Management of Nausea and Vomiting

Chemotherapeutic Agents and Emesis

Emetic Potential

The most accurate predictor of the risk of emesis is the chemotherapeutic agent that a patient is receiving. Several different classifications of commonly used chemotherapy agents have been devised. Table 1 is based on the consensus report of the Multinational Association of Supportive Care in Cancer (MASCC) as updated in April 2011.

The emetic potential of a chemotherapeutic combination is determined by identifying the most emetic agent in the combination. Other agents in a combination may also increase the risk.

In general, agents associated with the highest incidence of emesis also induce the most severe emesis. Differences occur among patients and even between identical treatment courses in the same patient. The dose, route, and schedule of administration of the chemotherapeutic agent can affect the incidence of nausea and vomiting.

Time of Onset of Emesis

In patients receiving initial chemotherapy of high emetic risk, nausea or vomiting typically begins between 1 and 2 hours after chemotherapy administration. Cyclophosphamide(Drug information on cyclophosphamide) and carboplatin(Drug information on carboplatin) may be associated with a late onset of emesis (ie, 8 to 18 hours following chemotherapy administration).

Antiemetic Agents for High–Emetic-Risk Chemotherapy

Careful antiemetic research has shown that numerous agents are safe and effective. Dosage and administration schedules for some of these agents are given in Table 2. Antiemetic therapy is commonly administered either orally or intravenously.

Among the best-studied agents are ondansetron, granisetron, palonosetron(Drug information on palonosetron), metoclopramide(Drug information on metoclopramide), haloperidol(Drug information on haloperidol), dexamethasone, aprepitant, fosaprepitant, lorazepam(Drug information on lorazepam), dronabinol, prochlorperazine(Drug information on prochlorperazine), and chlorpromazine(Drug information on chlorpromazine).

The combination of a single prechemotherapy dose of a 5-HT₃ antagonist and dexamethasone(Drug information on dexamethasone) is the most commonly used therapy to prevent emesis in patients receiving chemotherapy of high emetic risk (both cisplatin(Drug information on cisplatin) and noncisplatin) as listed in Table 1. Addition of an NK₁ antagonist such as aprepitant will increase the rate of antiemetic protection.

Serotonin Antagonists: Ondansetron, Granisetron(Drug information on granisetron), and Palonosetron

TABLE 1Emetic potential of chemotherapy agents

TABLE 2Dosage and administration schedules of antiemetic agents for acute emesis for chemotherapy of high emetic risk

Ondansetron, granisetron, and palonosetron are highly selective 5-HT₃ receptor antagonists. All are effective in controlling emesis induced by a variety of chemotherapeutic agents. Oral and intravenous routes of administration available for ondansetron(Drug information on ondansetron), granisetron, and palonosetron are effective, as demonstrated in large randomized trials. Granisetron is also now available as a transdermal patch (Sancuso). Single-dose regimens given before chemotherapy appear to be as effective as more cumbersome multiple- or continuous-dose regimens.

All three serotonin receptor antagonists are similar with regard to efficacy and side effects, although palonosetron has a significantly longer half-life of approximately 40 hours and may exhibit more noncompetitive binding and greater efficacy against delayed emesis. Doses of these agents are given in Table 2.

Side effects

Ondansetron, granisetron, and palonosetron have all demonstrated excellent safety characteristics over a large dosing range. Toxicities have been minor and have included headache, mild transient elevation of hepatic enzyme levels, constipation and, with some agents, prolongation of cardiac conduction intervals (particularly QT_c intervals).

Dystonic reactions and akathisia (restlessness), which may be treatment-limiting with antiemetic agents known to block dopamine(Drug information on dopamine) receptors, are not seen with serotonin antagonists, even when given on consecutive days. This finding is of particular importance for younger patients, in that several regimens used to treat malignancies in this age group use a schedule of daily chemotherapy.

Efficacy

The serotonin antagonists have been reported to achieve complete control of emesis in 30% to 50% of patients receiving cisplatin. These agents have also proved to be at least as effective against other chemotherapeutic agents, with complete control rates of about 70%.

Many trials have examined the benefit of adding corticosteroids to a serotonin antagonist. Typically, the complete control of emesis is improved by 10% to 20% in patients receiving highly emetic chemotherapy. Both the American Society of Clinical Oncology and the MASCC guidelines recommend that a corticosteroid be added whenever a serotonin antagonist is indicated (ie, in all patients receiving chemotherapy of high emetic risk).

Dexamethasone

The antiemetic mechanism of action of dexamethasone remains unclear. Several randomized trials and a meta-analysis have all confirmed its effectiveness in controlling emesis and its safety. Other corticosteroids, such as methylprednisolone, are also effective; however, dexamethasone is the most widely studied corticosteroid and it is available in oral and parenteral dosage forms as an inexpensive generic product. Dexamethasone is an excellent agent for use in combination antiemetic regimens and as a single agent for patients receiving chemotherapy of low emetic risk (< 30% incidence).

Dosage

Dexamethasone dosages have generally ranged from 4 to 20 mg/d. In a randomized trial in patients receiving chemotherapy of high emetic risk, a single 20-mg dose was superior in completely controlling both nausea and vomiting. Thus, the 20-mg dose is recommended in this setting. For patients receiving chemotherapy of moderate emetic risk, a single 8-mg dose may be used. In patients receiving aprepitant, which inhibits dexamethasone metabolism, a lower dose of dexamethasone may be sufficient.

Side effects

Toxicities associated with short courses of dexamethasone used for antiemetic therapy have been mild and generally consist of insomnia and mild epigastric burning. Care using this agent in patients with diabetes is particularly warranted.

Metoclopramide

Metoclopramide has proved to be generally safe and effective when given in high intravenous doses. Metoclopramide was thought to function as an antiemetic through blockade of dopamine receptors. However, high concentrations of this agent effectively block 5-HT₃ receptors as well.

Efficacy

High-dose metoclopramide is a second-choice agent, after the serotonin antagonists, in patients receiving cisplatin.

Side effects

Commonly observed side effects with metoclopramide include mild sedation, dystonic reactions, akathisia, anxiety, and depression. Dystonic reactions are age-related and route-related. In a report summarizing the experience of nearly 500 patients receiving metoclopramide, the incidence of trismus or torticollis was only 2% in those older than 30 years; in contrast, a 27% occurrence was reported in younger patients. Also, such reactions are more common when metoclopramide is administered by the oral route or is given over several consecutive days.

Acute dystonic reactions are not allergic in nature. Dystonic reactions and akathisia can be prevented or controlled by administering diphenhydramine(Drug information on diphenhydramine), benztropine (Cogentin), or a benzodiazepine. These reactions should not be viewed as a contraindication to further use of dopamine-blocking drugs.

Haloperidol

Haloperidol exerts its antiemetic action through dopaminergic blockade. A formal study comparing haloperidol with metoclopramide in patients receiving cisplatin found both agents to be effective, although metoclopramide afforded better emetic control. Haloperidol should therefore only be used as a salvage agent.

Dosage

Haloperidol in doses of 1 to 3 mg given intravenously every 4 to 6 hours has been used.

Side effects

Toxicities of haloperidol include sedation, dystonic reactions, akathisia, occasional hypotension, and cardiac conduction defects.

Benzodiazepines

Although lorazepam and other benzodiazepines are potent anxiolytic agents that can be useful additions to antiemetic therapy, they should not be used as single agents for chemotherapy-induced emesis. Lorazepam has been shown to achieve a high degree of patient acceptance and subjective benefit but only minor objective antiemetic activity. However, the anxiolytic properties of benzodiazepines may be particularly useful in the treatment of anticipatory nausea and vomiting.

Dosage

Lorazepam is usually given in doses of 0.5 to 1.5 mg/m² intravenously or 0.5 to 2 mg orally. These doses, especially the higher intravenous doses, can be associated with marked sedation lasting for several hours.

Cannabinoids

Many trials have tested the antiemetic effects of dronabinol (delta-9-tetrahydrocannabinol), a component of marijuana. Dronabinol has modest antiemetic activity, similar to that seen with oral prochlorperazine, but it may have a greater effect against nausea.

Semisynthetic cannabinoids such as nabilone have been tested but appear to have no clear advantage over dronabinol. The modest antiemetic activity and significant toxicity of cannabinoids make them a second choice for the control of chemotherapy-related emesis.

Dosage

Dronabinol has been tried in many doses and schedules. The most useful doses have ranged from 5 to 10 mg/m² orally every 3 to 4 hours. The usual dose of nabilone is 1 to 2 mg orally twice daily.

Side effects

Side effects frequently associated with cannabinoids, particularly in older adults, include dry mouth, sedation, orthostatic hypotension, ataxia, dizziness, euphoria, and dysphoria.

Phenothiazines

Although phenothiazines were the first effective antiemetics, the results of antiemetic trials with this class of agents against highly emetogenic chemotherapy have been poor. Randomized trials have found standard-dose prochlorperazine, given orally or intramuscularly, to be less effective than metoclopramide or dexamethasone and equivalent to or less effective than dronabinol. Intravenous administration is more effective than oral administration but can rarely cause profound hypotension (unlike serotonin antagonists or metoclopramide). Phenothiazines are seldom used as first-line antiemetic agents for highly or moderately emetogenic chemotherapy.

Side effects

Side effects of phenothiazines include sedation, akathisia, hypotension, and dystonic reactions.

NK₁ Antagonists

Aprepitant and fosaprepitant are the two NK₁ antagonist antiemetics currently available. NK₁ antagonists have demonstrated activity against a wide range of emetogenic stimuli. Although less effective than serotonin antagonists as single agents against acute emesis, NK₁ antagonists have shown superior activity against delayed emesis, suggesting the value of combination therapy.

In a multicenter, randomized, double-blind, phase III trial, 866 breast cancer patients being treated with cyclophosphamide with or without doxorubicin(Drug information on doxorubicin) or epirubicin(Drug information on epirubicin) were randomized to receive either a regimen of aprepitant (125 mg), ondansetron (8 mg bid), and dexamethasone (12 mg) on day 1 with aprepitant (80 mg/d) on days 2 and 3 or a standard regimen of ondansetron (8 mg bid) on days 1 to 3 and dexamethasone (20 mg) on day 1. Of the 857 evaluable patients, 50.8% in the aprepitant arm vs 42.5% in the standard-regimen arm achieved a complete response (P = .015). In addition, more patients in the aprepitant arm achieved a complete response during both acute (75.7% vs 69%; P = .034) and delayed (55.4% vs 49.1%; P = .064) phases. Both treatments were generally well tolerated.

In a recent randomized, double-blind, phase III trial, a single 150-mg dose of intravenous fosaprepitant was found to be equivalent to a 3-day oral aprepitant regimen when administered with ondansetron and dexamethasone against highly emetogenic chemotherapy.

Phase III trials of netupitant and rolapitant are ongoing.