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.