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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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Gemcitabine

Last Update: March 9, 2018.

OVERVIEW

Introduction

Gemcitabine is a cytosine analogue and intravenously administered antineoplastic agent used in the therapy of several forms of advanced, pancreatic, lung, breast, ovarian and bladder cancer. Gemcitabine is associated with a high rate of transient serum enzyme elevations during therapy but is a very rare cause of acute, clinically apparent liver injury.

Background

Gemcitabine (jem sye' ta been), 2,,2.-difluoro deoxycytidine, is a pyrimidine analogue that is widely used in solid tumor chemotherapy. Intracellularly, it is metabolized to diphosphate and triphosphate forms, both of which have antineoplastic activity inhibiting ribonucleotide reductase and competing with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is classified as an antimetabolite and is believed to act by inhibition of DNA synthesis in rapidly dividing cells. Gemcitabine was approved for use in cancer chemotherapy in the United States in 1996 and current indications include chemotherapy for advanced pancreatic, non-small cell lung, breast, ovarian and bladder cancers, either alone or in combination with other antineoplastic agents. Gemcitabine is administered intravenously and is available in vials of 10 and 50 mL in concentrations of 20 mg/mL generically and under the brand name Gemzar. The regimen of administration and dose vary by indication. A typical dosing regimen is 30 minute infusions of 1.0 to 1.2 g/m2 on days 1, 8 and 15 of each 28 day cycle of chemotherapy. Common side effects include bone marrow suppression, fatigue, diarrhea, nausea, gastrointestinal upset, rash, alopecia, and stomatitis.

Hepatotoxicity

Elevations in serum aminotransferase levels occur in 30% to 90% of patients receiving cyclic therapy with gemcitabine. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. ALT or AST elevations above 5 times the upper limit of the normal range occur in 1-4% of patients yet rarely lead to symptoms or clinically apparent liver injury. Serum bilirubin and alkaline phosphatase elevations are less common, but also typically transient and mild. Despite wide use, gemcitabine has only rarely been implicated in rare cases of acute liver injury with jaundice, and most published cases have been reported in patients with underlying chronic liver disease or extensive hepatic metastases. The clinical features of hepatotoxicity from gemcitabine have not been well described. Most cases were marked by a progressive cholestasis and hepatic failure developing after several cycles of therapy in patients with preexisting chronic liver disease (hepatitis C, alcoholic liver disease) or significant hepatic metastases or local invasion.

As with many antineoplastic agents and regimens, therapy with gemcitabine has also been associated rare cases of with reactivation of hepatitis B in persons with preexisting HBsAg in serum. At least one case of sinusoidal obstruction syndrome (veno-occlusive disease) has been reported with use of gemcitabine in a patient with underlying chronic hepatitis C who received no other antineoplastic agent.

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

Mechanism of Injury

The frequent mild-to-moderate serum aminotransferase elevations that occur during gemcitabine therapy are likely due to direct hepatic toxicity. The clinically apparent liver injury linked to gemcitabine (cholestasis, HBV reactivation, sinusoidal obstruction syndrome) has occurred mostly in persons with underlying, preexisting liver disease. Whether this injury is idiosyncratic or the result of mild direct hepatotoxicity superimposed on significant underlying liver dysfunction is unknown.

Outcome and Management

The severity of the liver injury linked to gemcitabine therapy is usually mild and self-limited, and dose modification or discontinuation is rarely necessary. However, the clinically apparent liver injury described with gemcitabine therapy tends to be severe and several fatal instances have been described. Virtually all of the clinically apparent liver injury related to gemcitabine has occurred in patients with underlying liver disease or extensive hepatic metastases or local invasion. In view of this, considerable care should be exercised in treating patients who have liver disease with gemcitabine. Furthermore, monitoring of routine liver tests before and during therapy is recommended with suspension of infusions if jaundice or clinically apparent liver injury arises. The possibility exists that the mild direct hepatotoxicity becomes clinically important in the presence of significant preexisting liver disease or dysfunction. The outcome of reexposure to gemcitabine after clinically apparent liver injury has not been reported. Also, there is no information on cross sensitivity to hepatic injury between gemcitabine and other antimetabolites or cytosine analogues such as cytarabine and capecitabine.

Drug Class: Antineoplastic Agents

Other Drugs in the Subclass, Pyrimidine Analogues: Azacitidine, Capecitabine, Cytarabine, Decitabine, Floxuridine, Fluorouracil, Trifluridine/Tipracil

CASE REPORTS

Case 1. Cholestatic liver injury arising during gemcitabine therapy.

[Modified from: Robinson K, Lambiase L, Li J, Monteiro C, Schiff M. Fatal cholestatic liver failure associated with gemcitabine therapy. Dig Dis Sci 2003; 48: 1804-8. PubMed Citation]

A 45 year old woman with metastatic breast adenocarcinoma was treated with eight cycles of taxotere, cyclophosphamide and daunorubicin and achieved remission. Liver tests were repeatedly normal before, during and after therapy. Two years later, she presented with symptoms of pain, nausea, vomiting and dehydration and was found to have elevations in liver tests (bilirubin 0.8 mg/dL, ALT 222 U/L, alkaline phosphatase 202 U/L). Tests for hepatitis B and C were negative and there were no abnormalities or clear evidence of metastatic disease on computerized tomography of the abdomen and chest. She, nevertheless, was started on gemcitabine and carboplatin for presumed recurrence of breast cancer. She improved somewhat but continued to have fever and poor appetite. Chemotherapy was continued. Twelve days after a fourth dose of gemcitabine and carboplatin, she was found to be jaundiced (bilirubin 6.4 mg/dL) and chemotherapy was stopped. Over the next two weeks, she developed worsening symptoms and required hospital admission for management. She had muscle wasting, peripheral edema, abdominal protuberance and tenderness, hepatomegaly and signs of hepatic failure (confusion and asterixis). Serum bilirubin was 14.7 mg/dL and other liver tests remained abnormal (Table). Serum ammonia was 49 µmol/L (normal <35) and INR was 1.4. Repeat CT scans showed marked ascites, pleural effusions, but no evidence of hepatic metastases. A liver biopsy showed patchy lobular necrosis, steatosis and marked cholestasis which was interpreted as compatible with drug induced liver injury. Her hepatic failure worsened and she died 2 days later, 5 days after hospitalization and 3 weeks after stopping gemcitabine and carboplatin.

Key Points

Medication:Gemcitabine (1300 mg intravenously once weekly)
Pattern:Cholestatic (R=0.6)
Severity:5+ (fatal)
Latency:Jaundice arising 5 weeks after initial dose
Recovery:None
Other medications:Carboplatin, morphine, oxycontin, anastrozole, methylprednisone, promethazine, esomeprazole, levofloxacin

Laboratory Values

Time After StartingDays After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
PrePre2222020.8Admission
0601600.6Albumin 2.7g/dL
Weekly infusions of gemcitabine and carboplatin started (x4)
5 days1582571.0
34 days0392136.4Chemotherapy stopped
55 days21 days7531214.7Admission
56 days22 days8630714.2INR 1.4
57 days23 days6927112.1Liver biopsy
60 daysDeath from hepatic failure
Normal Values <42 <128 <1.2

Comment

A relatively young woman with a history of breast cancer developed progressive liver disease with marked cholestasis and hepatic synthetic dysfunction concurrent with starting a regimen of carboplatin and gemcitabine for presumed recurrent, metastatic disease. Attribution of the injury to gemcitabine is difficult, as she was on other medications that are known to cause liver injury including anastrozole and carboplatin, which are perhaps more likely causes of the injury. Nevertheless, gemcitabine has been linked to cholestatic liver injury with modest serum aminotransferase and alkaline phosphatase elevations in patients with underlying liver disease. This patient had evidence of hepatic dysfunction before gemcitabine was started, and it well might have exacerbated the underlying condition. The course and outcome is somewhat reminiscent of fatty liver with lactic acidosis and hepatic dysfunction, which occurs with many nucleoside analogues in susceptible patients.

Case 2. Acute hepatocellular injury arising during gemcitabine therapy.

[Modified from: Saadati H, Peccerillo J, Kaley K, Schilsky ML, Saif MW. Gemcitabine-induced hepatitis in a pancreatic cancer patient receiving adjuvant therapy following metastasectomy. JOP 2009; 10: 573-5. PubMed Citation]

A 68 year old man with adenocarcinoma of the pancreas underwent a Whipple procedure, followed by three 28 day cycles of gemcitabine. He was then found to have hepatic metastasis and switched to the combination of gemcitabine and oxaliplatin which was continued for a year, at which time repeat imaging studies showed resolution of the hepatic masses. He was followed on no therapy and had no evidence of recurrence until 3 years later when a lung mass was detected and found to be a metastasis on resection. He was restarted on 28 day cycles of gemcitabine which were well tolerated until cycle six, when serum enzymes were found to be elevated and gemcitabine was held. He subsequently developed mild jaundice [bilirubin 3.7 mg/dL, ALT 1660 U/L, alkaline phosphatase 226 U/L] and he was admitted for evaluation. Tests for acute hepatitis were said to be negative and magnetic resonance imaging of the liver showed fatty infiltration, but no evidence of biliary obstruction or recurrence of hepatic metastases. He remained mildly jaundiced for several days, but complained of no symptoms and recovered rapidly and completely. In follow up, liver tests were normal. Gemcitabine was not restarted.

Key Points

Medication:Gemcitabine (six 28 day cycles; dose not given)
Pattern:Hepatocellular (R=27)
Severity:3+ (jaundice, hospitalization)
Latency:Approximately 5 months
Recovery:Within 3 weeks
Other medications:None mentioned

Laboratory Values

Time After StartingDays After StoppingALT* (U/L)Alk P* (U/L)Bilirubin* (mg/dL)Other
4 monthsPre200.4
4.5Pre2101651.0
5 months012002351.7
1 day14102262.4
2 days16602603.8
3 days15802263.7
4 days15502203.6
5 days15002103.9
7 days9502102.8
16 days1201101.1
22 days20700.6
Normal Values <25 <130 <1.2

* Several values estimated from Figure 1.

Comment

This patient with metastatic adenocarcinoma of the pancreas developed a mild, acute viral hepatitis-like syndrome after 5 cycles of gemcitabine. No other medications were mentioned. The report does not provide results of virologic and serological testing. Similar instances of acute hepatocellular injury with jaundice have not been reported with gemcitabine, and the possibility exists that the acute hepatitis was due to acute viral hepatitis (HEV or HCV are often difficult to diagnose in the acute setting).

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Gemcitabine – Generic, Gemzar®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Gemcitabine 95058-81-4 C9-H11-F2-N3-O4
Gemcitabine Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 09 March 2018

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  • Robinson K, Lambiase L, Li J, Monteiro C, Schiff M. Fatal cholestatic liver failure associated with gemcitabine therapy. Dig Dis Sci 2003; 48: 1804-8. [PubMed: 14561005]
    (45 year old woman with breast cancer with liver metastases and ALT elevations developed jaundice soon after starting gemcitabine [bilirubin 6.4 rising to 14.7 mg/dL, ALT 222 U/L, Alk P 202 U/L], with hepatic failure and death; liver biopsy showing fat, cholestasis and patchy hepatocellular necrosis: Case 1).
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    (68 year old man with advanced, metastatic pancreatic cancer developed dark urine and liver test abnormalities 5 cycles of gemcitabine [bilirubin 3.7 mg/dL, ALT 1660 U/L, Alk P 226 U/L], resolving within 7 weeks of stopping: Case 2).
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  • Ioka T, Katayama K, Tanaka S, Takakura R, Ashida R, Kobayashi N, Taniai H. Safety and effectiveness of gemcitabine in 855 patients with pancreatic cancer under Japanese clinical practice based on post-marketing surveillance in Japan. Jpn J Clin Oncol 2013; 43: 139-45. [PubMed: 23275642]
    (Among 890 patients with advanced pancreatic cancer treated with gemcitabine and reported to a Japanese registry, hepatic adverse events were reported in 1.3% of patients, but none were graded as severe).
  • Joerger M, Huitema AD, Koeberle D, Rosing H, Beijnen JH, Hitz F, Cerny T, et al. Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction. Cancer Chemother Pharmacol 2014; 73: 113-24. [PubMed: 24166106]
    (Among 12 patients with advanced pancreatic or biliary cancer and varying degrees of liver dysfunction, the toxicity of gemcitabine [largely hematologic] did not correlate with degree of liver dysfunction).
  • Yang ZY, Yuan JQ, Di MY, Zheng DY, Chen JZ, Ding H, Wu XY, et al. Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis. PLoS One 2013; 8: e57528. [PMC free article: PMC3589410] [PubMed: 23472089]
    (Review of literature on efficacy and safety of the combination of erlotinib and gemcitabine for advanced pancreatic cancer; the addition of erlotinib was associated with a prolongation of survival by 0.3 months and the adverse event rate was high "but not surprising"; no mention of hepatotoxicity).
  • Fuchs CS, Azevedo S, Okusaka T, Van Laethem JL, Lipton LR, Riess H, Szczylik C, et al. A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol 2015; 26 :921-7. [PMC free article: PMC4804122] [PubMed: 25609246]
    (Among 800 patients with metastatic pancreatic cancer treated with gemcitabine with or without ganitumab [monoclonal anti-IGF1R], overall survival was the same in all groups, and ALT elevations arose in 16% but were above 5 times ULN in less than 1%).
  • O'Neil BH, Scott AJ, Ma WW, Cohen SJ, Leichman L, Aisner DL, Menter AR, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol 2015; 26: 1923-9. [PMC free article: PMC4551155] [PubMed: 26091808]
    (Among 160 patients with metastatic pancreatic cancer treated with gemcitabine with or without rigosertib [a multikinase inhibitor], overall survival was the same in both groups and ALT elevations arose in 13% of patients and were above 5 times ULN in 1%).
  • Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, et al.; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 2016; 388: 248-57. [PubMed: 27265347]
    (Among 377 Japanese patients with pancreatic cancer given adjuvant chemotherapy with gemcitabine or "S-1", ALT elevations arose in 78% of patients and were above 5 times ULN in 4%).
  • 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. PubMed Citation. [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 [5.5%] were attributed to antineoplastic agents, but none were linked to use of gemcitabine).
  • Schultheis B, Reuter D, Ebert MP, Siveke J, Kerkhoff A, Berdel WE, Hofheinz R, et al. Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Ann Oncol 2017; 28: 2429-35. [PubMed: 28961832]
    (Among 192 patients with pancreatic cancer treated with gemcitabine with or without nimotuzumab [anti-EGFR], median overall survival was greater with the combination [8.6 vs 5.1 months] while adverse event rates were similar; ALT elevations and hepatotoxicity not mentioned).
  • Benson AB 3rd, Wainberg ZA, Hecht JR, Vyushkov D, Dong H, Bendell J, Kudrik F. A Phase II randomized, double-blind, placebo-controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist 2017; 22: 241-e15. [PMC free article: PMC5344644] [PubMed: 28246206]
    (Among 240 patients with metastatic pancreatic cancer treated with gemcitabine with or without simtuzumab [monoclonal anti-LOXL1], overall survival was similar in both groups as were adverse event rates with ALT elevations in 89% and 82% of subjects).
  • Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, et al.; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017; 389: 1011-24. [PubMed: 28129987]
    (Among 730 patients with resected pancreatic cancer given adjuvant chemotherapy with gemicitabine with or without capecitabine, overall survival was 25.5 vs 28.0 months while adverse event rates were only slightly higher with the combination; no mention of ALT elevations or hepatotoxicity).

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