Guide - Prevent..acute Nausea Vomit Due To Antineoplastic PDF

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Guideline for the prevention of acute nausea and

vomiting due to antineoplastic medication in
pediatric cancer patients†‡
1. L. Lee Dupuis MScPhm, ACPR, FCSHP1,2,3,4,* ,
2. Sabrina Boodhan BScPhm, ACPR1,4,
3. Mark Holdsworth PharmD, BCOP5,
4. Paula D. Robinson MD, MSc6,
5. Richard Hain MD7,
6. Carol Portwine MD, FRCPC, PhD8,
7. Erin O'Shaughnessy RN, MScN, CPHON9,
8. Lillian Sung MD, PhD2,3,10
Article first published online: 19 MAR 2013
DOI: 10.1002/pbc.24508
Copyright © 2013 Wiley Periodicals, Inc.
Issue
Pediatric Blood & Cancer

Volume 60, Issue 7, (/doi/10.1002/pbc.v60.7/issuetoc) pages 1073–1082, July 2013
Additional Information
How to Cite
Dupuis, L. L., Boodhan, S., Holdsworth, M., Robinson, P. D., Hain, R., Portwine, C., O'Shaughnessy, E. and
Sung, L. (2013), Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in
pediatric cancer patients. Pediatr. Blood Cancer, 60: 1073–1082. doi: 10.1002/pbc.24508
Author Information
1 Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada
2 Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada
3 Program in Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto,
Ontario, Canada
4 Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada
5 College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, Canada
6 Guideline Methodologist, Pediatric Oncology Group of Ontario, Ontario, Canada
7 Department of Child Health, Cardiff School of Medicine, University Hospital of Wales, Cardiff, Wales,
UK
8 Division of Haematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, Ontario,

Canada
9 Department of Nursing, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
10 Department of Paediatrics, University of Toronto, Ontario, Canada
Email: L. Lee Dupuis MScPhm, ACPR, FCSHP ([email protected])
* Department of Pharmacy, The Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada M5G
1X8.
† The guideline summarized in this manuscript has been endorsed by the Multi-National Association for
Supportive Care in Cancer and the C17 Research Network.
‡ Conflict of interest: Nothing to declare.
Publication History
1. Issue published online: 22 MAY 2013

2. Article first published online: 19 MAR 2013
3. Manuscript Accepted: 29 JAN 2013
4. Manuscript Received: 11 SEP 2012
Funded by
Pediatric Oncology Group of Ontario

Ministry of Health and Long Term Care, Ontario
Children's Oncology Group
Abstract (/doi/10.1002/pbc.24508/abstract)
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Keywords:
antiemetics; antineoplastic-induced nausea and vomiting; antineoplastics; chemotherapy-induced nausea and vomit
Abstract
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
10. Supporting Information
This guideline provides an approach to the prevention of acute antineoplastic-induced nausea and vomiting
(AINV) in children. It was developed by an international, inter-professional panel using AGREE and CAN-
IMPLEMENT methods. Evidence-based interventions that provide optimal AINV control in children receiving
antineoplastic agents of high, moderate, low, and minimal emetogenicity are recommended. Recommendations
are also made regarding selection of antiemetic agents for children who are unable to receive corticosteroids for
AINV control, the role of aprepitant and optimal doses of antiemetic agents. Gaps in the evidence used to
support the recommendations were identified. The contribution of this guideline to AINV control in children
requires prospective evaluation. Pediatr Blood Cancer 2013; 60: 1073–1082. © 2013 Wiley Periodicals, Inc.
INTRODUCTION
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
Nausea and vomiting as a result of antineoplastic medication continue to be negative influences on the lives of
children with cancer 1. Although acute antineoplastic-induced vomiting (AIV) may improve over the course of
treatment, antineoplastic-induced nausea (AIN) may actually become more problematic 2. The use of evidence- or
consensus-based guidelines for antiemetic selection has been shown to improve control of acute antineoplastic-
induced nausea and vomiting (AINV) in adults 3. The lack of a rigorously developed guideline for antiemetic
selection in children receiving antineoplastic therapy has likely been an impediment to optimizing AINV control in
children with cancer.
The purpose of this guideline is to provide health care providers who care for children receiving antineoplastic
medication aged 1 month to 18 years with an approach to the prevention of acute AINV. Its scope is limited to the
prevention of AINV in the acute phase (i.e., within 24 hours of administration of an antineoplastic agent) and does
not include anticipatory, breakthrough or delayed phase AINV, or nausea and vomiting that is related to radiation
therapy, disease, co-incident conditions or end-of-life care. In addition, this guideline is most applicable to children
who are naïve to antineoplastic therapy.
This guideline represents the second of a series of guidelines to address the need for, and the selection of, antiemetic
prophylaxis and intervention in children with cancer receiving antineoplastic medication. The first of this series has
been published 4. Full versions of both guidelines in this series are available on-line 5, 6.
METHODS
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
Guideline Development Group
The Pediatric Oncology Group of Ontario (POGO) is a collaboration of the five pediatric oncology programs in
Ontario, Canada. Members of the POGO AINV Guideline Development Panel were selected with a view to obtain
inter-professional representation from within POGO and from recognized experts in pediatric AINV.
Source Guideline Selection

Using established methods 7, 8, a source guideline was sought which addressed the health questions (Table I) that
framed the development of this guideline. A comprehensive search of bibliographic databases and the gray literature
was conducted in February 2010 with the assistance of a library scientist. Each guideline identified through the
search was independently evaluated by three or four panel members using the AGREE instrument 7.
Table I. Summary of the Health Questions That Guided Development of the

Guideline and the Recommendations Regarding Antiemetic Dosing for Prevention of
Acute AINV in Children Receiving Antineoplastic Medication
Strength of
recommendation
and level of
Health questions and recommendations evidence 10
1. How is optimal control of acute AINV defined?
We recommend that optimal control of acute AINV be defined as Strong

no vomiting, no retching, no nausea, no use of antiemetic agents recommendation
other than those given for AINV prevention and no nausea-related
Very low quality
change in the child's usual appetite and diet. This level of AINV
evidence
control is to be achieved on each day that antineoplastic therapy is
administered and for 24 hours after administration of the last
antineoplastic agent of the antineoplastic therapy block.
2a. What pharmacological interventions provide optimal control of acute AINV in

children receiving antineoplastic agents of high emetogenic risk?
We recommend that:
Children ≥12 years old and receiving antineoplastic agents of high Strong
emetic risk which are not known or suspected to interact with recommendation
aprepitant receive: ondansetron or granisetron + dexamethasone +
Very low quality
aprepitant.
evidence
aprepitant.
evidence
Children ≥12 years old and receiving antineoplastic agents of high Strong
emetic risk which are known or suspected to interact with aprepitant recommendation
receive: ondansetron or granisetron + dexamethasone.
Moderate quality
evidence
Children <12 years old and receiving antineoplastic agents of high Strong
emetic risk receive: ondansetron or granisetron + dexamethasone. recommendation
Moderate quality
evidence
2b. What pharmacological interventions provide optimal control of acute AINV in

children receiving antineoplastic agents of moderate emetic risk?
We recommend that children receiving antineoplastic agents of Strong

moderate emetogenicity receive: ondansetron or granisetron + recommendation
dexamethasone.
Moderate quality
evidence
2c. What pharmacological interventions provide optimal control of acute AINV in

children receiving antineoplastic agents of low emetic risk?
We recommend that children receiving antineoplastic agents of low Strong

emetic risk receive: ondansetron or granisetron. recommendation
Moderate quality
evidence
2d. What pharmacological interventions provide optimal control of acute AINV in

children receiving antineoplastic agents of minimal emetic risk?
We recommend that children receiving antineoplastic agents of low Strong

emetic risk receive: no routine prophylaxis. recommendation
Very low quality

evidence
3. What adjunctive non-pharmacological interventions provide control of acute

AINV in children receiving antineoplastic agents of any emetic risk?
We suggest that acupuncture, acupressure, guided imagery, music Weak
therapy, progressive muscle relaxation and psycho-educational recommendation

support and information may be effective in children receiving
antineoplastic agents. Virtual reality may convey benefit.
Very low quality evidence
We suggest that the following dietary interventions may be effective:
Eat smaller, more frequent meals;
Reduce food aromas and other stimuli with strong odors;
Avoid foods that are spicy, fatty or highly salty;
Take antiemetics prior to meals so that the effect is present during

and after meals; and
Measures and foods (e.g., “comfort foods”) that helped to

minimize nausea in the past.
4. What is the role of aprepitant in children receiving antineoplastic therapy?
We recommend that the use of aprepitant be restricted to children Strong

12 years of age and older who are about to receive highly recommendation
emetogenic antineoplastic therapy which is not known or suspected
Very low quality
to interact with aprepitant. There is no evidence to support the safe
evidence
and effective use of aprepitant in younger children.
5. What pharmacological interventions provide optimal control of acute AINV in

children receiving highly or moderately emetogenic antineoplastic agents in whom
corticosteroids are contra-indicated?
We suggest that children receiving highly emetogenic antineoplastic Weak

therapy who cannot receive corticosteroids receive: ondansetron or recommendation
granisetron + chlorpromazine or nabilone
Low quality
evidence
We suggest that children receiving moderately emetogenic Weak

antineoplastic therapy who cannot receive corticosteroids receive: recommendation
ondansetron or granisetron + chlorpromazine or metoclopramide or
ondansetron or granisetron + chlorpromazine or metoclopramide or
Low quality
nabilone
evidence
6. What doses of antiemetic agents are known to be effective in children receiving

antineoplastic agents?
We recommend the following aprepitant dose for children 12 years Strong

of age and older: recommendation
Day 1: 125 mg PO × 1; Days 2 and 3: 80 mg PO once daily. Moderate quality

evidence
We recommend the following chlorpromazine dose: 0.5 mg/kg/dose Strong

IV q6h. recommendation
Low quality
evidence
We suggest the following dexamethasone for children receiving Weak

highly emetogenic antineoplastic therapy: 6 mg/m2/dose IV/PO q6h. recommendation
Low quality
evidence
If given concurrently with aprepitant, reduce dexamethasone dose

by half.
We recommend the following dexamethasone for children receiving Strong

moderately emetogenic antineoplastic therapy: recommendation
Low quality evidence
≤0.6 m2: 2 mg/dose IV/PO q12h
>0.6 m2: 4 mg/dose IV/PO q12h.
If given concurrently with aprepitant, reduce dexamethasone dose

by half.
We recommend the following IV granisetron dose for children Strong

receiving highly emetogenic antineoplastic therapy: 40 mcg/kg/dose recommendation
IV as a single daily dose.
Low quality
evidence
receiving moderately emetogenic antineoplastic therapy: 40 recommendation

mcg/kg/dose IV as a single daily dose.
Moderate quality
evidence
We suggest the following oral granisetron dose for children Weak

mcg/kg/dose PO q12h.
Low quality
evidence

receiving antineoplastic therapy of low emetogenicity: 40 recommendation
mcg/kg/dose IV as a single daily dose.
Low quality
evidence
We suggest the following oral granisetron dose for children Weak

receiving antineoplastic therapy of low emetogenicity: 40 recommendation
mcg/kg/dose PO q12h.
Low quality
evidence
We recommend the following metoclopramide dose for children Strong

mg/kg/dose IV pre-therapy × 1 then 0.0375 mg/kg/dose PO q6h.
Low quality
evidence
Give diphenhydramine or benztropine concurrently.
We suggest the following nabilone dose: Weak

recommendation
<18 kg: 0.5 mg/dose PO twice daily Low quality

evidence
18–30 kg: 1 mg/dose PO twice daily
>30 kg: 1 mg/dose PO three times daily.
Maximum: 0.06 mg/kg/day.

We recommend the following ondansetron dose for children Strong
receiving highly emetogenic antineoplastic therapy: 5 mg/m2/dose recommendation

(0.15 mg/kg/dose) IV/PO pre-therapy × 1 and then q8h.
Moderate quality
evidence

mg/m2/dose (0.15 mg/kg/dose; maximum 8 mg/dose) IV/PO pre-
Moderate quality
therapy × 1 and then q12h.
evidence

receiving therapy of low emetogenicity: 10 mg/m2/dose (0.3 recommendation
mg/kg/dose; maximum 16 mg/dose IV) IV/PO pre-therapy × 1.
Low quality
evidence
Pediatric Evidence Identification and Synthesis

None of the guidelines identified specifically addressed antiemetic use for the prevention of acute AINV in children.
Therefore, a systematic review of primary pediatric oncology studies addressing this topic was conducted through
November 1, 2011 with the assistance of a library scientist. Panel members also reviewed their personal files for
papers that met inclusion criteria. The search strategy is available in the on-line version of the guideline 6. Studies
were included if they: were published in full text in English or French; reported pediatric data separately; provided
sufficient detail to allow assessment of the emetogenicity of the antineoplastic therapy administered using the POGO
classification guideline or provided an assessment by the study's author(s); provided an explicit or implicit definition
of complete acute AINV response; and reported the complete acute AINV response rate as a proportion or
percentage.
Citations were divided among panel members for screening for inclusion/exclusion. Full-text screening was
performed for citations identified as potentially relevant. Evidence summary tables were compiled and reviewed by
two panel members before consideration by the panel.
A meta-analysis was undertaken to evaluate the contribution of each antiemetic agent or antiemetic regimen to
complete AINV control. Because of the paucity of randomized controlled trials (RCTs), all outcomes were
described as proportions; for example, the proportion of patients with complete AINV control among a particular
group. Each study was weighted by the inverse variance. Given the anticipation of heterogeneity between studies, a
random effects model 9 was used for all analyses. Meta-analysis was performed using Review Manager (RevMan
Version 5.1.0, The Cochrane Collaboration, Oxford, England). Sub-groups were compared by evaluating
heterogeneity across sub-group results.
Therapeutic efficacy and safety were the primary determinants of recommendations made by the panel regarding
antiemetic choice. In the event of contradictory information regarding therapeutic efficacy, panel members took a
conservative approach; that is, the more aggressive, comprehensive antiemetic prophylaxis would be recommended
since this approach would be more likely to lead to complete AINV control.
Emetogenicity was defined as per the first POGO AINV guideline 4, 5. That is, high, moderate, low, and minimal
emetogenicity were defined as a >90%, 30 to <90%, 10 to <30% and <10% chance of causing emesis when
antiemetic prophylaxis was not provided. A listing of the emetogenicity of antineoplastic agents in children is
provided in Supplementary Tables I and II.
The authors of several studies categorized the emetogenicity of the antineoplastic regimens they studied as high or
moderate without providing sufficient detail to determine the emetic risk as per the first POGO AINV guideline 4, 5.
In making recommendations, less weight was placed on the results of these studies than those where the
emetogenicity of the antineoplastic regimens studied was able to be verified against the POGO classification.
Authors of some studies described the AINV experienced by children receiving antineoplastic therapy of varied
emetogenicity and reported the AINV control results for the group as a whole. When the results of these studies
were reported, a conservative approach was used: the study results were reported in the lowest emetogenic risk
category included. Authors of other studies described AINV control in children receiving multiple day antineoplastic
regimens where the emetogenicity varied between treatment days and where AINV control was reported for the
entire acute phase. In these, the study results were reported according to the individual agents of highest
emetogenicity given during the antineoplastic block.
Decisions were taken through panel discussions. Differences in interpretation were resolved by consensus. The
quality of evidence and strength of recommendations were assessed using the Grading of Recommendations,
Assessment, Development and Evaluation (GRADE) system 10 by one author (L.L.D.) and confirmed through
discussion by the remaining panel members.
External Review and Consultation Process

The draft guideline underwent an extensive two-stage external review: first by international experts in adult and
pediatric AINV and then by stakeholders from the Ontario pediatric oncology community. Seven content experts
provided a review; their comments were discussed in detail by the panel and a decision on each point was taken by
consensus. Thirty stakeholder responses were received. No changes were made to the recommendations based on
the stakeholders' comments. However, wording of the guideline was clarified and an appendix describing
recommended adult antiemetic doses was added.
RESULTS
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
Source Guideline Identification

The guideline search yielded 60 citations that were screened for inclusion. Of these, 13 guidelines were assessed
using the AGREE instrument. Two guidelines were selected for adaptation; these were developed by The American
Society of Clinical Oncology (ASCO) 11, 12 and by Tipton et al. 13. When it became available, the 2011 update
to the ASCO guideline 12 was compared to the previous version. Since the 2011 recommendations did not differ
substantially from those provided in the 2006 version with respect to the health questions of interest, the 2011
update was cited as the source guideline.
The ASCO guideline 12 was the primary framework used for the development of guidelines for AINV prevention in
pediatric cancer patients for pharmacological therapies. Although this guideline provides a general recommendation
for AINV prophylaxis in children, its focus is on antiemetic use for adult cancer patients and it is in this capacity that
the guideline is referenced as a source document. Tipton et al. 13 was used as the framework for non-
pharmacological interventions.
Primary Pediatric Literature Review

One thousand six hundred sixty references were identified resulting in 72 papers that met eligibility criteria (Fig. 1).
The recommendations of the POGO Guideline for the Prevention of Acute AINV in Children receiving
Antineoplastic Medication are summarized in Figure 2 and Table I. The evidence tables supporting these
recommendations are available at: http://www.pogo.ca/healthcare/practiceguidelines/acuteainvguideline/
(http://www.pogo.ca/healthcare/practiceguidelines/acuteainvguideline/). The rationale for the recommendations is
summarized below.
Figure 1. Literature Search for Pediatric Studies Results

Flowchart. Details of the literature search are available on-line at
http://www.pogo.ca/healthcare/practiceguidelines/
(http://www.pogo.ca/healthcare/practiceguidelines/).
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Figure 2. Summary of the Recommendations Regarding

Antiemetic Agent Selection for Prevention of Acute
Antineoplastic-induced Nausea and Vomiting in Children.
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How Is Optimal Control of Acute AINV Defined?

The source guidelines 12, 13 did not explicitly address this question and no pertinent evidence was identified. The
recommendation reflects the consensus of the guideline panel.
What Pharmacological Interventions Provide Optimal

Control of Acute AINV in Children Receiving Antineoplastic
Medications of High Emetic Risk?
The reported rates of complete AINV control in children receiving highly emetogenic antineoplastic agents (HEC)
were consistently low regardless of whether the emetogenicity of the antineoplastic regimens included in studies was
defined as per the POGO guideline (43%; 95% CI: 29, 56) or by the investigators (47%; 95% CI: 22, 72).
5-HT3 antagonist, corticosteroid plus aprepitant

The source guideline 12 recommends administration of a 5-HT3 antagonist, dexamethasone plus aprepitant to
adults receiving HEC. Minimal pediatric data regarding aprepitant has been published; nevertheless, anecdotally,
many pediatric clinicians have adopted it for routine use. Aprepitant is recommended for the age group where there
is published information regarding safety (12 years of age and older) and for patients who are not receiving
medications which may result in clinically important drug interactions with aprepitant. A subsequent health question
specifically addresses the use of aprepitant in children.
5-HT3 antagonist plus corticosteroid

Evaluations of the efficacy of a 5-HT3 antagonist plus dexamethasone in children receiving HEC are limited to four
studies 14–17. The emetogenicity of the antineoplastic agents administered in all four studies was able to be
determined using the POGO classification guideline. Synthesis of these studies observed a complete AINV control
rate of 50% (95% CI: 43%, 57%). Nausea assessment was included in the definition of complete control in two of
these studies 15, 16. The observed complete AINV control rate in these studies was similar (48%; 95% CI: 41%,
56%).
In the only pediatric RCT, the use of both ondansetron plus dexamethasone resulted in a higher rate of complete
vomiting control than did the use of ondansetron alone (61% vs. 23%; no P-value provided) 14. The
recommendation for the use of a 5-HT3 antagonist plus a corticosteroid for prevention of acute AINV in children
receiving HEC is also supported by a meta-analysis which observed that the addition of a corticosteroid to a 5-HT3
antagonist resulted in a relative risk (RR) of complete control of vomiting of 2.03 (95% CI: 1.35, 3.04) 18.

Medications of Moderate Emetic Risk?
The source guideline 12 recommends palonosetron plus dexamethasone for adults about to receive MEC. Synthesis
of all studies evaluating antiemetic efficacy in children receiving moderately emetogenic antineoplastic therapy
(MEC) observed a complete AINV control rate of 45% (95% CI: 31%, 58%). Until more evidence is available
regarding the efficacy and safety of palonosetron in children, it is not possible to include it in recommendations for
acute AINV control in children.
5-HT3 antagonist plus corticosteroid

No studies which defined the emetogenicity of the antineoplastic agents administered using the POGO guideline or
which defined complete AINV control as the control of both vomiting and nausea were identified. White et al. 19
evaluated the efficacy of dexamethasone plus either oral or IV ondansetron in an RCT in 428 children about to
receive what the authors described as MEC or HEC. On the first day of the antineoplastic block, complete control
of vomiting and retching was achieved in 78–81% of children whereas control of nausea was achieved in 70–73%.
These results may underestimate the degree of AINV control that may be possible in children receiving MEC since
some received HEC. Nevertheless, this relatively large study confirms the source guideline's recommendation of a
5-HT3 antagonist plus dexamethasone for patients about to receive MEC.
5-HT3 antagonist alone

A single study evaluated palonosetron in 53 children (mean age 6.6 years ± 4.5) over 138 MEC blocks observed
complete acute AINV control (no emesis and no rescue therapy) in 84.1% 20.

Medications of Low Emetic Risk?
The source guideline recommends dexamethasone alone for patients about to receive antineoplastic agents of low
emetic risk. There were no pediatric studies identified which addressed the efficacy of dexamethasone in this
population. In the complete absence of supporting evidence for its application to pediatrics, the panel did not adopt
the source guideline's recommendation. Synthesis of all studies that evaluated an antiemetic intervention in children
receiving antineoplastic agents of low emetic risk observed an overall complete control rate of 75% (95% CI: 66%,
85%).
5-HT3 antagonist alone

Synthesis of the studies which evaluated the AINV control provided by 5-HT3 antagonists alone observed a rate of
complete AINV control of 74% (95% CI: 62%, 87%). All identified studies evaluated the use of 5-HT3
antagonists alone in the setting of antineoplastic agents of low emetogenicity as defined by the POGO guideline and
included nausea control in their definition of complete AINV control. Three studies were RCTs 21–23. Reported
complete control rates ranged from 50% to 91%.
What Pharmacological Interventions Provide Control of

Acute AINV in Children Receiving Antineoplastic
Medications of Minimal Emetic Risk?
No pediatric studies which evaluated AINV control in children receiving antineoplastic agents of minimal emetic risk
without antiemetic prophylaxis were identified. The recommendation of the source guidelines 11, 12 to give no
routine antiemetic prophylaxis was therefore adopted.
What Adjunctive Non-Pharmacological Interventions

Provide Control of Acute AINV in Children Receiving
Antineoplastic Medications of Any Emetic Risk?
No pediatric evidence to support the source guideline's recommendation was identified. In the opinion of the panel,
the measures included in the source guideline's recommendation are unlikely to result in undesirable effects or
adversely affect quality of life and may convey benefit. The recommendations of the source guideline were therefore
adopted by the guideline panel despite the lack of pediatric supporting information.
What Is the Role of Aprepitant in Children Receiving

Antineoplastic Medication?
Published pediatric experience with aprepitant is exceedingly sparse and of poor quality. A single prospective trial
has been published to date but its primary aim was to describe the pharmacokinetics of aprepitant 24. The available
published pediatric descriptions of aprepitant use in children are also insufficient to judge its safety in this age group.
Gore et al. 24 observed a higher incidence of febrile neutropenia in children receiving aprepitant compared to
controls (25% vs. 11.1%). Choi et al. 25 describe hyperglycemia in 2 of 32 children included in a retrospective
review.
As a cytochrome P-450 isoenzyme 3A4 (CYP3A4) substrate and inhibitor and an inhibitor of CYP2C9/8 and
CYP2C19, aprepitant has the potential for increasing the dose intensity of other CYP3A4 substrates given
concurrently. Potential interactions between aprepitant and antineoplastic agents are of utmost concern due to their
potential impact on toxicity and long-term outcomes. Supplementary Tables III and IV list the antineoplastic agents
classified as highly emetogenic when given alone or with other antineoplastic agents which rely on CYP3A4 for their
metabolism or bioactivation or which are known to interact with aprepitant. The concurrent use of aprepitant with
these agents may lead to increased toxicity or, in some cases, decreased therapeutic effect.
To balance the desire to better control AINV against the large gaps in our knowledge about how best to dose and
administer aprepitant to children, the panel recommends that the routine use of aprepitant be reserved for patients in
the age group for which there is information to support a dosing guideline (12 years of age and older) and who are
about to receive highly emetogenic antineoplastic therapy whose dose intensity will not be altered by concurrent
administration with aprepitant.

Control of Acute AINV in Children Receiving Highly or
Moderately Emetogenic Antineoplastic Medication in Whom
Corticosteroids Are Contra-Indicated?
The source guidelines 12, 13 did not address this question. It is clear that prophylaxis with a 5-HT3 antagonist
alone leads to poor AINV control in patients receiving MEC and HEC. Synthesis of the three studies which
evaluated alternative antiemetic agents (chlorpromazine, metoclopramide) in children receiving HEC observed a
complete AINV control rate of 9% (95% CI: 0, 20). Given the scarcity of evidence-based options, the panel
recommended that nabilone or chlorpromazine be administered together with ondansetron or granisetron to children
receiving HEC in whom corticosteroids are contra-indicated. Metoclopramide is a third option for children receiving
MEC.
Chlorpromazine
Published experience with chlorpromazine for AINV prophylaxis is limited 26, 27 yet general pediatric experience
with it is extensive. The antiemetic activity of chlorpromazine has not been evaluated in combination with a 5-HT3
antagonist. Its use strictly in the in-patient setting seems prudent based on its sedating and hypotensive properties.
The concurrent use of diphenhydramine or benztropine to prevent chlorpromazine-induced extrapyramidal effects
may be considered.
Nabilone
A meta-analysis of experience with cannabinoids for the prevention of AINV concluded that cannabinoids were
better at controlling antineoplastic-induced vomiting (RR: 1.28, 95% CI: 1.08–1.51) and antineoplastic-induced
nausea (RR: 1.38; 95% CI: 1.18–1.62) than prochlorperazine, metoclopramide, domperidone, or haloperidol 28.
A randomized cross-over trial of the antiemetic activity of nabilone compared the antiemetic activities of nabilone
and prochlorperazine 29. A higher proportion of children experienced an improvement in emesis (21 of 30 vs. 9 of
30; P = 0.003) during the nabilone phase of the study and more patients preferred nabilone to prochlorperazine (20
of 30 vs. 5 of 30; P = 0.015). The most common adverse effects experienced by children in the nabilone phase
were dizziness and drowsiness; dose reduction improved these symptoms without reducing the therapeutic benefit.
Metoclopramide
A single RCT compared the AINV control provided by metoclopramide plus diphenhydramine versus ondansetron
in children receiving chemotherapy of low to high emetogenicity 21. Metoclopramide administration led to a higher
AINV complete control rate in children receiving antineoplastic therapy of low to moderate emetogenic potential
(74%) than of high emetic potential (11%).
What Doses of Antiemetic Agents Are Known to Be Effective

in Children Receiving Antineoplastic Medications?
Aprepitant
In all but two publications to date, children were given the recommended adult dose of aprepitant; that is, 125 mg
on Day 1 followed by 80 mg on Days 2 and 3 17, 24, 30–32. Choi et al. 25 gave this dose to children who
weighed greater than 20 kg and a lower dose (80 mg/day for 3 days) to children who weighed less than 20 kg. The
extent of AINV control afforded by each dosing scheme was not provided. Coppola et al. 33 reviewed the use of
aprepitant in 33 children less than 18 years old. Children weighing less than 40 kg were most often given aprepitant
80 mg on Day 1 and then 40 mg per day on Days 2 and 3. Details regarding the antineoplastic therapy and other
antiemetic agents given concurrently were not provided.
The pharmacokinetic disposition of aprepitant in adolescents has been shown to be similar to that observed in adults
24. It is therefore reasonable to administer the adult dose to adolescents. However, the pharmacokinetic disposition
of aprepitant in infants and pre-adolescent children is unknown and no dose-finding studies have been conducted in
this age group.
Chlorpromazine
The use of chlorpromazine for AINV control in children has been described in six studies, five of which were
blinded RCTs 26, 27, 34–37. Doses ranged from 0.3 to 1 mg/kg every 3–6 hours; Hahlen and Quintana 34
initiated their investigation using a dose of 0.5 mg/kg and later reduced it to 0.3 mg/kg due to excessive sedation.
Since higher doses within this range were most often evaluated, the guideline development panel recommended a
starting chlorpromazine dose of 0.5 mg/kg/dose IV given every 6 hours with consideration of a higher dose if AINV
is not controlled and sedation is not a concern.
Dexamethasone
Highly emetogenic antineoplastic therapy
Five studies were identified in which antineoplastic therapy was assessed as HEC using the POGO guideline or as
stated by the investigators. Four of these were RCTs 14, 17, 26, 38; one was a prospective descriptive study 16.
Of the RCTs, three were conducted exclusively in children 14, 26, 38. Doses ranged from approximately 6 to 24
mg/m2/day IV. In the largest of these studies, two dexamethasone dosing regimens (24 mg/m2/day: 8 mg/m2/dose
given IV pre-therapy × 1 and then 16 mg/m2/day IV either divided q6h or divided into two doses given q4h) were
given. However, the results were presented in aggregate 14. These studies did not evaluate AINV control using
common antiemetic backbones so comparison of the performance of the dexamethasone doses used is not possible.
The fourth RCT involved too few children to permit evaluation of the outcome in this subset 17.
The recommendation for dexamethasone dosing is based on the most robust, published evidence 14, 26, 38 in
children receiving HEC. Because assignment of a maximum dose would be arbitrary, no maximum dexamethasone
dose is recommended in this guideline. The dexamethasone dose should be halved in patients receiving aprepitant
concurrently.
Moderately emetogenic antineoplastic therapy
Three studies were identified in which chemotherapy was classified as MEC using the POGO guideline 5 or as
deemed by the investigators 19, 34, 39. All were randomized comparisons of varying antiemetic regimens, in which
at least one arm included dexamethasone. A single RCT evaluated AINV control provided by dexamethasone plus
either oral or IV ondansetron in children receiving MEC or HEC 19. Dexamethasone was given by mouth in a dose
based on body surface area (≤0.6 m2: 2 mg BID; >0.6 m2: 4 mg BID). This dosing regimen is approximately
equivalent to 5–20 mg/m2/day depending on the child's size. The complete antineoplastic-induced vomiting control
rate observed in this study was approximately 80%. No other study has evaluated the combination of
dexamethasone plus a 5-HT3 antagonist in children receiving MEC. The other two studies identified compared
dexamethasone doses ranging from 6 to 10 mg/m2/day combined with either chlorpromazine or metoclopramide 19,
34.
The panel's recommendation regarding the dexamethasone dose to be given to children receiving MEC stems from
the observations of White et al. 19. Given the highly variable dexamethasone clearance in children 40 and the lack
of specific information regarding bioavailability of dexamethasone in children, it is reasonable to recommend the
same dose IV in cases where the oral route of administration is not appropriate.
Granisetron
One randomized crossover trial compared two granisetron doses (20 or 40 mcg/kg/dose once daily) plus
dexamethasone in 13 children receiving HEC 41. All patients achieved complete AINV control regardless of the
granisetron dose administered. No patient required rescue antiemetic agents.
In an open prospective study, Miyajima et al. gave granisetron as a single daily dose of 40 mcg/kg and observed
complete AINV control in approximately 60% of children receiving HEC. Although the study protocol allowed for
the administration of a second granisetron dose in patients in whom AINV control was not ideal, no patient required
a second granisetron dose. This level of control is similar to that reported in children receiving HEC and single agent
5-HT3 antagonists for AINV prevention as reported in recommendation 2; that is, 66% (95% CI: 60, 72).
Granisetron 40 mcg/kg/day IV as a single daily dose is recommended for children receiving HEC. The very small
number of patients included in the dose comparison trial by Komada et al. 41 limits the confidence that giving a
granisetron dose of 20 mcg/kg/dose will achieve the same degree of AINV control as seen following a larger dose.
A maximum granisetron dose is not recommended since neither of the identified studies capped the dose.
IV Granisetron: Dose comparison studies in small numbers of children receiving MEC indicate no difference in rates
of complete AINV control offered by granisetron 20 mcg/kg/dose or 40 mcg/kg/dose 34, 41. Fujimoto et al. 42
made similar observations in children receiving antineoplastic therapy of unknown emetogenicity. However,
Tsuchida et al. 43 observed a significant difference in the complete AINV control rates achieved in children
receiving antineoplastic therapy of unknown emetogenicity depending on the granisetron dose administered (20
mcg/kg/dose vs. 40 mcg/kg/dose). Furthermore, the findings of improved control with repeated doses of granisetron
20 mcg/kg raise questions about the reliability of gaining complete AINV control with single granisetron doses of 20
mcg/kg 34, 44. For these reasons, the panel recommends that granisetron 40 mcg/kg be given as a single daily dose
to children receiving MEC. No maximum dose is recommended since all but one study had no dose limit.
Oral Granisetron: Based on the findings of Mabro et al. 45, the panel recommends that children receiving MEC
receive granisetron 40 mcg/kg/dose every 12 hours by mouth. No maximum dose is recommended.
Antineoplastic therapy of low emetogenic potential
Two randomized trials met the inclusion criteria 23, 46. Both administered granisetron in doses of 40 mcg/kg IV as
a single daily dose prior to antineoplastic therapy of low to high emetogenicity. In one study, the maximum
granisetron dose was 3 mg regardless of body weight 46.
Metoclopramide
Four randomized trials that evaluated the use of metoclopramide to prevent AINV in children were included and
support the recommended metoclopramide dose 21, 26, 39, 47. The recommended dose was associated with a
complete rate of vomiting control of 74% (17/23) 21. Concurrent administration of diphenhydramine is
recommended due to the high likelihood of dystonic reactions.
Nabilone
A single randomized trial met the criteria for inclusion in the evidence summary. It describes AINV control in 30
children receiving antineoplastic therapy 29. The panel based the recommended nabilone dose on this trial. A
maximum dose is recommended due to increased toxicity observed above this threshold 48.
Ondansetron
Three randomized trials evaluated acute AINV control in children receiving HEC 14, 17, 49. The number of
children involved in one of these trials is too small to allow interpretation 17. The remaining studies which assessed
AINV control after ondansetron administration were descriptive in nature 16, 50–54. The recommendation was
based on the findings of RCTs and supported by descriptive studies. The ondansetron dose was capped at 8 mg
q8h in a single open, non-comparative, prospective study of children receiving HEC 55. The small number of
children evaluated in this study and the low complete control rate observed did not support the inclusion of a
maximum ondansetron dose as a recommendation.
Five randomized trials meeting inclusion criteria administered ondansetron to children receiving MEC 19, 39, 56–
58. The findings of these and other descriptive studies 52, 55, 59 support the recommendation. The maximum single
dose of 8 mg is based on the findings of good AINV control in two RCTs 39, 56 and one prospective study 55
where the dose limit was 8 mg.
Antineoplastic therapy of low emetogenic potential
Two studies met inclusion criteria: one RCT 22 and another descriptive study 16. Both describe outcomes in a very
small number of patients. Neither study administered a maximum ondansetron dose; however, the panel
recommends a maximum single daily IV ondansetron dose of 16 mg due to the potential for QT interval
prolongation with higher doses 60. Based on the excellent bioavailability of ondansetron and its demonstrated
efficacy in children receiving HEC or MEC when given by mouth, the guideline development panel furthermore
included the oral route in the recommendation despite the absence of specific evidence to support its efficacy in
children receiving antineoplastic of low emetogenic potential.
RESEARCH GAPS
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
The number of significant gaps in the published evidence regarding interventions which may provide optimal AINV
control to children is extensive. Examples are presented in Table II.
Table II. Identified Research Gaps in the Domain of Prevention of Antineoplastic-

Induced Nausea and Vomiting in Children
Domain Issues
Outcomes Impact on each component of AINV control (vomiting, retching, nausea,

appetite and use of breakthrough antiemetic agents) on quality of life
Efficacy Highly emetogenic antineoplastic therapy:
5-HT3 antagonist plus a corticosteroid
5-HT3 antagonist, a corticosteroid plus aprepitant
Moderately emetogenic antineoplastic therapy:
5-HT3 antagonist plus a corticosteroid
5-HT3 antagonist plus aprepitant/fosaprepitant
Adjunctive antiemetic agent for use in children who cannot receive

corticosteroid
Novel antiemetic agents: aprepitant/fosaprepitant, casopitant, rolapitant,

palonosetron, diphenhydramine-lorazepam-dexamethasone, ginger,
metopimazine, olanzapine
Novel antiemetic interventions: acupressure, guided imagery, music

therapy, progressive muscle relaxation, psycho-educational support, virtual
reality, and food composition and presentation
Role of genetics on risk of AINV and antiemetic efficacy
Dosage Dose-finding studies including determination of maximum doses:

optimization dexamethasone, oral granisetron
Dose frequency (single vs. multiple daily doses): dexamethasone,

ondansetron
Dose strategies in obese children

Dose strategies in obese children
Safety Interaction between aprepitant/fosaprepitant and antineoplastic agents
Short and long term adverse effects of corticosteroid use such as mood
changes, sleep disturbance, fatigue and osteopenia
Product Oral liquid aprepitant, granisetron, nabilone, palonosetron

formulation
CONCLUSIONS
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
Recommendations for the prevention of AINV in children receiving antineoplastic agents are summarized in Table I
and Figure 2. Readers are encouraged to adapt these recommendations to their local context. The development of
an evidence-based approach to antiemetic selection in children receiving antineoplastic therapy is likely to improve
AINV control. However, there are many gaps in our knowledge. AINV control in children is not likely to be fully
optimized until specific information regarding the pediatric use of antiemetic agents known to be critical to AINV
control in adults is generated.
Acknowledgements
1. Top of page
2. Abstract
3. INTRODUCTION
4. METHODS
5. RESULTS
6. RESEARCH GAPS
7. CONCLUSIONS
8. Acknowledgements
9. REFERENCES
The assistance of Ms. Elizabeth Uleryk, Director, Hospital Library, The Hospital for Sick Children and the
administrative assistance of Ms. Carla Bennett, Coordinator of Clinical Programs, Pediatric Oncology Group of
Ontario, are gratefully acknowledged. The submission of a review from the following content reviewers is also
acknowledged with thanks: Dr. Christina Baggott, Dr. Steven Grunberg, Dr. Anne-Marie Langevin, Dr. Andrea
Orsey, Dr Robert Phillips, Dr. Marianne van der Wetering, and Ms. Deborah Woods. This study was supported by
the Pediatric Oncology Group of Ontario; Ministry of Health and Long Term Care, Ontario; Children's Oncology
Group (L.S. and L.L.D.). L.S. is supported by a New Investigator Award from the Canadian Institutes of Health
Research.
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5. RESULTS
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8. Acknowledgements
9. REFERENCES
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Guide - Prevent..acute Nausea Vomit Due To Antineoplastic PDF

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Guideline for the prevention of acute nausea and

Article first published online: 19 MAR 2013

Copyright © 2013 Wiley Periodicals, Inc.

Pediatric Blood & Cancer

4 Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada

5 College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, Canada

6 Guideline Methodologist, Pediatric Oncology Group of Ontario, Ontario, Canada

8 Division of Haematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, Ontario,

9 Department of Nursing, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada

10 Department of Paediatrics, University of Toronto, Ontario, Canada

Email: L. Lee Dupuis MScPhm, ACPR, FCSHP ([email protected])

‡ Conflict of interest: Nothing to declare.

1. Issue published online: 22 MAY 2013

Pediatric Oncology Group of Ontario

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Source Guideline Selection

Table I. Summary of the Health Questions That Guided Development of the

1. How is optimal control of acute AINV defined?

We recommend that optimal control of acute AINV be defined as Strong

2a. What pharmacological interventions provide optimal control of acute AINV in

2b. What pharmacological interventions provide optimal control of acute AINV in

We recommend that children receiving antineoplastic agents of Strong

2c. What pharmacological interventions provide optimal control of acute AINV in

We recommend that children receiving antineoplastic agents of low Strong

2d. What pharmacological interventions provide optimal control of acute AINV in

We recommend that children receiving antineoplastic agents of low Strong

Very low quality

3. What adjunctive non-pharmacological interventions provide control of acute

therapy, progressive muscle relaxation and psycho-educational recommendation

Very low quality evidence

We suggest that the following dietary interventions may be effective:

Eat smaller, more frequent meals;

Reduce food aromas and other stimuli with strong odors;

Avoid foods that are spicy, fatty or highly salty;

Take antiemetics prior to meals so that the effect is present during

Measures and foods (e.g., “comfort foods”) that helped to

4. What is the role of aprepitant in children receiving antineoplastic therapy?

We recommend that the use of aprepitant be restricted to children Strong

5. What pharmacological interventions provide optimal control of acute AINV in

We suggest that children receiving highly emetogenic antineoplastic Weak

We suggest that children receiving moderately emetogenic Weak

6. What doses of antiemetic agents are known to be effective in children receiving

We recommend the following aprepitant dose for children 12 years Strong

Day 1: 125 mg PO × 1; Days 2 and 3: 80 mg PO once daily. Moderate quality

We recommend the following chlorpromazine dose: 0.5 mg/kg/dose Strong

We suggest the following dexamethasone for children receiving Weak

If given concurrently with aprepitant, reduce dexamethasone dose

We recommend the following dexamethasone for children receiving Strong

Low quality evidence

≤0.6 m2: 2 mg/dose IV/PO q12h

>0.6 m2: 4 mg/dose IV/PO q12h.

If given concurrently with aprepitant, reduce dexamethasone dose

We recommend the following IV granisetron dose for children Strong

receiving moderately emetogenic antineoplastic therapy: 40 recommendation

We suggest the following oral granisetron dose for children Weak

We recommend the following IV granisetron dose for children Strong

We suggest the following oral granisetron dose for children Weak