Discussion:
We report a series of etoposide infusion related ADRs occurring at two free standing pediatric institutions. Specifically, our results highlight three key findings: 1) etoposide can be tolerated in patients who have experienced an etoposide ADR with premedication, extended infusion time, or change in formulation, 2) flushing and difficulty breathing were the most commonly encountered symptoms, and 3) we observed varying rates of ADRs between institutions and a clustering of etoposide infusion ADRs between 2017-2020.
Often times when a patient experiences an ADR, the patient is not re-challenged and a therapeutic alternative is prescribed.11 In cancer treatment, alternative therapeutic agents are often not an option. In our 10-year cohort all 32 patients that experienced etoposide ADRs were successfully re-challenged with either etoposide or etoposide phosphate in order to complete their prescribed regimen. Sixty percent of patients were empirically changed to the etoposide phosphate formulation which has been shown to be associated with fewer ADRs compared to standard etoposide formulations, but due to the higher price, it is not typically used first-line.7,11 The remaining 40% of patients received premedication and/or modifications of infusion rates and tolerated subsequent infusions. Interestingly, no ADRs were associated with etoposide phosphate.
Etoposide infusion related ADRs are reported in both the package insert and previously published literature with a wide variety of symptomology.1-5,7 Although in our cohort we present many possible symptoms, the ADRs observed in our population are homologous with 71% of patients experiencing flushing and respiratory distress. This is important, as monitoring for these symptoms should occur during etoposide infusions.
The rate of etoposide ADRs at CMH was twice that at RH, but more interestingly across both institutions, two ADRs occurred in 2012, one at each institution, and the remaining 30 ADRs all occurred during the four-year period between 2017–2020, with no etoposide ADRs reported in 2010, 2011, 2013-2016. This clustering prompted both centers to evaluate potential differences in practice between our institutions and during different time periods. Two distinct differences between institutional standard practices are infusion time and use of an in-line filter. At RH the standard infusion time for etoposide is 2hrs and the standard infusion time at CMH is 1hr. After extending the infusion time, 28% of CMH patients were able to tolerate future doses of etoposide. Rate of infusion has previously been associated with ADRs, as faster rates result in more ADRs.7 Additionally, the use of an in-line filter at CMH was standard of care to prevent precipitation starting in late 2017 and this was not used at RH. The presence or absence of a filter has not been discussed in previous reports of etoposide ADRs. In-line filters and faster infusion rates are potential risk factors for etoposide ADRs and evaluation of practice across institutions could be informative to determine strategies to minimize ADR risk.
Due to the retrospective nature of this study, it is possible that etoposide ADRs could have been missed, however multiple approaches were used to identify ADRs. Additionally, etoposide manufacture and lot numbers were not available; therefore, we were unable to determine any link to specific products and ADR. Our work highlights the importance of looking across sites at ADRs as variation in practice can provide key information about ADR phenotype and potential risk factors emphasizing the critical need for a systematic approach to identifying ADRs trends across institutions. Future etoposide ADRs may be prevented or quickly identified by implementing slower infusion times, standard premedication, and close monitoring for during infusions.