Prevention of Acute/Delayed Nausea and Vomiting (Emesis)

Antiemetic agents are the most common intervention in the management of treatment-related nausea and vomiting (emesis) (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.[1,2] 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. Most drugs with proven antiemetic activity can be categorized into one of the following groups:

• Competitive antagonists at dopaminergic (D2 subtype) receptors:
  • Phenothiazines.
  • Substituted benzamides.
  • Butyrophenones.
• Competitive antagonists at serotonergic (5-hydroxytryptamine-3 or 5-HT₃ subtype) receptors.
• Substance P antagonists (NK-1 receptor antagonists).
• Corticosteroids.
• Cannabinoids.
• Benzodiazepines.
• Olanzapine.

Although all routes of administration are listed for each of the following drugs, the intramuscular (IM) route should be 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

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, intravenously (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); thiethylperazine given in the 5- to 10-mg dose range orally, IM, and IV; and perphenazine. The primary consideration in selecting among 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, thiethylperazine, perphenazine, fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions (EPRs).

Prochlorperazine

Prochlorperazine is perhaps the most frequently (and empirically) used antiemetic and, in low doses, is generally effective in preventing nausea associated with radiation therapy and in treating N&V attributed to very low to moderately emetogenic chemotherapeutic drugs. Prochlorperazine is a phenothiazine and can be given orally, IM, IV, and rectally. It is usually given in the 10- to 50-mg dose range (pediatric dose for children who weigh >10 kg or who are >2 years: orally or rectally, 0.4 mg/kg/dose tid–qid; or IM, 0.1–0.15 mg/kg/dose tid–qid, maximum 40 mg/d). Higher prochlorperazine doses (e.g., 0.2–0.6 mg/kg/dose) are also given IV for patients receiving chemotherapy with high emetogenic potential.[3];[4][Level of evidence: I] Phenothiazines may be of particular value in treating patients who experience delayed N&V (postacute phase symptoms) on cisplatin regimens.[5][Level of evidence: I]

As with other dopaminergic antagonists, the most common side effects of prochlorperazine are EPRs (acute dystonias, akathisias, neuroleptic malignant syndrome [uncommon], and rarely, akinesias and dyskinesias) and sedation. Marked hypotension may also result if IV prochlorperazine is administered rapidly at high doses. Administration over at least 30 minutes appears adequate to prevent hypotensive episodes.[6,7,8]

Butyrophenones

Droperidol and haloperidol

Droperidol and haloperidol represent 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.[9,10] Haloperidol is administered IM, IV, or orally, typically from 1 to 4 mg every 2 to 6 hours.[11] Results of a small, uncontrolled, open-label study showed some efficacy for haloperidol in palliative care patients.[12] Both agents may produce EPRs, akathisia, hypotension, and sedation.

Dopamine 2 Antagonists

Metoclopramide

Metoclopramide is a substituted benzamide, which, prior to the introduction of serotonin (5-HT₃) receptor antagonists, 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 multiple intermittent dosing schedules.[13,14,15]

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.[7,16] 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:

• Switching to a lower potency neuroleptic for vomiting, if possible.
• Lowering the dose.
• Adding a benzodiazepine (e.g., lorazepam) or beta blocker (e.g., propranolol).

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.[17] The 5-HT₃ receptor antagonists may also block serotonin stimulation at the CTZ and other CNS structures.

Ondansetron

Several studies have demonstrated that ondansetron produces an antiemetic response that equals or is superior to high doses of metoclopramide, but ondansetron has a superior toxicity profile compared with dopaminergic antagonist agents.[18,19,20,21,22][Level of evidence: I][23,24] Ondansetron (0.15 mg/kg) is given IV 15 to 30 minutes prior to 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.[25][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.[26]

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. Patients older than 12 years should receive 4 mg per dose. Ondansetron is not approved for use in children younger than 4 years. Ondansetron clearance is diminished in patients with severe hepatic insufficiency; therefore, such patients should receive a single injectable or oral dose no higher than 8 mg. There is currently no information available 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.[25]

The major adverse effects include headache (which can be treated with mild analgesics), constipation or diarrhea, fatigue, dry mouth, and transient asymptomatic elevations in liver function tests (alanine and aspartate transaminases), which may be related to concurrent cisplatin administration.[27] Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events.[28] 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.[29][Level of evidence: II] A randomized, double-blind, placebo-controlled trial suggests that the addition of aprepitant, a neurokinin-1 (NK-1) receptor antagonist, may mitigate N&V.[30][Level of evidence: I] The optimal dose of aprepitant may be 125 mg on day 1 followed by 80 mg on days 2 to 5.[31][Level of evidence: I]

Granisetron

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 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 appears equally efficacious and equally safe.[32,33,34][Level of evidence: I] Both granisetron formulations are given before chemotherapy, as either a single IV dose of 10 µg/kg (0.01 mg/kg) or 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.

Dolasetron

Both oral and injection formulations of dolasetron are indicated for the prevention of N&V associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses. Oral dolasetron should be dosed as 100 mg within 1 hour before chemotherapy. Dolasetron should be given IV or orally at 1.8 mg/kg as a single dose approximately 30 minutes before chemotherapy.

The effectiveness of oral dolasetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) has been proven in a large randomized, double-blind, comparative trial of 399 patients.[35][Level of evidence: I] Oral dolasetron was administered in the range of 25 to 200 mg 1 hour prior to 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 as compared with dolasetron 25 or 50 mg. (CR was defined as no emetic episodes and no use of escape antiemetic medications.) Dolasetron injection has also been proven effective in the prevention of CINV.[36][Level of evidence: I]

Palonosetron

Palonosetron is a 5-HT₃ receptor antagonist (second generation) that has antiemetic activity at both central and gastrointestinal sites. In comparison to the older 5-HT₃ receptor antagonists, it 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.[37][Level of evidence: I] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[37] 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.[38];[39][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,[40][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 [41] reported that the CR rates for both acute and delayed CINV were maintained with single IV doses of palonosetron without concomitant corticosteroids. These data will require further review.

On the basis of the studies described above, palonosetron was approved by the FDA in July 2003 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. One randomized, double-blind, phase III trial compared palonosetron plus dexamethasone with granisetron plus dexamethasone for the prevention of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron was equivalent to granisetron in the acute phase (first 24 hours) and better than granisetron in the delayed phase (24–120 hours), with a comparable safety profile for the two treatments.[42][Level of evidence: I]

Comparison of agents

Clinicians should note that 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.[43];[44,45,46][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).[29,47,48]

Palonosetron, the second-generation 5-HT₃ receptor antagonist, has been approved for the control of delayed emesis for patients receiving moderately emetogenic chemotherapy.[38];[39][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.[29][Level of evidence: II];[49][Level of evidence: I][47,48]

Substance P Antagonists (NK-1 Receptor Antagonists)

The initial clinical studies using the NK-1 receptor antagonists [50,51,52][Level of evidence: I][53] demonstrated that the addition of an NK-1 receptor antagonist (CP-122,721, CJ-11,794, MK-0869 [aprepitant]) to a 5-HT₃ receptor antagonist plus dexamethasone prior to cisplatin chemotherapy improved the control of acute emesis compared with a 5-HT₃ receptor antagonist plus dexamethasone and improved the control of delayed emesis compared with placebo. In addition, as a single agent, aprepitant (MK-0869) had an effect similar to that of ondansetron on cisplatin-induced acute emesis but was superior in the control of delayed emesis. Subsequent studies [54,55][Level of evidence: I] showed that the combination of aprepitant and dexamethasone was similar to a 5-HT₃ receptor antagonist plus dexamethasone in controlling acute emesis but 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 [31,56][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.[30,57][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.[30] 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.[58][Level of evidence: I]

All of the initial studies using aprepitant were conducted in patients receiving highly emetogenic chemotherapy such as cisplatin-based chemotherapy regimens. Subsequently, one group [59][Level of evidence: I] presented a study on the use of aprepitant in 862 breast cancer patients receiving moderately emetogenic chemotherapy (e.g., cyclophosphamide, doxorubicin). Two regimens were compared. Because the chemotherapy was moderately emetogenic, steroids were omitted from both arms, as illustrated in Table 2.

Table 2. Comparison of Aprepitant and Standard Regimens

There was a significant improvement in CR (no emesis, no rescue) in the 24 hours after chemotherapy in the patients receiving aprepitant; however, there was no significant improvement in CR on days 2 to 5 in the postchemotherapy period when aprepitant alone was compared with ondansetron alone. The overall (days 1–5) CR was significantly improved for the aprepitant-containing regimen, most likely because of the improvement in the first 24 hours. The control of nausea in moderately emetogenic chemotherapy was not improved with the use of aprepitant without steroids on days 2 and 3 postchemotherapy. These results were consistent for multiple cycles of chemotherapy.[60] The role of aprepitant in moderately emetogenic chemotherapy remains undetermined. One open-label study demonstrated that in the 5 days postchemotherapy, aprepitant in combination with palonosetron and dexamethasone is safe and highly effective in preventing CINV in patients receiving moderately emetogenic chemotherapy.[61][Level of evidence: II] Another study reported that aprepitant combined with ondansetron and dexamethasone provided superior efficacy in the prevention of acute and delayed CINV in a broad range of patients receiving moderately emetogenic chemotherapy (both anthracycline-cyclophosphamide regimens and nonanthracycline-cyclophosphamide regimens).[62] It is not known whether aprepitant is necessary in all moderately emetogenic regimens.

Fosaprepitant dimeglumine, a water-soluble, phosphorylated analog of aprepitant, is rapidly converted to aprepitant after IV administration.[63] 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.[64]

Casopitant is a neurokinin-1 receptor antagonist that is being developed as a potential treatment for CINV and postoperative N&V.[65] Phase III clinical trials have been completed, demonstrating an improvement in chemotherapy-induced emesis when casopitant is added to the antiemetic combination of ondansetron and dexamethasone in patients receiving highly emetogenic chemotherapy [66,67][Level of evidence: I] or moderately emetogenic chemotherapy.[68] Applications to the FDA for these indications have been made and are pending. Casopitant appears to be very similar to aprepitant in terms of efficacy in controlling CINV. The current studies suggest that casopitant is effective as 1-day oral or IV dosing prior to chemotherapy, compared with the FDA-approved 3-day dosing of aprepitant.

Corticosteroids

Steroids are sometimes used as single agents against mildly to moderately emetogenic chemotherapy but are more often used in antiemetic drug combinations.[69][Level of evidence: II];[70,71][Level of evidence: I] 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). In combination with high-dose metoclopramide, steroids may mitigate adverse effects such as the frequency of diarrheal episodes.

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 in treating N&V in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally, IM, or IV in the dose range of 8 mg to 40 mg (pediatric dose: 0.25–0.5 mg/kg).[72,73,74,75,76] Methylprednisolone is also administered orally, IM, or IV at doses and schedules that vary from 40 mg to 500 mg every 6 to 12 hours for up to 20 doses.[71,77]

Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:

• Immunosuppression.
• Proximal muscle weakness (especially involving the thighs and upper arms).
• Aseptic necrosis of the long bones.
• Cataract formation.
• Hyperglycemia and exacerbation of preexisting diabetes or escalation of subclinical diabetes to clinical pathology.
• Adrenal suppression with hypocortisolism.
• Lethargy.
• Weight gain.
• GI irritation.
• Insomnia.
• Anxiety.
• Mood changes.
• Psychosis.

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).[78] As previously shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT₃ -blocking agents.[79,80,81,82,83] If given IV, dexamethasone should be given over 10 to 15 minutes, since rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[75,84,85,86]

Prednisone and adrenocorticotropic hormone (ACTH) given concomitantly with other active antiemetic agents have also demonstrated efficacy against N&V caused by cisplatin-containing chemotherapy during the acute phase (within 24 hours after receiving chemotherapy).[87,88,89] In a double-blind, randomized study of metoclopramide and dexamethasone with or without 1 mg of ACTH, patients receiving ACTH prophylaxis for cisplatin-containing chemotherapy experienced a significantly decreased incidence and severity of delayed emesis for up to 72 hours after treatment.[89]

Cannabis

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).[90] There are two FDA-approved products for CINV:

• Dronabinol (a synthetic delta-9-THC), as prophylaxis for CINV, 5 mg/m² orally 1 to 3 hours before chemotherapy and every 2 to 4 hours after chemotherapy, for a total of no more than 6 doses per day.
• Nabilone, 1 to 2 mg orally twice a day, for CINV that has failed to respond to other antiemetics.

With respect to CINV, Cannabis products probably target cannabinoid-1 (CB-1) and CB-2 receptors, which are in the central nervous system.[91] Another product, Sativex, a cannabidiol that is a buccal spray, is under investigation.[92,93]

Much of the research on this class of agent was conducted in the late 1970s and 1980s and compared Cannabis to older antiemetic agents that targeted the dopamine receptor, such as prochlorperazine (Compazine) and metoclopramide (Reglan).[90,94,95,96,97,98,99,100,101] This group of studies demonstrated that Cannabis was as effective for moderately emetogenic chemotherapy as dopaminergic antiemetics or was more effective than placebo.[90] Side effects of Cannabis products included euphoria, dizziness, dysphoria, hallucinations, and hypotension.[90] Despite earlier reports of efficacy, in at least one study, patients did not significantly prefer Cannabis agents because of the side effects.[94]

Research in nausea and vomiting since the 1990s 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 with these newer agents are few; therefore, limited conclusions can be drawn. In published trials, however, Cannabis has not demonstrated more efficacy than 5-HT₃ receptor antagonists, and synergistic or additive effects have not been fully investigated.[91,102,103]

In summary, the place of Cannabis in today's arsenal of antiemetics for the prevention and treatment of CINV is not known. Discussions with patients about its use should include responses to available agents, known side effects of Cannabis, and an assessment of the risks versus benefits of this therapy.[104]

For a broader discussion of the issues surrounding Cannabis use, refer to the PDQ summary on Cannabis and Cannabinoids.

Benzodiazepines

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 nausea and vomiting (ANV) associated with chemotherapy, especially with the highly emetogenic regimens given to children.[105,106,107] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents. Therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents.[108] Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, they markedly decrease the severity of EPRs, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.

Lorazepam

Lorazepam may be administered orally, IM, 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.[109][Level of evidence: I][105,110,111] 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.[112,113] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.[114]

The adverse effects of lorazepam include the following:[115]

• Sedation.
• Perceptual disturbances.
• Disorders of micturition and/or defecation.
• Visual disturbances.
• Hypotension.
• Anterograde amnesia.
• Psychological dependence.
• Confusion.
• Ataxia.
• Depressed mental acuity with intoxication.

Olanzapine

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-HT_2a, 5-HT_2c, 5-HT₃, and 5-HT₆ receptors; catecholamines at alpha-1 adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H₁ receptors.[116] Common side effects include the following:[117,118,119]

• Sedation.
• Dry mouth.
• Increased appetite.
• Weight gain.
• Postural hypotension.
• Dizziness.

Olanzapine has also been associated with increased risk of hyperlipidemia, hyperglycemia, new-onset diabetes and, in rare cases, diabetic ketoacidosis.[117,119,120] Olanzapine should be 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.[117] 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.

There have been case reports on the use of olanzapine as an antiemetic.[121][Level of evidence: II];[122,123,124,125] These case reports prompted a phase I study in which olanzapine was used for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.[126] The protocol was completed by 15 patients, and no grade 4 toxicities were seen. The maximum tolerated dose was 5 mg/day for 2 days prior to chemotherapy and 10 mg/day for 7 days postchemotherapy. On the basis of these 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. 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, M. D. 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.[127][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.[128] A large end study [129][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

Ginger

The antiemetic effect of ginger powder (Zingiber officinale) was explored in a double-blind, placebo-controlled, randomized trial among 32 children and young adults, aged 8 to 21 years, with newly diagnosed bone sarcomas.[130] Cycles of chemotherapy were randomly assigned to ginger powder (1,000 to 2,000 mg per day) or placebo on days 1 to 3 of treatment. Patients were allowed to receive the standard antiemetic medications ondansetron and dexamethasone. The primary endpoint was the incidence and severity of acute N&V (occurring =24 hours from the start of chemotherapy) and delayed N&V (occurring >24 hours after completion of chemotherapy).

The authors reported a reduction in the incidence of moderate to severe acute nausea in the experimental arm (55.6 % of cycles), compared with the placebo arm (93.3% of cycles) (P = .003). Decreased incidence of moderate to severe vomiting was found in the experimental arm (33.3%), compared with the placebo arm (76.7%) (P = .002). The authors also reported decreased incidence of moderate to severe delayed nausea (P < .001) and vomiting (P = .022) in the experimental arm, compared with placebo. No adverse events were reported.[130]

Although these results are encouraging, the study was limited by a small sample size, lack of stratification by antiemetic regimen, and no intra- or interindividual reporting. Subsequent studies are needed to confirm these preliminary findings.

Management of CINV

Current guidelines [131,132] recommend that prechemotherapy management of 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 postchemotherapy for the prevention of delayed emesis.

For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT₃ receptor antagonist and dexamethasone should be 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, should 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.[131,132]

Antiemetic guidelines [131,132] 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.[47]

Clinicians and other health care professionals who are involved in administering chemotherapy should be aware that studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners.[47,133,134] One study suggested that patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea.[135] 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.[47,48] One study reported the effective use of IV palonosetron and dexamethasone for the prevention of CINV in patients receiving multiple-day chemotherapy.[136]

Pre- and postchemotherapy recommendations by emetogenic potential are summarized in Table 3.

Table 3. Antiemetic Recommendations by Emetic Risk Categoriesa

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.

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