Drug-Induced Liver Injury due to Cancer Chemotherapeutic Agents

Abstract

Drug-induced liver injury (DILI) due to chemotherapeutic drugs is a significant cause of morbidity and mortality. Most cases of chemotherapy-induced hepatotoxicity are idiosyncratic and do not have a unique clinical or histological signature that is distinct from other agents that cause DILI. The major mechanisms underlying chemotherapy-related hepatotoxicity are based on the production of reactive metabolites generated by phase I oxidation reactions, immunological injury, or alterations in mitochondrial function. Underlying liver disease and hepatic involvement by tumor are important modifiers of liver injury, and reversibility is not universal after drug cessation. Chemotherapy can also exacerbate underlying liver disease, particularly hepatitis B, leading to worsening hepatic function. Diagnosing DILI due to chemotherapeutic agents is particularly challenging because competing etiologies, such as hepatotoxicity from other medications, opportunistic infections, radiation therapy, and pre-existing liver disease, are frequent.

Keywords

chemotherapy - drug-induced liver injury - hepatotoxicity - liver failure - hepatic dysfunction

• References

• 1 Lewis JH. Drug-induced liver disease. Med Clin North Am 2000; 84 (5) 1275-1311 , x
• 2 King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist 2001; 6 (2) 162-176
• 3 Larrey D. Drug-induced liver diseases. J Hepatol 2000; 32 (1, Suppl) 77-88
• 4 National Cancer Institute. Cancer Therapy Evaluation Program. National Cancer Institute; 2005 . Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/newadverse_2006.pdf. Accessed October 30, 2013
• 5 Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995; 333 (17) 1118-1127
• 6 Ceci G, Bella M, Melissari M, Gabrielli M, Bocchi P, Cocconi G. Fatal hepatic vascular toxicity of DTIC. Is it really a rare event?. Cancer 1988; 61 (10) 1988-1991
• 7 Asbury RF, Rosenthal SN, Descalzi ME, Ratcliffe RL, Arseneau JC. Hepatic veno-occlusive disease due to DTIC. Cancer 1980; 45 (10) 2670-2674
• 8 Le Couteur DG, Cogger VC, Markus AM , et al. Pseudocapillarization and associated energy limitation in the aged rat liver. Hepatology 2001; 33 (3) 537-543
• 9 Diehl AM. Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. Am J Physiol Gastrointest Liver Physiol 2002; 282 (1) G1-G5
• 10 Veteläinen R, van Vliet AK, van Gulik TM. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy. Ann Surg 2007; 245 (1) 44-50
• 11 DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002; 22 (1) 27-42
• 12 Shulman HM, Fisher LB, Schoch HG, Henne KW, McDonald GB. Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology 1994; 19 (5) 1171-1181
• 13 McDonald GB, Hinds MS, Fisher LD , et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118 (4) 255-267
• 14 Dix SP, Wingard JR, Mullins RE , et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant 1996; 17 (2) 225-230
• 15 Marsh JC. Hepatic vascular toxicity of dacarbazine (DTIC): not a rare complication. Hepatology 1989; 9 (5) 790-792
• 16 Morgan M, Dodds A, Atkinson K, Szer J, Downs K, Biggs J. The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation. Br J Haematol 1991; 77 (4) 529-534
• 17 Gill RA, Onstad GR, Cardamone JM, Maneval DC, Sumner HW. Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med 1982; 96 (1) 58-60
• 18 Stoneham S, Lennard L, Coen P, Lilleyman J, Saha V. Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 2003; 123 (1) 100-102
• 19 Joensuu H, Söderström KO, Nikkanen V. Fatal necrosis of the liver during ABVD chemotherapy for Hodgkin's disease. A case report. Cancer 1986; 58 (7) 1437-1440
• 20 Houghton AN, Shafi N, Rickles FR. Acute hepatic vein thrombosis occurring during therapy for Hodgkin's disease: a case report. Cancer 1979; 44 (6) 2324-2329
• 21 Julie C, Lutz M, Aust D. Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: results of the EORTC Intergroup phase III study 40983. J Clin Oncol 2007; 25 : abstract 241
• 22 Nakano H, Oussoultzoglou E, Rosso E , et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg 2008; 247 (1) 118-124
• 23 Guha C, Kavanagh BD. Hepatic radiation toxicity: avoidance and amelioration. Semin Radiat Oncol 2011; 21 (4) 256-263
• 24 Reed Jr GB, Cox Jr AJ. The human liver after radiation injury. A form of veno-occlusive disease. Am J Pathol 1966; 48 (4) 597-611
• 25 Hansen MM, Ranek L, Walbom S, Nissen NI. Fatal hepatitis following irradiation and vincristine. Acta Med Scand 1982; 212 (3) 171-174
• 26 Kun LE, Camitta BM. Hepatopathy following irradiation and adriamycin. Cancer 1978; 42 (1) 81-84
• 27 Tefft M, Traggis D, Filler RM. Liver irradiation in children: acute changes with transient leukopenia and thrombocytopenia. Am J Roentgenol Radium Ther Nucl Med 1969; 106 (4) 750-765
• 28 Ishak KG, Zimmerman HJ. Morphologic spectrum of drug-induced hepatic disease. Gastroenterol Clin North Am 1995; 24 (4) 759-786
• 29 Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11 (2) 272-276
• 30 Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997; 26 (3) 664-669
• 31 Jakse G, Madersbacher H. [Stauffer's syndrome. Reversible hepatic dysfunction in renal cell carcinoma (author's transl)]. Wien Klin Wochenschr 1978; 90 (8) 268-270
• 32 Chalasani N, Fontana RJ, Bonkovsky HL , et al; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135 (6) 1924-1934 , e1–e4
• 33 Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 2006; 43 (2) 209-220
• 34 Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50 (3) 661-662
• 35 Vento S, Cainelli F, Mirandola F , et al. Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus. Lancet 1996; 347 (8994) 92-93
• 36 de Pree C, Giostra E, Galetto A, Perrin L, Zulian GB. Hepatitis C virus acute exacerbation during chemotherapy and radiotherapy for oesophageal carcinoma. Ann Oncol 1994; 5 (9) 861-862
• 37 Torres HA, Davila M. Reactivation of hepatitis B virus and hepatitis C virus in patients with cancer. Nat Rev Clin Oncol 2012; 9 (3) 156-166
• 38 Frickhofen N, Wiesneth M, Jainta C , et al. Hepatitis C virus infection is a risk factor for liver failure from veno-occlusive disease after bone marrow transplantation. Blood 1994; 83 (7) 1998-2004
• 39 Strasser SI, Myerson D, Spurgeon CL , et al. Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology 1999; 29 (6) 1893-1899
• 40 Khan S, Ramwani JJ, O'Brien PJ. Hepatocyte toxicity of mechlorethamine and other alkylating anticancer drugs. Role of lipid peroxidation. Biochem Pharmacol 1992; 43 (9) 1963-1967
• 41 Brühl P, Günther U, Hoefer-Janker H, Hüls W, Scheef W, Vahlensieck W. Results obtained with fractionated ifosfamide massive-dose treatment in generalized malignant tumours. Int J Clin Pharmacol Biopharm 1976; 14 (1) 29-39
• 42 Paschke R, Worst P, Brust J, Queisser W. [Hepatotoxicity with etoposide-ifosfamide combination therapy]. Onkologie 1988; 11 (6) 273-275
• 43 Falkson G, Hunt M, Borden EC, Hayes JA, Falkson CI, Smith TJ. An extended phase II trial of ifosfamide plus mesna in malignant mesothelioma. Invest New Drugs 1992; 10 (4) 337-343
• 44 Aubrey DA. Massive hepatic necrosis after cyclophosphamide. BMJ 1970; 3 (5722) 588
• 45 Goldberg JW, Lidsky MD. Cyclophosphamide-associated hepatotoxicity. South Med J 1985; 78 (2) 222-223
• 46 Bacon AM, Rosenberg SA. Cyclophosphamide hepatotoxicity in a patient with systemic lupus erythematosus. Ann Intern Med 1982; 97 (1) 62-63
• 47 Floyd J, Mirza I, Sachs B, Perry MC. Hepatotoxicity of chemotherapy. Semin Oncol 2006; 33 (1) 50-67
• 48 Morris LE, Guthrie Jr TH. Busulfan-induced hepatitis. Am J Gastroenterol 1988; 83 (6) 682-683
• 49 Lee JH, Choi SJ, Lee JH , et al. Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol 2005; 84 (5) 321-330
• 50 Giralt S, Thall PF, Khouri I , et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97 (3) 631-637
• 51 Rai KR, Peterson BL, Appelbaum FR , et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343 (24) 1750-1757
• 52 Romagnuolo J, Sadowski DC, Lalor E, Jewell L, Thomson AB. Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998; 12 (7) 479-483
• 53 Small P, Lichter M. Probable azathioprine hepatotoxicity: a case report. Ann Allergy 1989; 62 (6) 518-520
• 54 Barrowman JA, Kutty PK, Ra MU, Huang SN. Sclerosing hepatitis and azathioprine. Dig Dis Sci 1986; 31 (2) 221-222
• 55 Ménard DB, Gisselbrecht C, Marty M, Reyes F, Dhumeaux D. Antineoplastic agents and the liver. Gastroenterology 1980; 78 (1) 142-164
• 56 Shorey J, Schenker S, Suki WN, Combes B. Hepatotoxicity of mercaptopurine. Arch Intern Med 1968; 122 (1) 54-58
• 57 McIlvanie SK, MacCarthy JD. Hepatitis in association with prolonged 6-mercaptopurine therapy. Blood 1959; 14 (1) 80-90
• 58 Pizzuto J, Avilés A, Ramos E, Cervera J, Aguirre J. Cytosine arabinoside induced liver damage: histopathologic demonstration. Med Pediatr Oncol 1983; 11 (4) 287-290
• 59 George CB, Mansour RP, Redmond III J, Gandara DR. Hepatic dysfunction and jaundice following high-dose cytosine arabinoside. Cancer 1984; 54 (11) 2360-2362
• 60 Koren G, Beatty K, Seto A, Einarson TR, Lishner M. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 1992; 26 (3) 363-371
• 61 Bateman JR, Pugh RP, Cassidy FR, Marshall GJ, Irwin LE. 5-fluorouracil given once weekly: comparison of intravenous and oral administration. Cancer 1971; 28 (4) 907-913
• 62 Aloia T, Sebagh M, Plasse M , et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006; 24 (31) 4983-4990
• 63 Twelves C, Glynne-Jones R, Cassidy J , et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1999; 5 (7) 1696-1702
• 64 Doria Jr MI, Shepard KV, Levin B, Riddell RH. Liver pathology following hepatic arterial infusion chemotherapy. Hepatic toxicity with FUDR. Cancer 1986; 58 (4) 855-861
• 65 Chang AE, Schneider PD, Sugarbaker PH, Simpson C, Culnane M, Steinberg SM. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987; 206 (6) 685-693
• 66 Hohn D, Melnick J, Stagg R , et al. Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol 1985; 3 (1) 98-102
• 67 Shepard KV, Levin B, Karl RC , et al. Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump. J Clin Oncol 1985; 3 (2) 161-169
• 68 Krivoy N, Raz R, Carter A, Alroy G. Reversible hepatic veno-occlusive disease and 6-thioguanine. Ann Intern Med 1982; 96 (6 Pt 1): 788
• 69 Larrey D, Fréneaux E, Berson A , et al. Peliosis hepatis induced by 6-thioguanine administration. Gut 1988; 29 (9) 1265-1269
• 70 Aapro MS, Martin C, Hatty S. Gemcitabine—a safety review. Anticancer Drugs 1998; 9 (3) 191-201
• 71 Teusink AC, Hall PD. Toxicities of gemcitabine in patients with severe hepatic dysfunction. Ann Pharmacother 2010; 44 (4) 750-754
• 72 Podurgiel BJ, McGill DB, Ludwig J, Taylor WF, Muller SA. Liver injury associated with methotrexate therapy for psoriasis. Mayo Clin Proc 1973; 48 (11) 787-792
• 73 Evans WE, Pratt CB. Effect of pleural effusion on high-dose methotrexate kinetics. Clin Pharmacol Ther 1978; 23 (1) 68-72
• 74 Avilés A, Herrera J, Ramos E, Ambriz R, Aguirre J, Pizzuto J. Hepatic injury during doxorubicin therapy. Arch Pathol Lab Med 1984; 108 (11) 912-913
• 75 Johnson PJ, Dobbs N, Kalayci C , et al. Clinical efficacy and toxicity of standard dose adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters. Br J Cancer 1992; 65 (5) 751-755
• 76 Chan KK, Chlebowski RT, Tong M, Chen HS, Gross JF, Bateman JR. Clinical pharmacokinetics of adriamycin in hepatoma patients with cirrhosis. Cancer Res 1980; 40 (4) 1263-1268
• 77 Erichsen C, Jönsson PE. Veno-occlusive liver disease after dacarbazine therapy (DTIC) for melanoma. J Surg Oncol 1984; 27 (4) 268-270
• 78 McClay E, Lusch CJ, Mastrangelo MJ. Allergy-induced hepatic toxicity associated with dacarbazine. Cancer Treat Rep 1987; 71 (2) 219-220
• 79 Ludwig R, Weirich A, Abel U, Hofmann W, Graf N, Tournade MF. Hepatotoxicity in patients treated according to the nephroblastoma trial and study SIOP-9/GPOH. Med Pediatr Oncol 1999; 33 (5) 462s-469
• 80 Lazarus HM, Gottfried MR, Herzig RH , et al. Veno-occlusive disease of the liver after high-dose mitomycin C therapy and autologous bone marrow transplantation. Cancer 1982; 49 (9) 1789-1795
• 81 Crooke ST, Bradner WT. Mitomycin C: a review. Cancer Treat Rev 1976; 3 (3) 121-139
• 82 Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R, Baker LH. The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 2000; 6 (4) 1255-1258
• 83 Minami H, Kawada K, Sasaki Y , et al. Population pharmacokinetics of docetaxel in patients with hepatic dysfunction treated in an oncology practice. Cancer Sci 2009; 100 (1) 144-149
• 84 National Institute of Health. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm. Accessed October 30, 2013
• 85 Desai ZR, Van den Berg HW, Bridges JM, Shanks RG. Can severe vincristine neurotoxicity be prevented?. Cancer Chemother Pharmacol 1982; 8 (2) 211-214
• 86 Hohneker JA. A summary of vinorelbine (Navelbine) safety data from North American clinical trials. Semin Oncol 1994; 21 (5, Suppl 10) 42-46 , discussion 46–47
• 87 Van den Berg HW, Desai ZR, Wilson R, Kennedy G, Bridges JM, Shanks RG. The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol 1982; 8 (2) 215-219
• 88 Tran A, Housset C, Boboc B, Tourani JM, Carnot F, Berthelot P. Etoposide (VP 16-213) induced hepatitis. Report of three cases following standard-dose treatments. J Hepatol 1991; 12 (1) 36-39
• 89 Johnson DH, Greco FA, Wolff SN. Etoposide-induced hepatic injury: a potential complication of high-dose therapy. Cancer Treat Rep 1983; 67 (11) 1023-1024
• 90 Stewart CF, Arbuck SG, Fleming RA, Evans WE. Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 1990; 8 (11) 1874-1879
• 91 Raymond E, Boige V, Faivre S , et al. Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 2002; 20 (21) 4303-4312
• 92 Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005; 200 (6) 845-853
• 93 Creemers GJ, Lund B, Verweij J. Topoisomerase I inhibitors: topotecan and irenotecan. Cancer Treat Rev 1994; 20 (1) 73-96
• 94 Hill JM, Loeb E, MacLellan A, Hill NO, Khan A, King JJ. Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases. Cancer Chemother Rep 1975; 59 (3) 647-659
• 95 Hruban RH, Sternberg SS, Meyers P, Fleisher M, Menendez-Botet C, Boitnott JK. Fatal thrombocytopenia and liver failure associated with carboplatin therapy. Cancer Invest 1991; 9 (3) 263-268
• 96 Christian MC. Two toxicities associated with carboplatin use: A. gross hematuria B. hepatic veno-occlusive disease. Department of Health & Human Services Bulletin. Bethesda, MD: National Institutes of Health, National Cancer Institute; 1989
• 97 Pollera CF, Ameglio F, Nardi M, Vitelli G, Marolla P. Cisplatin-induced hepatic toxicity. J Clin Oncol 1987; 5 (2) 318-319
• 98 Fakih MG. 5-fluorouracil leucovorin and oxaliplatin (FOLFOX) in the treatment of metastatic colon cancer with severe liver dysfunction. Oncology 2004; 67 (3-4) 222-224
• 99 Rubbia-Brandt L, Audard V, Sartoretti P , et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004; 15 (3) 460-466
• 100 Nordstrom BH, Fraeman KH, Luo W. Liver function test abnormalities in patients treated with small molecule tyrosine kinase inhibitors. Paper presented at: International Society for Pharmacoepidemiology Annual Meeting; August 19–22, 2010. ; Brighton, UK
• 101 Chang J, Rand M, Blumenthal G. FDA evaluation of hepatotoxicity related to tyrosine kinase inhibitors. J Clin Oncol 2011; 29: 3106
• 102 Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol 2011; 8 (4) 202-211
• 103 Miller AA, Murry DJ, Owzar K , et al. Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101. J Clin Oncol 2007; 25 (21) 3055-3060
• 104 Liu W, Makrauer FL, Qamar AA, Jänne PA, Odze RD. Fulminant hepatic failure secondary to erlotinib. Clin Gastroenterol Hepatol 2007; 5 (8) 917-920
• 105 Pellegrinotti M, Fimognari FL, Franco A, Repetto L, Pastorelli R. Erlotinib-induced hepatitis complicated by fatal lactic acidosis in an elderly man with lung cancer. Ann Pharmacother 2009; 43 (3) 542-545
• 106 Ho C, Davis J, Anderson F, Bebb G, Murray N. Side effects related to cancer treatment: CASE 1. Hepatitis following treatment with gefitinib. J Clin Oncol 2005; 23 (33) 8531-8533
• 107 Kikuchi S, Muroi K, Takahashi S , et al. Severe hepatitis and complete molecular response caused by imatinib mesylate: possible association of its serum concentration with clinical outcomes. Leuk Lymphoma 2004; 45 (11) 2349-2351
• 108 O'Brien SG, Guilhot F, Larson RA , et al; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348 (11) 994-1004
• 109 Cross TJ, Bagot C, Portmann B, Wendon J, Gillett D. Imatinib mesylate as a cause of acute liver failure. Am J Hematol 2006; 81 (3) 189-192
• 110 Ferrero D, Pogliani EM, Rege-Cambrin G , et al. Corticosteroids can reverse severe imatinib-induced hepatotoxicity. Haematologica 2006; ; 91 (6, Suppl) ECR27
• 111 Moy B, Rappold E, Williams L. Hepatobiliary abnormalities in patients with metastatic cancer treated with lapatinib. J Clin Oncol 2009; 27: 1043
• 112 Spraggs CF, Budde LR, Briley L. Hyperbilirubinemia in lapatinib treated patients is associated with Gilbert's syndrome UGT1A1 polymorphism. Cancer Res 2009; 69 (24) 69
• 113 Spraggs CF, Budde LR, Briley LP , et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 2011; 29 (6) 667-673
• 114 Sternberg CN, Davis ID, Mardiak J , et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28 (6) 1061-1068
• 115 Xu CF, Reck BH, Xue Z , et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer 2010; 102 (9) 1371-1377
• 116 Shibata SI, Chung V, Synold TW , et al. Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res 2013; 19 (13) 3631-3639
• 117 Xu CF, Reck BH, Goodman VL , et al. Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma. J Hepatol 2011; 54 (6) 1237-1243
• 118 Iclusig. [package insert]. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf . Accessed October 30, 2013
• 119 Stivarga. [package insert]. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf Accessed October 30, 2013
• 120 Sutent [package insert]. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021938s13s17s18lbl.pdf. Accessed October 30, 2013
• 121 Fairfax BP, Pratap S, Roberts IS , et al. Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC Cancer 2012; 12: 590
• 122 Miller AA, Murry DJ, Owzar K , et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009; 27 (11) 1800-1805
• 123 Avastin [package insert]. South San Francisco, CA: Genentech; 2004
• 124 Dent S, Oyan B, Honig A, Mano M, Howell S. HER2-targeted therapy in breast cancer: a systematic review of neoadjuvant trials. Cancer Treat Rev 2013; 39 (6) 622-631
• 125 Wolchok JD, Neyns B, Linette G , et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11 (2) 155-164
• 126 Robert C, Thomas L, Bondarenko I , et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364 (26) 2517-2526
• 127 Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30 (21) 2691-2697
• 128 Pectasides D, Dafni U, Bafaloukos D , et al. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol 2009; 27 (6) 939-944
• 129 Shindo M, Di Bisceglie AM, Hoofnagle JH. Acute exacerbation of liver disease during interferon alfa therapy for chronic hepatitis C. Gastroenterology 1992; 102 (4 Pt 1) 1406-1408
• 130 Nakagawa K, Miller FN, Sims DE, Lentsch AB, Miyazaki M, Edwards MJ. Mechanisms of interleukin-2-induced hepatic toxicity. Cancer Res 1996; 56 (3) 507-510
• 131 Fisher B, Keenan AM, Garra BS , et al. Interleukin-2 induces profound reversible cholestasis: a detailed analysis in treated cancer patients. J Clin Oncol 1989; 7 (12) 1852-1862