Etoposide and teniposide are semisynthetic analogues of podophyllotoxin that are used as antineoplastic agents in the therapy of several forms of solid tumors, leukemia and lymphoma, usually in combination with other agents. Both etoposide and teniposide are associated with an appreciable rate of serum enzyme elevations during therapy, and high doses have been implicated in causing clinically apparent acute liver injury including sinusoidal obstruction syndrome.


Etoposide (e toe' poe side) and teniposide (ten" i poe' side) are semisynthetic derivatives of podophyllotoxin, an extract from the mandrake plant (American May Apple: Podophyllum peltatum). Both drugs appear to act by binding to and inhibiting topoisomerase II, preventing the healing of DNA breaks that occur during the action of this enzyme in replicating cells. Both agents have antineoplastic activity in vitro and in animal models, and were introduced into clinical practice in the 1980s and 1990s as a part of combination chemotherapy for various leukemias, lymphomas and solid tumors. Etoposide (also known as VP-16) was approved for use in the United States in 1983 and teniposide (VP-26) in 1992. Current formal indications for etoposide include refractory testicular tumors and small cell lung cancer to be used in combination with other agents. Etoposide is available as a solution or lyophilized powder for injection in vials of varying concentrations, and as capsules of 50 mg for oral administration in generic forms and under the commercial name Toposar. The typical dose of etoposide varies by indication and is adjusted for body weight and renal function. The current single approved indication for teniposide is refractory childhood acute lymphoblastic leukemia in combination with other anticancer agents. Teniposide is available in solution in 50 mg vials generically and under the trade name Vumon. The typical dose varies by body weight. Side effects of etoposide and teniposide are similar and include bone marrow suppression, nausea, vomiting, abdominal pain, stomatitis, diarrhea, fatigue, hypotension, allergic reactions, hair loss and peripheral neuropathy. Uncommon, but potentially severe adverse reactions include severe myelosuppression, neutropenic fever or sepsis and anaphylactic reactions. Both agents should be administered only by physicians with experience in the use of chemotherapeutic agents and management of their toxicities.


Chemotherapy with etoposide or teniposide in combination with other agents is associated with serum enzyme elevations in 5% to more than 50% of patients, depending upon the dose and other agents used. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to etoposide or teniposide because of the exposure to other potentially hepatotoxic agents. Rare instances of clinically apparent liver injury have been reported in patients receiving etoposide, but the time to onset and pattern of injury has varied greatly. Onset can be as short as 1 to as long as 5 months after initiation of therapy. Some published cases of liver injury after regimens of chemotherapy that have included etoposide appear to represent sinusoidal obstruction syndrome. These cases have usually followed etoposide therapy in combination with an alkylating agent or total body irradiation. In addition, etoposide has been linked to cases of acute hepatitis arising after 1 to 5 months of treatment, which have generally been self-limiting, but occasionally severe. The role of etoposide in causing injury was not always clear. The pattern of serum enzyme elevation in reported cases has been hepatocellular. Immunoallergic features (rash, fever, eosinophilia) and autoantibodies were absent. The liver histology of etoposide hepatotoxicity has not been well characterized. The hepatotoxicity of teniposide has been less well defined than that of etoposide, probably because it has had limited use.

Likelihood score, etoposide: C (probable cause of clinically apparent liver injury).

Likelihood score, teniposide: E* (unproven but suspected cause of clinically apparent liver injury).

Mechanism of Injury

Etoposide is metabolized by the microsomal P450 drug metabolizing enzymes and inhibits the function of CYP 3A and 2D6, and injury may be the result of its activation to a toxic intermediate. Rapid recurrence with rechallenge is typical, but features of hypersensitivity are uncommon. In high doses, etoposide and teniposide may have direct hepatotoxic effects.

Outcome and Management

The hepatic injury caused by etoposide is usually reversible and etoposide has not been linked to cases of prolonged cholestasis or vanishing bile duct syndrome. The results of rechallenge after cases of clinically apparent insult have not been reported. Liver injury due to teniposide has been even less well characterized and there is no information on cross sensitivity to adverse events between these two agents.

Drug Class: Antineoplastic Agents

Other Drugs in the Subclass, Topoisomerase Inhibitors: Irinotecan, Topotecan


Case 1. Acute hepatitis attributed to etoposide therapy.

[Modified from Case 1 in: 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: 36-9. PubMed Citation]

A 52 old year man with metastatic small cell lung cancer developed jaundice at the start of a third course of chemotherapy. His liver tests were known to have been normal when he was initially diagnosed with lung cancer with cerebral metastases. He was started on combination chemotherapy with vindesin (a vinca alkaloid), cis-platinum, cyclophosphamide, adriamycin, methylprednisolone and etoposide (308 mg/m2). His liver tests were still normal two weeks later, but were mildly abnormal when he started a second course (Table). A third course was started one month later, but he was found to be jaundiced the following day, blood tests showing a total bilirubin of 12.5 mg/dL, ALT 2270 U/L, AST 1680 U/L and alkaline phosphatase 181 U/L. He drank alcohol but not to excess and had no previous history of liver disease. During the first two courses of chemotherapy, he had received 4 units of red blood cells. Serological testing showed the presence of anti-HBc without HBsAg or IgM anti-HBc and absence of IgM anti-HAV, anti-CMV and anti-EBV. Tests for hepatitis C were not available (before 1991). A liver biopsy showed acute hepatitis with numerous eosinophils and areas of focal necrosis. Chemotherapy was discontinued. Jaundice resolved spontaneously and all liver tests returned to normal during the following 10 weeks. A fourth course of chemotherapy was given without etoposide. His serum aminotransferase levels remained normal.

Key Points

Laboratory Values


This was one of three cases of acute hepatitis attributed to etoposide therapy. All three had a similar signature of an acute hepatitis arising after 2 to 5 months of cyclic chemotherapy, including use of intravenous, standard dose etoposide. The difficulty is that other diagnoses were possible for each of the three cases. Thus, the hepatitis C virus was first described in 1989 and serological tests were not available until 1991, well after these three patients had acute hepatitis. Furthermore, molecular tests for hepatitis B were not particularly sensitive (polymerase chain reaction tests were not available until the mid-1990s). Thus, the cases may have represented acute hepatitis C or reactivation of chronic hepatitis B, both of which this patient may have had (blood transfusions, preexisting anti-HBc reactivity). Other cases of an acute hepatitis-like syndrome have not been reported with etoposide, the majority of examples of hepatotoxicity being serum enzyme or bilirubin elevations or sinusoidal obstruction syndrome.



Etoposide – Generic, Toposar®

Teniposide – Generic, Vumon®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 25 February 2018

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