Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation

Barnoud, D; Pinçon, Claire; Bruno, Bénédicte; Béné, Johana; Gautier, Sophie; Lahoche, Annie; Petitpain, Nadine; Vasseur, Michèle; Barthélémy, Christine; Décaudin, Bertrand; Simon, Nicolas; Odou, Pascal

doi:10.1002/pbc.27038

Cited by 13 publications

(11 citation statements)

References 18 publications

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“…Etoposide and TOP2 poisons are highly efficacious chemotherapy agents. Yet, differences in resistance across tumors and the toxicity associated with such treatments undermines the risk/benefit ratio that this therapy can offer to individual patients 36, 37, 38, 39, 40, 41 . To overcome this, biomarkers for etoposide and doxorubicin response are necessary, but virtually non-existent.…”

Section: Discussionmentioning

confidence: 99%

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Chen

Bansal

et al. 2019

Preprint

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Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers. KeywordsCRISPR, Glioblastoma (GBM), Topoisomerase II poisons (TOP2: etoposide, doxorubicin), DNA damage and repair response, H2AX (gamma H2AX phosphorylation) FANCB, Protein Synthesis, Ribosomal proteins subunits: (RPS11, 16, and 18), APAF1, Pro-(BID, CASPASE3/7) and anti-apoptotic effectors (BCL2).

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Section: Discussionmentioning

confidence: 99%

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Chen

Bansal

et al. 2019

Preprint

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“…Etoposide phosphate is preferred to etoposide because the latter poses a high risk of precipitation when highly concentrated . Two recent reports have highlighted the risk of acute kidney injury (AKI) due to etoposide phosphate . The Odds ratio to develop AKI linked to the use of EP at 60 mg/kg compared to cyclophosphamide at 60 mg/kg over 2 days combined with TBI was computed at 6.0 with a loss of renal function ranging between −44.5 and −71% .…”

Section: Diagram Of the Strengths Weaknesses Opportunities And Thrmentioning

confidence: 99%

“…Two recent reports have highlighted the risk of acute kidney injury (AKI) due to etoposide phosphate . The Odds ratio to develop AKI linked to the use of EP at 60 mg/kg compared to cyclophosphamide at 60 mg/kg over 2 days combined with TBI was computed at 6.0 with a loss of renal function ranging between −44.5 and −71% . The presence of an excipient in the formulation of Etopophos ® , Dextran 40 (300 mg/vial), leads us to strongly suspect this drug of being involved in the observed phenomenon .…”

Section: Diagram Of the Strengths Weaknesses Opportunities And Thrmentioning

confidence: 99%

“…Moreover, it could expose patients to other unsafe excipients included in the formulation of etoposide, such as polysorbate 80, benzylic alcohol, and ethanol in substantial amounts (241 or 248 mg/ml according to the supplier). Considering the mean dose of EP (2,520 mg) observed in the population described by Barnoud et al., a huge amount of ethanol would be administered (around 30 g/administration) in the case of etoposide (that is, 126 ml of marketed etoposide solution) . This amount may vary according to the supplier.…”

Section: Diagram Of the Strengths Weaknesses Opportunities And Thrmentioning

confidence: 99%

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Should we replace etoposide phosphate by etoposide for allogeneic hematopoetic stem‐cell transplantation in children?

Simon

Barnoud

Bruno

et al. 2018

Pediatric Blood & Cancer

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“…The use of at-risk excipients has notably been studied in pediatric intensive care units. 4 A recent study found that etoposide phosphate (used in hematopoietic stem-cell transplantation) may induce acute kidney injury, 5 because of the presence of the excipient dextran 40. However, the replacement of etoposide phosphate by standard etoposide would expose children to an even higher dose of ethanol (30 g, on average).…”

Section: Introductionmentioning

confidence: 99%

Ethanol Exposure During the Intravenous Administration of Chemotherapeutic Drugs: An Analysis of Clinical Practice and a Literature Review

Hiver¹,

Henry

Vasseur

et al. 2022

JCO Oncology Practice

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PURPOSE: Injectable cytotoxics may be formulated with ethanol. This study sought to quantify the amount of ethanol exposure during chemotherapy infusions. MATERIALS AND METHODS: We first reviewed the antineoplastic drugs (Anatomical Therapeutic and Chemical code L01) and oncologic supportive care drugs (eg, antiemetics) currently available in France, to identify preparations containing ethanol. The amount of ethanol in the final chemotherapy preparation was calculated. Next, we performed a 2-year, single-center, retrospective analysis of injectable antineoplastic drug compounding in routine clinical practice in a French university medical center. Finally, we reviewed our results with regard to the literature data. RESULTS: Ten of the 60 cytotoxic products on the market contained ethanol at concentrations of up to 790 mg/mL, depending on the drug, formulation, and supplier. Several final preparations contained more than 3 g of ethanol per infusion (the maximum recommended by the European Medicines Agency); this was notably the case for gemcitabine, paclitaxel (up to 20 g ethanol per injection, for both), and etoposide (up to 50 g ethanol per infusion). The analysis of our compounding activity showed that 3,172 (4.99%) of the 63,613 chemotherapy preparations (notably paclitaxel) contained more than 3 g of ethanol. None of the oncologic supportive care drugs contained ethanol. CONCLUSION: Patients are exposed to ethanol during the infusion of antineoplastic drugs. With a view to better patient care, physicians and pharmacists should carefully evaluate the risk of ethanol exposure throughout the course of cytotoxic drug treatment.

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Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation

Abstract: This study shows that EP at high dosage or one of its excipients is probably responsible for AKI, as compared to CY. Further studies are required to explore the origin of this adverse effect.

Cited by 13 publications

References 18 publications

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

Should we replace etoposide phosphate by etoposide for allogeneic hematopoetic stem‐cell transplantation in children?

Ethanol Exposure During the Intravenous Administration of Chemotherapeutic Drugs: An Analysis of Clinical Practice and a Literature Review

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