Prevention and treatment of chemotherapy-induced nausea and vomiting: A review

Key Points

Abstract

Nausea and vomiting (emesis) are among the most distressing side effects of chemotherapy and are associated with significant clinical consequences and decreased health-related quality of life. The likelihood, severity, and duration of nausea and vomiting depend largely on the emetogenic potential of the chemotherapeutic agents. Four distinct types of chemotherapy-induced nausea and vomiting (CINV) have been described: acute, delayed, anticipatory, and breakthrough. The main therapeutic goal in the management of CINV is the prevention of both acute and delayed CINV beginning with the first chemotherapy cycle. Clinical practice guidelines provide specific recommendations for controlling the different types of CINV depending on the emetogenic potential of the chemotherapy regimen being used. Three classes of antiemetics are considered potent and well-tolerated options: 5-HT₃ serotonin-receptor antagonists, corticosteroids, and neurokinin-1-receptor antagonists. A combination of these agents is recommended for patients receiving chemotherapy with high or moderate emetogenic potential. Phenothiazines, butyrophenones, cannabinoids, metoclopramide, and benzodiazepines are also sometimes used to prevent CINV caused by minimally emetogenic chemotherapy or to treat breakthrough CINV. This article reviews the currently available antiemetic agents and clinical practice guidelines for the management of CINV. (Formulary. 2007;42:378–388.)

Four distinct types of CINV have been described: acute, delayed, anticipatory, and breakthrough.^1,6 Clinicians must recognize the differences among these CINV classifications in terms of pathogenesis, onset, and management. The most common type, acute CINV, occurs within 24 hours after chemotherapy treatment. Nausea and vomiting occurring >24 hours after chemotherapy is classified as delayed CINV. Delayed CINV typically persists for several days and is difficult to control. Delayed CINV is more common after cisplatin chemotherapy but can also occur after chemotherapy with carboplatin, cyclophosphamide, ifosfamide, and anthracyclines.^9,10 Anticipatory CINV can develop in patients who have experienced significant CINV during previous chemotherapy cycles.^1–3,6 Anticipatory CINV can be triggered by a number of stimuli, including smells and sights that have been associated with prior chemotherapy cycles. Controlling acute and delayed CINV significantly reduces the problem of anticipatory CINV. Breakthrough CINV can occur despite optimal preventive therapy.^1–3 Breakthrough CINV is typically difficult to control and is associated with a significant decrease in the patient's health-related quality of life.³

ANTIEMETIC DRUGS

Three classes of antiemetic agents are considered to have the highest therapeutic index according to ASCO: the 5-HT₃ serotonin-receptor antagonists, the corticosteroids, and the NK₁-receptor antagonists.¹ These 3 classes of antiemetic agents are highly effective, are associated with few significant adverse events, and can be administered in combination regimens. Dosing schedules for these agents are presented in Tables 2 and 3.^1–3

Palonosetron, the newest 5-HT₃-receptor antagonist, is available only through intravenous (IV) administration. This agent was developed because of its longer serum half-life and higher binding affinity to 5-HT₃ serotonin receptors.²⁴ Palonosetron has not been studied in comparison with metoclopramide administered alone or in combination with dexamethasone. However, this agent has been compared with ondansetron in patients receiving moderately emetogenic chemotherapy.²⁵ In a multicenter, double-blind, phase 3 study, 570 adult patients were randomized to receive a single IV dose of palonosetron 0.25 or 0.75 mg or ondansetron 32 mg. Patients were observed for 120 hours; no other prophylactic therapy was allowed. The primary end point was the proportion of patients who achieved complete response (no emetic episodes and no rescue medications during the 24 hours after chemotherapy). Secondary end points included complete response during the 5 days after chemotherapy (delayed CINV) and overall tolerability. Complete response rates were statistically higher with palonosetron 0.25 mg than with ondansetron during acute (0–24 hours), delayed (24–120 hours), and overall (0–120 hours) periods. Adverse events were similar among the 3 treatment arms, with headache and constipation reported most frequently.

In another study that compared palonosetron with ondansetron in 667 patients, both agents were administered in combination with corticosteroids.²⁶ No difference was observed between the agents on the primary end point (no emetic episodes and no rescue medications administered during the 24 hours after chemotherapy). Patients pretreated with the combination of palonosetron plus dexamethasone had significantly higher response rates during the delayed (24–120 hours) and overall (0–120 hours) periods compared with patients administered the combination of ondansetron plus dexamethasone. Palonosetron was also demonstrated to be as effective as dolasetron in preventing acute emesis (no other antiemetics prescribed) and was significantly better than dolasetron in preventing delayed emesis.²⁷

Palonosetron appears to be equally effective compared with other 5-HT₃-receptor antagonists in preventing acute CINV.^26,27 The clinical trials mentioned earlier compared palonosetron with a single dose of another 5-HT₃-receptor antagonist with a shorter half-life than palonosetron, which favored palonosetron in the delayed and overall control end points.^25–27 More information is needed from prospective studies designed specifically to compare the effects of palonosetron on delayed CINV with the effects of currently recommended therapies, including aprepitant, dexamethasone, and repeated doses of 5-HT₃-receptor antagonists. Palonosetron has not been recommended as a preferred 5-HT₃-receptor antagonist by the most recent guidelines.^1–3

5-HT₃-receptor antagonists are well tolerated, with mild headache, diarrhea, and constipation reported most commonly.^28–31 Somnolence, sedation, and transient asymptomatic elevations of serum transaminases have also been reported. These agents have a favorable drug-interaction profile, with no clinically significant interactions identified to date. None of the agents require dose adjustment in patients with renal or hepatic insufficiency. All currently available agents, except palonosetron, are available in both oral and IV forms. Oral formulations are as effective as IV formulations.^32–34 Ondansetron is also available as an orally disintegrating tablet that disperses rapidly when placed under the tongue and does not need to be swallowed with water.³⁰ This formulation is particularly useful in patients with dysphagia or anorexia.

Corticosteroids. Corticosteroids have been widely studied as single agents and in combination to prevent both acute and delayed CINV (off-label use). Dexamethasone monotherapy is effective in patients receiving drugs with low emetogenic potential.^1–3,35 When used in combination with 5-HT₃-receptor antagonists and/or aprepitant, dexamethasone increases the efficacy of these agents for the prevention of CINV caused by moderate or highly emetogenic chemotherapy.³⁶ A meta-analysis of 32 randomized trials demonstrated the superiority of dexamethasone compared with placebo or no treatment for complete protection from CINV in patients receiving moderately or highly emetogenic chemotherapy.³⁷ In these studies, dexamethasone decreased the incidence of vomiting by approximately 25% to 30%. In an analysis of 22 studies that compared dexamethasone plus a 5-HT₃-receptor antagonist versus a 5-HT₃-receptor antagonist alone, the addition of dexamethasone was observed to decrease the incidence of vomiting by 25%.³⁷

Dexamethasone is the most commonly studied corticosteroid for the prevention of CINV. This agent is available in multiple dosage forms and is inexpensive. However, at equivalent doses, all corticosteroids are similarly effective and safe; therefore, the drugs can be used interchangeably.¹ Single doses of dexamethasone administered for the prevention of acute CINV are well tolerated; however, changes in mood, sleep disturbances, epigastric bleeding, and elevations in glucose levels have been reported.³⁶ Corticosteroids are CYP3A4 substrates, so the plasma concentration and efficacy of these agents can be increased by CYP3A4 inhibitors such as aprepitant.³⁸ For the prevention of delayed CINV, dexamethasone is administered on Days 2 to 4 after patients receive highly emetogenic chemotherapy and on Days 2 and 3 after patients receive moderately emetogenic chemotherapy.^1–3 Adrenal insufficiency has not been observed with these short courses of corticosteroids.

Neurokinin-1-receptor antagonist. Substance P appears to play an important role in the pathogenesis of emesis.¹¹ Aprepitant is the first NK₁ receptor antagonist that blocks the binding of tachykinin substance P to NK₁ receptors.³⁸ These receptors are found in the gut and in the brain stem at the emetic center.

Aprepitant has been approved by FDA for use in combination with a 5-HT₃-receptor antagonist and dexamethasone for the prevention of CINV associated with highly emetogenic therapy. This approval was based on several clinical trials in patients receiving highly emetogenic chemotherapy.^39–41 Patients scheduled to receive high-dose cisplatin were randomized to either the aprepitant regimen (aprepitant, ondansetron, and dexamethasone on Day 1; aprepitant and dexamethasone on Days 2–3; dexamethasone on Day 4) or the control regimen (ondansetron and dexamethasone on Days 1–4).³⁹ During the 5 days of follow-up, complete response rates (no emetic episodes and no rescue medications) were higher overall in the aprepitant group than in the control group (72% vs 61%; P=.003). Complete response rates were also higher in the aprepitant group than in the control group during the acute (Day 1; 88% vs 79%; P=.005) and delayed (Days 2–5; 74% vs 63%; P=.004) phases of CINV. A pooled analysis of 2 randomized clinical trials demonstrated that adding aprepitant (on Days 1–3) to a standard regimen of a 5-HT₃-receptor antagonist on Day 1 and dexamethasone on Days 1 to 4 improved complete response rates (no emesis) during the 5 days after chemotherapy by 20% in patients who received high-dose cisplatin chemotherapy.⁴¹ This analysis also demonstrated that patients who received doxorubicin or cyclophosphamide in addition to high-dose cisplatin experienced a 33% improvement in complete response rates (no emesis) when aprepitant was added to standard antiemetic therapy.

Aprepitant has also received FDA approval for use in combination with a 5-HT₃-receptor antagonist and dexamethasone for the prevention of CINV associated with moderately emetogenic therapy.³⁸ This approval was based on data from a multicenter, double-blind study that compared an aprepitant-containing regimen versus a standard oral antiemetic regimen in 866 patients with breast cancer who were undergoing moderately emetogenic chemotherapy.⁴² Patients were randomized to receive a single dose of aprepitant 125 mg, 2 doses of ondansetron 8 mg, and a single dose of dexamethasone 12 mg on Day 1 followed by aprepitant 80 mg alone on Days 2 and 3, or 2 doses of ondansetron 8 mg and a single dose of dexamethasone 20 mg on Day 1 followed by ondansetron 8 mg every 12 hours on Days 2 and 3. Complete response rates (no emetic episodes and no rescue medications) during the 5 days after chemotherapy initiation were significantly higher in patients receiving the aprepitant regimen than in patients receiving the standard regimen (51% vs 42%; P=.015). Although the overall rate of adverse events was similar between the aprepitant and standard therapy groups (73% vs 75%), patients receiving aprepitant were more likely to experience alopecia (24% vs 22.2%), fatigue (21.9% vs 21.5%), neutropenia (8.9% vs 8.4%), dyspepsia (8.4% vs 4.9%), stomatitis (5.3% vs 4.4%), pharyngolaryngeal pain (3% vs 2.3%), and hot flushes (3% vs 1.4%).

Suggested aprepitant dosing regimens are listed in Tables 2 and 3.^1–3 Healthcare professionals should note that aprepitant is a substrate, a weak-to-moderate inhibitor (dose dependent), and an inducer of CYP3A4.³⁸ Aprepitant also induces CYP2C9. The effect of aprepitant on the pharmacokinetics of orally administered substrates of CYP3A4 is greater than its effect on IV-administered substrates due to first-pass metabolism. Co-administration of aprepitant with corticosteroids, which are CYP3A4 substrates, increases plasma concentrations of the corticosteroids.⁴³ However, clinical practice guidelines caution against dose reduction of corticosteroids if they are used as part of a chemotherapy regimen and not for antiemetic reasons (eg, when used as part of CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] or MOPP [mechlorethamine, vincristine, procarbazine, and prednisone] regimens).¹ Co-administration of aprepitant with inhibitors or inducers of CYP3A4 may result in increased or decreased aprepitant concentrations, respectively, so healthcare professionals should exercise caution when these agents are used concurrently. There has been no evidence that theoretical drug interactions between standard antiemetic doses of aprepitant and chemotherapy agents such as cyclophosphamide and docetaxel, which are partly cleared by CYP3A4, have any clinical significance.^38,44

Aprepitant has been demonstrated to induce the metabolism of warfarin, with a corresponding decrease in the prothrombin time.³⁸ In patients taking chronic warfarin therapy, the INR should be monitored closely for 2 weeks, particularly on Days 7 and 10 after a 3-day aprepitant regimen. Additionally, aprepitant decreases the efficacy of oral contraceptives; therefore, an alternative method of birth control must be used for ≥28 days after administration of the last dose of aprepitant. Aprepitant is well tolerated, with only fatigue and hiccups reported significantly more frequently in aprepitant groups than in standard therapy groups.³⁸

Before the advent of serotonin antagonists, phenothiazines were widely prescribed as antiemetic agents for the management of CINV.¹³ These drugs appear to block dopamine receptors in the chemoreceptor trigger zone. These agents are available in a variety of dosage forms and are inexpensive. Phenothiazines are most appropriate for the management of CINV in patients receiving chemotherapy with a low potential for emesis; these agents can also be used for breakthrough CINV.^1–3 Adverse drug reactions are numerous, including extrapyramidal reactions, liver dysfunction, and extensive sedation.¹³

Butyrophenones, such as haloperidol and droperidol, also work by blocking dopamine receptors in the chemoreceptor trigger zone.¹³ A boxed warning was recently added to the droperidol label stating that cases of QT prolongation and/or torsades de pointes have been reported in patients receiving recommended doses of droperidol; some of these cases occurred in patients with no known risk factors for QT prolongation, and some cases have been fatal.⁴⁵ The updated warning suggests reserving the use of droperidol for patients refractory to other antiemetics and suggests performing a 12-lead electrocardiogram (ECG) at baseline and at 2 to 3 hours after administration of droperidol. Butyrophenones have an unfavorable adverse drug reaction profile, including extrapyramidal reactions, anticholinergic and cardiovascular side effects, and extreme sedation. Butyrophenones are sometimes used (off-label) for the treatment of breakthrough CINV.^1–3

Metoclopramide, which is approved by FDA for the prevention of CINV, provides significant antiemetic effect by blocking dopaminergic receptors in the chemoreceptor trigger zone.^6,13 The agent also increases lower esophageal sphincter tone and gastric motility. Metoclopramide was used extensively at high doses for the prevention of CINV caused by highly emetogenic agents before the development of 5-HT₃-receptor antagonists, which are more effective and less toxic than metoclopramide.^1–3,13 The adverse-effect profile is unfavorable and similar to the other dopaminergic drugs discussed earlier.^1,2,13 High-dose therapy is associated with extrapyramidal effects, especially in patients aged <30 years; therefore, this agent is often administered with diphenhydramine or lorazepam to prevent these effects. Low-dose metoclopramide has been used for the management of CINV caused by low to moderately emetogenic agents and for the management of delayed CINV.³

Cannabinoids are class IIcontrolled substances that are also used for the management of CINV. The mechanism of action of these agents in the prevention of emesis is not completely understood. Exogenous cannabinoids activate the endocannabinoid system.⁴⁶ By binding to CB₁ receptors that are located in the higher cortical centers and in the medulla, cannabinoids may inhibit the release of neurotransmitters involved in nausea and vomiting, including serotonin, dopamine, and substance P. A meta-analysis of 30 randomized, controlled trials that compared cannabinoids (oral nabilone, oral dronabinol, and intramuscular levonantradol) with phenothiazines, butyrophenones, metoclopramide, or placebo in 1,366 patients demonstrated slight superiority of cannabinoids for all comparisons in patients receiving moderately emetogenic chemotherapy.⁴⁷ Cannabinoids were not more effective in patients receiving low or highly emetogenic chemotherapy. In this meta-analysis, patients reported higher preference for cannabinoids regardless of what type of chemotherapy they were receiving. Side effects occurred more often with cannabinoids than with any of the comparator agents and included a "high" feeling, euphoria, sedation and drowsiness, dizziness, dysphoria, depression, hallucinations, paranoia, and hypotension. Co-administration of prochlorperazine can decrease the euphoric side effects of cannabinoids.⁴⁸

Two cannabinoids are currently available in the United States. Nabilone, a synthetic cannabinoid, and dronabinol, a synthetic delta-9-tetrahydrocannabinol, are both approved by FDA for the treatment of CINV. Nabilone was investigated in several clinical studies before the advent of 5-HT₃-receptor antagonists.^49–51 These studies demonstrated that nabilone has efficacy equal to that of metoclopramide and prochlorperazine and that the combination of nabilone plus dexamethasone is more effective than therapy with nabilone alone.^49-51 Dronabinol was also demonstrated to have efficacy equal to that of prochlorperazine, with the combination of these 2 agents superior to either drug used alone.⁴⁸ Cannabinoids are used as options to control breakthrough CINV.^1–3

According to clinical practice guidelines, lorazepam and other benzodiazepines can be used (off-label) as adjunctive antiemetic agents and are not recommended as single agents.^1–3 The antiemetic activity of these agents is likely due to general central nervous system depression, inhibition of the vomiting center, and relief of anxiety.⁶ Because of their amnestic and antianxiety effects, benzodiazepines may play a role in the prevention and treatment of anticipatory CINV; however, no prospective clinical studies have evaluated the efficacy of benzodiazepines in this setting.³ Benzodiazepines have wide patient acceptance and preference and cause minimal toxicity, with sedation reported most frequently.^6,13 Antihistamines such as diphenhydramine are sometimes used (off-label) as adjunctive agents to control breakthrough CINV.^1–3 The antiemetic activity of these agents is due to histamine-receptor antagonism in the chemoreceptor trigger zone. These drugs are inexpensive and well tolerated, with sedation and anticholinergic side effects reported most often.¹³