels reduced but his bilirubin increased andlevetiracetam was stopped on day 15. His enzyme elevationscontinued to improve. He died of complications of agastrointestinal bleed on day 22.

Author comment: "[T]he DILIN [Drug-Induced Liver InjuryNetwork] investigators scored one case as definite, one ashighly likely, and two as probable. Competing diagnoses inthe two probable cases included chronic hepatitis C (case 2)and recent receipt of antibiotics capable of causingcholestatic liver injury . . . It is impossible to say that[levetiracetam] did not at least contribute to the liver injury."Grant LM, et al. Clinical and histological features of idiosyncratic acute liverinjury caused by temozolomide. Digestive Diseases and Sciences 58: 1415-1421,No. 5, May 2013. Available from: URL: http://dx.doi.org/10.1007/s10620-012-2493-9 - USA 803090492

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Reactions 27 Jul 2013 No. 14620114-9954/13/1462-0001/$14.95 Adis © 2013 Springer International Publishing AG. All rights reserved