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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Dacarbazine

Last Update: November 10, 2017.

OVERVIEW

Introduction

Dacarbazine (also known as DTIC) is an intravenously administered alkylating agent used in the therapy of Hodgkin disease and malignant melanoma. Dacarbazine therapy has been associated with serum enzyme elevations during therapy and occasional cases of severe and distinctive acute hepatic failure, probably caused by acute sinusoidal obstruction syndrome.

Background

Dacarbazine (da kar' ba zeen) is a triazene analogue of 5-aminoimidazole-4-carboxamide, a precursor in purine biosynthesis. Its mechanism of action in cancer chemotherapy is unclear. Dacarbazine may act as a purine analogue and antimetabolite. In addition, it is extensively metabolized in the liver and produces intermediates some of which have alkylating activity, causing methylation, modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis. Dacarbazine is popularly known as DTIC and was approved for use in the United States in 1975. Current indications include Hodgkin lymphoma and metastatic malignant melanoma usually in combination with other antineoplastic agents. Dacarbazine is available for injection in vials of 10 mg/mL and the recommended dose varies by indication and body weight (2 to 4.5 mg/kg/day or 150 mg/m2/day). Dacarbazine is given by intravenous infusion typically for five to ten days in cycles of every 3 to 4 weeks. Common side effects are hypotension, alopecia, anoxia, nausea, vomiting, headache, peripheral neuropathy, and flu-like illness. Rare potentially severe adverse events include severe bone marrow suppression, neutropenia, sepsis, embryo-fetal toxicity and de novo cancinogenesis from long term use.

Hepatotoxicity

Mild and transient elevations in serum aminotransferase levels are not uncommon during courses of systemic combination chemotherapy and the role of dacarbazine in these abnormalities is not clear. However, dose modification for serum enzyme elevations is rarely necessary. More importantly, dacarbazine is associated with a severe and distinctive liver injury which typically arises during the second or third cycle of therapy and most likely represents severe acute sinusoidal obstruction syndrome. Patients typically develop the sudden onset of severe abdominal pain, hemodynamic instability and rapidly rising levels of serum aminotransferase levels and prothrombin time, with death within 1 to 10 days (Cases 1 and 2). Liver biopsy and necropsy findings indicate centrolobular necrosis with occlusion of sinusoids and small and large hepatic veins. In some cases, hepatic infarcts are found as well. Eosinophilic infiltrations are common and peripheral eosinophilia may also be present. Unlike with other alkylating agents, sinusoidal obstruction syndrome caused by dacarbazine is associated with the usual chemotherapy doses, not the higher doses used in myeloablation in preparation for bone marrow transplantation. This syndrome is now rarely reported, probably because of use of dacarbazine in somewhat lower doses.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of hepatotoxicity from dacarbazine is not known; however, clinical and pathologic features suggest direct injury to sinusoidal endothelial cells causing their death and extrusion into sinusoids with subsequent obstruction. The injury may be immunologically mediated as it usually occurs with the second or third cycle and is accompanied by eosinophilia. In several cases, the initial cycle of dacarbazine was marked by eosinophilia and fever.

Outcome and Management

The severity of sinusoidal obstruction syndrome varies considerably, but most published cases have been severe and rapidly fatal. Anecdotal reports suggest that corticosteroids may be beneficial, but many cases have demonstrated fatal hepatic injury by the time of recognition. Rechallenge should not be done. Defibrotide has been approved for treatment of severe sinusoidal obstruction syndrome with solid organ failure in patients undergoing hematopoietic cell transplantation, but has not been specifically approved for the acute liver failure associated with dacarbazine use.

Drug Class: Antineoplastic Agents, Alkylating Agents

CASE REPORTS

Case 1. Acute hepatic failure after dacarbazine therapy.

[Modified from: Herishanu Y, Lishner M, Kitay-Cohen Y. The role of glucocorticoids in the treatment of fulminant hepatitis induced by dacarbazine. Anticancer Drugs 2002; 13: 177-9. PubMed Citation]

A 69 year old man with malignant melanoma developed fever, epigastric pain and nausea on day 2 of a second 5 day course of dacarbazine (DTIC: 250 mg/m2 daily). On examination, he was febrile (39.5 oC) and hypotensive (blood pressure 74/40 mmHg). His abdomen was distended and he had marked right upper quadrant tenderness. There was no jaundice or rash and no peripheral manifestations of chronic liver disease. The white blood cell count was normal without eosinophilia. Liver tests showed a total bilirubin of 1.1 mg/dL, ALT 7040 U/L, AST 6080 U/L, LDH 23,635 U/L, alkaline phosphatase 259 U/L and GGT 159 U/L. Serum creatinine was 2.1 mg/dL, and INR was 1.8. Abdominal ultrasound showed a moderate amount of ascitic fluid and two suspected metastases in the liver (~2.4 cm in diameter). On hospital day 3, the patient developed early hepatic encephalopathy and serum ammonia levels were elevated (95 μmol/L). On day 4, mild hypoglycemia occurred and he was treated with fluids, lactulose, neomycin and intravenous hydrocortisone (300 mg/day). On day 5, he was stuporous, but subsequently he began to improve clinically such that he could be discharged by the hospital day 10. Two weeks later he was minimally symptomatic, had no ascites, and serum enzymes had markedly improved.

Key Points

Medication: Dacarbazine (250 mg/m2 daily in 5 day cycles)
Pattern:Sinusoidal obstruction syndrome (hepatocellular)
Severity:4+ (acute liver failure with spontaneous survival)
Latency:2 days after starting a second 5 day cycle
Recovery:10 days
Other medications:Interferon-α and previous therapy with chlorambucil and prednisone

Comment

Most cases of acute hepatic necrosis due to dacarbazine are rapidly fatal. Typically, the injury arises abruptly during the second course of therapy with sudden onset of fever and abdominal pain followed by cardiovascular collapse and marked rises in serum aminotransferase levels and LDH. Coagulopathy is usually present early, while bilirubin elevations occur later and with progressive hepatic failure (ascites, hepatic encephalopathy). Many cases have a history of mild nausea and fever with peripheral eosinophilia during the first course of therapy, a clinical pattern that also occurs with halothane hepatotoxicity. While the cause of the dacarbazine hepatic injury is believed to be acute sinusoidal obstruction syndrome, other features resemble acute ischemic necrosis due to shock or hepatic infarction. The presence of eosinophilia suggests hypersensitivity which is also supported by the occurrence during reexposure and the history of fever with the initial cycle of treatment. Regardless, the syndrome is severe and corticosteroid therapy is not unreasonable if started early. Furthermore, patients who develop fever and eosinophilia during dacarbazine therapy should not receive a second course.

Case 2. Acute veno-occlusive disease and liver failure due to dacarbazine.

[Modified from: Ceci G, Bella M, Melissari M, Gabrielli M, Bocchi P, Cocconi G. Fatal hepatic toxicity of DTIC: Is It Really a Rare Event? Cancer 1985; 61: 1988-91. PubMed Citation]

A 52 year old man with metastatic malignant melanoma developed fever during day 2 of a second cycle of dacarbazine followed on day 4 by acute abdominal pain and shock. He had tolerated the first cycle of dacarbazine with only mild nausea and vomiting and a few days of fever of 38-39 oC immediately after the 5 day course. At the time of restarting dacarbazine, he was without symptoms and the tumor had decreased in size. On presentation with hepatic injury, he was hypotensive and had tender hepatomegaly. Laboratory tests showed total bilirubin of 2.8 mg/dL, ALT 2050 U/L, AST 2990 U/L, LDH 3270 U/L, alkaline phosphatase 153 U/L, and INR 1.64. Ultrasound of the abdomen showed an enlarged liver and ascites. Acute cholecystitis was suspected and a laparotomy was performed. The gallbladder showed signs of chronic inflammation but no perforation. The liver was enlarged and dark. A liver biopsy showed diffuse centrolobular hepatic necrosis and hemorrhage. After surgery, he developed multiorgan failure and progressive hepatic decompensation, dying on hospital day 8. At autopsy, the liver was enlarged and histology showed centrolobular necrosis and hemorrhage with occlusion of small and medium sized hepatic veins.

Key Points

Medication:Dacarbazine (250 mg/m2 for 5 days every 3 weeks)
Pattern:Hepatocellular ( R=~35)
Severity:5+ (fatal)
Latency:2 days (fever)
Recovery:None
Other medications:Metoclopramide for nausea

Comment

The acute hepatic injury attributed to dacarbazine has a very typical clinical presentation and course, with evidence of acute hepatic necrosis as shown by a marked early rise in ALT and LDH with coagulopathy that reverses rapidly if not fatal. The fever and nausea associated with the first course of dacarbazine is typical of subsequent acute liver injury. While the pathology demonstrates sinusoidal obstruction syndrome, there also appears to be an element of acute ischemic necrosis. The rapid appearance on reexposure and the frequent occurrence of fever and eosinophilia suggests a hypersensitivity reaction.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Dacarbazine – Generic, DTIC,® DTIC-Dome®

DRUG CLASS

Antineoplastic Agents, Alkylating Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Dacarbazine 4342-03-4 C6-H10-N6-O
Dacarbazine Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 10 November 2017

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    (50 year old woman with malignant melanoma developed abdominal pain and fever on day 2 of the second cycle of dacarbazine [ALT 2348 U/L, LDH 20,430 U/L, INR 3.9], with ascites, multiorgan failure and death 5 days later).
  • Herishanu Y, Lishner M, Kitay-Cohen Y. The role of glucocorticoids in the treatment of fulminant hepatitis induced by dacarbazine. Anticancer Drugs 2002; 13: 177-9. [PubMed: 11901312]
    (61 year old man with malignant melanoma developed fever and abdominal pain on second day of second cycle of dacarbazine [bilirubin 1.1 mg/dL, ALT 7040 U/L, LDH 23,635 U/L, Alk P 249 U/L, INR 1.8], with ascites, hypotension, and encephalopathy, with improvement after corticosteroid therapy and rapid recovery: Case 1).
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    (Review of liver complications of bone marrow [hematopoietic cell] transplantation, which have become less frequent with better understanding of their causes and means of prevention; the rate of sinusoidal obstruction syndrome has decreased because of avoidance of more aggressive ablative therapies [total body irradiation and high doses of cyclophosphamide] and better understanding of pharmacokinetics of the alkylating agents).
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    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, none of which were attributed to dacarbazine).
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    (Controlled trial of dacarbazine with or without ipilimumab [monoclonal anti-CTLA-4] in 502 patients with metastatic melanoma; ALT elevations occurred in 33% of combination versus 6% of dacarbazine alone treated patients and "immune related hepatitis" in 38% on ipilimumab, with no mortality, but delay in resolution averaging 10 weeks).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, 40 of which were attributed to antineoplastic agents, but none specifically to dacarbazine).
  • Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, Kreutz R, et al. Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. Br J Clin Pharmacol 2015; 79: 988-99. [PMC free article: PMC4456131] [PubMed: 25444550]
    (Among 198 patients with hepatitis of uniknown cause enrolled in a prospective database from 51 Berlin hospitals between 2002 and 2011, none were attributed to dacarbazine).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 cases were attributed to antineoplastic agents, but none to dacarbazine).

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