Review Article Hepatotoxicity Secondary to Chemotherapy Alla Grigorian and Christopher B. O’Brien Divisions of Liver and GI Transplantation, University of Miami School of Medicine, Miami, FL, USA Abstract enzyme activities (alanine aminotransferase’’ (ALT), aspar- tate aminotransferase (AST), alkaline phosphatase (ALP), The difficult problem faced by multiple generation of practi- and c-glutamyltransferase (GGT)) into mild (grade 1) if .ULN cing physicians is determining the cause of abnormal liver (upper limits of normal) to 2.56ULN; moderate (grade 2) if function tests in cancer patients on chemotherapy. .2.5 to 56ULN; severe (grade 3) if .5to206ULN; and life- Hepatotoxicity from chemotherapy occurs frequently from threatening (grade 4) if .206ULN; and with no definition for an unpredictable or idiosyncratic reaction. Despite remark- fatal (grade 5). Similarly, they graded serum total bilirubin able advances in our understanding of the mechanisms of concentration as mild if .ULN to 1.56ULN, moderate if .1.5 action, pharmacodynamics, and interrelationships between to 36ULN, severe if .3to86ULN, and life-threatening if the liver and chemotherapy, the underlying etiology of .86ULN. Although this grading system is commonly used, hepatic toxicity for various agents remains unexplained. this practice has been questioned since the elevation of Here, we present a concise review of the broad differential enzymes by itself does not always reflect dysfunction of the diagnosis for abnormal liver function tests (LFTs) in oncology liver and can therefore be misleading. patients. E 2014 The Second Affiliated Hospital of Chongqing Medical University. Published by XIA & HE Publishing Ltd. All rights National Institute of Health Drug Induced Liver Injury reserved. (DILI) network Introduction The National Institute of Health funded DILI network experts proposed to use clinical measures instead of laboratory In the complex world of cancer therapy, the administration of values and defined liver injury as follows: level 1 (mild) if medications intentionally designed to be cytotoxic inevitably patient has isolated elevation of ALT and or ALP, level 2 causes negative consequences. The liver is the primary site of (moderate) in presence of elevated bilirubin and coagulo- metabolism for many of these drugs, and this liver-drug pathy, level 3 (serious) if it results in hospitalization or interaction must be accounted for while dosing chemother- disability to do usual work; level 4 as acute liver failure, in apy. Preexisting liver disease can impair the process of which another organ that is dependent on liver function recovery after injury,1 and in preparation for chemotherapy, shows dysfunction (brain, encephalopathy; kidney, renal oncologists need to assess both liver function and potential insufficiency; etc.); and level 5 as death or liver transplanta- liver involvement by the cancer. tion.2 They also proposed a scale of increasing likelihood, ranging from unlikely to definite, of a suspected case of liver Guidelines for monitoring potential hepatotoxicity injury to be related to the imputed drug. National Cancer Institute (NCI) common toxicity criteria for adverse events Dose modification guidelines Close liver function monitoring is advised for patients starting Liver metabolized agents new chemotherapy regimen. It remains controversial how often liver testing should be performed and what constitutes liver dysfunction. The NCI in the ‘‘Common Toxicity Criteria There is agreement on the need for dose reduction for agents for Adverse Events’’ has classified elevations of serum that are dependent upon liver metabolism for clearance from the circulation. The major chemotherapeutic agents in this group include methotrexate, sorafenib, dactinomycin, ifosfa- Keywords: Hepatotoxicity; Drugs; Cancer; Chemotherapy; Liver. mide, gemcitabine, etoposide, irinotecan, procarbazine, 6- Abbreviations: 5-FU, 5-fluorouracil; 5FUDR, fluorodeoxyuridine; 6-MP, 6- mercaptopurine, cytarabine, crizotinib, and cyclophosphamide. mercaptopurine; 6-TG, 6-thioguanine; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AZA, azathioprine; DILI, drug induced liver injury; GGT, c-glutamyltransferase; HCC, hepatocellular Chemotherapy to be used with caution carcinoma; IBD, inflammatory bowel disease; MTX, methotrexate; NCI, National Cancer Institute; ULN, upper limits of normal; VOD, veno-occlusive disease. Received: 4 March 2014; Revised: 6 May 2014; Accepted: 22 May 2014 Certain chemotherapeutic agents must be used with extreme q DOI of original article: 10.14218/JCTH.2014.00011. caution in patient with preexisting liver disease. These Correspondence to: Alla Grigorian, Divisions of Liver and GI Transplantation, include the anthracyclines, taxanes, vinca alkaloids, temsir- University of Miami School of Medicine, 1500 NW. 12th Ave, Suite 1101, Miami, FL 33136, USA. Tel: +1-305-243-6956, Fax: +1-305-243-6681, Email: a.grigorian@ olimus, imatinib, axitinib, lapatinib, erlotinib, nilotinib, pazo- med.miami.edu panib, ponatinib, and ruxolitinib. Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 Journal of Clinical and Translational Hepatology JCTH-D-14-00011.3d 18/6/14 15:17:51 The Charlesworth Group, Wakefield +44(0)1924 369598 - Rev 9.0.225/W (Oct 13 2006) Grigorian A. et al.: Hepatotoxicity secondary to chemotherapy Overall guidelines transformation, veno-occlusive disease/sinusoidal obstruc- tion, and fulminant hepatic failure. Table 1 lists proposed The clinical presentations of hepatotoxicity vary from asymp- mechanisms of hepatic injury for commonly used chemother- tomatic, increase of liver chemistries, overt cholestatic apeutics; it is based mainly on evidence derived from case- hepatitis, progression to fibrosis and cirrhosis, malignant series and case reports. Table 1. Chemotherapy drugs and liver side effects Biliary Nodular Hyperplasia Veno-Occlusive Drug Hepatitis Cholestasis Stricture Steatosis Fibrosis Disease Actinomycin Rare Rare Arsenic Asparaginase Common Common Azathioprine Rare Rare Bleomycin Rare Bortezomib Rare Busulfan Rare Rare Rare Capecitabine Rare Carmustine Common Chlorambucil Rare Cyclophosphamide Rare Common Cytarabine Rare Common Dacarbazine Rare Docetaxel Rare Doxorubicin Rare Rare Rare Erlotinib Common Etoposide Rare Rare Floxuridine Common Common Common Fluorouracil Rare Common Rare Gefitinib Rare Gemcitabine Rare Rare Hydroxyurea Rare Ifosfamide Rare Imatinib Common Interferon Common Interleukin Common Irinotecan Rare Lomustine Rare Melphalan Rare Rare Mercaptopurine Rare Rare Methotrexate Common Common Mitomycin Rare Rare Oxaliplatin Rare Rare Common Paclitaxel Rare Pazopanib Common Procarbazine Rare Regorafenib Rare Sorafenib Rare Rare Streptozocin Rare Thioguanine Rare Rare Topotecan Rare Vincristine Rare Vinorelbine Rare 96 Journal of Clinical and Translational Hepatology 2014 vol. 2 | 95–102 Journal of Clinical and Translational Hepatology JCTH-D-14-00011.3d 18/6/14 15:19:49 The Charlesworth Group, Wakefield +44(0)1924 369598 - Rev 9.0.225/W (Oct 13 2006) Grigorian A. et al.: Hepatotoxicity secondary to chemotherapy Since there are no perfect laboratory tests that will predict Another study retrospectively evaluated the surgical specimen the likelihood of serious liver injury prior to administration of with focus on liver parenchyma not involved by the resected the drug, clinicians are tasked with detecting the early signs tumor.13 Overall, sinusoidal obstruction was present in 39 of injury and determining whether the drug should be stopped patients (10%), steatosis in 134 (35%), and steatohepatitis in due to hepatotoxicity or to continue chemotherapy if hepatic 16 (4%). A recent study which attempted to stratify patients adaptation and tolerance development are likely. In most based on degree of hepatic dysfunction reported no difference cases of DILI, the only effective treatment is discontinuation in the 5-FU clearance in patients with elevated bilirubin.14 of the causal agent and supportive care. In the context of life- threatening disease, the risk and benefit need to be Fluorodeoxyuridine (5FUDR) calculated based on the individual patient and disease course. In a study comparing regional intra-arterial versus contin- Specific chemotherapy uous systemic therapy with 5FUDR in patients with colorectal liver metastasis, there was considerable hepatotoxicity, Anti-metabolites including chemical hepatitis in 79% of patients and biliary sclerosis is 21% of patients. The small gain in survival seen 6-Mercaptopurine (6-MP) with regional therapy was offset by toxicity of intra-arterial FUDR.15 In later studies, biliary toxicity called for reduction of The largest series, Present et al. reported long-term results of the dose and the duration of therapy with more than half of 6-MP use in 396 patients with inflammatory bowel disease patients requiring treatment termination due to drug toxi- (IBD). There were 11 cases of hepatitis and one case of city.16 It is still a matter of debate whether bile duct injury is recurrence of jaundice after reinstitution of the drug.3 Severe related to drug toxicity or ischemia.17 cholestasis associated with the use of conventional doses of 6-MP has also been reported after liver transplantation.4 The Capecitabine most common pattern of described injury is intrahepatic cholestasis. Jaundice resolved with discontinuation of the Capecitabine is a drug that undergoes preferential conversion drug. Cases of fulminant hepatic failure occurred with the to