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\begin{document}

\title{Successful rechallenge after etoposide infusion related adverse drug
reactions}



\author[1]{Emma Tillman}%
\author[2]{Sarah Suppes}%
\author[1]{Nicholas Miles}%
\author[2]{Ashley Duty}%
\author[2]{Kelsey Kelley}%
\author[2]{Jennifer Goldman}%
\affil[1]{Indiana University School of Medicine}%
\affil[2]{Children's Mercy Hospital}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
Etoposide is an antineoplastic agent widely used for treatment of many
pediatric cancers and associated with infusion related adverse drug
reactions (ADRs). In this brief report we describe etoposide infusion
related ADRs that occurred over a 10-year period at two freestanding
pediatric hospitals. Infusion reactions occurred in 1\% of patients. Of
the 32 patients that experienced adverse reactions, 41\% were
rechallenged after the reaction and all were able to tolerate at least
one future dose with either pre-treatment or extending infusion
duration.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Etoposide is an antineoplastic agent used in more than a dozen pediatric
chemotherapeutic regimens. Case reports have described infusion related
adverse drug reactions (ADRs) with etoposide.\textsuperscript{1-4} The
package insert reports anaphylactic-like reactions including chills,
fever, tachycardia, bronchospasm, dyspnea, and hypotension occurring in
0.7-2\% of patients receiving etoposide.\textsuperscript{5} Primary
literature estimates infusion reactions occur in 1.3-27.1\% of patients
receiving etoposide.\textsuperscript{6,7} We present a ten-year
experience of etoposide, and describe infusion related reactions at two
freestanding pediatric hospitals.

\textbf{Methods:}

After institutional review board approval, etoposide infusion related
ADRs were retrospectively evaluated from January 1, 2010 - July 31, 2020
at Children's Mercy Hospital (CMH), Kansas City, MO, and Riley Hospital
for Children (RH), Indianapolis, IN. Both institutions identified
etoposide ADRs using multiple detection methods including ADRs entered
into the electronic medical record (EMR), international classification
of disease (ICD)-9 and ICD-10 codes for anaphylaxis, flushing, rash, or
hypotension, orders for diphenhydramine, hydrocortisone, or epinephrine
within 24 hours of etoposide dose, and orders for etoposide phosphate as
this formulation is used when patients have had an etoposide ADR. These
triggers prompted manual EMR review to collect data related to the ADR.
Both institutions used a standard etoposide concentration of 0.4mg/mL.
In-line filter use was standard protocol at CMH starting late 2017, and
no filters were used at RH. Etoposide was infused over 1hr and 2hr at
CMH and RH respectively, but could be modified by providers. A modified
Hartwig's Severity~Assessment Tool was used to classify ADR severity
(TABLE 1).\textsuperscript{8,9}

\textbf{Results:}

We identified 32 patients experiencing etoposide related ADRs (TABLE 2).
Two ADRs occurred in 2012, and 30 occurred between 2017-2020. Overall,
17,134 doses of etoposide were administered to 3,326 unique patients and
32 patients (1\%) experienced ADRs. At RH, 7,489 doses of etoposide were
administered to 577 patients and three patients (0.5\%) experienced
ADRs. At CMH, 9,645 doses of etoposide were administered to 2,749
patients and 29 patients (1\%) experienced ADRs.

The age of patients experiencing ADRs was 8.5\selectlanguage{ngerman}±5.8 years (mean ± SD),
with 17 male and 15 female patients, 27 (84\%) were white/non-Hispanic,
3 Hispanic (9\%), 1 black (3\%), and 1 multiracial (3\%). Fifty percent
of patients had a history of a previous food or drug allergy, and 19\%
had a documented past medical history of an allergic or inflammatory
condition.

Infusion reactions occurred with the first dose in 53\% patients.
Seventy-five percent were characterized as The ADR was characterized as
moderate in 75\% and 25\% as severe reactions, yet no patients required
admission to the intensive care unit and all fully recovered.

Eighty-eight percent of patients experienced multiple symptoms during
the etoposide infusion, with an average of 2.8±1.1 symptoms per patient.
The most common symptoms were flushing and difficulty breathing
(including chest or throat tightness) which occurred in 71\% of
patients. Coughing was described in 50\% of patients, facial or lip
swelling 45\%, redness or rash and nausea and vomiting were both
reported to occur in 33\% of patients.

Multiple treatments were administered to 59\% of patients with an
average of 2.2±1.5 treatments per patient. The most common treatment was
diphenhydramine which was given to 94\% of patients, hydrocortisone in
25\% of patients, histamine H2-receptor antagonist in 18\% of patients,
and IV fluids in 16\% of patients. The infusion time was extended in
28\% of patients,

Thirteen patients (41\%) were re-challenged with etoposide after the
reaction, and all were initially able to tolerate at least one future
dose with either pre-treatment, and/or extending infusion duration.
However, three of the 13 patients re-challenged did subsequently
experience a second reaction with etoposide resulting in a change to
etoposide phosphate formulation. Nineteen patients (59\%) were never
re-challenged with the standard etoposide formulation. Overall, 22
patients ultimately received etoposide phosphate and no ADRs were
reported with this formulation.

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.

\textbf{Conflict of Interest statement:}

No authors have any conflicts of interest to report.

\textbf{Acknowledgements:}

None

\textbf{References:}

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Hypersensitivity reactions to etoposide. A report of three cases and
review of the literature. Am J Clin Oncol 1994;17:387-9.

2. Hoetelmans RM, Schornagel JH, ten Bokkel Huinink WW, Beijnen JH.
Hypersensitivity reactions to etoposide. Ann Pharmacother
1996;30:367-71.

3. Kasperek C, Black CD. Two cases of suspected immunologic-based
hypersensitivity reactions to etoposide therapy. Ann Pharmacother
1992;26:1227- 30.

4. Ogle KM, Kennedy BJ. Hypersensitivity reactions to etoposide. A case
report and review of the literature. Am J Clin Oncol 1988;11:663-5.

5. Etoposide. Package insert. Fresenius Kabi USA, LLC; 2019.

6. Turgay Yagmur I, Guzelkucuk Z, Yarali N, et al. Evaluation of
hypersensitivity reactions to cancer chemotherapeutic agents in
pediatric patients. Ann Allergy Asthma Immunol 2020;124:350-6.

7. Stockton WM, Nguyen T, Zhang L, Dowling TC. Etoposide and etoposide
phosphate hypersensitivity in children: Incidence, risk factors, and
prevention strategies. J Oncol Pharm Pract 2020;26:397-405.

8. Hartwig SC, Siegel J, Schneider PJ. Preventability and severity
assessment in reporting adverse drug reactions. Am J Hosp Pharm
1992;49:2229-32.

9. Yu D, Sheets J, Suppes S, Goldman J. Characterization of Severe
Adverse Drug Reactions at a Free-Standing Children's Hospital. J Clin
Pharmacol 2019;59:1569- 72.

10. Meyboom R. Intentional rechallenge and the clinical management of
drug-related problems. Drug Saf 2013;36:163-5.

11. Collier K, Schink C, Young AM, How K, Seckl M, Savage P. Successful
treatment with etoposide phosphate in patients with previous etoposide
hypersensitivity. J Oncol Pharm Pract 2008;14:51-5.

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