Irinotecan and topotecan are semisynthetic derivatives of the plant alkaloid camptothecin and are used as antineoplastic agents in the therapy of colorectal, ovarian and non-small cell lung cancer. Both irinotecan and topotecan are associated with an appreciable rate of serum enzyme elevations during therapy, and irinotecan has been implicated in causing steatohepatitis when given as cyclic anticancer therapy.


Irinotecan (eye" ri noe tee' kan) and topotecan (toe" poe tee' kan) are semisynthetic derivatives of camptothecin, a plant alkaloid derived from the Chinese tree, Camptotheca acuminata. Both drugs appear to act by blocking DNA topoisomerase I, which is responsible for relaxation of supercoiled double stranded DNA so that replication can proceed. Topoisomerase I activity is particularly increased in cancer cells. Irinotecan and topotecan have antineoplastic activity against colorectal, non-small cell lung and breast cancer in vivo and in vitro. Irinotecan and topotecan were both approved for use in the United States in 1996 and continue to be used in oncology practice. Current formal indications for irinotecan are advanced colorectal cancer alone or in combination with other antineoplastic agents (usually fluorouracil). Irinotecan is available generically and under the brand name Camptosar in 2, 5 and 15 mL vials of 20 mg/mL. The typical dose varies is based upon body weight and is adjusted by whether it is used alone or in combination with other anticancer agents. The approved indications for topotecan include advanced or metastatic ovarian and cervical cancer and small cell lung cancer (after failure of first line chemotherapy). Topotecan is available in solution in 4 mg single dose vials generically and under the trade name Hycamtin. The typical dose varies by indication and body weight. Side effects of irinotecan and topotecan are similar and include bone marrow suppression, nausea, vomiting, abdominal pain, stomatitis, diarrhea, fatigue, hair loss and peripheral neuropathy. Infusions of irinotecan can be associated with severe diarrhea which is typically delayed and is treated with loperamide. Irinotecan also can cause an acute cholinergic syndrome marked by hypotension, diarrhea, sweating, lacrimation and fatigue, which is typically treated with atropine.


Chemotherapy with irinotecan and topotecan in combination with other agents is associated with serum enzyme elevations in up 15% of patients depending upon the dose, other agents used, the frequency of monitoring and degree of elevation that is reported. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. Marked elevations occur in 1% to 4% of patients, but rarely require dose modification. Genetic variants in hepatic transporters and metabolic enzymes have been associated with predisposition to irinotecan toxicity, including OATP 1B1 (SLC01B1), UGT1A1 and CYP 3A4. However, the major toxicities of irinotecan are hematologic and diarrhea, and liver test elevations are rare causes of drug interruption or dose modification.

Irinotecan has been linked to chemotherapy induced steatosis and steatohepatitis. This can be shown by imaging or histologically, but is usually associated with minimal symptoms or laboratory test abnormalities. Cyclic therapy with irinotecan is often used to treat hepatic metastases from colorectal cancer in preparation for hepatic resection, and both steatosis and steatohepatitis have been found to be frequent in the nontumorous part of the liver at the time of resection. These abnormalities are often associated with mild to moderate elevations in serum aminotransferase and alkaline phosphatase levels, but are rarely symptomatic or accompanied by jaundice. Intriguingly, the steatosis and steatohepatitis associated with chemotherapy tends to persist long term, as opposed to sinusoidal obstruction syndrome and nodular regenerative hyperplasia which tend to improve or resolve over time. Steatohepatitis may be associated with an increased rate of complications after hepatic resection probably as a result of inhibition of hepatic regeneration. On the other hand, steatohepatitis following adjuvant irinotecan therapy has not been clearly associated with a decrease in survival or an increeased rate of hepatic failure after major hepatic resection. In addition, irinotecan has not been clearly associated with instances of sinusoidal obstruction syndrome or nodular regenerative hyperplasia, the common complications of oxaliplatin therapy, which is a frequently used alternative to irinotecan in managing advanced and metastatic colorectal cancer.

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

Topotecan is a less frequently used topoisomerase inhibitor and has been associated with serum enzyme elevations in up to 50% of patients, but these have been transient, mild and not associated with jaundice or symptoms. Since licensure and more wide scale use, tocotecan has not been associated with instances of clinically apparent liver injury.

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

Mechanism of Injury

Irinotecan is extensively metabolized in the liver and undergoes modification by CYP 3A and uridine diphosphate-glucuronosyltransferase (UGT1A1), the enzyme responsible for conjugation of bilirubin and is partially deficit in persons with Gilbert syndrome. As a consequence, adverse events to irinotecan therapy (such as neutropenia and diarrhea) are more common in patients with hyperbilirubinemia and Gilbert syndrome. The cause of steatosis and steatohepatitis from irinotecan therapy is not known, but may relate to generation of toxic intermediates of its metabolism.

Outcome and Management

The hepatic injury caused by irinotecan and topotecan is usually mild and asymptomatic, and neither agent has 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.

Drug Class: Antineoplastic Agents

Other Drugs in the Subclass, Topoisomerase Inhibitors: Etoposide, Teniposide



Irinotecan – Generic, Camptosar®

Topotecan – Generic, Hycamtin®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 27 April 2018

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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 were attributed to antineoplastic agents [5.5%], but none were attributed to irinotecan to topotecan).
  • Goto K, Ohe Y, Shibata T, Seto T, Takahashi T, Nakagawa K, Tanaka H, Tet al; JCOG0605 investigators. Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2016; 17: 1147-57. [PubMed: 27312053]
    (Among 180 patients with relapsed small cell lung cancer treated with topotecan vs combination chemotherapy, overall survival was less with topotecan [12 vs 18 months], while adverse events were somewhat less including febrile neutropenia [7% vs 31%] and serious adverse events [4% vs 10%], while rates of ALT elevations were similar [37% vs 35% overall, above 5 times ULN 1% vs 2%], and there were 2 topotecan related deaths [both pulmonary]).
  • Vigano L, De Rosa G, Toso C, Andres A, Ferrero A, Roth A, Sperti E, Majno P, Rubbia-Brandt L. Reversibility of chemotherapy-related liver injury. J Hepatol. 2017; 67 (1): 84-91. [PubMed: 28284915]
    (Among 524 liver resections done on 429 patients, rates of sinusoidal obstruction were less in patients whose resection was done more than 270 days after chemotherapy [19% vs 40%] as was nodular regenerative hyperplasia [8% vs 24%], but not steatosis [24% vs 36%] or steatohepatitis [10% vs 16%], but only NRH correlated with an increased liver failure rate [8% vs 3%]).
  • Duwe G, Knitter S, Pesthy S, Beierle AS, Bahra M, Schmelzle M, Schmuck RB, et al. Hepatotoxicity following systemic therapy for colorectal liver metastases and the impact of chemotherapy-associated liver injury on outcomes after curative liver resection. Eur J Surg Oncol 2017; 43: 1668-81. [PubMed: 28599872]
    (Review of the hepatotoxicity of adjuvant therapy for metastatic colorectal cancer mentions that irinotecan is associated with steatosis and steatohepatitis which may impair hepatic regeneration, but have not been clearly linked to poor long term outcomes).
  • Poveda A, Del Campo JM, Ray-Coquard I, Alexandre J, Provansal M, Guerra Alía EM, Casado A, et al. Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer. Ann Oncol 2017; 28: 1280-7. [PMC free article: PMC5452066] [PubMed: 28368437]
    (Among 59 patients with refractory advanced ovarian cancer treated with topotecan or an experimental anticancer agent, ALT elevations occurred in 51% of topotecan treated subjects, but most were mild and all were transient and less than 5 times ULN).