Risks and mitigation strategies to prevent etoposide infusion-related reactions in children

Abstract

Etoposide is an antineoplastic agent widely used for treatment of many pediatric cancers. Etoposide has been associated with infusion-related reactions. In this brief report, we compare etoposide infusion-related reactions that occurred over a 10-year period at two freestanding pediatric hospitals. Infusion reactions occurred in 1% of patients at two hospitals across the study period. Rates of 4.8%, 3.4%, and 7.9% were observed at Children’s Mercy Hospital during 2018, 2019, and 2020, respectively, after the implementation of in-line filters during etoposide infusions in late 2017. Of the 32 patients who 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. This work highlights the importance of a multicenter approach to investigating adverse drug reactions (ADRs) as variation in practice can provide key information about ADRs and potential risk factors.

1 |. INTRODUCTION

Etoposide is an antineoplastic agent used in more than a dozen pediatric chemotherapeutic regimens including treatments for various leukemias, lymphomas, sarcomas, neuroblastomas, rhabdoid and germ cell tumors. Case reports have described infusion-related reactions with etoposide.^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.⁵ Primary literature estimates infusion reactions occur in 1.3%–27.1% of patients receiving etoposide.^6,7 We present a 10-year experience of etoposide use and describe infusion-related reactions at two freestanding pediatric hospitals.

2 |. METHODS

After institutional review board approval, total doses of etoposide and etoposide phosphate were identified and infusion-related reactions were retrospectively evaluated from January 1, 2010 to July 31, 2020 at Children’s Mercy Hospital (CMH), Kansas City, MO, and Riley Hospital for Children (RH), Indianapolis, IN. Both institutions used a standard etoposide concentration of 0.4 mg/ml. In-line filter (ICU Medical, 12" Ext Set w/ MicroClave^®, 0.2 Micron Low Protein Binding Filter) use was standard protocol for etoposide administration at CMH starting in October 2017, due to potential for precipitation and recommendation in the package insert.⁵ No filters were used at RH during the study period. Etoposide was infused over 1 h at CMH and 2 h at RH, but infusion rate could be modified by providers. Both institutions identified etoposide infusion reactions using multiple detection methods including adverse drug reactions (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 h of etoposide dose; and orders for etoposide phosphate as this formulation is used when patients have had an etoposide infusion reaction. These triggers prompted manual EMR review to collect data related to the infusion reaction. modified Hartwig’s Severity Assessment Tool was used to classify ADR severity.⁸ A mild reaction is when a drug was continued without any treatment, a moderate reaction is when the drug was stopped and/or required treatment, and a severe reaction caused hospital admission, permanent disability, delayed discharge, or was life threatening.^8,9 CMH has a prospective pharmacovigilance program; therefore, a clinical pharmacist was available to review EMR documentation and interview patients or clinicians to gather any additional data that was absent from the EMR. However, data collection at RH was completed retrospectively. Statistical significance between groups was evaluated using a chi-square analysis.

3 |. RESULTS

We identified 32 patients experiencing etoposide infusion-related reactions (Table 1). Overall, 17,134 doses of etoposide were administered to 3445 unique patients and 32 patients (1%) experienced etoposide infusion-related reactions (Figure 1). At RH, 7489 doses of etoposide were administered to 652 unique patients and three patients (0.5%) experienced etoposide infusion-related reactions. At CMH, 9645 doses of etoposide were administered to 2793 unique patients and 29 patients (1%) experienced infusion-related reactions over the 10-year period. Twenty-eight of these etoposide infusion-related reactions occurred at CMH between 2018 and 2020 with ADR rates of 4.8%, 3.4%, and 7.9% during 2018, 2019, and 2020, respectively (Figure 2). Incidence of etoposide infusion-related reaction with respect to filter was compared using a chi-square analysis. At CMH, only one reaction occurred in 2198 patients prior to filter use and 28 reactions occurred in 566 patients after filter (p < 0.01). Overall, at CMH and RH, four reactions occurred in 2847 patients when no filter was used and 28 reactions occurred in 566 patients when a filter was used (p < 0.01).

TABLE 1.

Etoposide infusion reaction patient data

Institution/patient	Year of ADR	Age (months)	BSA (m2)	Sex	Ethnicity	Etoposide dose number at time of reaction	Infusion time (min)	Etoposide rate (mg/m2/h)	Symptoms	Severity	Treatment	Rechallenged	Able to tolerate future doses	Intervention for future doses
RH1	2012	78	1.1	Female	Black	1	60	180	Anaphylaxis, shortness of breath, flushing, throat tightness	Severe	Diphenhydramine	No	–	Etoposide Phosphate
RH2	2017	147	1.25	Male	White/Non-Hispanic	1	120	78	Chest tightness	Moderate	Diphenhydramine	Yes	Yes	Pretreat with APAP and diphenhydramine
RH3	2020	178	1.51	Female	White/Non-Hispanic	1	120	60	Flushing, nausea, lip swelling	Severe	Diphenhydramine, lorazepam, ondansetron	Yes	Yes	Pretreat with APAP and diphenhydramine
CMH1	2012	142	1.4	Female	White/Non-Hispanic	22	180	33	Flushing, redness	Moderate	Diphenhydramine	Yes	Yes	Diphenhydramine
CMH2	2018	12.7	0.42	Male	White/Non-Hispanic	1	60	140	Facial swelling, flushing, redness, cough	Moderate	Hydrocortisone, diphenhydramine, IV fluids	No	–	Etoposide phosphate
CMH3	2018	232.2	2.2	Male	White/Non-Hispanic	1	60	100	Cough, numbness of face, redness, shortness of breath	Moderate	Hydrocortisone, diphenhydramine, oxygen	No	-	Etoposide phosphate
CMH4	2018	190.6	1.6	Male	White/Non-Hispanic	6	60	100	Throat tightness, shortness of breath	Moderate	Diphenhydramine	Yes	Yes, but second reaction	Pretreat with diphenhyd ramine, 2 h infusion. Second reaction and changed to etoposide phosphate
CMH5	2018	140.4	1.53	Male	White/Non-Hispanic	13	60	150	Headache, nausea, coughing, shortness of breath, flushing	Moderate	Diphenhydramine	Yes	Yes	Pretreat with diphenhydramine and 2 h infusion.
CMH6	2018	186.9	1.9	Male	White/Non-Hispanic	7	60	125	Flushing, nausea, pressure	Moderate	Extended infusion time to 3 h, cetirizine, prednisone, diphenhydramine	Yes	Yes	3-h infusion, cetirizine, prednisone
CMH7	2018	65.2	0.77	Male	White/Non-Hispanic	1	60	100	Abdominal pain, flushing	Moderate	Hydrocortisone, famotidine	No	–	Etoposide Phosphate
CMH8	2018	110	1.33	Female	White/Non-Hispanic	1	60	101	Throat irritation, difficulty breathing	Moderate	Diphenhydramine, ranitidine	Yes	Yes	2-h infusion, diphenhydramine
CMH9	2018	32.9	0.61	Male	White/Non-Hispanic	1	60	120	Difficulty breathing, cyanosis, nausea, cough, lip swelling	Severe	Albuterol, diphenhydramine, epinephrine, hydrocortisone, IV fluids	No	–	Etoposide Phosphate
CMH10	2018	22.6	0.51	Male	White/Non-Hispanic	4	60	53	Rash, flushing, gagging	Moderate	Diphenhydramine	Yes	Yes, but second reaction	2 h infusion, diphenhydramine, famotidine; Second reaction, changed to etoposide phosphate
CMH11	2018	90.4	0.92	Male	White/Non-Hispanic	6	60	100	Flushing, facial paresthesia, labored breathing	Moderate	Diphenhydramine, famotidine	Yes	Yes, but second reaction	2 h infusion, diphenhydramine, famotidine; Second reaction, changed to etoposide phosphate
CMH12	2018	61	0.69	Male	White/Non-Hispanic	1	60	100	Anaphylaxis, coughing, hypotension, chest pain, periorbital swelling, flushing	Severe	Diphenhydramine, famotidine, epinephrine, hydrocortisone, IV fluids	No	–	Etoposide phosphate
CMH13	2019	76.5	0.74	Female	Other	4	60	88	Flushing, facial swelling, throat irritation, cough	Moderate	Infusion stopped	No	–	Etoposide phosphate
CMH14	2019	14.8	0.44	Male	White/Non-Hispanic	1	60	52	Wheezing, redness, swelling	Severe	Diphenhydramine, epinephrine, hyd rocortisone, IV fluids, racemic epinephrine	No	–	Etoposide phosphate
CMH15	2019	104.5	1.23	Female	Multiracial	12	60	90	Coughing, nausea, flushing	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH16	2019	13.9	0.43	Female	Hispanic	1	60	51	Coughing, flushing, emesis	Moderate	Diphenhydramine	Yes	Yes	2 h infusion, diphenhydramine
CMH17	2019	76.2	0.88	Female	White/Non-Hispanic	1	60	100	Coughing, difficulty breathing	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH18	2019	40.6	0.58	Female	Hispanic	6	60	97	Coughing, itching, flushing, lip swelling	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH19	2019	156.5	1.4	Male	White/Non-Hispanic	1	60	100	Shortness of breath, cyanosis, respiratory depression	Severe	Diphenhydramine, oxygen	No	–	Etoposide phosphate
CMH20	2020	185.1	1.25	Female	White/Non-Hispanic	1	60	125	Abdominal pain, throat discomfort	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH21	2020	73.9	0.78	Female	White/Non-Hispanic	4	60	100	Urticaria	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH22	2020	201.4	1.74	Female	White/Non-Hispanic	1	60	125	Difficulty breathing, nausea, flushing	Severe	Diphenhydramine, oxygen	No	–	Etoposide phosphate
CMH23	2020	197.4	1.73	Female	White/Non-Hispanic	14	120	50	Flushing, dyspnea, tachycardia	Moderate	Diphenhydramine	Yes	Yes	3 h infusion
CMH24	2020	40.7	0.58	Male	White/Non-Hispanic	1	60	57	Itching, edema, cough, rash	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH25	2020	25.8	0.56	Female	White/Non-Hispanic	11	60	107	Nausea, cough, flushing	Moderate	Diphenhydramine, famotidine, hydrocortisone	Yes	Yes	2 h infusion, diphenhydramine
CMH26	2020	19.1	0.46	Female	White/Non-Hispanic	1	60	70	Cyanosis, coughing, agitation	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH27	2020	214.6	2.2	Male	White/Non-Hispanic	5	60	125	Anaphylaxis, facial swelling, chest tightness, shortness of breath	Severe	Diphenhydramine, hydrocortisone, epinephrine, albuterol, famotidine, IV fluids	No	–	Etoposide phosphate
CMH28	2020	25.1	0.57	Male	White/Non-Hispanic	5	60	116	Flushing, hypotension	Moderate	Diphenhydramine	No	–	Etoposide phosphate
CMH29	2020	128.4	1.37	Male	Hispanic	8	60	100	Flushing, rash	Moderate	Diphenhydramine	Yes	Yes	2 h infusion, diphenhydramine

Abbreviations: ADR, adverse drug reaction; APAP, acetaminophen; BSA, body surface area; CMH, Children’s Mercy Hospital; RH, Riley Hospital for Children.

FIGURE 1.

Etoposide patients. This figure shows the breakdown of how many patients initially received etoposide, patients who tolerated future doses, and patients who were changed to etoposide phosphate. ADR, adverse drug reaction

FIGURE 2.

Total etoposide patients and ADRs. Years are shown on the x-axis, total unique patients that received etoposide are shown in histogram plotted on the primary y-axis with CMH shown in dark bars and RH in the outlined bars. The overlaid lines are showing the ADRs that occurred at each institution per year plotted on the secondary y-axis, with the solid line for CMH and the broken line for RH. The arrow marks the beginning of standard of care in-line filter use at CMH in October 2017. ADR, adverse drug reaction; CMH, Children’s Mercy Hospital; RH, Riley Hospital for Children

The age of patients experiencing etoposide infusion-related reactions was 8.5 ± 5.8 years (mean ± standard deviation (SD)), with 17 male and 15 female patients, 26 (81%) patients were white/non-Hispanic, 3 Hispanic (9%), 1 black (3%), 1 multiracial (3%), and 1 race marked as other. Sixteen patients (50%) had a history of a previous food or drug allergy, and six patients (19%) had a documented past medical history of an allergic (seasonal allergies, 1 patient) or inflammatory condition (asthma, 3 patients; eczema, 2 patients).

Infusion reactions occurred with the first dose in 17 (53%) patients. These etoposide infusion-related reactions were not associated with a single manufacturer or lot number, as a variety of manufacturers and lots were administered over this time period. Seven (22%) of the etoposide infusion-related reactions were characterized as severe and 25 (78%) were characterized as moderate. No patients required admission to the intensive care unit and all fully recovered.

Twenty-eight patients (88%) 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 23 patients (71%), coughing in 16 patients (50%), facial or lip swelling in 14 (44%), redness or rash in 11 (34%), and nausea and vomiting in 11 patients (33%).

Multiple treatments were administered to 19 patients (59%) with an average of 2.2 ± 1.5 treatments per patient. The most common treatment was diphenhydramine which was given to 30 patients (94%), hydrocortisone in 8 patients (25%), histamine H2-receptor antagonist in 6 patients (19%), and intravenous fluids in 5 patients (16%). The infusion time was extended in 9 patients (28%).

Thirteen patients (41%) were rechallenged 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. Twelve patients were pre-treated with a histamine-1 antagonist (diphenhydramine or cetirizine), two patients were pre-treated with a histamine-2 antagonist (famotidine), and 10 had the infusion time extended. However, despite pre-treatment, 3 of the 13 patients rechallenged did subsequently experience a second reaction with etoposide resulting in a change to etoposide phosphate formulation. Nineteen patients (59%) were never rechallenged with the standard etoposide formulation, and treatment was changed to etoposide phosphate. Overall, 22 patients (69%) ultimately received etoposide phosphate and no infusion reactions were reported with this formulation.

4 |. DISCUSSION

We report a series of etoposide infusion-related reactions occurring at two free standing pediatric institutions. Specifically, our results highlight three key findings: (1) etoposide infusion-related reactions appear to be associated with high rates when in-line filters are used during infusion, (2) most patients who have experienced etoposide infusion-related reactions will tolerate subsequent administrations by premedicating with antihistamine drugs and slowing of the infusion rate, and (3) flushing and difficulty breathing were the most commonly encountered symptoms and should be monitored for closely during an etoposide infusion.

The rate of etoposide infusion-related reactions at CMH was more than twice that at RH, but more interestingly across both institutions, two etoposide infusion-related reactions occurred in 2012, one at each institution, and the remaining 30 ADRs all occurred during the 4-year period between 2017 and 2020, with no etoposide infusion-related reactions reported in 2010, 2011, 2013–2016. The increased number of etoposide infusion-related reactions at CMH was not associated with an increased number of patients receiving etoposide as the rates of ADRs per unique patients were 4.8%, 3.4%, and 7.9% in 2018, 2019, and 2020, respectively. This increased rate of etoposide infusion-related reactions and clustering over this time period at CMH prompted both centers to evaluate potential differences in practice between our respective institutions and during the 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 2 h and the standard infusion time at CMH is 1 h. 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 etoposide infusion-related reactions, as faster rates result in more reactions.⁷ The standard infusion times at each institution did not change during this study period, but the ability of clinicians to modify infusion times on a patient-by-patient basis is a potential limitation to our report. single-center study evaluating etoposide infusion-related reactions, a higher rate of infusion reactions occurred during the period when filters were used.¹¹ Although not conclusive, the clustering of etoposide infusion-related reaction between 2017 and 2020 at CMH occurred during the time when a filter was being used in clinical practice. The association with filters and anaphylaxis is not unique to etoposide. Four patients with thalassemia were reported to experience a type I allergic hypersensitivity reaction following transfusion that was linked to the ethylene oxide that was used to sterilize the heat sensitive leucocyte filter.¹² Although the filter used at CMH

The use of an in-line filter at CMH was standard of care to prevent precipitation as recommended by the package insert starting in late 2017.⁵ Filters were not used at RH during this study period. The use of a filter has been discussed as a possible factor for anaphylactic infusion reactions with etoposide in previous reports.^10,11 Ina was not sterilized with ethylene oxide, it is uncertain if another component of this filter could be associated with these infusion-related reaction. Although filters may not be the first thing one would associate with an ADR, it is important to evaluate all components of the filter and properties of the drug being filtered.¹³ At this point, our findings are observational and further evaluation is needed to understand the mechanism associated with the use of a filter in relation to etoposide infusion-related reactions. In-line filters and faster infusion ates are potential risk factors for etoposide infusion-related reactions and evaluation of practice across institutions could be informative o determine strategies to minimize ADR risk.

Often times when a patient experiences an ADR, the patient is not rechallenged and a therapeutic alternative is prescribed.¹⁴ In cancer treatment, alternative therapeutic agents are often not an option. In our 10-year cohort, all 32 patients who experienced etoposide infusion-related reactions were successfully rechallenged 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 comparable efficacy and has been shown to be associated with fewer infusion-related reactions compared to standard etoposide formulations, but due to the higher price, it is not typically used as first-line therapy.^7,15 The hospital cost of a 100-mg dose of the standard etoposide formulation would be approximately $5 compared to approximately $112 for a 100-mg dose of etoposide phosphate. The remaining 40% of patients who experienced etoposide reactions received premedication and/or modifications of infusion rates and tolerated subsequent infusions. Interestingly, no infusion-related reactions were associated with etoposide phosphate which although less likely than the standard etoposide formulation, it has been previously reported to occur.⁷

Etoposide infusion-related reactions 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, 71% of patients experienced flushing and respiratory distress. This is important, as monitoring for these symptoms should occur during etoposide infusions.

Due to the retrospective nature of this study, it is possible that some etoposide infusion-related reactions could have been missed, however, multiple approaches were used to identify reactions. There is the potential that a mild or early reaction could have been quickly aborted by an attentive clinician who adjusted the rate, thus avoiding a severe reaction which would have then warranted treatment. Our work highlights the importance of looking across sites at ADRs as variation in practice can provide key information about ADR and potential risk factors emphasizing the critical need for a systematic approach to identifying ADR trends across institutions. Future etoposide infusion-related reactions may be prevented or quickly identified by implementing slower infusion times, eliminating in-line filter use, administering standard premedication, and closely monitoring patients during infusions.