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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Prevention and control of nausea and vomiting (emesis) (N&V) are paramount in the treatment of cancer patients. Chemotherapy-induced N&V is one of the most distressing acute side effects of cancer treatment; it occurs in up to 80% of patients and can have a significant impact on a patient's quality of life. N&V can also result in the following:
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
Nausea is the subjective phenomenon of an unpleasant, wavelike sensation experienced in the back of the throat and/or the epigastrium that may culminate in vomiting (emesis). Vomiting is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching involves the gastric and esophageal movements of vomiting without expulsion of vomitus; it is also referred to as dry heaves.
Progress has been made in understanding the neurophysiologic mechanisms that control nausea and vomiting (N&V). Both are controlled or mediated by the central nervous system but by different mechanisms. Nausea is mediated through the autonomic nervous system. Vomiting results from the stimulation of a complex reflex that includes a convergence of afferent stimulation from the following:[1,2]
Neurotransmitters (including serotonin, substance P, and dopamine) found in the CTZ, the vomiting center (thought to be located in the nucleus tractus solitarius), and enterochromaffin cells in the gastrointestinal tract then release efferent impulses that are transmitted to the abdominal musculature, salivation center, and respiratory center. The relative contribution from these multiple pathways culminating in N&V symptoms is complex and is postulated to account for the variable emetogenicity (intrinsic emetogenicity and mitigating factors [i.e., dosage, administration route, and exposure duration]) and emetogenic profile (i.e., time to onset, symptom severity, and duration) of agents.[3,4]
Although most patients receiving chemotherapy are at risk of nausea and vomiting (emesis) (N&V), the onset, severity, triggers, and duration vary. Factors related to the tumor, treatment, and patient all contribute to N&V, including tumor location, chemotherapy agents used, and radiation exposure.[1,2,3]
Patient-related factors may include the following:
Additional causal factors may include the following:
Clinicians treating N&V must be alert to all potential causes and factors, especially in cancer patients who may be receiving combinations of several treatments and medications. (Refer to the Adverse effects section in the Opioids section of the PDQ summary on Cancer Pain for more information about opioid-induced N&V.)
N&V has been classified as acute, delayed, anticipatory, breakthrough, refractory, and chronic, as outlined below:[7,8,9]
The National Cancer Institute has published a descriptive terminology that can be used for adverse event reporting (refer to Table 1). A grading (severity) scale is provided for each term.
The prevalence of anticipatory nausea and vomiting (ANV) has varied, owing to changing definitions and assessment methods. However, anticipatory nausea appears to occur in approximately 29% of patients receiving chemotherapy (about one of three patients), while anticipatory vomiting appears to occur in 11% of patients (about one of ten patients). With the introduction of new pharmacologic agents such as 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, it was anticipated that the prevalence of ANV might decline; however, studies have shown mixed results. One study found a lower incidence of ANV, and three studies found comparable incidence rates.[2,4,5] It appears that the 5-HT3 agents reduce postchemotherapy vomiting but not postchemotherapy nausea,[2,5] and the resulting impact on ANV is unclear.
Although other theoretical mechanisms have been proposed, ANV appears to be best explained by classical conditioning (also known as Pavlovian or respondent conditioning). In classical conditioning, a previously neutral stimulus (e.g., smells of the chemotherapy environment) elicits a conditioned response (e.g., ANV) after a number of pairings or learning trials. In cancer chemotherapy, the first few chemotherapy infusions are the learning trials. The chemotherapy drugs are the unconditioned stimuli that elicit postchemotherapy nausea and vomiting (N&V) (in some patients). The drugs are paired with a variety of other neutral, environmental stimuli (e.g., smells of the setting, presence of the oncology nurse, chemotherapy room). These previously neutral stimuli then become conditioned stimuli and elicit ANV in future chemotherapy cycles. ANV is not an indication of psychopathology but is rather a learned response that, in other life situations (e.g., food poisoning), results in adaptive avoidance.
A variety of correlational studies provide empirical support for classical conditioning. For example, the prevalence of ANV before treatment with any chemotherapy is very rare, and few patients ever experience ANV without previous postchemotherapy nausea. Also, most studies have found (1) a higher probability of ANV with increasing numbers of chemotherapy infusions, and (2) the intensity of ANV increasing as patients get closer to the actual time of their infusion. In one experimental study, it was shown that a novel beverage could become a conditioned stimulus to nausea when paired with several chemotherapy treatments.
Variables Correlated with ANV
Many variables have been investigated as potential risk factors that correlate with the incidence of ANV. There is no agreement on which factors predict ANV. A patient with fewer than three of the first eight characteristics listed below, however, is unlikely to develop ANV, and screening after the first chemotherapy infusion could identify patients at increased risk.
Variables Found to Correlate With ANV
Treatment of ANV
Antiemetic drugs do not seem to control ANV once it has developed; however, a variety of behavioral interventions have been investigated. These include the following:
Progressive muscle relaxation with guided imagery, hypnosis, and systematic desensitization has been studied the most and should be considered as treatment. Referral to a psychologist or other mental health professional with specific training and experience in working with cancer patients should be considered when ANV is identified. The earlier ANV is identified, the more likely treatment will be effective; thus, early screening and referral are essential. However, physicians and nurses underestimate the incidence of chemotherapy-induced N&V.[Level of evidence: II]
Clearly, the most important aspect of ANV is prevention of acute and delayed N&V associated with chemotherapy. Most antiemetics have not shown benefit for the treatment of ANV, but the use of antiemetics during chemotherapy may have a dramatic effect in decreasing the incidence of ANV. The only class of medication that has shown benefit in some studies is benzodiazepines, most commonly lorazepam.[Level of evidence: IV]
Acute Nausea and Vomiting (N&V)
The incidence of acute N&V with moderate- or high-risk chemotherapy ranges from 30% to 90%.[1,2,3] It can result in significant morbidity and can negatively affect quality of life. However, in recent years many new antiemetic medications and combinations have become available, dramatically decreasing the incidence and severity of this dreaded complication. Risk factors include the emetogenic potential of the specific drug, the dose used, the treatment schedule, and how chemotherapy agents are combined. For example, a drug with a low emetogenic potential given in high doses may cause a dramatic increase in the potential to induce N&V. Standard doses of cytarabine rarely produce N&V, but N&V is often seen with high doses of this drug. Another influencing factor is the use of drug combinations. Because most patients receive combination chemotherapy, the emetogenic potential of all of the drugs combined and individual drug doses need to be considered.[5,6,7,8,9]
Other risk factors include the following:
The American Society of Clinical Oncology (ASCO) provides a summary of intravenous chemotherapeutic agents and their respective risk of acute and delayed emesis.
ASCO provides a summary of oral chemotherapeutic agents and their respective risk of acute and delayed emesis.
Delayed (or late) N&V occurs more than 24 hours after chemotherapy administration. Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or given on 2 or more consecutive days.[1,11,12]
Several organizations—including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Pediatric Oncology Group of Ontario—have published antiemetic guidelines for their members. It is not the policy of PDQ to endorse specific guidelines, but examples can be found in the literature.[1,2,3,4]
Antiemetic agents are the most common intervention in the management of treatment-related nausea and vomiting (N&V). The basis for antiemetic therapy is the neurochemical control of vomiting. Although the exact mechanism is not well understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and numerous other endogenous neurotransmitters.[5,6] Many antiemetics act by competitively blocking receptors for these substances, thereby inhibiting stimulation of peripheral nerves at the CTZ and possibly at the vomiting center.
Current guidelines [2,7] recommend that prechemotherapy management of chemotherapy-induced N&V (CINV) be based on the emetogenic potential of the chemotherapy agent(s) selected. For patients receiving regimens with high emetogenic potential, the combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, neurokinin-1 (NK-1) receptor antagonist, and dexamethasone with or without olanzapine is recommended prechemotherapy. Aprepitant (if chosen as the NK-1 receptor antagonist prechemotherapy), olanzapine, and dexamethasone are recommended for the prevention of delayed emesis.
For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT3 receptor antagonist and dexamethasone is used prechemotherapy. Patients receiving carboplatin (area under the curve [AUC] ≥4 mg/mL) may also receive an NK-1 receptor antagonist. Postchemotherapy, a 5-HT3 receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.
For regimens with low emetogenic potential, dexamethasone or a 5-HT3 receptor antagonist is recommended. For regimens with minimal emetogenic risk, no prophylaxis is recommended.[2,7]
Antiemetic guidelines [2,7] have included the available oral 5-HT3 receptor antagonists as optional therapy for the prevention of delayed emesis, but the level of evidence supporting this practice is low.
Studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners.[8,9,10] One study suggested that patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea. In addition, the current and new agents have been used as prophylaxis for acute and delayed CINV and have not been studied for use in established CINV. One study reported the effective use of intravenous (IV) palonosetron and dexamethasone for the prevention of CINV in patients receiving multiple-day chemotherapy.
Pre- and postchemotherapy recommendations by emetogenic potential are summarized in Table 2.
Most drugs with proven antiemetic activity can be categorized into one of the following groups:
Although all routes of administration are listed for each drug in Table 3, the intramuscular (IM) route is used only when no other access is available. IM delivery is painful, is associated with erratic absorption of drug, and may lead to sterile abscess formation or fibrosis of the tissues. This is particularly important when more than one or two doses of a drug are to be given.
Competitive Dopamine (D2) Antagonists
Phenothiazines act on dopaminergic receptors at the CTZ, possibly at other central nervous system (CNS) centers, and peripherally.
In selecting phenothiazines, the primary consideration is assessing differences in adverse effect profiles, which correlate with the structural classes of the drugs. Generally, aliphatic phenothiazines (e.g., chlorpromazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine) are associated with less sedation but higher incidence of extrapyramidal symptoms (EPS) (acute dystonias, akathisia, neuroleptic malignant syndrome [uncommon], and, rarely, akinesias and dyskinesias). Marked hypotension may also result if IV doses are administered rapidly at high doses. The concomitant use of H1 blockers, such as diphenhydramine, can often decrease the risk and severity of EPS. Phenothiazines may be of particular value in treating patients who experience delayed N&V with cisplatin regimens.[24,25,26,27,28][Level of evidence: I] Given their anticholinergic properties, phenothiazines are listed among the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.
Droperidol and haloperidol represent butyrophenones, another class of dopaminergic (D2 subtype) receptor antagonists that are structurally and pharmacologically similar to the phenothiazines. While droperidol is used primarily as an adjunct to anesthesia induction, haloperidol is indicated as a neuroleptic antipsychotic drug; however, both agents have some antiemetic activity. Droperidol is typically administered from 1 mg to 2.5 mg IM or IV every 2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[30,31] Haloperidol is typically administered from 1 mg to 4 mg IM, IV, or orally, every 2 to 6 hours. Results of a small, uncontrolled, open-label study showed some efficacy for haloperidol in palliative care patients. Both agents may produce EPS, akathisia, hypotension, and sedation.
Metoclopramide is a substituted benzamide, which, before serotonin (5-HT3) receptor antagonists were introduced, was considered the most effective antiemetic agent against highly emetogenic chemotherapy. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given IV at high doses, probably because it is a weak competitive antagonist (relative to other serotonin antagonists) at 5-HT3 receptors. It may act on the CTZ and the periphery. Metoclopramide also increases lower esophageal sphincter pressure and enhances the rate of gastric emptying, which may factor into its overall antiemetic effect. Metoclopramide has also been safely given by IV bolus injection at higher single doses (up to 6 mg/kg) and by continuous IV infusion, with or without a loading bolus dose, with efficacy comparable to that of multiple intermittent dosing schedules.[34,35,36]
Metoclopramide is associated with akathisia and dystonic EPS; akathisia is seen more frequently in patients older than 30 years, and dystonic EPS are seen more commonly in patients younger than 30 years. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize EPS. While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia is best treated by lowering the metoclopramide dose, changing to a different agent, or adding a benzodiazepine.
Trimethobenzamide is believed to act centrally on the CTZ by blocking emetic impulses. It has been studied in a limited number of oncology patients experiencing nausea from various chemotherapy regimens. Compared with placebo, trimethobenzamide 200 mg IM every 6 hours for 2 days significantly reduced episodes of N&V.
5-HT3 Receptor Antagonists
Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron, and palonosetron—are available in the United States. Agents in this class are thought to prevent N&V by preventing serotonin, which is released from enterochromaffin cells in the gastrointestinal (GI) mucosa, from initiating afferent transmission to the CNS via vagal and spinal sympathetic nerves.[38,39,40] The 5-HT3 receptor antagonists may also block serotonin stimulation at the CTZ and other CNS structures. Major side effects of this class of medications include mild headache and constipation. Multiple studies have shown that the 5-HT3 receptor antagonists are most effective when given in conjunction with steroids.
Comparison of agents
Studies suggest that there are no major differences in efficacy or toxicity of the three first-generation 5-HT3 receptor antagonists (dolasetron, granisetron, and ondansetron) in the treatment of acute CINV. These three agents are equivalent in efficacy and toxicity when used in appropriate doses.[41,42]; [Level of evidence: I] Although these agents have been shown to be effective in the first 24 hours postchemotherapy (acute phase), they have not been demonstrated to be effective on days 2 to 5 postchemotherapy (delayed phase).
Palonosetron, the second-generation 5-HT3 receptor antagonist, has been approved for the control of acute emesis with highly and moderately emetogenic chemotherapy and approved for delayed emesis in patients receiving moderately emetogenic chemotherapy.; [Level of evidence: I]
Despite the use of both first-generation and second-generation 5-HT3 receptor antagonists, the control of acute CINV, and especially delayed N&V, is suboptimal, and there is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.[8,46,47,48]
Several studies have demonstrated that ondansetron produces an antiemetic response that is equal or superior to that of high doses of metoclopramide, but ondansetron has an improved toxicity profile, compared with that of dopaminergic antagonist agents.[49,50,51,52][Level of evidence: I][53,54] A randomized trial of ondansetron, 8 mg and 32 mg, given prophylactically to patients receiving cisplatin found no difference between the doses. A single-center retrospective chart review has reported ondansetron-loading doses of 16 mg/m2 IV (maximum, 24 mg) to be safe in infants, children, and adolescents. However, data reported to the U.S. Food and Drug Administration (FDA) raise concerns about QT prolongation and potentially fatal arrhythmias with a single 32-mg IV dose. Current drug labeling calls for a maximum single 16-mg IV dose.
Currently, the oral and injectable ondansetron formulations are approved for use without dosage modification in patients older than 4 years, including elderly patients and patients with renal insufficiency. Oral ondansetron is given 3 times daily starting 30 minutes before chemotherapy and continuing for up to 2 days after chemotherapy is completed. Ondansetron clearance is diminished in patients with severe hepatic insufficiency; therefore, such patients receive a single injectable or oral dose no higher than 8 mg. There is currently no information evaluating the safety of repeated daily ondansetron doses in patients with hepatic insufficiency. Other effective dosing schedules such as a continuous IV infusion (e.g., 1 mg/h for 24 h) or oral administration have also been evaluated.
The major adverse effects of ondansetron include the following:
Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events. Rare electrocardiogram changes in the form of QTc prolongation may occur. In addition, a few case reports have implicated ondansetron in causing EPS. However, it is not clear in some cases whether the events described were in fact EPS; in other reports, the evidence is confounded by concurrent use of other agents that are known to produce EPS. Nevertheless, the greatest advantage of serotonin receptor antagonists over dopaminergic receptor antagonists is that they have fewer adverse effects. Despite prophylaxis with ondansetron, many patients receiving doxorubicin, cisplatin, or carboplatin will experience acute and delayed-phase N&V. Randomized, double-blind, placebo-controlled trials support the addition of aprepitant, an NK-1 receptor antagonist, for additional mitigation of N&V.[62,63][Level of evidence: I]
Granisetron has demonstrated efficacy in preventing and controlling N&V at a broad range of doses. In the United States, granisetron injection, extended-release injection, transdermal patch, and oral tablets are approved for initial and repeat prophylaxis for patients receiving emetogenic chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically and pharmacokinetically distinct from ondansetron; however, clinically it is equally efficacious and equally safe.[61,62,63,64][Level of evidence: I]
The subcutaneous extended-release formulation of granisetron was compared with palonosetron in the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy in a randomized, double-blind noninferiority phase III trial. Patients were randomly assigned to receive IV palonosetron, 0.25 mg; or subcutaneous granisetron, 5 mg or 10 mg. Patients who received palonosetron in cycle 1 were then randomly assigned to receive granisetron in cycles 2 through 4. Both subcutaneous doses of granisetron were noninferior to palonosetron in cycle 1 of moderately emetogenic chemotherapy (74.8% and 76.9% for granisetron 5 mg and 10 mg, respectively, vs. 75.0% for palonosetron) and highly emetogenic chemotherapy (77.7% and 81.3% for granisetron 5 mg and 10 mg, respectively, vs. 80.7% for palonosetron). Superiority of subcutaneous granisetron versus palonosetron in the prevention of delayed CINV after highly emetogenic chemotherapy was not established.
Currently, granisetron is approved for use without dosage modification in patients older than 2 years, including elderly patients and patients with hepatic and renal insufficiency.
Oral formulations of dolasetron are indicated for the prevention of N&V associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses; however, the drug may be difficult to obtain from the manufacturer. Oral dolasetron may be dosed as 100 mg within 1 hour before chemotherapy. Dolasetron was given IV or orally at 1.8 mg/kg as a single dose approximately 30 minutes before chemotherapy; however, injection formulations are no longer approved for CINV because of the risk of QTc interval prolongation.
The effectiveness of oral dolasetron in the prevention of CINV has been proven in a large randomized, double-blind, comparative trial of 399 patients.[Level of evidence: I] Oral dolasetron was administered in the range of 25 to 200 mg 1 hour before chemotherapy. The other study arm consisted of oral ondansetron (8 mg) administered 1.5 hours before chemotherapy and every 8 hours after chemotherapy for a total of three doses. Rates of complete response (CR), defined as no emetic episodes and no use of escape antiemetic medications, improved with increasing doses of dolasetron. Both dolasetron 200 mg and ondansetron had significantly higher CR rates than did dolasetron 25 or 50 mg.
Palonosetron is a 5-HT3 receptor antagonist (second generation) that has antiemetic activity at both central and GI sites. Palonosetron is FDA approved for the prevention of acute N&V associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy and for the prevention of delayed N&V associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Compared with the older 5-HT3 receptor antagonists, palonosetron has a higher binding affinity to the 5-HT3 receptors, a higher potency, a significantly longer half-life (approximately 40 hours, four to five times longer than that of dolasetron, granisetron, or ondansetron), and an excellent safety profile.[Level of evidence: I] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[69,70,71,72,73]
In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and delayed periods for patients who received 0.25 mg of palonosetron alone, compared with either ondansetron or dolasetron alone.; [Level of evidence: I] Dexamethasone was not given with the 5-HT3 receptor antagonists in these studies, and it is not yet known whether the differences in CR would persist if dexamethasone was used. In another study,[Level of evidence: I] 650 patients receiving highly emetogenic chemotherapy (cisplatin ≥60 mg/m2) also received either dexamethasone and one of two doses of palonosetron (0.25 mg or 0.75 mg) or dexamethasone and ondansetron (32 mg). Single-dose palonosetron was as effective as ondansetron in preventing acute CINV with dexamethasone pretreatment; it was significantly more effective than ondansetron throughout the 5-day postchemotherapy period. In an analysis of the patients in the above studies who received repeated cycles of chemotherapy, one author  reported that the CR rates for both acute and delayed CINV were maintained with single IV doses of palonosetron without concomitant corticosteroids.
NK-1 Receptor Antagonists (Substance P Antagonists)
Substance P, found in the vagal afferent neurons in the nucleus tractus solitarius, the abdominal vagus, and the area postrema, induces vomiting. NK-1 receptor antagonists, including aprepitant, fosaprepitant, netupitant, and rolapitant block substance P from binding the NK-1 receptor. In combination with a 5-HT3 receptor antagonist and a corticosteroid, NK-1 receptor antagonists are indicated for the prevention of acute and delayed N&V associated with initial and repeat courses of high and moderately emetogenic chemotherapy. There have been no randomized trials comparing the individual NK-1 receptor antagonists. All are considered effective at their FDA-approved doses.
Clinical trials [76,77,78,79] demonstrated that the addition of aprepitant to a 5-HT3 receptor antagonist plus dexamethasone before cisplatin chemotherapy improved the control of acute emesis, compared with a 5-HT3 receptor antagonist plus dexamethasone; this regimen also improved the control of delayed emesis, compared with placebo. In two randomized, double-blind, parallel, controlled studies, patients received cisplatin (≥70 mg/m2) and were randomly assigned to receive either standard therapy with ondansetron and dexamethasone prechemotherapy and dexamethasone on days 2 to 4 postchemotherapy; or standard therapy plus aprepitant prechemotherapy on days 2 and 3.[80,81][Level of evidence: I] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute and the delayed periods. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[Level of evidence: I]
The benefit of aprepitant has been demonstrated outside of highly emetogenic chemotherapy. The addition of aprepitant to ondansetron and dexamethasone before moderately emetogenic chemotherapy versus ondansetron and dexamethasone alone resulted in improved CINV outcomes.[83,84,85] An alternative dosing strategy was evaluated in a randomized, double-blind, placebo-controlled, phase III cross-over study in patients receiving 5-day cisplatin combination chemotherapy for germ cell tumors. In addition to standard antiemetic therapy, patients received aprepitant 125 mg on day 3 followed by aprepitant 80 mg on days 4 through 7. There was a significant improvement in CINV CR with the three-drug regimen.
Fosaprepitant dimeglumine, a water-soluble, phosphorylated analog of aprepitant, is rapidly converted to aprepitant after IV administration. Fosaprepitant is approved as a single dose of 150 mg before chemotherapy on day 1, as an alternative to the 3-day oral aprepitant regimen. As demonstrated in a randomized, double-blind study of patients receiving cisplatin chemotherapy, single-dose IV fosaprepitant (150 mg) given with ondansetron and dexamethasone was noninferior to the standard 3-day dosing of oral aprepitant in preventing CINV. Fosaprepitant is formulated with polysorbate 80, a solubilizing agent, which can cause rare but serious hypersensitivity reactions.[88,89] Aprepitant is also available as a parenteral emulsion form, which has a reduced risk of thrombophlebitis and hypersensitivity reactions.
Netupitant is a competitive antagonist to the NK-1 receptor that is marketed as an oral or IV fixed-combination product containing 300 mg of netupitant and 0.5 mg of palonosetron (NEPA). It is given with dexamethasone before chemotherapy for the prevention of both acute and delayed CINV. This drug combination has been used successfully for prevention of CINV in a single cycle of both highly and moderately emetogenic chemotherapy regimens.[91,92] The antiemetic benefit of NEPA was demonstrated throughout multiple cycles of chemotherapy in a randomized, double-blind, controlled trial.[Level of evidence: I] Patients starting combination anthracycline/cyclophosphamide regimens were randomly assigned to receive oral fixed-dose NEPA with 12 mg of dexamethasone or 0.5 mg of oral palonosetron with 20 mg of dexamethasone. The percentage of patients with a CR (defined as no emesis, no rescue medication) was significantly greater for NEPA than for oral palonosetron for cycles 1 to 4. The most common treatment-related side effects were headache and constipation, which were similar between the two arms.
Rolapitant is an oral competitive NK-1 receptor inhibitor. It is approved for the prevention of delayed N&V associated with highly and moderately emetogenic chemotherapy. In addition to granisetron and dexamethasone, rolapitant significantly increases CINV CR (no emesis, no rescue) versus standard therapy plus placebo for patients receiving both highly and moderately emetogenic chemotherapy. Unlike other drugs in its class, rolapitant has no effect on cytochrome P450 3A4 enzymes; therefore, no dose adjustment for dexamethasone is required.[94,95,96] The IV formulation has been associated with hypersensitivity reactions, including anaphylaxis, which have limited its use.
Steroids are commonly used in combination with other antiemetics. Their antiemetic mechanism of action is not fully understood, but they may affect prostaglandin activity in the brain. Clinically, steroids quantitatively decrease or eliminate episodes of N&V and may improve patients' mood, thus producing a subjective sense of well-being or euphoria (although they also can cause depression and anxiety). Steroids are sometimes used as single agents against mildly emetogenic chemotherapy but are more often used in antiemetic drug combinations.[98,99][Level of evidence: I]
Steroids are given orally or intravenously before chemotherapy and may be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice for N&V in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally or intravenously in the dose range of 8 mg to 40 mg (pediatric dose, 0.25–0.5 mg/kg).[101,102] Methylprednisolone is also administered orally or IV at doses and schedules that vary from 40 mg to 500 mg every 6 to 12 hours for up to 20 doses.[99,103]
Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:[104,105,106]
A study that examined chemotherapy in a group of patients with ovarian cancer found that short-term use of glucocorticoids as antiemetics had no negative effects on outcomes (e.g., overall survival or efficacy of chemotherapy). As previously shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT3 –blocking agents.[104,108] If administered intravenously, dexamethasone may be given over 10 to 15 minutes because rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[109,110,111,112]
Benzodiazepines such as lorazepam and alprazolam have become recognized as valuable adjuncts in the prevention and treatment of anxiety and the symptoms of anticipatory N&V associated with chemotherapy, especially with the highly emetogenic regimens given to children.[104,105,106] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents; therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents. Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, benzodiazepines markedly decrease the severity of EPS, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.
The adverse effects of lorazepam include sedation, perceptual and vision disturbances, anterograde amnesia, confusion, ataxia, and depressed mental acuity.;[Level of evidence: I][116,117] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.
Olanzapine is an antipsychotic in the thienobenzodiazepine drug class that blocks multiple neurotransmitters: dopamine at D1, D2, D3, and D4 brain receptors; serotonin at 5-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at alpha-1 adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H1 receptors. Common side effects include the following:[119,120]
Olanzapine's activity at multiple receptors, particularly at the D2 and 5-HT3 receptors that appear to be involved in N&V, suggests that it may have significant antiemetic properties.[Level of evidence: II] Subsequent studies have shown the effectiveness of olanzapine as a CINV antiemetic.[122,123][Level of evidence: II] A large study [Level of evidence: I] demonstrated that in patients receiving either highly emetogenic chemotherapy or moderately emetogenic chemotherapy, the addition of olanzapine to azasetron and dexamethasone improved the CR of delayed CINV.
A randomized, double-blind, phase III trial evaluated olanzapine versus placebo in addition to standard antiemetics for the prevention of CINV associated with highly emetogenic chemotherapy.[Level of evidence: I] Chemotherapy-naïve patients receiving either cisplatin at least 70 mg/m2 of body surface area (BSA) with or without additional agents, or doxorubicin 60 mg/m2 of BSA with cyclophosphamide 600 mg/m2 of BSA, were randomly assigned to receive olanzapine 10 mg orally on days 1 through 4 or matching placebo with guideline-directed antiemetics. The antiemetic regimen included an NK-1 antagonist (fosaprepitant or aprepitant), 5-HT3 antagonist (palonosetron, granisetron, or ondansetron), and dexamethasone 12 mg on day 1 followed by 8 mg orally daily on days 2 through 4. Patients were stratified by sex, chemotherapy regimen, and the specific 5-HT3 antagonist chosen. The primary endpoint, no nausea, was defined as a score of 0 on the visual analog scale of 0 to 10 and assessed at three time points postchemotherapy: early, 0 to 24 hours; later, 25 to 120 hours; and overall, 0 to 120 hours.
The percentage of patients experiencing no nausea was significantly higher in the olanzapine group than in the placebo group at the early (74% vs. 45%; P = .002), later (42% vs. 25%; P = .002), and overall time points (37% vs. 22%; P = .002). CR (no emesis, no rescue) rate and freedom from clinically significant nausea (a score lower than 3 on the visual analog scale of 0–10) were also significantly improved with the addition of olanzapine at all time points. Patients receiving olanzapine reported increased sedation from baseline on day 2, which resolved on days 3 through 5. On the basis of these data and additional clinical trials, olanzapine appears to be safe and effective in controlling acute and delayed CINV in patients receiving highly emetogenic and moderately emetogenic chemotherapy.[125,126]
Other Pharmacologic Agents
The plant Cannabis contains more than 60 different types of cannabinoids, or components that have physiologic activity. The most popular, and perhaps the most psychoactive, is delta-9-tetrahydrocannabinol (delta-9-THC). There are two FDA-approved Cannabis products for CINV:
With respect to CINV, Cannabis products probably target cannabinoid-1 (CB-1) and CB-2 receptors, which are in the CNS.
Much of the research on agents in this class was conducted in the late 1970s and 1980s and compared nabilone, dronabinol, or levonantradol to older antiemetic agents that targeted the dopamine receptor, such as prochlorperazine (Compazine) and metoclopramide (Reglan).[129,130,131,132,133] This group of studies demonstrated that cannabinoids were as effective for moderately emetogenic chemotherapy as dopaminergic antiemetics or were more effective than placebo. Side effects included euphoria, dizziness, dysphoria, hallucinations, and hypotension. Despite earlier reports of efficacy, in at least one study, patients did not significantly prefer nabilone because of the side effects.
Since the 1990s, research in N&V has elucidated newer and more physiologic targets, namely 5-HT3 and NK-1 receptors. Subsequently, 5-HT3 and NK-1 receptor antagonists have become standard prophylactic therapy for CINV. Studies investigating the role of Cannabis extract and cannabinoids with these newer agents are few; therefore, limited conclusions can be drawn. In published trials, however, Cannabis extract and cannabinoids have not demonstrated more efficacy than 5-HT3 receptor antagonists, and synergistic or additive effects have not been fully investigated.[134,135]
In summary, the place of Cannabis and cannabinoids in today's arsenal of antiemetics for the prevention and treatment of CINV is not known. Discussions with patients about its use may include responses to available agents, known side effects of Cannabis, and an assessment of the risks versus benefits of this therapy.
Refer to the PDQ summary on Cannabis and Cannabinoids for more information.
A phase III, randomized, dose-finding trial of 576 patients with cancer evaluated 0.5 g, 1 g, and 1.5 g of ginger versus placebo in twice-a-day dosing for the prevention of acute nausea (defined as day 1 postchemotherapy) in patients experiencing some level of nausea (as measured on an 11-point scale) caused by their current chemotherapy regimen, despite standard prophylaxis with a 5-HT3 receptor antagonist. Patients began taking ginger or placebo capsules 3 days before each chemotherapy treatment and continued them for 6 days. For average nausea, 0.5 g of ginger was significantly better than placebo; both 0.5 g and 1 g were significantly better than placebo for "worst nausea." Effects for delayed N&V were not significant. This trial did not control for emetogenicity of the chemotherapy regimens. Adverse events were infrequent and were not severe.
Regimens that include chemotherapy doses on multiple sequential days (multiday chemotherapy) present a unique challenge to preventing CINV because after the first dose of chemotherapy, nausea may be both acute and delayed. Although there is no standard antiemetic regimen for multiday chemotherapy, a corticosteroid and a 5-HT3 antagonist should be given with each day of highly and moderately emetogenic chemotherapy.[7,137] Evidence demonstrates benefit for the addition of an NK-1 antagonist to highly and moderately emetogenic multiday chemotherapy.[2,7,13,137] The choice of antiemetic drugs and their schedule should be matched to the emetogenicity of the individual chemotherapy agents and their sequence. In addition, the length of delayed nausea varies and will depend on the emetogenicity of the last day's chemotherapy.
Dexamethasone is scheduled on each day of a multiday chemotherapy regimen, and for 2 to 3 days after if there is risk of delayed nausea. Additional dexamethasone is not necessary if the chemotherapy regimen contains a corticosteroid. It is not known whether dexamethasone 20 mg given each day of a 5-day cisplatin regimen provides additional antiemetic benefit, and it may add toxicity.[13,138] Therefore, an alternative dexamethasone schedule (20 mg on days 1 and 2 followed by 8 mg twice daily on days 6 and 7, and 4 mg twice daily on day 8), based on the timing of CINV and to reduce the total steroid dose, has been studied in patients receiving 5-day cisplatin regimens.[12,13]
Standard antiemetic prophylaxis includes a 5-HT3 antagonist given before the first chemotherapy dose each day of a multiday chemotherapy regimen.[2,7,13,137] No 5-HT3 antagonist is favored over other agents in the class for multiday chemotherapy. Palonosetron is a 5-HT3 antagonist with a longer half-life and higher receptor-binding affinity than other members in its class, allowing it to be given less frequently. A prospective, uncontrolled trial demonstrated that palonosetron, as a single IV dose with dexamethasone 20 mg before two 3-day chemotherapy regimens, resulted in an 80% CR (no vomiting, no rescue). Palonosetron was also studied with dexamethasone as prophylaxis for a 5-day cisplatin-based regimen for germ cell tumors. When palonosetron plus dexamethasone was given on days 1, 3, and 5, 51% of patients experienced no emesis on days 1 to 5, and 83% experienced no emesis on days 6 to 9. Alternative methods of 5-HT3 antagonist delivery have been studied.
Granisetron as a 7-day continuous transdermal patch was compared to daily oral granisetron in patients receiving multiday chemotherapy in a double-blind, phase III, noninferiority study. The patch demonstrated complete control in 60% of patients, while the oral formulation did so in 65% of patients, achieving noninferiority.
The NK-1 antagonist aprepitant and its IV formulation, fosaprepitant, have been studied with multiday chemotherapy in dosing schedules that differ from their FDA-approved schedules. A nonrandomized trial evaluated the use of aprepitant, granisetron, and dexamethasone for CINV prophylaxis with 3- and 5-day highly and moderately emetogenic chemotherapy. Aprepitant was given at 125 mg orally before the first dose of chemotherapy, then 80 mg orally on each day of chemotherapy and for 2 following days (total, 5–7 days). CR was seen in 57.9% and 72.5% of patients receiving highly and moderately emetogenic chemotherapy, respectively. Similarly promising results were found in a subsequent single-arm trial looking at a 7-day oral aprepitant regimen with dexamethasone and a 5-HT3 antagonist for 5-day cisplatin-based chemotherapy.
A randomized, double-blind, placebo-controlled crossover trial of aprepitant, a 5-HT3 antagonist, and dexamethasone was conducted in patients receiving 5-day cisplatin-based chemotherapy for germ cell tumors. Oral aprepitant 125 mg was given on day 3, followed by oral aprepitant 80 mg daily on days 4 to 7. More patients achieved CR with aprepitant than with placebo, 42% versus 13% (P < .001). IV fosaprepitant 150 mg given on days 3 and 5 was studied in a small phase II trial evaluating its use with a 5-HT3 antagonist and dexamethasone in 5-day cisplatin-based chemotherapy. Preliminary results showed a CR rate of 28.1%, lower than results of the oral aprepitant trial conducted by the same institution.
High-Dose Chemotherapy with Stem Cell Transplantation
Prevention of emesis during high doses of chemotherapy with or without total-body irradiation continues to be a challenging area of patient care. Current guidelines address primarily single-day therapies; in addition, while emesis prevention for the multiple days of chemotherapy or radiation therapy used in this setting is based on single-day experiences, additional research is needed to improve symptom control for these patients. This has led to the addition of NK-1 antagonists to the daily dosing of a serotonin antagonist plus dexamethasone.[143,144,145] Additional evidence is needed to determine optimal combinations as CR rates range as low as 30%. Also, experience has primarily been with aprepitant; the newer NK-1 antagonists may offer additional benefit.
Overall, these antiemetic combinations are well tolerated, with most side effects involving the dexamethasone component; in addition, while drug interactions were originally a concern, they do not appear to be clinically significant. Also, emesis is controlled to a much greater extent than is nausea, which continues to be challenging for many patients.[143,147] Finally, a randomized phase III trial studied the use of aprepitant, granisetron, and dexamethasone for the prevention of CINV in multiple myeloma patients receiving high-dose melphalan with autologous stem cell transplantation. A statistically positive benefit, without an increase in side effects, was seen in patients who received the three-drug regimen.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Nonpharmacologic strategies are also used to manage nausea and vomiting (N&V). These include the following:
Guided imagery, hypnosis, and systematic desensitization as means to progressive muscle relaxation have been the most frequently studied treatments for anticipatory N&V (ANV) and are the recommended treatments for this classically conditioned response. (Refer to the Treatment of ANV section of this summary for more information.)
Radiation therapy (RT) is an important cause of nausea and vomiting (N&V) in the cancer patient. Observational studies suggest an 80% overall cumulative incidence rate of some degree of N&V among patients undergoing RT. Risk factors for developing N&V are known. Radiation-induced N&V (RINV) worsens quality of life, leading to treatment delays and cancelled appointments, compromising cancer control.[2,3]
Two large prospective observational studies provide information on the frequency of RINV and antiemetic measures. The Italian Group for Antiemetic Research in Radiotherapy analyzed the incidence of RINV in 1,020 patients receiving various kinds of radiation therapy. Overall, nausea, vomiting, or both were reported by 28% of patients. The median time to the first episode of vomiting was 3 days. Antiemetic drugs were administered to 17% of the patients, including 12% treated prophylactically and 5% given rescue therapy. In a second cohort of 368 patients receiving RT, the overall incidence rate for nausea was 39% and for vomiting, 7%. Nausea was more frequent in those receiving RT to the lower abdomen or pelvis (66%) compared with patients receiving RT to the head-and-neck area (48%). Antiemetics during RT are underprescribed.
The pathophysiology of RINV is incompletely understood. Serotonin, substance P, and dopamine are neurotransmitters involved in radiation-induced emesis. RINV bears a close similarity to chemotherapy-induced N&V (CINV). The effectiveness of serotonin antagonists in RINV supports a role for serotonin in radiation-induced emesis. Substance P antagonists have not been used in RINV as extensively as they are in CINV. Preclinical work suggests a role for substance P in RINV. Substance P antagonists are only beginning to be studied for RINV. Substance P may play a role in prolonged N&V after the administration of RT.
Radiation site, volume, fractionation schedule, and single and total dose determine the incidence and severity of RINV. The most important factor appears to be the radiation field. Table 4 shows risk categories suggested by the Multinational Association of Supportive Care in Cancer (MASCC), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO). Risk of nausea is not considered in the classification. The risk of N&V for a patient being treated with RT depends on multiple other factors in addition to the emetogenicity of the specific RT regimen. Patient-specific factors include the simultaneous administration of chemotherapy, age, gender, alcohol consumption, anxiety, and previous experience of RINV or CINV.
The body of literature describing treatments for RINV is much smaller than that for CINV. Most of the studies done were for patients with moderate- to high-risk features for RINV.
Antiemetic therapy: prevention and treatment of N&V
Several studies show the superiority of serotonin antagonists for the prophylaxis of RINV.[12,13,14,15,16,17] Ondansetron and dolasetron showed superiority over placebo or metoclopramide. Dosing of the serotonin antagonists have been single-dose pretreatment or for consecutive days (up to 5–7 days total). Most studies have been conducted in patients at moderate to high risk of RINV.
Recommended dosing is ondansetron 8 mg, regardless of schedule given. Granisetron dosing is 2 mg orally per day. A recent meta-analysis covering nine clinical trials showed differing rates of control when emesis versus nausea is considered. Compared with placebo, fewer patients had residual emesis (40% vs. 57%; relative risk [RR], 0.7), and fewer patients required rescue medication (6.5% vs. 36%; RR, 0.18). The control of nausea seems to be more difficult. Most patients developed RT-induced nausea despite treatment (70% vs. 83% with placebo; RR, 0.84). In summary, these trials show that patients receiving upper-abdomen irradiation have a greater benefit using 5-hydroxytryptamine-3 (5-HT3) receptor antagonists than metoclopramide, phenothiazines, or placebo to control RINV.[12,13,14,15,16,17]
The adverse effects of 5-HT3 receptor antagonists are generally mild, consisting mainly of headache, constipation, and asthenia. Randomized trials in RINV have examined the use of different 5-HT3 receptor antagonists. There are no data comparing those different 5-HT3 receptor antagonists, and there is no consensus on optimal dosing for RINV. A systematic review including 25 randomized and nonrandomized trials revealed that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT. Optimal duration and timing of 5-HT3 use before, during, and after the administration of RT needs to be determined. With regard to palonosetron, the appropriate dosing and frequency in the RINV setting are still unclear, with once-weekly dosing possible when the drug is combined with other agents.
Corticosteroids are an attractive therapeutic antiemetic option because of their widespread availability and low cost. For short-term use, the side effects are few and do not outweigh the benefit of these agents. One randomized trial showed that dexamethasone was significantly more effective than placebo in patients receiving RT to the upper abdomen. Combining corticosteroids with a 5-HT3 receptor antagonist was assessed in a well-designed randomized trial in which a 5-day course of dexamethasone plus ondansetron was compared with ondansetron plus placebo in 211 patients who received RT to the upper abdomen. During the first 5 days, there was a statistically nonsignificant trend toward complete control of nausea (50% vs. 38% with placebo) and vomiting (78% vs. 71%), which was the primary objective of the trial. The effects of dexamethasone extended beyond the initial 5-day period, and significantly more patients had complete control of emesis over the entire course of RT (23% vs. 12% with placebo), a secondary objective of the trial. The trial demonstrates that the addition of dexamethasone has a modest effect on RINV and is potentially a useful addition to a 5-HT3 receptor antagonist in this setting.
Neurokinin-1 (NK-1) receptor antagonists
NK-1 receptor antagonists have an established role in the management of CINV; however, no studies have evaluated the impact of this drug class solely on the risk of RINV. Although preclinical data indicate that RINV is mediated in part by substance P, recommendation of these agents is premature. Therefore, NK-1 receptor antagonists are not reflected in the antiemetic guidelines for RINV. A phase III, randomized, placebo-controlled trial compared an NK-1 receptor antagonist, fosaprepitant, together with palonosetron and dexamethasone, to palonosetron and dexamethasone alone in the prevention of N&V in patients receiving concomitant radiation therapy and cisplatin.[Level of evidence: I] Patients received fractionated radiation therapy with weekly cisplatin, 40 mg/m2. All patients received dexamethasone on the same schedule: 16 mg on day 1, 8 mg twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once on day 4. More patients receiving the three-drug regimen reached a complete response: 48.7% for the placebo group and 65.7% for the fosaprepitant group.
Older, less-specific antiemetic drugs such as prochlorperazine, metoclopramide, and cannabinoids have shown limited efficacy in the prevention or treatment of RINV, although they may have a role in treating patients with milder symptoms and as rescue agents.
Duration of Prophylaxis
The appropriate duration of antiemetic prophylaxis for patients receiving fractionated RT is not clear. There have been no randomized trials using 5-HT3 receptor antagonists that compared a 5-day course of treatment with a more protracted course. A systematic review that included 25 randomized and nonrandomized trials revealed that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT. Despite a lack of evidence, the current National Comprehensive Cancer Network guidelines recommend that the decision about whether to continue antiemetic prophylaxis beyond the first week should be based on an assessment of the risk of emesis and relevant individual factors.
The benefit of 5-HT3 receptor antagonists once nausea or vomiting occurs has been suggested in all studies, but there are no trials specifically in this setting. The emerging role of olanzapine in breakthrough emesis in patients with CINV has not been studied in RINV.
Guidelines and Patient Management
For patients at high risk of developing RINV, prophylaxis with a 5-HT3 receptor antagonist is recommended in the clinical practice guidelines from both MASCC and ASCO. On the basis of results from patients receiving highly emetogenic chemotherapy, the addition of dexamethasone to the 5-HT3 receptor antagonist is suggested. The antiemetic clinical practice guidelines from both MASCC and ASCO recommend that patients receiving moderately emetogenic RT be administered prophylaxis with a 5-HT3 receptor antagonist, with or without a short course of dexamethasone. There are no fully published comparative clinical trials on the use of NK-1 receptor antagonists in preventing RINV; therefore, its use cannot be recommended.
Antiemetic dosing suggestions for the prevention of RINV are summarized in Table 5.
Published Pediatric Antiemetic Guidelines for Acute Nausea and Vomiting (N&V)
Chemotherapy-induced N&V (CINV) is an important problem in the pediatric population. As in adults, nausea in children is more of a problem than vomiting. Nausea was identified by parents of children receiving active antineoplastic therapy in Ontario as the fourth most prevalent and bothersome treatment-related symptom in their children. Current approaches to the selection of appropriate and effective measures to prevent CINV are based on an accurate description of the potential of antineoplastic therapies to cause N&V. Current recommendations are based on published guidelines. These recommendations include patients aged 1 month to 18 years. Published recommendations are based on patients naïve to antineoplastic therapy who are about to receive their first course of antineoplastic therapy. Recommendations focus on the prevention of acute CINV (i.e., within 24 hours of administration of an antineoplastic agent).
Guidelines recommend that optimal control of acute CINV be defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention, and no nausea-related change in the child's usual appetite and diet. This level of CINV control is to be achieved on each day that antineoplastic therapy is administered and for 24 hours after administration of the last agent in the antineoplastic therapy cycle.
In children receiving antineoplastic agents who were not given antiemetic prophylaxis or who were given prophylaxis known to be ineffective, expected rates of complete CINV control were as follows: high emetic risk, less than 10%; moderate emetic risk, 10% to less than 30%; low emetic risk, 30% to less than 90%; and minimal emetic risk, more than 90%. The expected rate of complete CINV control in children receiving modern antiemetic prophylaxis (5-hydroxytryptamine-3 [5-HT3] antagonist with or without dexamethasone) is more than 70% to 80%. Each chemotherapy agent carries an inherent risk of causing emesis, which is the first issue to be considered in the assessment of an individual's risk when planning treatment with chemotherapy. Refer to Table 3 for more information about the prevention of acute or delayed CINV.
Highly emetogenic chemotherapy
Guidelines [2,3] recommend that children aged 12 years and older who are receiving antineoplastic agents of high emetic risk that are not known or suspected to interact with aprepitant receive aprepitant plus a 5-HT3 antagonist plus dexamethasone. Children who cannot receive dexamethasone should receive a 5-HT3 antagonist plus aprepitant. Children who cannot receive aprepitant should receive a 5-HT3 antagonist plus dexamethasone.
Moderately emetogenic chemotherapy
Children receiving antineoplastic agents of moderate emetogenicity should receive ondansetron, granisetron, or palonosetron plus dexamethasone. Children who cannot receive dexamethasone should receive 5-HT3 antagonist plus aprepitant.
Low emetogenic chemotherapy
Children receiving antineoplastic agents of low emetogenicity should receive a 5-HT3 antagonist.
Minimal emetogenic potential
Children receiving antineoplastic agents of low emetogenicity should receive no routine prophylaxis.
Other Antiemetic Modalities
Current consensus is that acupuncture, acupressure, guided imagery, music therapy, progressive muscle relaxation, and psychoeducational support and information may be effective in children receiving antineoplastic agents. Virtual reality may convey benefit. Other recommendations (low level of evidence) include eating smaller, more-frequent meals; reducing food aromas and other stimuli with strong odors; avoiding foods that are spicy, fatty, or highly salty; taking antiemetics before meals so that the effect is present during and after meals; and using measures and foods (e.g., "comfort foods") that helped to minimize nausea in the past. Despite a lack of strong evidence, most experts feel that these recommendations are unlikely to result in undesirable effects or to adversely affect quality of life and may convey benefit.
Prophylaxis with a 5-HT3 antagonist alone leads to poor CINV control in patients receiving antineoplastic agents of moderate and high emetic risk. A synthesis of the three studies that evaluated alternative antiemetic agents (chlorpromazine and metoclopramide) in children receiving highly emetogenic chemotherapy observed a complete CINV control rate of 9% (95% confidence interval: 0, 20). When corticosteroids are contraindicated, it is recommended that nabilone or chlorpromazine be administered together with ondansetron or granisetron to children receiving highly emetogenic chemotherapy. Metoclopramide is a third option for children receiving moderately emetogenic chemotherapy. It is also recommended that corticosteroids be combined with a serotonin antagonist for patients receiving highly and moderately emetogenic chemotherapy.
Antiemetic dosing suggestions for pediatric patients are summarized in Table 6.
Multiagent single-day chemotherapy regimens
Experience in pediatrics and guidelines recommend basing the emetogenicity of combination antineoplastic regimens on that of the agent of highest emetic risk of many combinations. The emetogenicity of the antineoplastic combinations in the following list appears to be higher than would be appreciated by assessment of the emetic risk of the individual agents.
High Level of Emetic Risk (>90% Frequency of Emesis in Absence of Prophylaxis)
In adults, delayed nausea and vomiting (N&V) is well documented, and strategies exist to control it. Delayed N&V remains a significant problem despite major improvements in the control of acute N&V and nausea immediately following the administration of chemotherapy. The nature and prevalence of delayed N&V in children after administration of antineoplastic agents have not been well described. Additionally, most pediatric chemotherapy regimens give multiple days of chemotherapy, making the onset and duration of risk for delayed versus acute N&V unclear.
Work in the area of chemotherapy-induced N&V (CINV) in children has been limited in part by the lack of assessment tools and the subjective nature of nausea. In the pediatric population, vomiting is more easily recognizable and measurable than is nausea. Difficulties in assessing nausea in young children may contribute to the common perception that young children experience CINV less frequently than do older children. In addition, caregivers may have a higher tolerance for vomiting in young children and may miss detecting nausea. In view of these limitations, studies often use dietary intake to assess the extent of nausea.
Several investigators have attempted to determine the prevalence of delayed N&V in the pediatric population. Early work suggested a low incidence of delayed N&V. In a large study, the nature and prevalence of delayed CINV in children was assessed. Nausea was self-assessed daily using a numeric scale reflecting the effect of nausea on activities and a faces scale for children aged 3 to 6 years. Diet was also assessed daily. Results showed a 33% incidence of delayed vomiting in patients receiving antineoplastic agents (cyclophosphamide, cisplatin, or carboplatin) and an 11% incidence in those who received other antineoplastic agents. No antiemetics were given on 412 (79%) of 522 study days; nevertheless, 381 (93%) of the 412 study days on which patients did not receive antiemetic support during the delayed phase were completely free from vomiting. Antiemetics were most often given as single agents (ondansetron, on 54 study days; dimenhydrinate, on 17 study days; dexamethasone, on 6 study days). Diet was not affected. The authors concluded that antineoplastic-induced delayed N&V may be less prevalent in children than in adults. The high percentage of children not experiencing delayed vomiting may reflect a lack of significant emetogenic potential among many of the regimens in the study; in 100 of 174 chemotherapy cycles, no antiemetics were administered. In addition, there was no characterization of antiemetic response among moderate and severe chemotherapy regimens.
Another study evaluated the incidence of delayed N&V in pediatric patients receiving moderately and highly emetogenic chemotherapy and also receiving premedications in the form of ondansetron alone or with dexamethasone, depending on a treatment's emetogenic potential. In this study, investigators measured nausea severity and duration, vomiting severity, the number of vomiting episodes, interference with daily activities by the nausea or vomiting, and assessment of appetite. The authors found that delayed N&V occurred with both moderately and highly emetogenic regimens. The severity of N&V varied between the moderately emetogenic and highly emetogenic chemotherapy regimens. The investigators also found that toddlers had better antiemetic control than did older children, which may be the result of anxiety differences between the age groups. The reasons for greater complete control in the toddler patient population are unclear but are consistent with the authors' previous study of nausea and vomiting control rates in children. Anxiety and patient perception may be important contributors to N&V in older children; the authors found a relationship between control of acute N&V and the occurrence of delayed N&V.
Another study suggests a higher incidence of delayed N&V. In a sample of pediatric cancer patients (N = 40) receiving chemotherapy, N&V was measured from the child's perspective using the Adapted Rhodes Index of Nausea and Vomiting for Pediatrics; from the primary caregiver's perspective using the Adapted Rhodes Index of Nausea and Vomiting for Parents; and among their nurses using the National Cancer Institute Nausea and Vomiting Grading Criteria. The highest frequency of nausea occurred in the delayed period, with 60% of patients (n = 24) having reported delayed nausea. The authors concluded that chemotherapy-induced N&V occurred throughout the chemotherapy course, with delayed N&V occurring most frequently and with greater severity and distress. Delayed N&V in the pediatric population requires further study.
Because well-designed studies on the prevention of delayed N&V in children are not available, no formal recommendation is possible. In the absence of such data, current consensus is to treat children in a manner similar to adults, with appropriately adjusted doses.
Cancer patients who have received chemotherapy may experience nausea and vomiting (N&V) when anticipating chemotherapy. Differences in methodology, timing, and assessment instruments and a focus on nausea or vomiting but not both has led to difficulties in capturing the actual prevalence of anticipatory N&V (ANV) in children. Small study sample sizes preclude capturing the actual frequency of ANV in the pediatric population. Accurate prevalence is also prevented by the use of parent or caregiver proxy reports of nausea and the use of nonvalidated nausea assessment tools.
When ANV was evaluated longitudinally in patients receiving 5-hydroxytryptamine-3 (5-HT3) antagonists and corticosteroids as antiemetic agents, approximately one-third of adults experienced ANV, while anticipatory vomiting was reported in 6% to 11%. A single group of investigators has evaluated ANV in children in the pre–5-HT3 antagonist era. The study reported anticipatory nausea in 23 (29%) of 80 children and anticipatory vomiting in 16 (20%) of 80 children who had received 11 cycles of antineoplastic therapy, on average, before evaluation. In the post–5-HT3 era, the reported prevalence of anticipatory nausea in children has ranged from 0% to 59%. Similar to observations in adult patients, the reported prevalence of anticipatory nausea was always higher than that of anticipatory vomiting, with one exception: one study reported an equivalent prevalence (5 [26%] of 19 patients) for anticipatory nausea and anticipatory vomiting.
This section focuses on the management of ANV in children aged 1 month to 18 years who are receiving antineoplastic medication. Optimal control of ANV is defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for the prevention or treatment of chemotherapy-induced N&V (CINV), and no nausea-related change in the child's usual appetite and diet. This level of ANV control is to be achieved during the 24 hours before administration of the first antineoplastic agent of the upcoming planned antineoplastic cycle.
Approaches to Prevent ANV in Children
ANV appears to be a conditioned response to CINV experienced in the acute phase (24 hours after administration of chemotherapy) and delayed phase (more than 24 hours after and within 7 days of administration of chemotherapy). The anxiety and distress attendant to CINV reinforce the conditioned response. It follows, therefore, that a higher rate of complete acute and delayed CINV control would result in lower rates of ANV. Adherence to evidence-based guideline recommendations regarding CINV prevention has been shown to substantially improve complete acute CINV control.
Given that ANV appears to be a conditioned response, optimization of acute and delayed CINV control may help minimize exposure to the negative stimuli required for conditioning to occur. Consensus recommendations are that antiemetic interventions be based on published guidelines used for the prevention of acute CINV in children receiving antineoplastic agents, including antineoplastic agent–naïve patients. Once antineoplastic therapy has been initiated, the selection of antiemetic interventions should be informed by evidence-based guidelines and tailored on the basis of the extent of CINV control experienced by the patient and any adverse effects associated with antiemetic agents.
Interventions to Control ANV
Hypnosis has been defined as an intervention that "provides suggestions for changes in sensation, perception, cognition, affect, mood, or behavior." Two trials evaluated the role of hypnosis in controlling ANV in children. One study recruited 54 children aged 5 to 17 years who had reported experiencing anticipatory nausea, anticipatory vomiting, or both in a previous study and who were about to receive at least two identical antineoplastic treatment courses. On average, children were 15.8 months (range, 0.5–118 months) from their cancer diagnosis at the time of the study. The control group had received antineoplastic therapy for much longer than the other two groups (29.5 months vs. 8 or 11.5 months).
Although it is not possible to precisely ascertain the emetogenicity of the antineoplastic therapy that the children received, it appears that most received highly emetogenic treatment, as assessed by current classifications of chemotherapy emetogenicity. The antiemetic agents received for prophylaxis were not reported, but children's antiemetic regimens were unchanged during the trial. The severity of N&V was assessed through semistructured interviews. Children were randomly assigned to receive one of three possible interventions: hypnosis training (imagination-focused therapy), active cognitive distraction (relaxation), or contact with a therapist (control). The authors reported a significant improvement in complete control of anticipatory vomiting in the group who received hypnosis training (12 [57%] of 21 patients at baseline vs. 18 [86%] of 21 patients after hypnosis training; P < .05). Complete control of anticipatory nausea increased from 5 (24%) of 21 patients at baseline to 8 (38%) of 21 patients after hypnosis training.
Another study evaluated hypnosis as a means of preventing ANV in 20 children aged 6 to 18 years who were naïve to chemotherapy. Controls were matched for age (±3 years) and the emetogenicity of their antineoplastic treatment. Insufficient information is available to determine the emetogenicity of the antineoplastic regimens. Children randomly assigned to receive hypnosis did not receive antiemetic prophylaxis but did receive antiemetic agents as needed. Children in the control group received standard antiemetic prophylaxis for 4 to 6 hours after antineoplastic therapy. Ondansetron was given to more children in the control group (7 of 10 patients) than in the hypnosis group (3 of 10 patients).
Children randomly assigned to receive hypnosis were taught self-hypnosis during the initial antineoplastic treatment; children in the control group spent equivalent time in conversation with a therapist. ANV was assessed by means of a daily structured interview with the child. The presence of ANV was assessed at 1 to 2 months, and at 4 to 6 months after diagnosis. At the time of first assessment of ANV, children who had been taught self-hypnosis reported significantly less anticipatory nausea than did the control group, although the incidence was not reported. The rate of anticipatory vomiting was identical in each group (1 of 10 patients). By the time of the second assessment, there was no difference between the groups in the rate of anticipatory nausea. The rate of anticipatory vomiting between the groups was also similar (hypnosis, 0 of 10 patients vs. control, 2 of 10 patients).
Studies of pharmacologic interventions for ANV have been conducted only in adults and are limited to benzodiazepines. Because patients who experience ANV have been observed to be more anxious than patients who do not experience ANV, anxiolytics have been studied. Studies in adults (two randomized trials) have evaluated the contribution of benzodiazepines as a treatment for ANV.[11,12] Adult cancer patients received placebo or lorazepam 2 mg by mouth the night before antineoplastic treatment, the morning of treatment, and at bedtime for the next 5 days over 180 antineoplastic treatment courses containing cisplatin. Patients also received metoclopramide 2 mg/kg per dose, clemastine, and dexamethasone for antiemetic prophylaxis. At the time of randomization, approximately two-thirds of patients were naïve to antineoplastic agents. ANV was defined as nausea, vomiting, or both that occurred within 12 hours before antineoplastic therapy or 1 hour after the start of antineoplastic therapy. A significantly higher proportion of treatments in which lorazepam was given were associated with complete ANV control, compared with the control group (52% vs. 32%; P < .05). Few adverse effects were attributed to lorazepam; mild sedation occurred in 76% of the patients who received lorazepam and 32% of the control patients.
Women with breast cancer who were naïve to antineoplastic treatment were enrolled in a double-blind placebo-controlled trial comparing the incidence of ANV after relaxation training and either alprazolam (29 patients) or placebo (28 patients). Alprazolam 0.25 mg or placebo was given twice daily by mouth for 6 to 12 months. Triazolam was also given as needed to patients in both study arms to manage insomnia. The proportion of patients who experienced complete control of anticipatory nausea and anticipatory vomiting before the fourth antineoplastic treatment was similar in both study arms (26% vs. 25% and 4% vs. 0%, respectively). Diazepam 5 mg twice daily was given to 29 adult cancer patients with ANV for 3 days before each of four consecutive antineoplastic treatment courses. Thirteen patients (45%) experienced complete ANV control at some time over the four antineoplastic treatment courses.
While the improvement in complete control of ANV provided by psychological interventions such as hypnosis or systematic desensitization may not be dramatic, these interventions may convey benefit to individual patients with minimal risk. For this reason, one guideline development panel recommends that interventions be offered to age-appropriate patients who experience ANV where the expertise and resources exist to deliver them.
Despite the lack of evidence to support the use of benzodiazepines for the treatment of ANV in children, guidelines recommend using lorazepam for ANV in children, based on clinical experience. The recommended initial lorazepam dose was based on current pediatric dosing recommendations, with the usual adult dose as the maximum dose. This dose should be titrated to the needs of each child, with dose lowering recommended for excessive sedation. Guidelines also recommend that dosing be of short duration.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the prevention and control of treatment-related nausea and vomiting in cancer patients. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Supportive and Palliative Care Editorial Board. PDQ Treatment-Related Nausea and Vomiting. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389491]
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Last Revised: 2018-09-20
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