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Prevention and control of nausea and vomiting (emesis) (N&V) are paramount in the treatment of cancer patients. Chemotherapy-induced N&V (CINV) 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:
Health Care Costs
Severe N&V may result in prolonged hospitalizations, inability to continue usual activities, need for additional support, and depression, producing greater effects on health care costs. One review of 12 published studies  found that despite the high costs associated with prophylaxis against CINV, the direct cost of care was higher for patients who did not receive adequate CINV prophylaxis. Indirect costs related to lost work hours were also higher for patients with uncontrolled CINV. Another study examined 178 patients receiving highly or moderately emetogenic chemotherapy for their first chemotherapy course. Despite prophylaxis, 61% still experienced CINV. Higher direct and indirect health care costs and lower Functional Living Index—Emesis (FLIE) scores for quality of life were seen in patients who failed prophylaxis. One group of investigators looked at the Premier Perspective database to study 19,139 patients, all of whom received prophylaxis. In those with uncontrolled CINV, the overall mean additional costs were $5,299 per episode.
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 and 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 for nausea and vomiting (emesis) (N&V), the onset, severity, triggers, and duration vary. Tumor-related, treatment-related, and patient-related factors all contribute, including tumor location, chemotherapy agents used, and radiation exposure.[1,2,3]
Patient-related factors may include the following:
Additional causal factors unrelated to the chemotherapy treatment 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 PDQ summary on 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 prevalence of anticipatory nausea and vomiting (emesis) (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 (5-hydroxytryptamine-3 or 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 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 factors that correlate with the incidence of ANV in hopes of developing a list of risk factors. There is currently 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 is the recommended treatment. Referral to a psychologist or other mental health professional with specific training and experience in working with cancer patients is recommended 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 has developed a rating system for 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.[1,12,13]
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 [7,8] 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-HT3 receptor antagonist, aprepitant, and dexamethasone is recommended prechemotherapy; lorazepam may also be used. Aprepitant and dexamethasone are recommended starting with chemotherapy 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, with or without lorazepam. Patients receiving the combination of an anthracycline and cyclophosphamide and select patients receiving certain other agents of moderate emetic risk, such as cisplatin (<50 mg/m2) or doxorubicin, may also receive aprepitant. Postchemotherapy, a 5-HT3 receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.
For regimens with low emetogenic potential, dexamethasone is recommended with or without lorazepam. For regimens with minimal emetogenic risk, no prophylaxis is recommended.[7,8]
Antiemetic guidelines [7,8] 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.[9,10,11] 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 of the following drugs, 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.
Phenothiazines act on dopaminergic receptors at the CTZ, possibly at other central nervous system (CNS) centers, and peripherally. With the exception of thioridazine, many phenothiazines possess antiemetic activity, including chlorpromazine given in the 10- to 50-mg dose range orally, IM, IV, and rectally (pediatric dose for patients >12 years: 10 mg every 6–8 hours; for patients <12 years: 5 mg every 6–8 hours); and perphenazine.
The primary consideration in selecting phenothiazines are differences in their adverse effect profiles, which substantially correlate with their structural classes. Generally, aliphatic phenothiazines (e.g., chlorpromazine, methotrimeprazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine, perphenazine, fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions (EPRs) (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 extrapyramidal side effects. Phenothiazines may be of particular value in treating patients who experience delayed N&V (postacute phase symptoms) on cisplatin regimens.[15,16,17,18,19][Level of evidence: I]
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 administered IM or IV, typically from 1 to 2.5 mg every 2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[20,21] Haloperidol is administered IM, IV, or orally, typically from 1 to 4 mg 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 EPRs, akathisia, hypotension, and sedation.
Metoclopramide is a substituted benzamide, which, before serotonin (5-HT3) receptor antagonists were introduced, was considered the most effective single antiemetic agent against highly emetogenic chemotherapy such as cisplatin. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given IV at high doses (e.g., 0.5–3 mg/kg/dose), 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. It can be administered IV at the U.S. Food and Drug Administration (FDA)–approved dose of 1 to 2 mg/kg every 2 hours (or less frequently) for three to five doses. 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.[24,25,26]
Metoclopramide is associated with akathisia and dystonic extrapyramidal effects; akathisia is seen more frequently in patients older than 30 years, and dystonic extrapyramidal effects are seen more commonly in patients younger than 30 years. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize EPRs. While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia—the subjective sense of restlessness or inability to sit still—is best treated by the following:
Although less commonly used in the United States, metoclopramide is still very commonly used in other countries.
5-HT3 Receptor Antagonists
Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron, and palonosetron—are available in the United States. Tropisetron, while not approved by the FDA, is available internationally. 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.[28,29,30] 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, constipation, and/or diarrhea. 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.[31,32]; [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 in 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 delayed emesis for 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.[9,36,37,38]
Several studies have demonstrated that ondansetron produces an antiemetic response that equals or is superior to that of high doses of metoclopramide, but ondansetron has an improved toxicity profile, compared with that of dopaminergic antagonist agents.[39,40,41,42][Level of evidence: I][43,44] Ondansetron (0.15 mg/kg) is given IV 15 to 30 minutes before chemotherapy and is repeated every 4 hours for two additional doses. Alternatively, for patients older than 18 years, a large multicenter study determined that a single 32-mg dose of ondansetron is more effective in treating cisplatin-induced N&V than a single 8-mg dose and is as effective as the standard regimen of three doses at 0.15 mg/kg given every 4 hours starting 30 minutes before chemotherapy.[Level of evidence: I] A single-center retrospective chart review has reported ondansetron-loading doses of 16 mg/m2 (maximum, 24 mg) IV to be safe in infants, children, and adolescents. However, data reported to the FDA raises concern about QT prolongation and potentially fatal arrhythmias with a single IV dose of 32 mg. Current drug labeling calls for a maximal single IV dose of 16 mg.
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 include the following:
Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events. In addition, a few case reports have implicated ondansetron in causing EPRs. However, it is not clear in some cases whether the events described were in fact EPRs; in other reports, the evidence is confounded by concurrent use of other agents that are known to produce EPRs. 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. A randomized, double-blind, placebo-controlled trial suggests that the addition of aprepitant, an NK-1 receptor antagonist, may mitigate N&V. The optimal dose of aprepitant may be 125 mg on day 1 followed by 80 mg on days 2 and 3.[52,53][Level of evidence: I]
Granisetron has demonstrated efficacy in preventing and controlling N&V at a broad range of doses (e.g., 10–80 µg/kg and empirically, 3 mg/dose). In the United States, granisetron 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.[50,51,53,54][Level of evidence: I] Both granisetron formulations are given before chemotherapy, either as a single IV dose of 10 µg/kg (0.01 mg/kg) or as 1 mg orally every 12 hours.
Both granisetron formulations and ondansetron injection share the same indication against highly emetogenic chemotherapy. In contrast, the oral ondansetron formulation has been approved only for use against N&V associated with moderately emetogenic chemotherapy.
Currently, granisetron injection is approved for use without dosage modification in patients older than 2 years, including elderly patients and patients with hepatic and renal insufficiency. Oral granisetron has not yet been approved for use in pediatric patients.
Oral formulations of dolasetron are indicated for the prevention of N&V associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses. Oral dolasetron may be dosed as 100 mg within 1 hour before chemotherapy. Dolasetron is given IV or orally at 1.8 mg/kg as a single dose approximately 30 minutes before chemotherapy. 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. Complete response (CR) rates improved with increasing doses of dolasetron. Both dolasetron 200 mg and ondansetron had significantly higher CR rates than did dolasetron 25 or 50 mg. (CR was defined as no emetic episodes and no use of escape antiemetic medications.)
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.[58,59,60,61,62]
In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and the delayed period 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.
Substance P Antagonists (NK-1 Receptor 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, and netupitant, have been developed.
The initial clinical studies using the NK-1 receptor antagonists [65,66,67,68] demonstrated that the addition of aprepitant (CP-122,721, CJ-11,794, MK-0869) 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 addition, as a single agent, aprepitant had an effect similar to that of ondansetron on cisplatin-induced acute emesis but was superior in the control of delayed emesis.
Subsequent studies [69,70][Level of evidence: I] showed that the combination of aprepitant and dexamethasone was inferior in controlling acute emesis, compared with triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone). These studies also confirmed the improvement of delayed emesis with the use of aprepitant, compared with placebo. Two studies [71,72][Level of evidence: I] have also shown an improvement in cisplatin-induced delayed emesis with the combination of aprepitant and dexamethasone, compared with dexamethasone alone, with the improvement maintained over repeat cycles of cisplatin chemotherapy.
In two randomized, double-blind, parallel, multicenter, controlled studies (520 patients in each study), patients received cisplatin (≥70 mg/m2) and were randomly assigned to receive either standard therapy with a 5-HT3 receptor antagonist (ondansetron) and dexamethasone prechemotherapy and dexamethasone postchemotherapy (days 2–4); or standard therapy plus aprepitant prechemotherapy and on days 2 and 3 postchemotherapy.[52,73][Level of evidence: I] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute period (83%–89%) and the delayed period (68%–75%), compared with the CR of the standard therapy group in the acute period (68%–78%) and delayed period (47%–56%). Nausea was improved in the aprepitant group for some, but not all of the various specific measures of nausea.
The studies discussed above formed the basis for the approval of aprepitant by the FDA in March 2003. In combination with other antiemetics, aprepitant is indicated for the prevention of acute and delayed N&V associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[Level of evidence: I] Another randomized phase III trial studied the use of aprepitant, granisetron, and dexamethasone for the prevention of CINV in multiple myeloma transplant 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 were given this regimen.[75,76,77,78,79]
Fosaprepitant is a prodrug for aprepitant and is available in IV formulation. It is indicated in patients who are unable to tolerate oral medications because of mucositis, swallowing difficulties, or GI disturbance. Preliminary studies have shown safety and efficacy similar to that of oral aprepitant. Fosaprepitant is approved at a dose of 115 mg on day 1, followed by oral aprepitant on days 2 and 3. Fosaprepitant dimeglumine, a water-soluble, phosphorylated analog of aprepitant, is rapidly converted to aprepitant after IV administration. Fosaprepitant (115 mg) was approved by the FDA as an alternative to the 125-mg oral aprepitant dose on day 1 of a 3-day 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.
Netupitant is a competitive antagonist to the NK-1 receptor that is marketed as an oral fixed-combination product containing 300 mg of netupitant and 0.5 mg of palonosetron; it is dosed as a single product with dexamethasone before chemotherapy for the prevention of both acute and delayed CINV. This drug combination has been used successfully for prevention in both highly and moderately emetogenic chemotherapy regimens.[82,83]
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 to moderately emetogenic chemotherapy but are more often used in antiemetic drug combinations.[84,85][Level of evidence: I]
Steroids are often given IV before chemotherapy and may or may not 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 IV in the dose range of 8 mg to 40 mg (pediatric dose: 0.25–0.5 mg/kg).[87,88] 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.[85,89]
Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:[90,91,92]
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.[90,94] If administered IV, 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.[95,96,97,98]
Benzodiazepines such as lorazepam, midazolam, 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.[90,91,92] 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 EPRs, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.
Lorazepam may be administered orally, IV, and sublingually. Dosages range from 0.5 to 3 mg (alternatively, 0.025–0.05 mg/kg, or 1.5 mg/m2, but ≤4 mg per dose) in adults and 0.03 to 0.05 mg/kg in children every 6 to 12 hours.[Level of evidence: I][101,102] Midazolam produces mild-to-marked sedation for 1 to 4.5 hours at doses equal to 0.04 mg/kg given IV over 3 to 5 minutes.[103,104] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.
The adverse effects of lorazepam include the following:
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:[108,109]
Olanzapine has also been associated with increased risk of hyperlipidemia, hyperglycemia, new-onset diabetes and, in rare cases, diabetic ketoacidosis.[110,111] Olanzapine is used with caution in elderly patients; it has been associated with increased risk of death and increased incidence of cerebrovascular adverse events in patients with dementia-related psychosis and carries a boxed warning to that effect. 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]; [113,114]
A phase I study used olanzapine for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan. The protocol was completed by 15 patients, and no grade 4 toxicities were observed. The maximum tolerated dose was 5 mg/day for 2 days before chemotherapy and 10 mg/day for 7 days postchemotherapy. On the basis of these phase I data, olanzapine appeared to be a safe and effective agent for the prevention of delayed emesis in chemotherapy-naive cancer patients receiving cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.
Using the maximum tolerated dose of olanzapine in the phase I trial, a phase II trial was performed for the prevention of CINV in patients receiving their first course of either highly emetogenic or moderately emetogenic chemotherapy.[Level of evidence: II] Olanzapine was added to granisetron and dexamethasone prechemotherapy and to dexamethasone postchemotherapy. CR (no emesis, no rescue) was 100% for the acute period (24 hours postchemotherapy), 80% for the delayed period (days 2–5 postchemotherapy), and 80% for the overall period (0–120 hours postchemotherapy) in ten patients receiving highly emetogenic chemotherapy (cisplatin, ≥70 mg/m2). CR was also 100% for the acute period, 85% for the delayed period, and 85% for the overall period in 20 patients receiving moderately emetogenic chemotherapy (doxorubicin, ≥50 mg/m2). Nausea was very well controlled in the patients receiving highly emetogenic chemotherapy, with no patient having nausea (0 on a scale of 0–10 on the MD Anderson Symptom Inventory) in the acute or delayed periods. Nausea was also well controlled in patients receiving moderately emetogenic chemotherapy, with no nausea in 85% of patients in the acute period and in 65% of patients in the delayed and overall periods. There were no grade 3 or 4 toxicities. On the basis of these data, olanzapine appeared to be safe (sedation was the only dose-limiting toxicity) and effective in controlling acute and delayed CINV in patients receiving highly emetogenic and moderately emetogenic chemotherapy in these very small preliminary studies.[Level of evidence: II]
Subsequent studies have shown the effectiveness of olanzapine as an antiemetic. Olanzapine combined with a single dose of dexamethasone and a single dose of palonosetron was very effective in controlling acute and delayed CINV in patients receiving either moderately emetogenic chemotherapy or highly emetogenic chemotherapy. A large end 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.
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. Another product, Sativex, contains a combination of delta-9-THC and cannabidiol and is a buccal spray; it is under clinical investigation.[121,122]
Much of the research on this class of agent 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).[123,124,125,126,127] 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.[128,129]
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 a broader discussion of the issues surrounding Cannabis use.
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.
Current Clinical Trials
Check NCI's list of cancer clinical trials for U.S. supportive and palliative care trials about nausea and vomiting therapy that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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.)
Patients receiving radiation to the gastrointestinal (GI) tract or brain have the greatest potential for nausea and vomiting (N&V) as side effects. Because cells of the GI tract are dividing quickly, they are quite sensitive to radiation therapy. Radiation to the brain is believed to stimulate the brain's vomiting center or chemoreceptor trigger zone. Similar to chemotherapy, radiation dose factors also play a role in determining the possible occurrence of N&V. In general, the higher the daily fractional dose and the greater the amount of tissue that is irradiated, the higher the potential for N&V. In addition, the larger the amount of GI tract irradiated (particularly for fields that include the small intestine and stomach), the higher the potential for N&V. Total-body irradiation before bone marrow transplant, for example, has a high probability of inducing N&V as acute side effects.
N&V from radiation may be acute and self-limiting, usually occurring 30 minutes to several hours after treatment. Patients report that symptoms improve on days that they are not being treated. There are also cumulative effects that may occur in patients receiving radiation therapy to the GI tract.
Complete control rates with 5-HT3 receptor antagonists for total-body irradiation vary from 50% to 90%.[2,3,4] The role of corticosteroids in combination with 5-HT3 receptor antagonists has not been studied.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of nausea and vomiting (emesis) (N&V). 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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National Cancer Institute: PDQ® Nausea and Vomiting. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-pdq. Accessed <MM/DD/YYYY>.
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