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.

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

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.

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.

• 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.

• 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.

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.

• 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.

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.