Pediatric Chemotherapy-Induced Nausea and Vomiting

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.

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.[4, 5]

In order to determine the emetogenic potential of combination chemotherapy regimens, the following must be considered:

• Determine the category of the most emetogenic agent in the regimen.

• Add one level for all level 2 agents or each level 3 agent included in the regimen.

• Level 1 agents do not contribute to the emetogenicity of a given regimen.

Sex- and age-related demographics

Although both sexes are affected by chemotherapy-induced nausea and vomiting, some studies have suggested that females are somewhat more susceptible.

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. A prospective study by Eliasen et al found that acute chemotherapy-induced nausea was more common among children and adolescents aged 8-18 years than among infants and children aged 0-3 years.[6]

Selection and modification of appropriate antiemetic therapy based on emetogenic potential of chemotherapy scheduled, prior patient experience, and patient risk factors increase the opportunity for administration of chemotherapy without emetic complications.

Morbidity/mortality

Nausea and vomiting are a significant cause of morbidity in pediatric patients.

Complications

Complications of chemotherapy-induced nausea and vomiting may include the following:

• Patient discomfort

• Electrolyte imbalance

• Dehydration

• Poor nutrition

• Prolonged hospitalizations

Emphasize to patients the following:

• Importance of adequate hydration

• Adherence to scheduled antiemetic regimen

• Maintaining chemotherapy treatments as scheduled

• Dietary modifications to decrease emesis risk

History

The history is useful in eliciting information to help establish an effective antiemetic regimen and in ruling out other potential causes beyond chemotherapy-induced nausea and vomiting. The timing of symptoms in relation to chemotherapy administration may suggest adjustments to the antiemetics or adjuvant that are used for a particular patient.

Physical examination

The physical examination should assess for other potential causes of nausea and vomiting, including a funduscopic examination to look for signs of increased intracranial pressure, any signs of GI system obstruction or ileus, and signs of dehydration.

Laboratory studies

In cases of severe or persistent emesis, monitoring serum electrolyte levels may be warranted.

Imaging studies

Imaging studies are useful if chemotherapy is not thought to be solely responsible for the nausea and vomiting. Abdominal imaging (radiography or CT scanning) or CNS imaging (head CT scanning) may be indicated depending on the potential cause under investigation.

The goal of antiemetic therapy is to prevent nausea and vomiting associated with chemotherapy administration. The appropriate pharmacologic treatment should be chosen by evaluating the emetogenic risk of chemotherapy as a single agent or as combination therapy (see the Table and specific recommendations below). In the event of uncontrolled nausea or vomiting, several medical complications may arise, including fluid and electrolyte imbalances, poor nutrition status, prolonged hospitalization, and delay in subsequent chemotherapy administration cycles

For most children, receiving any chemotherapy that has emetogenic potential (ie, any agents except those in level 1), a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist should form the backbone of antiemetic therapy.[1, 7] No studies have demonstrated superiority of any 5-HT3 antagonist over another when used optimally (see Medication for dosing guidelines). For maximum efficacy, these agents should be started 30 minutes prior to chemotherapy, continued throughout chemotherapy, and continued for several days after completion.

Children who are receiving highly emetogenic chemotherapy may benefit from additional antiemetics. If no contraindications to dexamethasone are noted, adding this agent to a 5-HT3 agonist may be beneficial, particularly in those patients receiving cisplatin-containing chemotherapy regimens. This can help with both acute and delayed nausea. Relative contraindications to dexamethasone include hyperglycemia, systemic infection, and hypertension. Dexamethasone should generally be avoided in patients receiving chemotherapy regimens that include corticosteroids and was found to increase the risk of postoperative bleeding in patients after tonsillectomy.[8]

Aprepitant is a neurokinin receptor (NK)-1 antagonist that is indicated in combination with other antiemetic agents for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic and highly emetogenic cancer chemotherapy (including high-dose cisplatin).[9]  In September 2015, its indication for CINV was expanded to include children aged ≥12 years or children < 12 years who weigh at least 30 kg. In December 2015, the indication was expanded to include children aged 6 months or older.

Approval of aprepitant in children was based on findings from a randomized, double-blind, active-comparator-controlled trial in children aged 6 months to 17 years that compared aprepitant plus ondansetron with ondansetron alone (control group). Each group was allowed to receive IV dexamethasone at the discretion of the physician. The primary endpoint was complete response (no vomiting, retching and no use of rescue medication) in the acute phase (0 to 24 hours) and in the delayed phase (25 to 120 hours following initiation of chemotherapy). Seventy-seven (51%) of 152 patients in the aprepitant group and 39 (26%) of 150 in the control group achieved a complete response in the delayed phase (p< 0.0001). For patients aged 12-17 years and patients < 12 years who weighed at least 30 kg (n=132), a higher complete response was observed in the acute and delayed phases with the aprepitant regimen (55.6% and 49.2%) compared with the control regimen (37.7% and 18.8%).[10]

Table. Emetogenic Risk of Intravenously Administered Antineoplastic Agents ^{[4, 5, 11]} (Open Table in a new window)

In addition to the scheduled antiemetics determined by the emetogenic potential of the planned regimens, medications must also be available as needed for breakthrough nausea, vomiting, or both. Commonly used antiemetics or adjuncts include the combination of diphenhydramine and promethazine (not recommended in children < 2 y), lorazepam, metoclopramide, and dronabinol. See below and Medication for dosing guidelines.

Lorazepam is particularly useful when anticipatory nausea is a contributing factor. Dronabinol is most useful when started prior to chemotherapy (ie, started in anticipation of a second cycle of chemotherapy in a patient who experienced significant nausea or emesis during the first cycle). Diphenhydramine, promethazine, and lorazepam may cause drowsiness, and, in some cases, a balance must be reached by the patient in terms of emesis relief and sleepiness.

• Acute and delayed nausea and vomiting

  • Monitor serum electrolytes, with special attention to sodium, potassium and bicarbonate status. In patients with uncontrolled vomiting and poor oral intake, replacement with intravenous fluids that contain sodium chloride and potassium chloride may be necessary.

  • Monitor the number of vomiting episodes and quantify fluid loss. Encourage oral intake of liquids. If unable to tolerate oral intake, replace losses with intravenous fluids to prevent dehydration.

  • If unable to maintain appropriate caloric intake enterally, consider initiation of parenteral nutrition.

  • Acupuncture, as an addition to standard antiemetic medication, is associated with a reduction in the need for subsequent rescue antiemetic medications.[12, 13]

• Anticipatory nausea and vomiting: Hypnosis is a behavioral intervention technique that reduces anticipatory and post chemotherapy nausea and vomiting.[14, 15]

Specific recommendations are as follows:

• Anticipatory nausea, emesis, or both: Add lorazepam (0.02-0.05 mg/kg/dose intravenously every 6 h as needed) to the regimen.

• Breakthrough and refractory emesis: If nausea and vomiting is controlled, continue breakthrough medication on a scheduled regimen (ie, not "as needed").

  • 5-HT3 serotonin-receptor antagonist (eg, ondansetron [0.15 mg/kg/dose IV for 3 doses; not to exceed 16 mg/dose]) with or without promethazine (0.25-1 mg/kg/dose IV q4-6h prn [with or without diphenhydramine])

  • Prochlorperazine: 0.1 mg/kg/dose intravenously every 8-12 h as needed (with or without diphenhydramine to decrease risk of extrapyramidal adverse effects), and with or without the following:

    • Metoclopramide (plus diphenhydramine to decrease risk of extrapyramidal adverse effects): 1 mg/kg/dose intravenously or orally every 6 h as needed

    • Lorazepam: 0.02-0.05 mg/kg/dose intravenously or orally every 6 h as needed

    • Diphenhydramine: 1 mg/kg/dose intravenously or orally every 6 h as needed

    • Dronabinol: 5 mg/m2/dose orally every 4-6 h as needed

Consult a clinical dietician for recommendations of intravenous fluid replacement or parenteral nutrition formulas to meet age-appropriate caloric and fluid intake goals in patients with fluid and electrolyte problems due to uncontrolled vomiting.

Consult a psychologist or other mental health professional experienced in working with patients with cancer if evidence of anticipatory nausea or vomiting are observed.

Instruct patients as follows:

• Eat small, frequent meals or snacks.

• Drink plenty of water and noncaffeinated liquids to avoid dehydration.

• Avoid greasy or spicy foods.

• Eat dry foods such as crackers, toast, or dry cereals.

• Eat soft, bland foods that are easy to digest

Further inpatient care

Monitor serum laboratory values and correct for abnormalities of fluid and electrolyte status due to episodes of chemotherapy-induced vomiting.

Monitor and supplement nutritional needs as appropriate for the child’s age.

Monitor the patient’s weight loss, if the patient is not able to maintain oral intake.

Further outpatient care

Ensure episodes of emesis are well controlled prior to discharge.

Monitor serum laboratory levels in the ambulatory setting and correct for abnormalities of fluid and electrolyte status due to vomiting.

Educate patients and caregivers on mechanisms of rehydration and the importance of oral hydration during chemotherapy and following periods of vomiting.

Verify patients and caregivers are able to maintain proper nutritional status for patients at home. Provide nutrition supplements as needed.

Inpatient and outpatient medications

Antiemetic prophylaxis should always be initiated prior to administration of emetogenic chemotherapy.

If infusions are administered in an ambulatory setting, provide patients and caregivers with appropriate prescriptions and instructions prior to initiation of emetogenic chemotherapy.

American Society of Clinical Oncology (ASCO)

ASCO recommendations for antiemetic therapy in pediatric cancer patients are as follows[4, 5] :

• High emetic risk antineoplastic agents - A 5-HT ₃ receptor antagonist, dexamethasone, and aprepitant or fosaprepitant. Patients unable to take aprepitant or fosaprepitant should be offered a 5-HT ₃ receptor antagonist and dexamethasone; those unable to take dexamethasone should be offered palonosetron and aprepitant or fosaprepitant.
• Moderate emetic risk antineoplastic agents - A 5-HT ₃ receptor antagonist and dexamethasone. Patients unable to take dexamethasone should be offered a 5-HT ₃ receptor antagonist and aprepitant or fosaprepitant.
• Low emetic risk antineoplastic agents - Ondansetron or granisetron.
• Minimal emetic risk antineoplastic agents - Do not offer routine antiemetic prophylaxis.

Various prevention and treatment options are available and contribute to the overall successful treatment of cancer.[1, 5, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]  For guidance regarding selection of antiemetic regimen, see the table above. For treatment of anticipatory, breakthrough, or refractory emesis, see the recommendations above.

Class Summary

These agents bind serotonin receptors to prevent chemotherapy-induced nausea and vomiting.

QT prolongation may occur with use of 5-HT3 antagonists (eg, ondansetron, dolasetron, granisetron). Avoid use in patients with long QT syndrome. Correct hypokalemia and hypomagnesemia before initiating. EKG monitoring may be warranted when coadministered with other drugs that may prolong QT interval, bradyarrhythmias, or congestive heart failure.

IV dolasetron is no longer indicated for CINV because of risk for QT prolongation. Palonosetron has been studied for its effect on QT interval, and results showed no significant effect at doses of as much as 2.25 mg. Although the increased QT interval warning with palonosetron use has been removed by the manufacturer, monitoring patients receiving other drugs known to cause QT interval prolongation may still be wise.

In June 2012, the 32 mg IV dose of ondansetron was removed from the prescribing information because of dose-related QT prolongation. The recommended dose for ondansetron IV for chemotherapy-induced nausea and vomiting is 3 doses of 0.15 mg/kg (not to exceed 16 mg/dose) IV 30 minutes before chemotherapy and repeated 4 and 8 hr after the first dose.[30]

In May 2014, palonosetron was approved by the US Food and Drug Administration (FDA) for prevention of CINV in children as young as 1 month. Approval was based on a randomized, double-blind, noninferiority, pivotal trial that compared single-dose IV palonosetron (20 mcg/kg given 30 min prior to chemotherapy) with the current standard of care, IV ondansetron regimen (0.15 mg/kg given 30 min prior to chemotherapy), followed by infusions 4 hours and 8 hours after the first dose of ondansetron. Within the first 24 hours after chemotherapy, complete response, defined as no vomiting, no retching, and no antiemesis rescue medication, was achieved in 59.4% of patients who received palonosetron compared with 58.6% of those who received the ondansetron regimen.[31, 32]

Dolasetron (Anzemet)

Prevents nausea and vomiting by binding to 5-HT3 receptors located on chemotherapy trigger zone (CTZ) and vagal neurons in GI tract. Prophylaxis with antiemetic agents prior to and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Granisetron (Sancuso)

Used for prevention of chemotherapy-induced nausea and vomiting. At CTZ, peripherally and centrally blocks serotonin on vagal nerve terminals.

Ondansetron (Zofran, Zuplenz)

Selective 5-HT3 -receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy.

Palonosetron (Aloxi)

Selective 5-HT3 -receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Peripherally and centrally blocks 5-HT3 receptors in CTZ.

Class Summary

These agents are used to prevent nausea and vomiting caused by chemotherapy regimens with level 3 and level 4 agents. The antiemetic mechanism for corticosteroids is unknown, but inhibition of prostaglandin synthesis and cell membrane permeability are thought to be involved.

Dexamethasone

Antiemetic mechanism for corticosteroids is unknown. Used in combination with other agents as part of an antiemetic regimen.

Methylprednisolone (Depo-Medrol)

Antiemetic mechanism for corticosteroids is unknown. Used in combination with other agents as part of an antiemetic regimen.

Class Summary

NK-1 receptors are highly concentrated in the vomiting center of the brain and bind a neurokinin termed substance P; Activation of NK-1 receptors by substance P plays a central role in eliciting chemotherapy-induced nausea and vomiting.

Aprepitant (Emend)

Neurokinin receptor (NK)-1 antagonist. NK-1 receptors are highly concentrated in the vomiting center of the brain and bind a neurokinin termed substance P. Blocking the interaction of substance P at the NK-1 receptor improve the management of nausea and vomiting.

It is approved in the United States for adults and children aged ≥6 months. It is indicated in combination with other antiemetic agents for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (including high-dose cisplatin). It is also indicated for nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Fosaprepitant (Emend IV)

Class Summary

These agents decrease anxiety associated with chemotherapy-induced nausea and vomiting.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Class Summary

Consider adding these agents in patients with breakthrough or resistant nausea and vomiting.

Metoclopramide (Reglan, Metozolv ODT)

Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, which provides important antiemetic activity.

Class Summary

Consider adding these agents in patients with breakthrough or resistant nausea and vomiting.

Promethazine (Phenergan, Phenadoz, Promethegan)

For symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in treating emesis. Blocks postsynaptic mesolimbic dopaminergic receptors in brain and reduces stimuli to brainstem reticular system.

Prochlorperazine (Compazine, Compro)

May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system. In addition to antiemetic effects, has the advantage of augmenting hypoxic ventilatory response, acting as a respiratory stimulant at high altitude.

Class Summary

Consider adding these agents in patients with breakthrough or resistant nausea and vomiting.

Dronabinol (Marinol)

Synthetic cannabinoid for PO administration. Antiemetic effect attributed to action within cannabinoid receptor system (ie, CB1 receptor) located in neural tissues.

Indicated for nausea and vomiting associated with cancer chemotherapy in patients who have inadequate response to conventional antiemetic treatments. This restriction is required because a substantial proportion of patients treated with dronabinol experience disturbing psychotomimetic reactions not observed with other antiemetic agents.

Nabilone (Cesamet)

Synthetic cannabinoid for PO administration. Antiemetic effect thought to be due to action within cannabinoid receptor system (ie, CB1 receptor) located in neural tissues. Indicated for nausea and vomiting associated with cancer chemotherapy in patients who have inadequate response to conventional antiemetic treatments. This restriction is required because a substantial proportion of patients treated with nabilone will experience disturbing psychotomimetic reactions not observed with other antiemetic agents.