Management of Nausea and Vomiting

April 1, 2005

The development of new and effective antiemetic agents has contributed to significant progress in the supportive care of cancer patients. Discoveries made in the last decade have changed our view of chemotherapy-induced nausea and vomiting from an inevitable problem or the norm to an exceptional and unacceptable occurrence.

Types of EmesisPhysiologyFactors Influencing EmesisMethodology of Antiemetic TrialsAntiemetic AgentsCombination RegimensManagement of Delayed EmesisManagement of Anticipatory EmesisOther Management ConsiderationsReferences

The development of new and effective antiemetic agents has contributed to significant progress in the supportive care of cancer patients. Discoveries made in the last decade have changed our view of chemotherapy-induced nausea and vomiting from an inevitable problem or the norm to an exceptional and unacceptable occurrence.

In this section, we will review the types of chemotherapy-induced nausea and vomiting, their physiology, factors that affect emesis and its control, the antiemetic agents available-with a major emphasis on new advances-and an up-to-date approach to the management of this problem.

Types of Emesis

Chemotherapy causes three types of emesis. The first, most common, and best understood is acute emesis, arbitrarily defined as emesis occurring within the first 24 hours of chemotherapy. Despite major advances in its management, acute emesis still occurs in one third of patients receiving high doses of cisplatin (Platinol) and may cause patients to refuse further therapy [1,2].

The second type of chemotherapy-related emesis is delayed emesis, defined as emesis occurring 24 hours or more after chemotherapy administration. The physiology of delayed emesis is poorly understood. Known risk factors for delayed emesis include female sex, a cisplatin dose exceeding 100 mg/m², and prior acute emesis following chemotherapy [3]. Delayed emesis has been reported in 20% to 50% of all cisplatin-treated patients and in up to 93% of patients treated with high-dose cisplatin [4–6]. This emetic syndrome may affect patients who do not have acute emesis and may be quite severe. In one study, delayed emesis necessitated hospital readmission in 11% of patients treated with high-dose cisplatin [7]. The occurrence and patterns of delayed emesis following non-cisplatin chemotherapy have not been well described.

The third type of chemotherapy-related emesis is anticipatory emesis, which begins prior to the administration of chemotherapy, usually in patients whose emesis was poorly controlled during a previous chemotherapy cycle. Anticipatory emesis affects nearly 25% of patients who have received several rounds of chemotherapy [8] and is believed to be a conditioned response to the hospital environment or other treatment-related associations.

Physiology

Neurologic structures involved in the chemotherapy-induced emetic reflex include the vomiting center, or emetic center, in the lateral reticular formation of the medulla; the chemoreceptor trigger zone (CTZ) in the area postrema of the medulla; the cerebral cortex; and the vagal and splanchnic afferents from the gut to the vomiting center and CTZ [9].

The vomiting center is the final common pathway for vomiting stimuli and coordinates the act of vomiting. This reflex center receives stimuli from the vestibular areas, the pathway involved in motion sickness; from the cerebral cortex, the pathway believed to be involved in anticipatory vomiting; from the CTZ; and from the gut through vagal and greater splanchnic afferents.

Because the CTZ is in the area postrema, an area of the medulla characterized by the absence of an effective blood-brain barrier, this center may be directly stimulated by chemotherapeutic agents or their metabolites. Until recently, such stimulation was considered the fundamental emetogenic mechanism in patients receiving chemotherapy. However, evidence now shows that chemotherapeutic agents induce vomiting by stimulating neuroreceptors in the gastrointestinal tract as well.

Early research focused on dopamine receptors because of the therapeutic benefit obtained from two types of dopamine-receptor antagonists, the phenothiazines and metoclopramide. The histaminic and muscarinic receptors were also known to be involved [10,11]. However, because metoclopramide lacks activity as an antiemetic at low doses, despite adequate dopamine-receptor blockade, the role of dopamine receptors was questioned. At higher doses, metoclopramide becomes more effective and displays significant antagonism against serotonin receptors [12].

Serotonin has since been identified as the principal mediator of chemotherapy-induced emesis. Subsequent investigations have allowed separation of efficacy, eg, serotonin-mediated effects, from toxicity, eg, dopamine-mediated effects. More recently, attention has shifted to the 5-hydroxytryptamine (5-HT3), or serotonin type-3, receptor. Recent receptor-binding studies have identified four distinct receptors, some of which possess distinct subtypes [10].

Figure 1 provides a new model of the pathogenesis of chemotherapy- and radiotherapy-induced emesis [13]. Enterochromaffin cells of the gastrointestinal tract, when damaged by chemotherapy or radiotherapy, release serotonin, which activates peripheral and/or central 5-HT3 receptors. Receptors for 5-HT3 have been found in vagal afferents from the upper gastrointestinal tract and in neurons of the area postrema [14]. Urinary 5-hydroxyindoleacetic acid (5-HIAA) is derived mainly from serotonin in the gastrointestinal tract, and 80% of total body serotonin is found in the enterochromaffin cells of the gastrointestinal tract close to the vagal afferents. In clinical studies, urinary 5-HIAA levels increased significantly in patients treated with cisplatin, and these increases correlated with the number of vomiting episodes [13].

FIGURE 1: Pathogenesis of chemotherapy- and radiotherapy-induced emesis. Enterochromaffin cells of the GI tract, when damaged by chemotherapy or radiotherapy, release serotonin, which acitvates peripheral and/or cerebral receptors for 5-hydroxytryptamine (5-HT2), or serotonin type 3. CTZ = chemoreceptor trigger zone. Adapted from Cubeddu et al [130].

Agents that block 5-HT3 receptors control emesis caused by non-cisplatin chemotherapy and by abdominal irradiation. Research continues on 5-HT3 and other neuroreceptors, such as the opiate µ receptors, which may be important in other emetogenic circumstances, as shown in Figure 2.

FIGURE 2: Central, peipheral, and humoral pathways of emesis and some of the neuroreceptors believed to be involved in the pathogenesis of chemotherapy-induced nausea and vomiting. Major physiologic pathways are indicated by the larger arrows. CTZ - chemoreceptor trigger zone; 5-HT3 = 5-hydroxytryptamine; GABA = gamma-aminobutyric acid.

Factors Influencing Emesis

Factors that affect emesis and its control can be divided into those inherent to the patient and those related to the chemotherapeutic regimen or the antiemetic program, as shown in Table 1 [15]. An appreciation of these factors should assist the clinician in selecting the appropriate antiemetic regimen and the investigator in interpreting and designing clinical studies.

Prior exposure to chemotherapy
Age
Gender
History of alcohol abuse
History of motion sickness

Emetogenic potential and pattern of each agent
Dose, route, schedule
Combination of agents

Efficacy and side effects
Dose, route, schedule
Combination of agents
Concomitant nonpharmacologic agents

Factors predisposing patients to emesis include younger age [15], female sex [15], and susceptibility to motion sickness [16]. Prior chemotherapy, particularly with poor control of emesis, increases the likelihood of emesis with subsequent treatments, independent of the anticipatory component [17]. In one prospective and two retrospective studies, acute emesis was more easily controlled in chronic heavy drinkers (ie, those who consumed more than 100 mg of alcohol [five mixed drinks] daily) than in other patients [18,19].

Age also influences the patient's predisposition to antiemetic side effects. Patients younger than 30 years have a 13-fold greater risk of extrapyramidal side effects from dopamine-receptor antagonists than do older patients (27% vs 2%) [20]. When these drugs are used for several consecutive days, dystonic reactions are even more common [21].

Chemotherapeutic agents differ in their emetic potential and cause different patterns of emesis onset and duration. Cisplatin tends to cause almost immediate acute emesis, whereas the acute emesis associated with cyclophosphamide tends to have a more delayed onset, usually 8 to 12 hours after drug administration [22]. Table 2 groups agents into four categories according to their emetogenic potential.

AgentOnset (h)Duration (h)
Cisplatin1-624-48
Dacarbazine1-31-12
Mechlorethamine0.5-28-24
High-dose melphalan3-66-12
Carmustine2-44-24
Cyclophosphamide4-1212-24
Procarbazine24-27Variable
High-dose etoposide4-624+
Doxorubicin4-66+
Mitoxantrone4-66+
Fluorouracil3-624+
Carboplatin4-612-24
Bleomycin3-6-
Cytarabine6-123-5
Etoposide3-8-
Melphalan6-12-
Ifosfamide1-2Extended
Mercaptopurine4-8-
Methotrexate4-123-12
Mitomycin1-448-72
Vinblastine4-8-
Vincristine4-8-
Chlorambucil48-72-

The emetogenic potential and pattern of any chemotherapeutic agent can vary, sometimes markedly, based on the dose, route, and schedule of administration. Melphalan (Alkeran), for example, has low emetogenic potential at standard doses but becomes intensely emetogenic at high doses. When agents are given in daily, fractionated doses or by continuous infusion, the intensity of the emetic reactions is generally lowered, but emesis is more prolonged. Combinations of chemotherapeutic agents result in more intense emesis and more complex emetic patterns. Knowledge of the emetic intensity and pattern of a chemotherapeutic regimen (peak activity, duration, and delayed phase) is fundamental to the planning of appropriate antiemetic therapy.

Furthermore, the efficacy and adverse effects of antiemetics vary with the dose, route, and schedule of administration and with the other agents or nonpharmacologic therapeutic modalities with which they are combined. These things may also affect the pattern of emesis following chemotherapy.

Methodology of Antiemetic Trials

Because of the subjectivity of endpoints such as nausea and the multiplicity of potential variables, the most suitable type of study for assessing antiemetics is a prospective, randomized, double-blind, parallel group trial with stratification for established prognostic factors [15,23,24]. Crossover studies are complicated by the loss of participants on the second course, the influence of the first course outcome on the response to the crossover regimen, and the impossibility of assessing efficacy during subsequent courses. These limitations offset the advantages that crossover studies offer-namely, the requirement for smaller patient populations and the ability of participants to express their preference for one regimen. Trials with a placebo-controlled arm in highly emetogenic chemotherapy are unethical.

Close attention should be paid to trial design and the manner in which endpoints are chosen, defined, and evaluated. Ideally, trials should stratify participants for variables such as age, sex, prior chemotherapy, emetogenicity of chemotherapy, cancer type, and history of chronic alcohol abuse. Whether episodes of dry retching are included with vomiting episodes will affect the end result of the study and, eventually, how effective a drug is considered to be. The only objective endpoint in antiemetic trials remains complete absence of nausea and vomiting.

Assessment of response to antiemetic therapy is becoming more standardized [15] as descriptors such as “mild” or “severe” are being replaced with more objective definitions. “Complete response” is defined as no vomiting or dry retching episodes in 24 hours, and “major response” as only one or two such episodes. The assessment of nausea by means of visual analog scales also is more objective and reliable.

During the development of the 5-HT3-receptor antagonists, control of vomiting, not of nausea, was the primary endpoint. Since strict criteria for rescue treatment were used, dose-finding studies usually established a partially effective dose rather than a completely effective dose. Also, these drugs were compared with cocktails containing corticosteroids, benzodiazepines, or diphenhydramine. Matching an antiemetic treatment that is given once a day, ie, granisetron (Kytril) or tropisetron, with a cocktail requires that the patients receive placebo injections or dummy drugs. This has been difficult to justify, and, thus, many trials have been unblinded [25].

Antiemetic Agents

In general, antiemetic therapy consists of a combination of agents. Table 3 summarizes the doses, schedules of administration, and side effects of the most commonly used agents.

AgentDose/RouteFrequencyMajor side effects
Granisetron40 µg/kg IVDailyHeadache, constipation
1 mg PODaily
Ondansetron0.15 mg/kg IV4-8 hHeadache, constipation
8-32 mg IVDaily
8 mg (1 mg/h) IVContinuous
8 mg PO8 h (tid)
Tropisetron5 mg IV/PODailyHeadache, constipation
Metoclopramide2-3 mg/kg IV2-3 hDystonia, akathisia, hypotension, sedation, extrapyramidal reactions, diarrhea
1-3 mg/kg PO3-4 h
20 mg PO8 h (tid)
Haloperidol1-3 mg IV2-6 hDystonia, akathisia, hypotension, sedation
1-2 mg PO3-6 h
Droperidol0.5-2 mg IVq4hExtrapyramidal reactions
Prochlorperazine5-10 mg PO3-4 hExtrapyramidal reactions, sedation, dystonia, hypotension, anticholinergic effects, akathisia
10-20 mg PO8-12 h
25 mg rectally4-6 h
10-20 mg IM3-6 h
Chlorpromazine25-50 mg PO3-6 hExtrapyramidal reactions, sedation, dystonia, hypotension, anticholinergic effects, akathisia
25 mg IM/IV3-6 h
Thiethylperazine10 mg PO/rectally4 hExtrapyramidal reactions, sedation, dystonia, hypotension, anticholinergic effects, akathisia
Dexamethasone10-20 mg IVDailyHyperglycemia, euphoria, insomnia, rectal pain
4 mg PO4-12 h
Methylprednisolone250-500 mg IVDailyHyperglycemia, euphoria, insomnia, rectal pain
Lorazepam0.025 mg/kg IV4-8 hSedation, amnesia, confusion, hypotension
1-2 mg PO4-8 h
Diphenhydramine25-50 mg IV/PO6 hAnticholinergic effects, sedation
Delta-9-tetrahydrocannabinol (dronabinol)5-10 mg/m² PO3-4 hDysphoria, confusion, ataxia, hypotension, tachycardia, hallucination
Nabilone2 mg PO6-12 hDysphoria, confusion, ataxia, hypotension, tachycardia, hallucination

Phenothiazines

Phenothiazines, which include prochlorperazine and chlorpromazine, were the first antiemetics to be used to control chemotherapy-induced emesis. However, at standard doses, they are clearly inferior to other available agents, including ondansetron (Zofran), granisetron, tropisetron, metoclopramide, dexamethasone, and tetrahydrocannabinol [26-31]. Phenothiazines prevent emesis by blocking dopamine type-2 receptors in the CTZ. The advantage of the phenothiazines is their convenience of administration: These agents can be given orally, intramuscularly, intravenously, or rectally. Like metoclopramide, phenothiazines may become more effective when given at higher doses [32], but their adverse effects also are likely to become more pronounced. Side effects include extrapyramidal symptoms, dystonic reactions, akathisia, sedation, anticholinergic effects, and orthostatic hypotension.

Substituted Benzamides

Of the substituted benzamides, metoclopramide is the most frequently used for controlling chemotherapy-induced emesis. Its failure at low doses, as demonstrated by the lack of superiority over placebo [33], called into question both the prominent role of dopamine receptors in chemotherapy-induced nausea and vomiting and the old theory that emesis was induced by decreased lower esophageal sphincter tone and delayed gastric emptying.

In the early 1980s, high-dose metoclopramide was demonstrated to be safe and effective in treating chemotherapy-induced emesis [17]. At a dosage of 1 to 3 mg/kg IV every 2 hours, metoclopramide was superior to placebo and to prochlorperazine in cisplatin-treated patients [26]. High-dose metoclopramide then became the gold standard for treatment, and comparative studies demonstrated its superiority over all other antiemetics available until the late 1980s. As a single agent, high-dose metoclopramide achieves complete control of emesis in up to 40% of patients receiving high-dose cisplatin [26]. Combined with dexamethasone, high-dose metoclopramide completely controls emesis in up to 60% of patients [34,35].

Side effects such as extrapyramidal symptoms (especially dystonia in younger patients) and akathisia are a major problem [20]. These effects may be prevented by the addition of an antihistamine, such as diphenhydramine, or lorazepam [36]. Another disturbing side effect is diarrhea, which can be significantly reduced by the addition of dexamethasone [34].

High-dose oral metoclopramide appears to be safe and as effective as the intravenous form [37-39]. It is not approved by the US Food and Drug Administration (FDA) as an antiemetic, however. Oral metoclopramide, like all oral antiemetics, should be used only as a prophylactic measure or in patients who fully respond to this route of administration, since nausea and vomiting might preclude its intake. An intranasal preparation is under investigation [40].

Serotonin-Receptor Antagonists

There are two FDA-approved 5-HT3-receptor-selective antagonists available for the prevention and treatment of chemotherapy-induced nausea and vomiting. Ondansetron and granisetron are available in the United States intravenously and orally. A third such drug, tropisetron, is available in both forms only in Europe. The pharmacologic profiles of these three agents are somewhat different [41,42], but no clear difference has manifested in the available clinical experience. Their doses and schedules are given in Table 3.

Ondansetron: Ondansetron was the first serotonin-receptor antagonist to be approved by the FDA for chemotherapy-induced nausea and vomiting. With various intravenous schedules, ondansetron achieved complete control of emesis in 40% to 75% of patients receiving cisplatin-based chemotherapy, partial control in an additional 20% to 30%, and a significant delay in emesis [13,43-46]. Ondansetron was superior to metoclopramide for multiple-day, cisplatin-based regimens [47]. None of these early studies, however, demonstrated better control of delayed nausea and vomiting by either metoclopramide or ondansetron. Ondansetron has also been tested with the highly emetogenic dacarbazine and is very effective [48-51].

In the United States, intravenous ondansetron has been approved for use at a dosage of 0.15 mg/kg every 4 hours for a total of three doses. This agent, however, is active at a broad range of doses and has marked flexibility. The most effective dose and schedule have not yet been determined. Single daily doses (8 or 32 mg) and continuous low-dose infusions have been found to be equally effective [52].

In a recent multicenter, stratified, randomized, double-blind, parallel-group study evaluating 699 patients treated with cisplatin, a single 32-mg dose of ondansetron was somewhat more effective than a single 8-mg dose and at least as effective as the standard regimen of three 0.15-mg/kg doses [53]. However, a similarly designed European study did not show any significant difference among single 8- or 32-mg doses or an 8-mg dose followed by a continuous infusion [54]. Unfortunately, no study has evaluated a single intermediate dose of ondansetron. Single lower-dose schedules may be very cost effective if proved as efficacious as the 32-mg dose.

Ondansetron is also available in oral form (4- and 8-mg tablets). Since its efficacy by this route appears comparable to that of the injectable formulation, at least for non-cisplatin-induced emesis, intravenous administration is not needed in most instances if the oral form is started prior to chemotherapy. In breast cancer patients treated with cyclophosphamide (Cytoxan, Neosar), doxorubicin (Adriamycin, Rubex), and fluorouracil, dosages of 1, 4, and 8 mg three times daily were found effective, with dose-related efficacy and no dose-related increase in toxicity. All three ondansetron dosages were more effective than a conventional, partly intravenous antiemetic regimen given to a fourth group [55].

A larger, multicenter randomized study assessing the same oral dosages in cancer patients who received non-cisplatin therapy showed similar efficacy for the 4- and 8-mg tablets and a dose-effect trend [56]. Two multicenter randomized trials have shown that 8 mg of oral ondansetron twice a day is as effective as 8 mg three times a day for the prevention of nausea and vomiting in cyclophosphamide-based chemotherapy [57,58].

A major advantage of ondansetron is its lack of dystonic reactions and the other extrapyramidal effects seen with dopamine-receptor antagonists such as metoclopramide, butyrophenones, and phenothiazines. The side effects of ondansetron include headache (which is easily controlled by nonnarcotic analgesics), constipation, mild sedation, and a transient increase in serum transaminases. Recent studies have indicated that combinations of ondansetron and prochlorperazine for emesis prophylaxis may increase clearance of cyclophosphamide and cisplatin [59,60].

Granisetron: Dose-ranging studies of granisetron have established that 10 to 40 µg/kg as a single intravenous dose prior to cisplatin chemotherapy achieves complete control of emesis in 40% to 61% of patients, with one third of patients free of nausea, and also significantly delays time to first emetic episode [61,62]. Interestingly, granisetron in these studies also had a positive effect on appetite, with 50% of these patients able to eat within 24 hours of chemotherapy at granisetron doses greater than 10 µg/kg [61].

A randomized, double-blind, phase III trial comparing granisetron (a single intravenous dose of 80 µg/kg) with the combination of metoclopramide, dexamethasone, and diphenhydramine showed equivalent complete control of emesis (46% vs 44%). However, delayed emesis and nausea were controlled slightly better by the cocktail [63]. Other studies comparing the efficacy of 40 µg/kg and 160 µg/kg reported no statistical difference in efficacy or safety between the doses but did document the efficacy of granisetron as a rescue treatment as well as the safety of dosing up to 240 µg/kg within a 24-hour period [64].

While cisplatin produces profound emetogenic effects with 1 to 2 hours of administration, other agents, such as cyclophosphamide or carboplatin, have peak effects at 6 to 18 hours. A single intravenous dose of 40 µg/kg of granisetron given as prophylaxis prior to such moderately emetogenic chemotherapy achieves complete control of vomiting in 68% of patients vs 47% of patients receiving a chlorpromazine and dexamethasone cocktail as prophylaxis [65,66]. Combining granisetron with dexamethasone given intravenously prior to moderately emetogenic chemotherapy provided complete control of vomiting in a recent trial [67].

Two single-blind studies have compared granisetron to various combinations of metoclopramide, dexamethasone, and alizapride (an investigational agent available in the European market), over a 5-day fractionated chemotherapy regimen containing cisplatin [68,69]. Initial complete control of vomiting was superior in the granisetron arm (87% vs 66%). Throughout the 5-day period, control of emesis was seen in 47% to 54% receiving granisetron vs 44% of patients receiving the combination. Extrapyramidal side effects were observed in 5% to 21% of patients receiving the combination therapy.

Two open-label studies have evaluated the efficacy of granisetron (40 µg/kg in a single intravenous dose) over multiple cycles of chemotherapy. Overall, 60% 87% of patients had either no vomiting or only one episode during eight or more cycles of cisplatin-containing chemotherapy, and the incidence of adverse events did not increase with multiple cycles [70,71].

An oral formulation of granisetron was recently released in the United States. A double-blind study comparing the 1-mg oral dose of granisetron given twice a day with a 10-mg oral dose of prochlorperazine given twice a day in moderately emetogenic chemotherapy showed granisetron was significantly better in achieving total control (defined as no emetic episodes, no nausea of any severity, and no need for antiemetic rescue) in both genders and at 24 hours [72]. Moreover, oral granisetron (1 mg twice daily) with or without dexamethasone is as effective as high doses of metoclopramide and dexamethasone for cisplatin-induced emesis [73,74].

Like that of ondansetron, the side effect profile of granisetron is favorable across many different chemotherapy regimens and patient populations [75]. Headache, mild to moderate in severity, has been seen in 15% of patients at doses of 2 to 160 µg/kg. Constipation has occurred in 7%, especially in patients receiving multiple-day therapy. No patients have reported extrapyramidal symptoms. Other adverse effects, such as hypertension, diarrhea, agitation, and somnolence, have been reported in less than 10% of patients [75].

Tropisetron: Tropisetron is currently available only in Europe, where most of the clinical trials have been conducted. The first results reported were from an open-label trial of patients who had experienced severe nausea and vomiting during prior chemotherapy. Complete control of vomiting was seen in 66% of chemotherapy courses at a tropisetron dose of 20 mg (given in two 15-minute intravenous infusions)[76].

Several double-blind dose-finding studies have defined a single 5-mg intravenous or oral dose prior to chemotherapy as effective [42,77]. Other trials have evaluated tropisetron as a single 5-mg intravenous dose on day 1 of chemotherapy followed by 5 mg once daily on subsequent days and compared this with combinations of lorazepam and metoclopramide [78,79]. Complete control of vomiting was seen in 45% to 67% of patients receiving tropisetron vs 22% of patients receiving the cocktail, although the incidence of nausea was equal and delayed nausea and vomiting were not affected.

The efficacy of tropisetron during fractionated or multiple cycles of chemotherapy awaits formal study but can be inferred from many studies to be at least equivalent to that of the other 5-HT3 receptor antagonists available [42].

Comparative Trials: There are few trials comparing the three 5-HT3-receptor antagonists. A recent randomized, double-blind study comparing single doses of granisetron, 10 µg/kg and 40 µg/kg IV, vs three 0.15-mg/kg IV doses of ondansetron in chemotherapy-naive patients receiving cisplatin did not demonstrate any significant differences between treatment groups in control of emesis, nausea, or side effects [80,81].

In another open-label, prospective, randomized trial, no difference was seen between granisetron, 3 mg IV, ondansetron, 24 mg IV [82], or tropisetron, 5 mg IV [83]. Two randomized, double-blind, parallel-group studies comparing granisetron in a single, daily 3-mg IV dose with ondansetron, 8 mg IV two [84] or three [85] times daily for patients receiving cisplatin-based chemotherapy also did not show a difference in efficacy (both greater than 88%). Cost comparisons of these agents with each other and with conventional antiemetics are needed.

Corticosteroids

The mechanism by which corticosteroids act as antiemetics is still unclear. The two corticosteroids most commonly used as antiemetics are dexamethasone and methylprednisolone. Neither has a known therapeutic advantage over the other. Although their role as single agents is minor but definite [27,86], they are essential to some combination antiemetic regimens.

Dexamethasone, at intravenous doses of 10 to 20 mg, improved the efficacy of high-dose metoclopramide in cisplatin-treated patients by 20% [34]. Dexamethasone also improved the efficacy of ondansetron in a similar patient population by 27% (91% vs 64% with ondansetron alone)[87]. However, dexamethasone may decrease the incidence of extrapyramidal side effects of dopamine-receptor antagonists as well as the incidence of diarrhea associated with metoclopramide administration [34].

Dexamethasone and methylprednisolone are safe and well tolerated. Blood sugar monitoring is recommended when corticosteroids are used in diabetics. Acute transient rectal pain has been reported with rapid infusion [40].

Benzodiazepines

The short-acting benzodiazepine lorazepam has a distinctive role in the management of chemotherapy-induced nausea and vomiting. It is a drug with documented antiemetic, amnesic, and anxiolytic effects [88]. When lorazepam was given before and after cisplatin, at doses of 0.025 mg/kg (not exceeding 4 mg), 46% of patients did not recall receiving chemotherapy, regardless of whether they vomited or not, and 80% had no significant anxiety following chemotherapy. These data support the use of lorazepam for the prevention of anticipatory vomiting, although it is not clear whether the prophylactic effect is related to the drug's amnesic properties.

As discussed earlier, lorazepam may also significantly decrease the incidence of dystonic reactions to metoclopramide [36]. Side effects of lorazepam include perceptual disturbances, urinary incontinence, hypotension, diarrhea, sedation, and amnesia.

Antihistamines

The most commonly used antihistamine, diphenhydramine, has modest antiemetic activity as a single agent. Its main use is in antiemetic combinations to reduce the extrapyramidal side effects of dopamine-receptor antagonists. Side effects of diphenhydramine include sedation and anticholinergic effects.

Butyrophenones

The butyrophenones, typified by haloperidol and droperidol, also work by blocking dopamine receptors in the CTZ. At dosages of 1 to 3 mg IV every 2 to 6 hours, haloperidol has definite antiemetic activity, although it is less effective than high-dose metoclopramide in controlling emesis [5,89]. Higher doses of haloperidol given intravenously and more frequently have been reported to achieve better results. Side effects of haloperidol include akathisia, dystonic and extrapyramidal reactions, and hypotension.

Cannabinoids

Tetrahydrocannabinol and nabilone are second-line antiemetics with limited efficacy [28,29,90]. Their mechanism of action is unclear. Side effects, which include euphoria, dizziness, paranoid ideation, and somnolence, are more common in older patients.

Combination Regimens

Combining antiemetics can improve efficacy over that of a single agent or counteract the toxicity of one of the agents. The most effective combinations prior to the availability of the 5-HT3-receptor antagonists generally included a dopamine type-2 neuroreceptor blocker, a glucocorticoid, and an antihistamine and/or a benzodiazepine. The number of agents used and their doses and schedule depended on the expected emetogenic potential and emetic pattern of the chemotherapeutic regimen employed. These antiemetic combinations are the standards against which newer agents have been evaluated. Table 4 lists commonly used antiemetic combinations, including those that employ 5-HT3-receptor antagonists instead of dopamine-receptor antagonists.

Recommended useAntiemetic regimenSchedule

Ondansetron, 0.15 mg/kg IV,

and

and, possibly,40 min prior to chemotherapy
lorazepam, 1.5 mg/m² IV35 min prior to chemotherapy
Acute emesis (cisplatin and non-cisplatin regimens)Ondansetron, 8-32 mg IV,
and30 min prior to chemotherapy
and, possibly,30-45 min prior to chemotherapy
lorazepam, 1.5 mg/m² IV30-45 min prior to chemotherapy
Acute emesis (cisplatin and non-cisplatin regimens, multiple-day regimens)Granisetron, 1 mg IV,
and30 min prior to chemotherapy and daily during chemotherapy
dexamethasone, 20 mg IV40 min prior to chemotherapy
Acute emesis (cisplatin and non-cisplatin regimens, multiple-day regimens)Tropisetron, 5 mg IV day 1, then 5 mg PO daily during chemotherapy,
and30 min prior to chemotherapy
dexamethasone, 8-20 mg IV40 min prior to chemotherapy
Acute emesis (high-dose cisplatin)Metoclopramide, 3 mg/kg IV,
and30 min prior to chemotherapy, followed by a second dose 90 min after chemotherapy is given
and40 min prior to chemotherapy
lorazepam, 1.5 mg/m² IV35 min prior to chemotherapy
Acute emesis (moderate-dose cisplatin, non-cisplatin regimens)Metoclopramide, 2 mg/kg IV,
and30 min prior to chemotherapy, followed by a second dose 90 min after chemotherapy is given
and40 min prior to chemotherapy
or35 min prior to chemotherapy
Delayed emesis (cisplatin)Metoclopramide, 0.5 mg/kg PO,
andOn 1st and 2nd day after chemotherapy is given, then as needed on 3rd and 4th day
andOn 1st and 2nd day after chemotherapy is given
dexamethasone, 4 mg POOn 3rd and 4th day after chemotherapy is given

The enhanced efficacy of combinations over single agents has been demonstrated by the improved management of acute and delayed emesis achieved by adding dexamethasone to high-dose intravenous metoclopramide (60% vs 40%)[34], oral metoclopramide (57% vs 35%)[91], and intravenous ondansetron (91% vs 64%)[87] and by the improved overall efficacy achieved by adding dexamethasone to the butyrophenones [7]. Amelioration of toxicity is exemplified by the decreased incidence of dystonic reactions to dopamine-receptor antagonists when diphenhydramine or lorazepam is added [36]. The incidence of diarrhea from metoclopramide is significantly reduced when it is combined with dexamethasone [34].

Very encouraging early reports suggest that the efficacy of ondansetron may be increased when it is used in combination with other antiemetics. The combination of ondansetron and dexamethasone achieved complete emetic control in 91% of patients receiving cisplatin doses exceeding 50 mg/m², whereas ondansetron alone was completely effective in only 64% of patients [87]. The same combination was recently compared with a three-agent regimen of metoclopramide, dexamethasone, and diphenhydramine and found to be more effective and more tolerable [92]. In another study, the addition of a dopamine-receptor blocker in standard doses appeared to enhance the activity of ondansetron against moderately emetogenic chemotherapy [93].

Tropisetron has been combined with dexamethasone or haloperidol to increase control of both acute and delayed nausea and vomiting in patients receiving cisplatin-based chemotherapy or high-dose alkylating agents [94,95]. Total control of acute nausea and vomiting was increased to 75% with tropisetron and dexamethasone, and delayed nausea and vomiting were also significantly controlled [94]. Haloperidol, 0.5 mg every 12 hours, given with tropisetron improved control of vomiting in the first 24 hours of chemotherapy [95].

Management of Delayed Emesis

Effective therapy for delayed emesis remains inadequate, probably because this problem is not well understood. Regimens with proven efficacy include the combination of oral metoclopramide and dexamethasone (Table 4), which in a double-blind, randomized trial proved to be superior to placebo (81% vs 61%) [90]. Dexamethasone as a single agent has more limited efficacy [91].

Based on the conflicting and inconclusive results of four trials, oral ondansetron alone does not appear promising for the management of delayed emesis [45,96-98]. In contrast, combinations of ondansetron with oral dexamethasone, especially starting 16 hours after chemotherapy administration, protected 86% of patients from acute emesis and 65% from delayed emesis [99]. However, in one randomized, double-blind, multicenter trial, the combination of granisetron and dexamethasone for delayed nausea and vomiting caused by high-dose cisplatin chemotherapy was not significantly different from that of dexamethasone alone [100].

Management of Anticipatory Emesis

Since anticipatory emesis is believed to be a conditioned response that usually occurs in patients in whom emesis was poorly controlled during previous chemotherapy, good control of emesis during the first chemotherapy course remains the most effective means of prevention. Although different approaches have been tried, including behavioral modification therapy, counseling, desensitization, and hypnosis, treating this problem once it has occurred is generally difficult. Pharmacologic therapy has been limited to lorazepam, as previously discussed. Other benzodiazepines, such as alprazolam, may be similarly effective.

Other Management Considerations

Table 5 lists various general principles for the management of chemotherapy-induced emesis. The rationale underlying most of these principles has been given earlier, along with specific examples and recommendations for putting them into practice.

Be aware of the chemotherapy- and patient-related factors that influence the patterns and intensity of emesis, and choose the antiemetic regimen accordingly.

Combinations of antiemetic agents provide better protection; more agents may be required with more intensely emetogenic chemotherapy.

Prevention is more effective than treating established emesis; initiating an appropriate antiemetic regimen before emetogenic chemotherapy also will reduce emesis and anticipatory emesis with subsequent chemotherapy administrations.

Treat emesis for the expected duration with scheduled antiemetics rather than "as needed" administration.

Nonpharmacologic antiemetic modalities may enhance the success of antiemetic therapy.

Limit use of expensive antiemetics; however, control of nausea and vomiting should take precedence over cost.

When dealing with emesis in patients receiving chemotherapy, other causes of nausea and vomiting should always be kept in mind. Cancer patients may develop nausea and vomiting as a result of bowel obstruction, fecal impaction, brain metastasis, leptomeningeal disease, hypercalcemia and other metabolic problems, narcotic analgesics, autonomic neuropathy induced by vinca alkaloids or paraneoplastic syndromes, or advanced cancer itself, independent of other factors [101,102]. These possible causes are particularly relevant to delayed or anticipatory emesis.

Finally, the cost of antiemetic agents should be considered [103,104]. Although newer agents may have shown higher efficacy in selected groups of patients, these agents tend to be more expensive. Older agents with time-honored safety and efficacy may be considerably less expensive and sometimes of equal or better efficacy for specific indications, such as for delayed or anticipatory emesis or with less intensely emetogenic chemotherapy. Thus, as long as control of nausea and vomiting remains optimal, judicious use of the newer, more expensive agents is highly recommended.

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