Nausea and vomiting is a distressing complication of paediatric chemotherapy but it is on the decrease thanks to the introduction of new classes of antiemetics
Department of Pharmacy
Ghent University Hospital
Chemotherapy-induced nausea and vomiting (CINV) is a well-recognised complication of treatment of childhood malignancies. It is considered one of the most distressing adverse effects.
Insufficient control of CINV can result in deleterious effects (eg, electrolyte imbalance, dehydration, aspiration pneumonia and anorexia). Apart from the reduction in the quality of life, CINV can also cause interruption or discontinuation of curative or palliative care.
Fortunately, for the last two decades, the number of children reporting these side-effects has decreased remarkably. This is mainly due to a better understanding of the underlying pathophysiology, the introduction of several new classes of antiemetics (particularly the serotonin-3 (5-HT3) receptor antagonists) and a more correct adherence to international guidelines for prevention of CINV.[1–5]
Today, most children can receive chemotherapy without intractable nausea or vomiting.[1,3,4] In some children, however, multiple interventions are still needed to minimise nausea and emetic episodes.
Pathophysiology of CINV
The central nervous system plays a crucial role in the pathophysiology of emesis. For a long time, the concept of a vomiting (or emetic) centre located in the medulla was proposed to serve as a final common pathway for processing impulses initiating emesis. It is now thought that an anatomically discrete vomiting centre is unlikely to exist[2,5] but that neuronal areas within the medulla interact in order to coordinate the emetic reflex. These are termed a ‘central pattern generator’.[2,5]
The central pattern generator receives input from the nucleus tractus solitarius, the chemoreceptor trigger zone, the vestibular system and the gastrointestinal tract. The emetic process is initiated by the stimulation of dopamine, opiate, histamine, acetylcholine, neurokinin-1 (NK-1), or 5-HT3 receptors.
Classification of CINV
CINV is classified according to the time relative to chemotherapy administration that nausea, retching, or vomiting occur.
Anticipatory CINV occurs before the administration of chemotherapy. Once established, this cycle can be very difficult to break. Primary prevention is paramount.
For some children, the experience of nausea and vomiting during a previous administration of chemotherapy is often associated with the clinical environment, ie, on arrival at the oncology unit, or approaching the hospital, they become nauseated.
Acute nausea or vomiting is defined as that occurring within the first 24 hours after administration of chemotherapy.
Delayed nausea or vomiting begins at least 24 hours after administration of the last dose of chemotherapy and may persist for up to 7 days.
Breakthrough nausea and vomiting occurs despite administration of appropriate antiemetic therapy. In children with breakthrough CINV, all efforts should be made to exclude other causes of nausea and vomiting (eg, increased intracranial pressure, hypercalcaemia and medications other than chemotherapy).[1,3]
Contributing factors and emetic risk
The primary factor influencing the severity and frequency of CINV is the emetic potential (emetogenicity) of the individual cytotoxic agent. The emetic potential is defined as the intrinsic capacity of a chemotherapy agent to produce an emetic episode in a patient receiving the agent. The emetogenic classification provides a tool for predicting the incidence of CINV prior to prescribing and treatment, accordingly.
Cytotoxics have been classified into four groups according to the emesis risk without antiemetics. These are classified as high, moderate, low and minimal.
High (emesis risk >90% without antiemetics;
Anthracycline combination defined as either doxorubicin or epirubicin with cyclophosphamide; carmustine >250mg/m2; cisplatin ≥ 50mg/m2 ; cyclophosphamide > 1,500mg/m2; dacarbazine.
Moderate (emesis risk 30–90% without antiemetics; level 3)
Carboplatin, carmustine ≤250mg/m2; cisplatin <50mg/m2; cyclophosphamide ≤1,500mg/m2; cytarabine >1g/m2; daunorubicin, doxorubicin, epirubicin, ifosfamide.
Low (emesis risk 10–30% without antiemetics; level 2)
Cytarabine 100–200mg/m2; etoposide, 5-Fluorouracil, methotrexate >50–250mg/m2; mitoxanthrone.
Minimal (emesis risk <10% without antiemetics;
Asparaginase, bleomycin, fludarabine, methotrexate ≤50mg/m2; vinblastine, vincristine.
If combination chemotherapy is used as treatment, the most highly emetogenic agent should be considered as the base level or ‘score’, with the addition of other agents as follows:
- Adding a level ‘1’ emetogenic agent does not contribute to the emetogenic ‘score’ of the combination (+0).
- Adding one or more level ‘2’ emetogenic agent(s) increase(s) the emetogenic ‘score’ by one greater than the most emetogenic agent (+1).
- Adding a level ‘3’ or ‘4’ agent increases the emetogenic ‘score’ by one (for each additional agent) greater than the most emetogenic agent.
Therefore, the combination emetogenicity level = base level + adjustment.
Healthcare providers need to assess their patients and intended treatment protocols properly in order to determine their risk for developing CINV.
Other factors contributing to the overall risk of CINV are: use of high drug doses; prior CINV (significant risk factor); gender (females more than males); younger patients (especially adolescents); anxiety; higher tumour burden; history of morning sickness or motion sickness; and rapid rate of infusion.
Clinical guidelines and practical recommendations have been established by several cancer associations such as the Multinational Association of Supportive Care in Cancer (MASCC), the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN);[6–8] however, these have all been formulated for adults. Only a few studies on the prevention of CINV have been carried out in children.
In paediatrics, often more aggressive treatment schedules are used than in adult treatment. This, combined with differences in pharmacokinetics between adults and children, means that it is inappropriate to assume that all results obtained in adults can be applied directly to children.[5–15]
Antiemetic research in paediatric populations is still hampered by a small patient population. Current recommendations suggest the combination of a 5-HT3 antagonist plus a corticosteroid before chemotherapy in children receiving chemotherapy of high or moderate emetic risk.[6,7] An increasing number of clinical trials and dose-finding studies (eg, ‘appropriate dosing regimen of aprepitant and fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in pediatric patients from 6 months to 17 years of age’) are ongoing.[15–19]
5-HT3 receptor antagonists
Serotonin is released by entero-endocrine cells in the gastrointestinal tract following administration of cytotoxics. 5-HT3 receptor antagonists bind to 5-HT3-receptors and thereby produce the antiemetic effect. These drugs are among the most widely used and effective antiemetic agents for CINV. They are highly effective in prevention or management of acute CINV, particularly in highly or moderately emetogenic chemotherapy agents. Without doubt, they are the most effective antiemetics in the prophylaxis of acute CINV. To date, five serotonin antagonists are available: ondansetron; granisetron; tropisetron; dolasetron; and palonosetron. So far, no comparative studies of different ‘setrons’ in paediatrics have been reported.
5-HT3 antagonists are considered to be equally effective and to be interchangeable. However, differences in pharmacokinetics (eg, differences in plasma half-life, drug–drug interactions, metabolism) and pharmacodynamics (receptor-binding affinity) are evident.[6–8, 12–14]
Orally and intravenously administered antiemetics are generally equivalent in efficacy and safety. The decision as to what formulation to use should be based on patient-specific factors and the cost for the hospital.
Generally, the adverse effects of ‘setrons’ are mild and no signs of extrapyramidal symptoms or dry mouth that occur with alternative antiemetics are seen.
Although not approved as an antiemetic, dexamethasone plays a major role in the prevention of acute and delayed CINV. It has become an integral component of almost all antiemetic regimens.[6–8] The increased efficacy of serotonin antagonists combined with dexamethasone makes this combination the standard of care for prevention of acute CINV induced by moderately to highly emetogenic chemotherapy in both adults and children[6,9] unless contraindicated.
However, corticosteroids should be prescribed with caution because there is evidence that they interfere with the antineoplastic effect of chemotherapy (eg, in osteosarcoma). They may also reduce the delivery of chemotherapy to brain tumours by reparing damage in the blood–brain barrier (1).
Patients may experience short-term hyperglycaemia with the administration of dexamethasone. In addition, immunosuppression and adrenal suppression can occur when corticosteroids are used for a prolonged period.
NK-1 receptor antagonists
Substance P/NK-1 receptor antagonists, represent a new class of antiemetic agents. Substance P is a peptide, present in the brain and gastrointestinal tract, which plays a role in signal transmission that induces emesis. The actions of substance P are mediated through the NK-1 receptor, classified as a G-protein, which is coupled to the inositol phosphate signal transduction pathway.
Aprepitant is the first therapeutic antiemetic NK-1 receptor antagonist, disabling or reducing the emesis signal pathway initiated by substance P. It was approved in 2004 for the use in combination with other antiemetic agents (eg, ‘setrons’ and corticosteroids) for the prevention of acute and delayed CINV in initial and repeat courses of highly emetogenic chemotherapy, including high-dose cisplatin.
Aprepitant has been studied extensively studied in adults. The experience in children is so far limited to a number of case reports in adolescents.[16,17] Clinical trials are ongoing.[15,18,19]
Metoclopramide was part of former MASCC, ASCO and NCCN guidelines and was suggested for the prevention of delayed emesis. Its use in children is associated with extrapyramidal side effects; these appear to be more common in younger adults than in older adults.
Domperidone is less likely to cross the blood–brain barrier than other agents, and is less prone to producing extrapyramidal reactions. Administration to the young population as first-line treatment is not recommended.
Some paediatric institutions have incorporated domperidone into their antimetic guidelines; however, rigorous evaluation of its contribution to prevention of CINV in children is required.
Alizapride is used in antiemetic schedules (available in Europe). The most common adverse effect is drowsiness and its use is associated with extrapyramidal symptoms.[1,3]
Benzodiazepines are a useful addition to antiemetic regimens in patients with anticipatory CINV or in patients with refractory and breakthrough emesis.[6–8]
Cannabinoids have been shown to decrease CINV in younger patients. However, their use is limited by side effects (hallucinations, dysphoria, dizziness). Cannabinoids might have a place in patients intolerant or refractory to ‘setrons’ or steroids and aprepitant.
There are no published paediatric experiences with olanzapine, an atypical antipsychotic drug, but studies in adults showed it to be effective in controlling acute and delayed CINV.
In children, the use of non-pharmacological strategies, such as music therapy, progressive muscle relaxation, hypnosis, diversion therapy, acupressure and acupuncture, guided imagery and dietary modifications, may be valuable adjuvants.
Assessment of nausea
Nausea is a highly subjective and internal state and external validity might be more difficult to measure than for emesis (expressed as frequency). A more objective assessment might be obtained by using nausea assessment tools, eg, by using the Paediatric Nausea Assessment Tool (PeNAT).[20,21]
Over the past years, the number of children with CINV has decreased remarkably. This is mainly owing to a better understanding of its underlying pathophysiology and the introduction of several new classes of antiemetics. Existing guidelines and recommendations for the prevention of CINV in children are still constrained by the lack of robust evidence and paediatric physicians are often forced to extrapolate from adult experiences to optimise CINV treatment in children.
The combination of a 5-HT3 receptor antagonist and a corticosteroid remains the ‘gold standard’ for prevention of acute CINV in children on moderately to highly emetogenic chemotherapy. In children whose emesis is not under control, alternative strategies should be considered.
Large, robust clinical trials are still needed to determine dosing schedules of antiemetics, and the safety and efficacy of agents for children with CINV.
1. Dupuis LL, Nathan PC. Paediatr Drugs 2010;12(1):51–61.
2. Hesketh PJ. N Engl J Med 2008;358(23):2482–94.
3. Dupuis LL, Nathan PC. Paediatr Drugs 2003;5(9):597–613.
4. ASHP Commission on Therapeutics. Am J Health Syst Pharm 1999;56:729–64.
5. Van Ryckeghem F, Van Belle S. Belg J Med Oncol 2009(3)5;212–17.
6. Kris MG, et al. J Clin Oncol. 2006;24(18):2932–47.
7. National Comprehensive Cancer Network (NCCN). Guidelines for supportive care; emesis. www.nccn.org/professionals/physician_gls/f_guidelines.asp
8. Multinational Association of Supportive Care in Cancer (MASCC). http://www.mascc.org/
9. Roila F, et al. Support Care Cancer 2005;13(2):129–31.
10. Licitra L, et al. Crit Rev Oncol Hematol 2002;43(1):93–101.
11. Foot AB, Hayes C. Arch Dis Child. 1994;71(5):475–80.
12. Antonarakis ES, et al. Pediatr Blood Cancer 2004;43(6):651–8.
13. Jordan K, et al. Oncologist 2007;12:1143–50.
14. Holdsworth MT, et al. Cancer 2006;15;106(4):931–40.
16. Gore L et al. Pediatr Blood Cancer 2009;52:242–7.
17. Smith A, et al. Pediatr Blood Cancer 2005;45:857–60.
18. Study NCT00572572. http://clinicaltrials.gov/ct2/show/NCT00572572
19. Study NCT00080444. http://clinicaltrials.gov/ct2/show/NCT00080444
20. Dupuis LL, et al. Pharmacotherapy 2006;26(9):1221–31.
21. Tyc VL, et al. J Dev Behav Pediatr 1993;14(4):236–41.