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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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Vinca Alkaloids

Last Update: September 12, 2020.




The vinca alkaloids include vincristine, vinblastine and vinorelbine which are important antineoplastic agents used in many chemotherapeutic regimens for a wide variety of cancers. Despite their cytotoxic activity against cancer cells, the vinca alkaloids have rarely been implicated in causing clinically apparent acute liver injury.


The vinca alkaloids are antineoplastic agents that act by binding to intracellular tubulin, the basic protein subunit of microtubules which are important in many intracellular processes including mitosis and cell division. The vinca alkaloids inhibit cell division by blocking mitosis; they also inhibit purine and RNA synthesis causing death of rapidly dividing cells. Vincristine and vinblastine were initially isolated from periwinkle (vinca rosea), extracts of which were found to have antitumor activity. Subsequently, they have been synthesized, although their structure is quite complex. Vinorelbine is a semisynthetic derivative of extracts of periwinkle. Vincristine (vin kris' teen) was approved for use in cancer chemotherapy in 1963, vinblastine (vin blas' teen) in 1965 and vinrelbine (vin or' el been) in 1994. Vincristine and vinblastine have become major components of many combination anticancer regimens, used particularly in treatment of acute leukemia, Hodgkin disease and other lymphomas, various sarcomas, Wilms tumor, neuroblastoma, and breast and lung cancer. Vinorelbine has had a more restricted use and is approved only for advance non-small cell lung cancer. The vinca alkaloids are given intravenously, typically at one or two week intervals in cycles with other agents. Importantly, the vinca alkaloids should only be given intravenously; if given intrathecally, they cause a progressive neurological syndrome, ascending paralysis and death. The vinca alkaloids are available in generic forms and under the trade names Oncovin (vincristine), Velban (vinblastine) and Navelbine (vinorelbine). Side effects are common and include nausea, vomiting, fatigue, headache, dizziness, peripheral neuropathy, hoarseness, ataxia, dysphagia, urinary retention, constipation, diarrhea, bone marrow suppression, alopecia and phlebitis at the infusion site. Uncommon but potential severe adverse events include severe neutropenia, bleeding, peripheral neuropathy, pulmonary toxicity, hypersensitivity reactions and embryo-fetal toxicity.


Despite being cytotoxic for cancer cells and metabolized actively by the liver, the vinca alkaloids have only rarely been associated with significant hepatic toxicity. Because they are usually given with other anticancer agents and/or radiotherapy, which may also be hepatotoxic, the role that they play in causing liver injury is not always clear. When given on their own, the vinca alkaloids are associated with transient and asymptomatic elevations in serum aminotransferase levels in 5% to 10% of patients. However, clinically apparent liver injury attributed to the vinca alkaloids has been rare and not well defined. Both vincristine and vinblastine may increase the risk of sinusoidal obstruction syndrome, also known as venoocclusive disease of the liver, caused by radiation, dactinomycin or the alkylating agents, but not when given on their own. In these situations, the risk of sinusoidal obstruction syndrome is greater with higher doses of radiation, dactinomycin or cyclophosphamide and younger age (in children).

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

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

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

Mechanism of Injury

The reason why the vinca alkaloids are not particularly toxic to liver cells is not known, but cell division and mitosis (the major targets of vincristine and vinblastine) are rare in the resting liver. Both agents are extensively metabolized in the liver and excreted in bile.

Outcome and Management

Serum enzyme elevations are not uncommon during cancer chemotherapy and may occasionally be dose limiting; however, the vinca alkaloids are rarely the sole or major reason for significant or persistent enzyme elevations or clinically apparent liver injury. Patients who develop sinusoidal obstruction syndrome, but recover, can be safely treated with further courses of vincristine alone or combined with reduced doses of the alkylating agent or dactinomycin.

Drug Class: Antineoplastic Agents


Case 1. Fatal sinusoidal obstruction syndrome after abdominal irradiation and vincristine therapy.(1)

A 30 year old woman with poorly differentiated lymphocytic nodular lymphoma was treated with prednisone and weekly infusions of vincristine and once weekly oral streptonigrin (an antibiotic and bioreductive antineoplastic agent). Vincristine was withdrawn after 4 cycles because of neuropathy. After 6 cycles of chemotherapy, she underwent mediastinal (2000 rads) and abdominal (2225 rads) irradiation over a two month period with another cycle of vincristine (day 88). On day 111, which was 10 days after finishing radiation therapy and 33 days after the fifth and last infusion of vincristine, she developed pancytopenia, fever, abdominal pain, ascites and jaundice. Serum aminotransferase levels were markedly elevated with only modest increases in alkaline phosphatase. The fever and pancytopenia resolved with antibiotic therapy, but she developed progressive jaundice and hepatic failure and died 4 weeks later. Autopsy showed an enlarged, congested liver with sinusoidal obstruction and severe centrilobular necrosis. The autopsy showed no residual evidence of lymphoma.

Key Points

Medication:Vincristine, hepatic irradiation
Pattern:Hepatocellular (R=~100)
Severity:5+ (hepatic failure and death)
Latency:111 days after starting vincristine, 10 days after irradiation
Other medications:Prednisone, streptonigrin

Laboratory Values

Days After
Alk P
1Started oral prednisone and weekly doses of vincristine and streptonigrin
11V & S91050.8
17V & S10100
24V & S11105
88Rad & V25140
111Admission40002555.8Jaundice, ascites, fever
113Day 215502306.0
117Day 618526510.0
122Day 118840520.0
131Day 206234020.5
141Day 30Died of hepatic failure
Normal Values <30 <275 <1.2

Abbreviations: Rad=radiation therapy, S=oral streptonigrin, V=vincristine infusion.


The clinical presentation with weight gain, abdominal pain, ascites and jaundice is typical of sinusoidal obstruction syndrome. Hepatic irradiation, dactinomycin, and the alkylating agents (dacarbazine, cyclophosphamide, myleran and busulfan) are most frequently associated with this form of liver injury. The injury is probably due to direct toxicity to sinusoidal lining cells with their subsequent necrosis and extrusion into the sinusoidal spaces, which causes obstruction, hemorrhage and local ischemia to hepatocytes. Signs of portal hypertension appear early, followed (in severe cases) by jaundice and hepatic failure. The dose of radiation used in this patient (<3000 rads) was not considered adequate to cause sinusoidal obstruction syndrome on its own, which suggested that vincristine might have increased the risk of this complication.



Vinblastine – Generic, Velban®

Vincristine – Generic, Oncovin®

Vinorelbine – Generic, Navelbine®


Antineoplastic Agents




Product labeling at DailyMed, National Library of Medicine, NIH


Vinblastine 865-21-4 C46-H58-N4-O9 image 134980402 in the ncbi pubchem database
Vincristine 57-22-7 C46-H56-N4-O10 image 134970704 in the ncbi pubchem database
Vinorelbine 71486-22-1 C45-H54-N4-O8 image 135049333 in the ncbi pubchem database


Hansen MM, Ranek L, Walbom S, Nissen NI. Fatal hepatitis following irradiation and vincristine. Acta Med Scand. 1982;212:171–4. [PubMed: 7148508]


References updated: 12 September 2020

Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine and dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone; CHOP, chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine and prednisone; G-CHOP, obinutuzumab with CHOP; R-CHOP, rituximab with CHOP; SOS, sinusoidal obstruction syndrome.

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    (30 year old woman with lymphoma developed SOS after liver irradiation and chemotherapy with vincristine [bilirubin 6.0 rising to 21.0 mg/dL, AST 4000 U/L, Alk P 250 U/L], with progressive multiorgan failure and death 4 weeks later: Case 1).
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    (Retrospective analysis of 154 children with Wilms tumor treated with dactinomycin and vincristine found higher rate of hepatotoxicity with higher single dose dactinomycin [14%] than with lower [4%] or split doses [3%]; clinical presentation with ascites, elevated AST [529 to 8208 U/L] and 50% with jaundice).
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    (Among 511 children with Wilms tumor treated with dactinomycin and vincristine with or without other agents or irradiation, 64 [12%] had hepatotoxicity including 41 [8%] with SOS [all with hepatomegaly, 83% ascites, 28% jaundice, 6% fatal]; rates higher in children <1 years of age and those who received irradiation [12% vs 7%]).
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    (Among 821 children [ages 2 to 15 years] with rhabdomyosarcoma treated with vincristine, dactinomycin and cyclophosphamide, 10 [1.2%] developed SOS and 1 died; single major risk factor was higher doses of cyclophosphamide).
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    (Among 10 patients with desmoid tumors given methotrexate [50 mg/week] and vinblastine [10 mg/week], severe side effects were common and 2 developed transient ALT elevations [3 to 10 times ULN] without jaundice).
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    (Among 339 children with rhabdomyosarcoma treated with vincristine, dactinomycin and cyclophosphamide, 18 [6%] developed hepatotoxicity and 3 died [1%]; risk of liver injury was greater in children <3 years of age [15% vs 4%]).
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    (Among 48 patients with refractory metastatic breast cancer treated with cisplatin combined with either vinorelbine or gemcitabine, objective response rates were similar [46%], as was time to progression and adverse events; mild [grade 1 or 2] “hepatic dysfunction” arose in 27% of both groups and did not require dose modification or progress to clinically apparent liver injury).
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    (79 year old woman with Hodgkin disease was found unconscious 3 hours after completing a first cycle of ABVD [doxorubicin, bleomycin, vinblastine and dacarbazine], with liver injury arising over the next 24 hours [bilirubin 2.6 mg/dL on day 2, ALT 980 U/L, Alk P 126, lactate 5.3 mmol/L], with rapid recovery).
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    (Among 10,475 adverse drug reaction reports made to a Canadian pharmacovigilance registry between 2005 and 2017 from 26 medical centers, 73% were pediatric and the most commonly implicated drugs were antineoplastic agents, including methotrexate, vincristine, doxorubicin, cisplatin, L-asparaginase, cyclophosphamide, dexamethasone, cytarabine and etoposide, hepatotoxicity being the 10th most common type of reaction [194 cases]).
  • Peng S, Yang K, Xu Z, Chen S, Ji Y. Vincristine and sirolimus in the treatment of kaposiform haemangioendothelioma. J Paediatr Child Health. 2019;55:1119–24. [PubMed: 30604513]
    (Metaanalysis of trials of vincristine and sirolimus for Kaposiform hemangioendothelioma identified 5 studies in 75 patients of vincristine, with adverse event reports from 16 subjects, the most common events being neuropathy [38%], abdominal pain [19%], anorexia [6%] and transient ALT elevations [12%]; no mention of clinically apparent liver injury).
  • Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, et al. PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285–95. [PMC free article: PMC6553835] [PubMed: 30901302]
    (Among 838 patients with large B cell lymphoma treated with R-CHOP with or without ibrutinib, overall survival was not improved by ibrutinib, but serious side effects were greater [53% vs 34%]; no mention of ALT elevations or hepatotoxicity).
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    (Among 592 patients with B cell non-Hodgkin lymphoma treated with 6 cycles of R-CHOP vs 4 cycles with 2 further cycles of rituximab alone, progression free survival was similar in the two groups while adverse events were more with the 6 cycles; no mention of ALT elevations or hepatotoxicity).
  • Brühwiler LD, Schwappach DL. Safe vincristine use in Switzerland: still a long way to go? J Oncol Pharm Pract. 2020;26:51–9. [PubMed: 30866715]
    (The medical error of administration of vincristine intrathecally instead of intravenously leads to progressive decerebration and death within a few days, and international recommendations to prevent this error have not been rigorously adopted as shown by surveys of pharmaceutical services in Switzerland).
  • Sehn LH, Martelli M, Trněný M, Liu W, Bolen CR, Knapp A, Sahin D, et al. A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA. J Hematol Oncol. 2020;13:71. [PMC free article: PMC7276080] [PubMed: 32505213]
    (Among 1414 patients with large B cell lymphoma treated with CHOP and either rituximab [R-CHOP] or obinutuzumab [G-CHOP] [both monoclonal antibodies to CD20], progression-free survival rates were similar [64% and 63%] as were total adverse events, but serious events were more frequent with G-CHOP [44% vs 38%]; no mention of ALT elevations or hepatotoxicity).
  • Dalal M, Gupta J, Price K, Zomas A, Miao H, Ashaye A. Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review. Expert Rev Hematol. 2020 Aug 4;:1–16. Epub ahead of print. [PubMed: 32749937]
    (Systematic review of first line therapies of advance Hodgkin disease focused on ABVD [doxorubicin, bleomycin, vinblastine and dacarbazine] and BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone], discussing side effects of pulmonary toxicity, secondary malignancies, neutropenia and peripheral neuropathy but not hepatotoxicity or ALT elevations).


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