5HT3 and Dexamethasone in Pediatric Patients

5HT3 and Dexamethasone in Pediatric Patients

PEP Topic 
Chemotherapy-Induced Nausea and Vomiting—Pediatric
Description 

5-hydroxytryptamine (5-HT3) receptor antagonists (RAs) are a class of antiemetics used to relieve nausea and vomiting associated with chemotherapy. At this time, four 5-HT3 RAs are approved by the Food and Drug Administration (FDA) for use in the United States: ondansetron, granisetron, dolasetron, and palonosetron. Dexamethasone is a corticosteroid. These drugs have been evaluated for use in pediatric patients  to treat acute emesis associated with highly or moderately emetogenic chemotherapy.

 

Likely to Be Effective

Guideline/Expert Opinion

Dupuis, L.L., Boodhan, S., Holdsworth, M., Robinson, P.D., Hain, R., Portwine, C., ... Sung, L. (2013). Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatric Blood & Cancer, 60(7), 1073–1082. 

PROFESSIONAL GROUP: Pediatric Oncology Group of Ontario (POGO)

doi: 10.1002/pbc.24508
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Purpose & Patient Population:

PURPOSE: To summarize evidence and provide antiemetic recommendations for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) among children receiving chemotherapy
 
TYPES OF PATIENTS ADDRESSED: Pediatric oncology patients receiving chemotherapy

Type of Resource/Evidence-Based Process:

RESOURCE TYPE: Evidence-based guideline  
 
PROCESS OF DEVELOPMENT: Articles were identified through a search of databases and independently reviewed and scored by three to four members of the Guideline Development Panel using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Evidence summary tables were compiled and reviewed by two panel members before an article was considered for inclusion in a meta-analysis completed by the panel.     
 
DATABASES USED: Medline, Embase, Cochrane Central Register of Controlled Trials (CCTR), Allied and Complementary Medicine (AMED), Health Technology Assessment (HTA), National Health Service Economic Evaluation Database (NHS EED), EBSCOhost, and Google
 
KEYWORDS: N/A
 
INCLUSION CRITERIA: Full-text articles published in English or French reporting pediatric data separately, reporting emetogenicity of the chemotherapy used, providing an explicit or implicit definition of complete acute antineoplastic-induced nausea and vomiting (AINV) response, and reporting the complete acute AINV response rate as a proportion or percentage
 
EXCLUSION CRITERIA: Articles only available as abstracts.

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Pediatrics 

Results Provided in the Reference:

Table of antiemetic recommendations and strength of evidence of recommendations

Guidelines & Recommendations:

Antiemetic therapies with a “strong” recommendation: 
  1. Children ≥ 12 years, high emetogenicity, no known interaction with aprepitant-ondansetron or granisetron and dexamethasone and aprepitant, if interaction with aprepitant–ondansetron or granisetron and dexamethasone 
  2. Children < 12 years, high emetogenicity: Ondansetron or granisetron and dexamethasone
  3. No age restriction, moderate emetogenicity: Ondansetron or granisetron and dexamethasone
  4. No age restriction, low emetogenicity: Ondansetron or granisetron
  5. No age restriction,  minimal emetogenic risk: No routine prophylaxis
  6. Aprepitant should be restricted to children 12 years of age and older who are about to receive highly emetogenic chemotherapy, which is not known to interact with aprepitant. There is no evidence to support the safe and effective use of aprepitant in younger children.
  7. Aprepitant dose recommendations: Day 1, 125 mg PO x 1; Days 2 and 3, 80 mg PO once daily
  8. Chlorpromazine dose recommendations: 0.5 mg/kg/dose IV q6h
  9. Dexamethasone dose recommendations: ≤ 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. 
  10. Granisetron dose recommendations: High emetogenicity, 40 mcg/kg/dose IV as a single daily dose; moderate emetogenicity, 40 mcg/kg/dose IV as a single daily dose; low emetogenicity, 40 mcg/kg/dose IV as a single daily dose 
  11. Metoclopramide dose recommendations: Moderate emetogenicity, 1 mg/kg/dose IV pretherapy x 1 and then 0.0375 mg/kg/dose PO q6h. Give diphenhydramine or benztropine concurrently. 
  12. Ondansetron dose recommendations: High emetogenicity, 5 mg/m2/dose (0.15 mg/kg/dose) IV/PO pretherapy x 1 and then q8h; moderate emetogenicity, 5 mg/m2/dose (0.15 mg/kg/dose, maximum 8 mg/dose) IV/PO pre-therapy x 1 and then q12h; low emetogenicity, 10 mg/m2/dose (0.3 mg/kg/dose, maximum 16 mg/dose IV or 24 mg/dose PO) pretherapy x 1   

Limitations:

Limited evidence exists for the prevention of CINV in pediatric populations making conclusions and guidelines difficult to establish.

Nursing Implications:

When managing acute CINV in pediatric patients, nurses can make informed decisions by consulting evidence-based guidelines.

Jordan, K., Roila, F., Molassiotis, A., Maranzano, E., Clark-Snow, R. A., Feyer, P., & MASCC/ESMO. (2011). Antiemetics in children receiving chemotherapy. MASCC/ESMO guideline update 2009. Supportive Care in Cancer, 19(Suppl 1), 37-42.

doi:10.1007/s00520-010-0994-7
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Purpose & Patient Population:

To provide a consensus statement derived from published articles as well as expert opinion about antiemetic therapy in children younger than 18 years

Type of Resource/Evidence-Based Process:

This resource is a guideline, developed by the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO).

A panel of 23 oncology professionals determined the level of evidence and confidence according to EMSO and MASCC criteria. Between 2004 and June 2009, eight articles were published regarding 5-HT3 receptor antagonists (RAs) in pediatric populations (two regarding safety issues, four dose-finding or -optimizing studies, and two comparative studies), four articles reported on the NK1 RA aprepitant (one randomized study, two case reports, and one study on the liquid formulation of aprepitant), and two miscellaneous studies looked at the impact of an antiemetic pump and the value of metopimazine when added to ondansetron. Recommendations were classified using the MASCC level of scientific confidence and consensus.

Pertinent information from the published literature from 2004 to June 2009 was retrieved and reviewed for the creation of this guideline.  

Database searched was Medline.

Search keywords were antiemetics, chemotherapy-induced emesis, children, neoplasms, nausea, vomiting, serotonin antagonists, neurokinin 1 receptor antagonists, phenothiazines, butyrophenones, cannabinoids, corticosteroids, and metoclopramide.

No inclusion criteria were identified.

Articles were excluded if they were review articles or addressed emesis not caused by chemotherapy.

Phase of Care and Clinical Applications:

  • All patients were in active treatment.
  • This guideline has application for pediatrics.

Guidelines & Recommendations:

  • No designated 5-HT3 RA was recommended. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was II and grade of recommendation was B.)
  • No verifiable, high-level evidence-based consensus was possible on the dose of the individual 5-HT3 RAs.
  • Corticosteroids were found to be effective antiemetics for CINV, especially when combined with a 5-HT3 RA. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was II and grade of recommendation was B.) Safety issues when administering corticosteroids in children must strongly be considered.                                                                                                       
  • No recommendations was made regarding ​neurokinin 1 (NK1) RAs, but they showed promising activity. The guideline panel recommended development of more well-designed, three-agent trials testing the addition of a NK1 RA to draw firm conclusions for a recommendation.                                                                       
  • The guideline recommended that all pediatric patients receive antiemetic prophylaxis with a combination of a 5-HT3 RA and dexamethasone for the acute phase of highly emetogenic chemotherapy. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was III and grade of recommendation was B.)                                                                                                          
  • For the acute phase of moderately emetogenic chemotherapy, all pediatric patients are recommended to receive antiemetic prophylaxis with a combination of a 5-HT3 RA and dexamethasone. (The MASCC level of confidence was moderate and level of consensus was high. The ESMO level of evidence was II and grade of recommendation was B.)                                                                                                          
  • For the acute phase of low and minimal emetogenic chemotherapy, not enough studies in children have been produced to make a recommendation.

Nursing Implications:

Children receiving chemotherapy should receive a 5-HT3 RA and dexamethasone for antiemetic prophylaxis both in highly emetogenic and moderately emetogenic chemotherapy. A significant lack of well-designed randomized studies exist to evaluate the problem of chemotherapy-induced emesis in children. Optimal dosing in children and management of delayed and anticipatory CINV in children is not yet clear. Investigation is needed regarding the potential role of NK1 RAs and the 5-HT3 RAs palonosetron and transdermal granisetron for future consideration in pediatrics.

Systematic Review/Meta-Analysis

Phillips, R.S., Gopaul, S., Gibson, F., Houghton, E., Craig, J.V., Light, K., & Pizer, B. (2010). Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane Database of Systematic Reviews (Online), 9, CD007786.

doi: 10.1002/14651858.CD007786.pub2
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Purpose:

To assess effectiveness, adverse events, and quality of life associated with pharmacologic interventions for control of anticipatory nausea and vomiting in children about to receive chemotherapy and for control of acute and delayed nausea and vomiting in children receiving chemotherapy

Search Strategy:

Databases searched were MEDLINE, Embase, LILACS, and Cochrane CENTRAL register of clinical trials to February or March 2008.

Search keywords included the specific names of all drugs used for nausea and vomiting, including cannabinoids. Extensive listing of terms and Medical Subject Heading (MeSH) terms were provided in appendices. Multiple terms were included for pediatric cases. MeSH Nausea, MeSH Vomiting and anticipatory vomiting, Cancer and associated terms, and Chemotherapy. Manual reference screening and author contact for further information also was used.

Studies were included in the review if they 

  • Were randomized controlled trials (RCTs) where an antiemetic, cannabinoid, or benzodiazepine was compared to either a placebo or an alternative intervention.
  • Involved participants under age 18 with a cancer diagnosis receiving chemotherapy and a pharmacologic antiemetic.

Studies were excluded if they 

  • Incorporated neurokinin 1 (NK1) receptor antagonists (RAs).
  • Used nonpharmacologic approaches.

Literature Evaluated:

Initial searching provided 844 references. Of these, 67 were identified for detailed screening. A final sample of 27 articles reporting on 28 trials was included. Evaluation included assessment of study quality and risk of bias.

Sample Characteristics:

  • Across all studies, 1,719 patients were included. Sample sizes of included studies ranged from 12 to 428 participants, with a median of 30 participants.
  • Quantitative synthesis incorporated findings from five trials in which pooled analyses were done for different doses of granisetron and for the addition of dexamethasone to 5-HT3 RAs.

Results:

  • No data were available on anticipatory nausea and vomiting or for any valid quality-of-life measures.
  • Data on outcomes beyond the first 24 hours of chemotherapy often were found.
  • Data on nausea were inconsistently reported, and they were most often reported using measurement scales that were not validated.
  • Most results were for acute emesis only.
  • Effects of interventions were as follows.
    • Cannabinoids
      • Four studies compared cannabinoids with alternative antiemetics. These demonstrated different results.
      • Two studies showed benefits of tetrahydrocannabinol over prochlorperazine and metoclopramide for control of nausea and vomiting.
      • Two other studies showed no benefit in comparison with domperidone and prochlorperazine.
    • Corticosteroids:
      • Steroids as a sole intervention were used in two studies compared to metoclopramide. Results of these two studies were completely different.
      • Two studies examined addition of steroids to 5-HT3 RAs. Addition of steroids showed good benefit in pooled results for complete control of vomiting (RR = 2.10, CI = 95%, 1.62–2.72)
    • 5-HT3 receptor antagonists:
      • Three studies looked at the effectiveness of 5-HT3 RAs in comparison to concurrent dexamethasone and either metoclopramide or chlorpromazine. One study found no differences among groups, and two studies found ondansetron and granisetron to be more effective.
      • Seven studies compared doses of granisetron, ondansetron, and tropisetron. Higher dosages and differing schedules did not demonstrate any advantage for reducing acute vomiting.
      • One study compared oral ondansetron versus IV dexamethasone. No differences were found between these groups.
    • Other agents: Three studies examined chlorpromazine versus metoclopramide and a cocktail of lorazepam, dexamethasone, metoclopramide, and benztropine (LDMB).
      • Chlorpromazine was more effective than a similar dose of metoclopramide in terms of duration of nausea.
      • Domperidone was more effective than metoclopramide regarding duration of nausea.
      • The LDMB cocktail was more effective than chlorpromazine for complete control of vomiting.

A broad range of adverse events were reported for 5-HT3 RAs. Those reported most frequently were headache, sedation/somnolence, and abdominal pain. The main side effects reported with cannabinoids were drowsiness, dizziness, mood alteration, and increased appetite. Only a few studies reported side effects with metoclopramide or chlorpromazine.

Conclusions:

This review concluded that knowledge of the most effective antiemetics to prevent chemotherapy induced nausea and vomiting in children is incomplete and imprecise. Nausea often was reported with different methods that were not validated. No information was available about delayed or anticipatory nausea. Conclusions from these trials were that 5-HT3 RAs appear to be more effective than older antiemetic agents, even when those agents are combined with steroids. Additionally, 5-HT3 RAs with dexamethasone were effective in patients who were to receive highly emetogenic chemotherapy, although the addition of steroids was unclear. Cannabinoids were found to probably be effective. Related side effects may be experienced as adverse by some patients but not others.

Limitations:

  • No information was provided about delayed or anticipatory nausea.
  • No clear definition of preferred route or dose of antiemetics was provided in this review.
  • No information about the use of antiemetics in multiday and multiagent trials was included, and effectiveness of antiemesis following the last dose of chemotherapy was unclear.

Nursing Implications:

The following areas for research were identified. 

  • Clarify if there are important differences among the 5-HT3 RAs.
  • Determine the most beneficial doses and duration of dexamethasone.
  • Study the role of new agents, such as substance-P antagonists.

Future research should incorporate the use of validated measures and examination of appropriate schedules and doses to deal with anticipatory and delayed symptoms.

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