Background
The outcome for children with cancer has dramatically improved over the past several decades, in part because of the ability to effectively and safely deliver higher and more intense courses of chemotherapy. Two of the most common side effects of this treatment modality are nausea and vomiting. [1] These side effects have a significant impact on quality of life and can interfere with the ability to deliver intensive care. Fortunately, improvements in supportive and adjunctive care have also been attained, and current treatments for nausea and vomiting are effective in mitigating these adverse effects in most patients.
Distinguishing several terms used in this article is important. Vomiting refers to the expulsion of stomach contents. Retching refers to the act of vomiting without expulsion of stomach contents. Although these can be quantified using the number of episodes experienced, nausea, which is the child’s perception of needing to vomit, is purely subjective.
Acute vomiting refers to symptoms that occur within 24 hours of the administration of chemotherapy. Delayed vomiting refers to vomiting 2-5 days after the administration of chemotherapy.
Anticipatory vomiting, which is a particularly challenging phenomenon in children and teenagers, is vomiting prior to the administration of chemotherapy. Anticipatory vomiting is a learned response that is best prevented by the use of an adequate antiemetic regimen during the patient’s first experience with chemotherapy. Also, this type of vomiting is more likely in children who have a history of motion sickness or who have had a particularly negative postchemotherapy nausea or vomiting experience. [2]
Pathophysiology
Research into the mechanism through which chemotherapeutic agents induce nausea and vomiting has elucidated some of the critical pathways involved; however, much is still unknown. The chemotherapy trigger zone (CTZ) is located in a medullary center located in the area postrema, which is susceptible to emetic stimuli delivered through the blood system or cerebrospinal fluid (CSF). The chemotherapy trigger zone stimulates the vomiting center, an area of the medulla oblongata that acts by stimulating the phrenic, spinal, and visceral nerves. These efferent signals induce vomiting by their effects on the diaphragm, abdominal muscles, and stomach. The vomiting center also receives signals of increased intracranial pressure from visceral organs, the inner ear labyrinthine apparatus, and higher CNS structures.
Vomiting reflex.
How individual chemotherapeutic agents affect the chemotherapy trigger zone is less clear. Chemotherapeutic agents are presumed to cause release of emetic transmitters. These substances bind to receptors in the chemotherapy trigger zone and probably bind to other areas of the brain and GI system. The most important transmitters and their receptors include serotonin and the 5-HT3 receptor, dopamine, dopamine receptor and substance P, and the neurokinin 1 (NK1) receptor. Most antiemetics function as competitors of the emetogenic transmitters; therefore, by binding to the receptors, they prevent binding of the emetogenic transmitters. For this reason, using antiemetics prior to administration of emetogenic chemotherapy is important.
Epidemiology
Frequency
The frequency of nausea and vomiting is related to the emetogenic risk of the particular chemotherapeutic agent or combination of drugs being administered (see the table below). Cisplatin is one of the most emetogenic agents and is known to produce nausea in more than 99% of patients if no antiemetics are used. [2]
In order to determine the emetogenic potential of combination chemotherapy regimens, the following must be considered:
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Determine the category of the most emetogenic agent in the regimen.
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Add one level for all level 2 agents or each level 3 agent included in the regimen.
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Level 1 agents do not contribute to the emetogenicity of a given regimen.
Mortality/Morbidity
Nausea and vomiting are a significant cause of morbidity in pediatric patients.
Sex
Although both sexes are affected by chemotherapy-induced nausea and vomiting, some studies have suggested that females are somewhat more susceptible.
Age
Chemotherapy-induced nausea and vomiting affects children of all ages; however, children younger than 6 years have been shown to have a lower incidence than older children when receiving similar agents. By contrast, adolescents appear to be more susceptible.
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Vomiting reflex.
Tables
Emetogenic Risk level |
Antineoplastic Agents |
Antiemetic Regimen |
level 4 (High): More than 90% of patients who receive these agents experience nausea and vomiting. |
Carmustine, cisplatin, cyclophosphamide (>1500 mg/m2), dacarbazine, dactinomycin, mechlorethamine, streptozotocin |
Serotonin-receptor antagonist, dexamethasone, and aprepitant |
level 3 (Moderate): Nausea and vomiting occurs in 30-90% of patients who receive these agents. |
Carboplatin, cyclophosphamide (< 1500 mg/m2), cytarabine (>1 g/m2), daunorubicin, doxorubicin, epirubicin, idarubicin, ifosfamide, irinotecan, oxaliplatin |
Serotonin-receptor antagonist and dexamethasone |
level 2 (Low): Nausea and vomiting occurs in 10-30% of patients who receive these agents. |
Bortezomib, cetuximab, cytarabine (< 1 g/m2), docetaxel, etoposide, fluorouracil, gemcitabine, methotrexate, mitomycin, mitoxantrone, paclitaxel, pemetrexed, topotecan, trastuzumab |
Serotonin-receptor antagonist |
level 1 (Minimal): Less than 10% of patients who receive these agents experience nausea and vomiting. |
Bevacizumab, bleomycin, busulfan, 2-chlorodeoxyadenosine, fludarabine, rituximab, vinblastine, vincristine, vinorelbine |
No antiemetic routinely administered* |
*If antiemetic required for individual patients, may use a single dose of serotonin-receptor antagonist |
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