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.
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.
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.
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.
||Gemcitabine (1300 mg intravenously once weekly)|
|Pattern:|| Cholestatic (R=0.6)|
||Jaundice arising 5 weeks after initial dose
|Other medications:||Carboplatin, morphine, oxycontin, anastrozole, methylprednisone, promethazine, esomeprazole, levofloxacin|
|Time After Starting
||Days After Stopping
||Alk P (U/L)
|Weekly infusions of gemcitabine and carboplatin started (x4)|
|34 days||0||39||213||6.4||Chemotherapy stopped|
|55 days||21 days||75||312||14.7||Admission|
|56 days||22 days||86||307||14.2||INR 1.4|
|57 days||23 days||69||271||12.1||Liver biopsy|
|60 days||Death from hepatic failure|
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.
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.
||Gemcitabine (six 28 day cycles; dose not given)|
|Pattern:|| Hepatocellular (R=27)|
||3+ (jaundice, hospitalization)
||Approximately 5 months
||Within 3 weeks
|Other medications:||None mentioned|
|Time After Starting
||Days After Stopping
||Alk P* (U/L)
* Several values estimated from Figure 1.
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).
REPRESENTATIVE TRADE NAMES
Gemcitabine – Generic, Gemzar®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
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References updated: 09 March 2018
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Savage DG, Rule SA, Tighe M, Garrett TJ, Oster MW, Lee RT, Ruiz J, et al. Gemcitabine for relapsed or resistant lymphoma. Ann Oncol 2000; 11: 595-7. PubMed Citation (Study of 15 patients with relapsed or resistant lymphoma treated with gemcitabine makes no mention of ALT elevations or hepatotoxicity).
Samlowski WE, Gundacker H, Kuebler JP, Giguere JK, Mills GM, Schuller DE, Ensley JF. Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study. Invest New Drugs 2001; 19: 311-5. PubMed Citation (Among 26 patients with advanced head and neck cancer, one died of liver failure after the initial infusion, thought to be due to progressively enlarging liver metastases).
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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 Citation (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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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 (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).
Tanaka H, Takamori H, Eto S, Ozaki N, Akaboshi S, Nakahara O, Ida S, et al. [Acute liver injury with hepatic encephalopathy associated with gemcitabine administration for adjuvant chemotherapy in an HBV carrier with pancreatic cancer]. Gan To Kagaku Ryoho 2010; 37: 1783-6. Japanese. PubMed Citation (75 year old HBsAg positive woman with pancreatic cancer developed jaundice after a 6th weekly dose of gemcitabine [bilirubin 3.7 mg/dL, ALT 37 U/L, Alk P 471 U/L, INR 1.9, ammonia 72 rising to 300 µg/dL], without change in hepatitis B markers [HBV DNA undetectable], resolving within 4 weeks of stopping therapy).
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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 Citation (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).
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- 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. PubMed Citation (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%).
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2015; 26: 1923-9. PubMed Citation (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%).
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Lancet 2016; 388: 248-57. PubMed Citation (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 (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,
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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 Citation (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. PubMed Citation (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).
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