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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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Irinotecan

Last Update: April 27, 2018.

OVERVIEW

Introduction

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.

Background

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.

Hepatotoxicity

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

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Irinotecan – Generic, Camptosar®

Topotecan – Generic, Hycamtin®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Irinotecan100286-90-6C33-H38-N4-O6.Cl-H
Irinotecan Chemical Structure
Topotecan119413-54-6C23-H23-N3-O5.Cl-H
Topotecan Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 27 April 2018

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    (Among 406 patients undergoing hepatic resection for colorectal metastases, preoperative chemotherapy with oxaliplatin was associated with sinusoidal dilatation [19% vs 2%], whereas irinotecan was associated with steatohepatitis [20% vs 4.4%], which was associated with higher 90 day mortality rates).
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    (Among 212 patients with metastatic colorectal cancer undergoing resection, 55 had received irinotecan of whom 15 [27%] had marked steatosis and 2 [4%] steatohepatitis, compared to 59 patients who did not undergo chemotherapy of whom 2 [3%] had marked steatosis and none steatohepatitis).
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    (Among 100 patients with metastatic small cell lung cancer treated with topotecan and carboplatin in up to six cycles of either 3 or 5 days, hematologic toxicity [largely neutropenia] was the main side effect; no mention of ALT levels or hepatotoxicity).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J. 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: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, several cases were attributed to antineoplastic agents [such as mercaptopurine, cyclophosphamide, docetaxel, temozolomide, bortezomib and imatinib], but none to irinotecan or topotecan).
  • Kudo D, Tsutsumi S, Akasaka H, Jin H, Ohashi T, Muroya T, Hasebe T, et al. [Predictive factors for histopathological liver injury in the patients who received preoperative systemic chemotherapy for colorectal liver metastases]. Gan To Kagaku Ryoho 2009; 36: 2025-7. Japanese. [PubMed: 20037312]
    (Abstract only; among 47 patients undergoing hepatic resections for metastatic colorectal cancer, sinusoidal dilation but not steatohepatitis was more common among those who received preoperative oxaliplatin chemotherapy).
  • Cleary JM, Tanabe KT, Lauwers GY, Zhu AX. Hepatic toxicities associated with the use of preoperative systemic therapy in patients with metastatic colorectal adenocarcinoma to the liver. Oncologist 2009; 14: 1095-105. [PubMed: 19880627]
    (Review of hepatic complications of chemotherapy for colorectal cancer; steatohepatitis has been associated with irinotecan therapy and BMI and linked to poor outcomes).
  • Choti MA. Chemotherapy-associated hepatotoxicity: do we need to be concerned? Ann Surg Oncol. 2009 Sep; 16: 2391-4. [PubMed: 19554374]
    (Review on chemotherapy associated liver injury and its impact on surgical outcome after hepatic resection for colorectal cancer; irinotecan and 5-FU have been linked to steatosis and steatohepatitis).
  • Ramachandran R, Kakar S. Histological patterns in drug-induced liver disease. J Clin Pathol 2009; 62: 481-92. [PubMed: 19474352]
    (Review of histology of drug induced liver injury discusses the "chemotherapy induced steatohepatitis" that is seen most frequently after irinotecan therapy).
  • Masi G, Loupakis F, Pollina L, Vasile E, Cupini S, Ricci S, Brunetti IM, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/ leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg 2009; 249: 420-5. [PubMed: 19247029]
    (Among 196 patients with metastatic colorectal cancer who received chemotherapy, 37 were ultimately eligible for hepatic resection of the metastasis among whom all had sinusoidal dilation and 76% steatosis, which was severe in only 5% and associated with steatohepatitis in only 1).
  • Khan AZ, Morris-Stiff G, Makuuchi M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J Hepatobiliary Pancreat Surg 2009; 16: 137-44. [PubMed: 19093069]
    (Review of liver injury from neoadjuvant therapy of colon cancer metastases and its clinical implications; irinotecan has been linked to steatosis and steatohepatitis, which may affect outcome of subsequent surgical resection of metastases).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Review of the role and liver toxicity of chemotherapy for colorectal metastases; oxaliplatin is associated with sinusoidal injury and irinotecan with chemotherapy induced steatohepatitis [CASH]).
  • Chaudhury P, Hassanain M, Bouganim N, Salman A, Kavan P, Metrakos P. Perioperative chemotherapy with bevacizumab and liver resection for colorectal cancer liver metastasis. HPB (Oxford) 2010; 12: 37-42. [PMC free article: PMC2814402] [PubMed: 20495643]
    (Among 35 patients with metastatic colorectal cancer who received bevacizumab before hepatic resection of liver metastases, 9 also received irinotecan but only 4 developed steatohepatitis and 2 jaundice postoperatively, but relationship of these events to irinotecan was not provided).
  • Takamoto T, Hashimoto T, Sano K, Maruyama Y, Inoue K, Ogata S, Takemura T, et al. Recovery of liver function after the cessation of preoperative chemotherapy for colorectal liver metastasis. Ann Surg Oncol 2010; 17: 2747-55. [PubMed: 20425145]
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  • Ryan P, Nanji S, Pollett A, Moore M, Moulton CA, Gallinger S, Guindi M. Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am J Surg Pathol 2010; 34: 784-91. [PubMed: 20421779]
    (Among 334 patients undergoing hepatic resection for colorectal cancer metastases, marked hepatic steatosis was uncommon [9%] and correlated with BMI rather than chemotherapy, while sinusoidal lesions were present in 35% of cases and correlated with oxaliplatin use; neither correlated with immediate operative outcome).
  • Makowiec F, Möhrle S, Neeff H, Drognitz O, Illerhaus G, Opitz OG, Hopt UT, zur Hausen A. Chemotherapy, liver injury, and postoperative complications in colorectal liver metastases. J Gastrointest Surg 2011; 15: 153-64. [PubMed: 21061183]
    (Among 102 patients undergoing hepatic resections for colorectal cancer metastases, steatosis was most common in those who had preoperative chemotherapy regardless of regimen [46% vs 18%], but BMI was a stronger risk factor and steatosis did not correlate with poor outcome).
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    (Review of types of liver injury from chemotherapy; oxaliplatin is associated with vascular and sinusoidal injury, whereas irinotecan is linked to steatohepatitis).
  • Narita M, Oussoultzoglou E, Chenard MP, Fuchshuber P, Rather M, Rosso E, Addeo P, et al. Liver injury due to chemotherapy-induced sinusoidal obstruction syndrome is associated with sinusoidal capillarization. Ann Surg Oncol 2012; 19: 2230-7. [PubMed: 22402811]
    (Among 98 patients with colorectal cancer undergoing hepatic resection for metastases, 39 [36 of whom had received oxaliplatin] had changes of sinusoidal obstruction syndrome, and degree of changes correlated with isocyanine green [ICG] retention and overexpression of CD34, indicating capillarization of hepatic sinusoids).
  • Robinson SM, Wilson CH, Burt AD, Manas DM, White SA. Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis. Ann Surg Oncol 2012; 19: 4287-99. [PMC free article: PMC3505531] [PubMed: 22766981]
    (Histologic evaluation in 506 patients undergoing hepatic resection for colorectal cancer, showed that steatohepatitis was associated with irinotecan regimens, higher BMI and diabetes, whereas sinusoidal dilatation was not associated with chemotherapy; neither chemotherapy nor liver histology correlated with complications or deaths).
  • Lu QY, Zhao AL, Deng W, Li ZW, Shen L. Hepatic histopathology and postoperative outcome after preoperative chemotherapy for Chinese patients with colorectal liver metastases. World J Gastrointest Surg 2013; 5: 30-6. [PMC free article: PMC3615301] [PubMed: 23556058]
    (Among 106 patients undergoing hepatic resections of colorectal cancer metastases after chemotherapy, 5 of 9 [56%] who received irinotecan had liver toxicity, including steatosis in 2 and steatohepatitis in 3).
  • Oshita F, Sugiura M, Murakami S, Kondo T, Saito H, Yamada K. Phase II study of nedaplatin and irinotecan in patients with extensive small-cell lung cancer. Cancer Chemother Pharmacol 2013; 71: 345-50. [PubMed: 23124649]
    (Among 25 patients with small cell lung cancer treated with 4 cycles of nedaplatin and irinotecan, ALT elevations occurred in 10 [40%], but were transient and less than 5 times ULN in all).
  • Wolf PS, Park JO, Bao F, Allen PJ, DeMatteo RP, Fong Y, Jarnagin WR, et al. Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience. J Am Coll Surg 2013; 216: 41-9. [PubMed: 23041049]
    (Among 384 patients undergoing liver resection for colorectal cancer metastases who had liver histology assessment, 35% had steatosis and 4% steatohepatitis, both of which were associated with higher BMI, diabetes and irinotecan chemotherapy, but these histologic featuers were not associated with major complications or death and no deaths were liver related).
  • von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, Steins M, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 2014; 32: 4012-9. [PubMed: 25385727]
    (Among 637 patients with small-cell lung carcinoma treated wtih amrubicin or topotecan, overall survival was similar [7.5 vs 7.8 months] while hematologic adverse events were more common with topotecan, non-hematologic events rates were similar; no mention of ALT elevations or hepatotoxicity).
  • Enomoto Y, Inui N, Imokawa S, Karayama M, Hasegawa H, Ozawa Y, Matsui T, et al. Safety of topotecan monotherapy for relapsed small cell lung cancer patients with pre-existing interstitial lung disease. Cancer Chemother Pharmacol 2015; 76: 499-505. [PubMed: 26134440]
    (Among 77 patients with relapsed small cell lung cancer treated with 1 to 7 courses of intravenous topotecan, adverse events were frequent including neutropenia [57%], febrile neutropenia [26%, one death] and exacerbation of preexisting interstitial lung disease [22%: 3 deaths]; no mention of hepatotoxicity).
  • Vincenzi B, Imperatori M, Picardi A, Vespasiani Gentilucci U, Gallo P, Fausti V, et al. Liver toxicity in colorectal cancer patients treated with first-line FOLFIRI-containing regimen: a single institution experience. Expert Rev Anticancer Ther 2015; 15: 971-6. [PubMed: 26112080]
    (Among 156 patients with coloreactal cancer treated with a "backbone" regimen of folinic acid, fluorouracil and irinotecan ["FOLFIRI"], most had serum enzyme elevations before starting [64%], and serum enzymes rose overall during the first 3 months of treatment [median peak level of ALT 168 U/L, Alk P 289 U/L, and bilirubin 1.2 mg/dL], while abnormal liver tests led to course delay in 16%, dose reduction in 8%, but discontinuation in only 2% and death in 0% of patients).
  • 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 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).

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