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Prevention and treatment of chemotherapy-induced nausea and vomiting
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Nov 4, 2011.

INTRODUCTION — Few side effects of cancer treatment are more feared by the patient than nausea and vomiting. Although nausea and emesis (vomiting and/or retching) can result from surgery, opiates, or radiotherapy, chemotherapy-induced nausea and vomiting (CINV) is potentially the most severe and most distressing. Although significant progress has been made, CINV remains an important adverse effect of treatment.

Three distinct types of CINV have been defined, with important implications for both prevention and management:

  • Acute emesis, which most commonly begins within one to two hours of chemotherapy and usually peaks in the first four to six hours
  • Delayed emesis, occurring more than 24 hours after chemotherapy
  • Anticipatory emesis, occurring prior to treatment as a conditioned response in patients who have developed significant nausea and vomiting during previous cycles of chemotherapy

The objective of antiemetic therapy is the complete prevention of CINV, and this should be achievable in the majority of patients receiving chemotherapy, even with highly emetic agents (table 1 and table 2). The three categories of drugs with the highest therapeutic index for the management CINV include type three 5-hydroxytryptamine (5-HT3) receptor antagonists, the neurokinin-1 (NK1) receptor antagonists aprepitant and fosaprepitant, and glucocorticoids (table 3) [1].

The use of these drugs alone and in combination for antiemetic prophylaxis in patients receiving cancer chemotherapy will be reviewed here. The pathophysiology of CINV is discussed separately. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Characteristics of antiemetic drugs".)

CHEMOTHERAPY DRUG EMETOGENICITY — The management of CINV has been greatly facilitated by the development of classification schemes that reflect the likelihood of emesis developing following treatment with particular agents. A 1997 classification scheme gained broad acceptance and was utilized as the basis for treatment recommendations by guideline panels [2].

A modification of this schema was proposed at the 2004 Perugia Antiemetic Consensus Guideline meeting [3]. Chemotherapy agents were divided into four categories (table 1 and table 2):

  • Highly emetic — >90 percent risk of emesis
  • Moderately emetic — >30 to 90 percent risk of emesis
  • Low emetogenicity— 10 to 30 percent risk of emesis
  • Minimally emetic — <10 percent risk of emesis

This drug classification schema is utilized in both the updated antiemetic guidelines of the Multinational Association of Supportive Care in Cancer (MASCC) and the American Society of Clinical Oncology (ASCO) [4,5]. For combination regimens, the emetic level is determined by identifying the most emetic agent in the combination and then assessing the relative contribution of the other agents. As an example, cyclophosphamide and doxorubicin are both moderately emetogenic agents, but when given together, the regimen is highly emetic [2,4,5]. In updated antiemetic guidelines from ASCO, combined anthracycline and cyclophosphamide regimens have been reclassified as highly emetic [5].

The NCI Common Terminology Criteria for Adverse Events (CTCAE) grading schema for classifying the severity of CINV is presented in the table (table 4) [6].

ACUTE EMESIS — Extensive clinical trials have evaluated the 5-HT3 receptor antagonists, aprepitant and fosaprepitant, and glucocorticoids in patients with acute and delayed CINV. These trials have focused primarily on patients receiving either highly or moderately emetic chemotherapy regimens. Although not all antiemetic regimens have been evaluated with all chemotherapy combinations, it is reasonable to extrapolate data to other chemotherapy regimens of comparable emetogenicity.

5-HT3 receptor antagonists — A key advance in the prevention of CINV was the development of selective type three 5-hydroxytryptamine (5-HT3) receptor antagonists, a drug class that has a high therapeutic index for prevention of CINV [1].

Randomized trials have shown that single-agent 5-HT3 receptor antagonists are more effective than less specific agents such as high-dose metoclopramide and as effective as the combination of high-dose metoclopramide and dexamethasone. When 5-HT3 antagonists are used in combination with dexamethasone, they are more effective than high-dose metoclopramide plus dexamethasone [7-10]. In addition to increased efficacy, these agents are easier to administer and are associated with significantly fewer serious side effects than the less specific serotonin inhibitor metoclopramide.

Four first-generation 5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, and tropisetron) and one second-generation agent (palonosetron) are available (table 3). An orally disintegrating formulation of ondansetron also is available that disperses rapidly when placed on the tongue and does not need to be swallowed with water [11]. This formulation may be particularly useful for patients with dysphagia or anorexia. A granisetron transdermal system is also available. (See 'Granisetron transdermal patch' below.)

First generation agents — A large number of randomized trials have clarified the properties of the first-generation 5-HT3 receptor antagonists. Key findings include the following:

  • The first-generation 5-HT3 receptor antagonists all appear equally effective at preventing CINV at the recommended doses. At least two meta-analyses have shown no clear advantage for either ondansetron or granisetron in the prophylaxis of acute or delayed emesis [12,13].
  • There is a plateau in therapeutic efficacy at a definable dose level for each drug, and further dose escalation does not improve outcome [14].
  • A single dose of a 5-HT3 receptor antagonist prior to chemotherapy is therapeutically equivalent to a multiple dose schedule [15-19].
  • The efficacy of 5-HT3 receptor antagonists is significantly improved when they are combined with glucocorticoids. (See 'Glucocorticoids' below.)
  • Oral formulations of these agents are as effective as intravenous formulations [14,20,21].

EKG interval changes and cardiac arrhythmias — EKG interval changes are a class effect of the first-generation 5HT3 antagonists, including ondansetron, granisetron, and dolasetron. They appear to be most prominent one to two hours after a dose of these agents, are mostly small and clinically insignificant, and return to baseline within 24 hours [22-24]. However, potentially fatal cardiac arrhythmias, including torsade to pointes, have been reported in association with QTc prolongation [22,24-26]. The US FDA has issued the following warnings/precautions regarding cardiotoxicity of these agents:

Dolasetron — Due to the risk of QTc prolongation from increased drug exposure the injection form of dolasetron is contraindicated for prophylaxis of CINV in both children and adults [27]. The risk of developing an abnormal heart rhythm with oral dolasetron is less than that seen with the injection form. However, there is still a potential risk.

The US Food and Drug Administration recommends the following precautions in patients receiving oral dolasetron [27]:

  • Potassium and magnesium levels should be assessed, and if abnormal, corrected before initiation of treatment with dolasetron. These electrolytes should be monitored after administration as clinically indicated.
  • Use electrocardiographic monitoring in patients with heart failure, a slow heart rate, underlying cardiac disease, the elderly, and in patients with renal impairment.
  • Use of dolasetron should be avoided in patients with congenital long-QT syndrome (table 5).
  • Drugs known to prolong the PR (eg, verapamil) or QRS interval (eg, flecainide, quinidine) should be avoided in patients taking dolasetron.

Ondansetron — FDA has issued a warning about QTc prolongation and potentially fatal cardiac arrhythmias in patients treated with ondansetron [26]. Revised labeling includes a recommendation to avoid use in patients with congenital long-QT syndrome and to use ECG monitoring in certain patients, including those with hypokalemia or hypomagnesemia, heart failure, bradyarrhythmias, and in patients taking other medications that increase the risk of QTc prolongation (table 5).

Palonosetron — The second-generation agent palonosetron has a 30- to 100-fold higher affinity for the 5-HT3 receptor and a significantly longer half-life (40 hours) compared to first generation 5-HT3 receptor antagonists (table 3). In contrast to first-generation 5-HT3 antagonists, QTc prolongation has not been described with palonosetron [28].

As a single agent, palonosetron is more effective than ondansetron or dolasetron at preventing emesis due to moderately emetic chemotherapy [29-31]. This was illustrated by a multicenter trial in 592 patients, the majority of whom received doxorubicin and cyclophosphamide for breast cancer. Subjects were randomly assigned to a single IV dose of palonosetron at one of two dose levels (0.25 or 0.75 mg IV) or dolasetron (100 mg) [29]. More patients treated with palonosetron (0.25 mg) had complete control of both acute (63 versus 53 percent) and delayed emesis (54 versus 39) compared to dolasetron. A dose of 0.75 mg was not significantly superior compared to 0.25 mg.

When used in combination with glucocorticoids, palonosetron provides superior control of delayed emesis compared to first-generation 5-HT3 receptor antagonists combined with glucocorticoids:

  • In a phase III double-blind, double-dummy trial, 1143 patients receiving cisplatin or an anthracycline/cyclophosphamide combination were randomly assigned to dexamethasone plus either palonosetron or granisetron on day 1 prior to chemotherapy followed by dexamethasone alone on days 2 and 3 [32]. During the acute phase, the rate of complete control of CINV was similar (75 versus 73 percent with palonosetron and granisetron, respectively), but during the delayed phase (24 to 120 hours), complete responses occurred in significantly more patients receiving palonosetron (57 versus 45 percent). An unresolved question arising from this study design is whether the efficacy differences noted would have persisted with the addition of aprepitant, which all evidence-based guidelines recommend in this setting.
  • In a second phase III trial, in which 667 patients receiving cisplatin-based chemotherapy were randomly assigned to palonosetron (0.25 mg), palonosetron (0.75 mg) or ondansetron (32 mg), no significant differences in antiemetic control were noted between palonosetron and ondansetron [33]. Approximately two-thirds of patients received concomitant dexamethasone. In this subset of patients, complete response rates were numerically higher in both palonosetron arms compared to ondansetron during the first 24 hours. During the delayed (24 to 120 hours) phase, complete response was significantly higher on the 0.25 mg palonosetron arm compared to the ondansetron arm (42 versus 29 percent, p = 0.021).

Updated antiemetic guidelines from the American Society of Clinical Oncology (ASCO) recommend palonosetron as the preferred 5-HT3 antagonist for patients who receive moderately emetic chemotherapy [5].

An oral formulation of palonosetron is approved. A non-inferiority trial documented similarity between the oral and IV formulations and validated the correct dose (0.5 mg oral) (table 3) [34].

Aprepitant and fosaprepitant — The introduction of the NK1 receptor antagonist aprepitant has significantly improved the ability to prevent both acute and delayed CINV in patients receiving highly and moderately emetic chemotherapy (table 1 and table 2). A parenteral formulation of aprepitant (fosaprepitant, a water-soluble prodrug of aprepitant) is available in the United States [35]. The initially approved dose was 115 mg IV 30 minutes prior to chemotherapy on day 1 followed by 80 mg of aprepitant orally on days 2 and 3. However, sale of the 115 mg dose was discontinued by the manufacturer as of December 30, 2010; the FDA has approved a single dose fosaprepitant regimen (150 mg on day 1 with no aprepitant on day 2 or 3). (See 'One versus three-day administration' below.)

Cisplatin — The benefit of combining aprepitant with 5-HT3 receptor antagonists and glucocorticoids for the prevention of CINV was initially shown in two phase III trials that included 1099 patients receiving cisplatin-containing chemotherapy (≥70 mg/m2 per cycle) [36,37]. In both trials, patients were randomly assigned to ondansetron (day 1) plus dexamethasone (days 1 to 4) with either aprepitant (125 mg by mouth on day 1, followed by 80 mg orally on days 2 and 3) or placebo. The end point of both studies was complete protection from emesis with no need for any rescue antiemetics.

Acute emesis was blocked more effectively in patients receiving aprepitant (overall 86 percent versus 73 percent with placebo). No benefit was observed in terms of the incidence of nausea (70 versus 68 percent). The aprepitant-containing regimen maintained its advantage in controlling CINV over multiple treatment cycles [38].

Similar results were seen in a third phase III trial, in which patients were randomly assigned to a three-drug regimen including aprepitant, ondansetron, and dexamethasone or to ondansetron plus dexamethasone only [39]. The overall, acute, and delayed complete response rates were significantly better with the aprepitant regimen (72 versus 61, 88 versus 79, and 74 versus 63 percent, respectively) compared to ondansetron plus dexamethasone alone.

Need for a 5-HT3 agent — Although aprepitant improved control of CINV when combined with a 5-HT3 receptor antagonist and dexamethasone, aprepitant plus dexamethasone alone was not as effective as the three-drug combination regimen. A 5-HT3 receptor antagonist remains necessary in patients receiving cisplatin-based chemotherapy.

This was illustrated by a randomized trial in which patients receiving cisplatin chemotherapy were randomly assigned to the combination of aprepitant plus granisetron, granisetron, or aprepitant (on one of two schedules) [40]. All patients also received dexamethasone (20 mg orally) before cisplatin. While the three-drug combination blocked emesis in 80 percent of patients, dexamethasone plus either granisetron or aprepitant were effective in only 57 percent and 43 to 46 percent of cases, respectively.

Doxorubicin and cyclophosphamide — NK1 receptor antagonists are also useful antiemetic agents for patients receiving some combinations of drugs that are classified as moderately emetic agents, such as an anthracycline plus cyclophosphamide (table 1):

  • In a multicenter trial ,866 patients receiving cyclophosphamide plus an anthracycline for breast cancer were randomly assigned to a standard antiemetic regimen consisting of ondansetron plus dexamethasone on day 1 or the same combination plus aprepitant on days 1 through 3 [41]. Significantly more patients receiving the three-drug regimen including aprepitant reported no vomiting (76 versus 59 percent with ondansetron plus dexamethasone), and more achieved a complete response (no vomiting and no use of rescue antiemetics) during both the acute phase (76 versus 69 percent) and the delayed phase (54 versus 49 percent) of the first cycle of chemotherapy.
  • Additional evidence for a role for aprepitant comes from an extension of this trial, in which 744 patients were treated with multiple courses of chemotherapy and 650 completed all four planned cycles of treatment [42]. Significantly more patients achieved a complete response (no vomiting or no use of rescue medication) on the aprepitant regimen for all four cycles compared to ondansetron and dexamethasone alone (34 versus 24 percent).
  • Benefit from aprepitant is also supported by another phase III trial in which 848 patients receiving moderately emetogenic chemotherapy (including 52 percent who received non-anthracycline/cyclophosphamide regimens) were randomly assigned to ondansetron plus dexamethasone with or without aprepitant [43]. Neither group received dexamethasone on days 2 or 3, but the ondansetron group received additional doses of ondansetron (8 mg twice daily) on days 2 and 3. Emetic control was significantly better in the aprepitant group regardless of the type of chemotherapy regimen utilized.

One versus three-day administration — In the United States, both aprepitant and fosaprepitant are approved for use in three-day schedules. A single-day dosing schedule for fosaprepitant was approved by the FDA based upon the results of a phase III trial involving 2247 patients receiving single-day cisplatin (>70 mg/m2) based chemotherapy [44]. The control group received aprepitant administered in the standard three-day schedule along with ondansetron plus dexamethasone; this was compared to a single 150 mg dose of fosaprepitant combined with ondansetron on day 1 plus dexamethasone on days 2, 3, and 4. Complete antiemetic response rates were nearly identical between the aprepitant and fosaprepitant arms (72.3 versus 71.9 percent).

Issues related to inhibition of CYP3A4 — NK1 receptor antagonists such as aprepitant and fosaprepitant are moderate inhibitors of the cytochrome P450 enzyme CYP3A4, which is particularly important in drug metabolism [45].

CYP3A4 is responsible for the metabolism of glucocorticoids, and thus the dose of dexamethasone was reduced in clinical trials from 20 mg to 12 mg on day 1 and from 8 mg twice daily to 8 mg daily on days 2 and 3 when given concurrently with aprepitant [36,37,41]. This dose reduction applies only when glucocorticoids are used as antiemetics in conjunction with NK1 receptor antagonists, not when given as an antitumor component of a chemotherapy regimen [5].

Theoretically, aprepitant could decrease the clearance of drugs metabolized by CYP3A4 (cyclophosphamide, docetaxel, etoposide, irinotecan, vinca alkaloids), resulting in prolonged exposure and increased toxicity. However, there is no clinical evidence that this actually occurs [41,46].

Casopitant — The addition of casopitant, another NK1 receptor antagonist (as a single day-one oral dose or in a mixed intravenous plus oral three day schedule) to dexamethasone and ondansetron also significantly improved control of CINV from highly-emetogenic and moderately emetogenic chemotherapy in randomized phase III trials [47-49]. The relative efficacy of casopitant (which is not commercially available) and aprepitant was not addressed in this or any other trial.

Glucocorticoids — Short courses of glucocorticoids are widely used both as single agents for regimens with low risk of causing CINV and in combination with 5-HT3 receptor inhibitors and/or NK1 receptor antagonists for more emetic chemotherapy regimens. When used in this fashion, glucocorticoids have a high therapeutic index. Although the various glucocorticoids are probably equally effective when used at an appropriate dose, dexamethasone has been the most extensively evaluated and is the most widely used.

Single agent — Single agent dexamethasone has been compared to either placebo or no treatment in a number of randomized trials. A meta-analysis of 32 randomized trials evaluated 5613 patients who received moderately or highly emetogenic chemotherapy [50]. Dexamethasone was superior to placebo or no treatment for complete protection from both acute emesis (risk ratio [RR] 1.30) and delayed emesis (RR 1.30). However, dexamethasone as a single agent is insufficient to control CINV in most of these patients [5].

Combination with a 5-HT3 antagonist — Glucocorticoids alone represent insufficient first-line therapy for patients receiving either moderate or highly emetic chemotherapy agents. However, the antiemetic efficacy of the 5-HT3 receptor antagonists is significantly enhanced by the addition of a glucocorticoid [7,51-55].

Benefit for combined therapy was shown in a meta-analysis of 3791 patients enrolled in 22 randomized trials in which a 5-HT3 receptor antagonist plus dexamethasone was compared with a 5-HT3 antagonist plus placebo or no treatment in patients receiving moderate or highly emetic chemotherapy [50]. The pooled risk ratio for emesis protection was 1.25, indicating that the addition of dexamethasone increased the chance of no acute vomiting by 25 percent.

Dose — The impact of glucocorticoid dose was explored in a double-blind trial that randomly assigned 531 patients receiving cisplatin ≥50 mg/m2 to one of four intravenous doses of dexamethasone administered by a 15-minute infusion prior to cisplatin administration [56]. All patients received 8 mg of ondansetron as well. At doses of 20, 12, 8, and 4 mg, complete protection from vomiting was achieved in 83, 79, 69, and 69 percent of patients, respectively, and nausea was prevented in 71, 67, 61, and 61 percent.

The optimal dose of dexamethasone for highly to moderately emetic chemotherapy not containing cisplatin was evaluated by the Italian Group for Antiemetic Research [57]. In this trial, all patients received IV ondansetron and were randomized to one of three schedules of dexamethasone following chemotherapy (either 8 or 24 mg IV prior to chemotherapy, or 8 mg IV before treatment followed by 4 mg every six hours). Rates of complete protection from acute or delayed emesis were similar among the groups, and the authors concluded that a single 8 mg IV dose prior to chemotherapy represented the appropriate dexamethasone regimen.

As noted above, the dose of dexamethasone is reduced when it is in combination with an NK1 receptor antagonist. (See 'Issues related to inhibition of CYP3A4' above.)

Other agents — Other agents that have been used in the treatment or prevention of CINV include phenothiazines (eg, prochlorperazine) metoclopramide, butyrophenones, and cannabinoids. These agents have a lower therapeutic index than the 5-HT3 receptor antagonists, aprepitant, and glucocorticoids for highly or moderately emetogenic chemotherapy regimens. Their use should be restricted to patients who are intolerant of or refractory to these first line agents. The benefits of synthetic oral cannabinoids in this setting remain controversial given the lack of evidence on their safety and efficacy [58-61]. .Phenothiazines could be used as an alternative to single agent dexamethasone for those receiving chemotherapy with a low risk of emesis, if a glucocorticoid is contraindicated [5]. (See "Characteristics of antiemetic drugs" and 'Poor emesis control' below.)

Other drugs that may be useful as adjuncts to conventional antiemetic agents include lorazepam and diphenhydramine. These are not recommended as single agent antiemetics [5].

Use of the antipsychotic olanzapine for prevention of delayed nausea in patients receiving high-risk regimens is discussed below. (See 'Olanzapine' below.)

DELAYED EMESIS — Delayed emesis is defined by its occurrence more than 24 hours after chemotherapy. Although it is most common following high-dose cisplatin [62-64], delayed emesis may occur with other agents as well [19].

Regimens with a high risk of delayed emesis — The risk of delayed emesis after cisplatin (doses >70 mg/m2) ranges between 60 and 90 percent in the absence of effective prophylaxis. The risk of delayed emesis without any prophylaxis is estimated to be between 20 and 30 percent in patients receiving chemotherapy with an anthracycline plus cyclophosphamide [65].

Although the risk of delayed emesis has been best studied with high-dose cisplatin and the combination of doxorubicin plus cyclophosphamide, other moderately emetogenic agents are also associated with delayed emesis. These include doxorubicin ≥40 mg/m2 as a single agent or ≥25 mg/m2 in combination with other chemotherapeutic agents, epirubicin ≥75 mg/m2 as a single agent or ≥50 mg/m2 when given in combination with other agents, combinations of cyclophosphamide ≥600 mg/m2 in combination with other drugs, carboplatin ≥300 mg/m2, oxaliplatin (as used in the FOLFOX [oxaliplatin plus short-term infusional fluorouracil and leucovorin] regimen for advanced colorectal cancer), and cisplatin at doses between 20 and 50 mg/m2 [19,66-68]. One study found that among 68 patients treated with one of these regimens who had no post-chemotherapy vomiting in the 24 hours after administration of prechemotherapy ondansetron and dexamethasone, 28 (41 percent) vomited in the next four days when no further antiemetics were given [19]. This frequency was reduced to 15 of 75 (20 percent) when ondansetron was continued.

Management — Many of the regimens associated with delayed emesis are classified as high-emetic risk, and guidelines from ASCO recommend the use of an NK1 receptor antagonist (either aprepitant on days 1 to 3 or fosaprepitant on day 1 only), plus a glucocorticoid on days 1 to 4, and a 5-HT3 receptor antagonist on day 1 (table 6) [5]. This regimen is effective against both acute and delayed emesis. The data supporting the individual components of this regimen are reviewed below.

Glucocorticoids — The value of maintenance therapy with oral glucocorticoids following treatment of acute CINV was shown in patients treated with cisplatin-based chemotherapy regimens in at least two randomized trials [62,64]. However, glucocorticoids alone are often not sufficient to prevent delayed emesis.

NK1 receptor antagonists — The addition of aprepitant to dexamethasone for maintenance was superior to maintenance therapy with dexamethasone alone in the two randomized trials that evaluated the efficacy of aprepitant in cisplatin-treated patients, discussed above [36,37]. In another trial, the combination of aprepitant plus dexamethasone on days 2 and 3 was superior to the use of the 5-HT3 receptor antagonist ondansetron plus dexamethasone in preventing delayed emesis [39]. (See 'Aprepitant and fosaprepitant' above.)

The value of aprepitant alone in preventing delayed emesis in patients receiving doxorubicin plus cyclophosphamide was shown in the previously cited multicenter trial of 866 patients treated for breast cancer, in which the addition of aprepitant not only lowered the frequency of acute CINV but also decreased the incidence of delayed emesis during the first cycle of chemotherapy (54 versus 49 percent, without aprepitant) [41]. Glucocorticoids were not administered in conjunction with aprepitant on days 2 and 3 in this trial.

Fosaprepitant is a parenteral formulation of aprepitant that is now available in the United States. The benefit of a single dose fosaprepitant regimen (150 mg on day 1 with no aprepitant on day 2 or 3) for prophylaxis of both acute and delayed emesis in conjunction with a glucocorticoid on days 1 through 4 was shown in a phase III trial of patients treated with cisplatin, as outlined above [44]. (See 'Aprepitant and fosaprepitant' above.)

5-HT3 antagonists — Conflicting results have been described with the use of first generation 5-HT3 receptor antagonists as single agents for protection against delayed emesis [62,69-73]. Although some benefit has been seen when these agents are used as monotherapy, the benefit was not as great as that seen with corticosteroids. Furthermore, continuing a 5-HT3 receptor antagonist beyond 24 hours along with glucocorticoids did not confer additional benefit compared to corticosteroids alone. Thus the use of the 5-HT3 receptor antagonists as a sole maneuver to prevent delayed emesis in patients receiving cisplatin is not recommended.

There is evidence to suggest that the second generation 5-HT3 receptor antagonist palonosetron is superior to other 5-HT3 receptor antagonists for the treatment of delayed emesis due to cisplatin-based chemotherapy:

  • In a phase III trial of patients receiving cisplatin-based chemotherapy, palonosetron (at one of two doses, either 0.25 mg or 0.75 mg) yielded higher rates of emetic control compared to ondansetron in preventing delayed emesis (complete response rates of 45 and 48 versus 39 percent, respectively), although the results were not statistically significant [33]. However, in a subset analysis, palonosetron 0.25 mg was superior to ondansetron for control of delayed and overall emesis in patients receiving concomitant dexamethasone.
  • The superiority of palonosetron for prevention of delayed emesis was also shown in another phase III trial in which 1114 patients receiving cisplatin or an anthracycline/cyclophosphamide (AC) combination were randomly assigned to a single dose of palonosetron or granisetron 30 minutes prior to chemotherapy with all patients receiving dexamethasone for three days [32]. Significantly better control of delayed emesis was achieved in both the cisplatin and AC subgroups on the palonosetron arm (complete response 57 versus 45 percent with granisetron).

Although these results suggest the superiority of palonosetron over other 5-HT3 antagonists for the prevention of delayed emesis, it is unclear whether this difference would persist with the addition of an NK1 receptor antagonist. To date, there are no randomized trials in which the combination of palonosetron and an NK1 receptor antagonist has been compared to a first generation 5-HT3 receptor antagonist plus an NK1 receptor antagonist.

Olanzapine — Conventional antiemetics are more successful at preventing emesis than in preventing nausea. The superiority of the antipsychotic olanzapine over aprepitant for the prevention of delayed nausea was suggested in a phase III trial conducted in 247 patients receiving cisplatin or doxorubicin plus cyclophosphamide [74]. Patients were randomly assigned to olanzapine (10 mg orally on the day of chemotherapy, and then 10 mg once daily on days 2 through 4), or aprepitant (125 mg orally prior to chemotherapy, followed by 80 mg orally on days 2 and 3), both in combination with palonosetron (0.25 IV on the day of chemotherapy) plus dexamethasone. Dexamethasone (20 mg) was only given on the day of chemotherapy, while the aprepitant group received dexamethasone 12 mg on the day of chemotherapy followed by dexamethasone 4 mg twice daily on days 2 and 3.

Following cycle 1, rates of prevention of acute nausea (87 percent in both the olanzapine and aprepitant groups), and of complete control of acute (97 versus 87 percent) and delayed vomiting (77 versus 73 percent) were similar. However, patients treated with olanzapine had a significantly higher rate of nausea control in the delayed period (69 versus 38 percent). The results were maintained during cycles 2 to 4.

While these data are intriguing, these findings need to be replicated in a larger study.

Moderate risk agents — The incidence of delayed emesis following treatment with moderate risk agents other than the combination of cyclophosphamide plus an anthracycline is not well characterized. Other cyclophosphamide or doxorubicin-based regimens, as well as carboplatin and oxaliplatin, can cause delayed emesis. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Delayed emesis'.)

The contribution of aprepitant to control of delayed emesis with these drugs was shown in a phase III trial in patients receiving a broad range of moderate risk agents [43] and demonstrated significantly less delayed vomiting in patients receiving aprepitant.

Glucocorticoids are also consistently useful agents. The value of maintenance dexamethasone was demonstrated in a randomized placebo controlled trial of patients undergoing cyclophosphamide-based chemotherapy [63]. In this trial, 98 patients were given granisetron and dexamethasone before chemotherapy and randomized to receive either oral dexamethasone 4 mg twice daily as maintenance or no maintenance. Maintenance dexamethasone was associated with a higher rate of compete (57 versus 33 percent) and major control (33 versus 15 percent) of delayed emesis.

The 5-HT3 receptor antagonists also have activity as single agents for delayed emesis with cyclophosphamide-based chemotherapy [19]. However, there is no evidence that they are superior to dexamethasone alone or that combination therapy with dexamethasone is superior to dexamethasone alone [65,66].

A randomized trial of 708 patients receiving moderately emetogenic chemotherapy and concurrent antiemetics illustrates the relative roles of dexamethasone and 5-HT3 receptor antagonists in the management of delayed emesis [65]:

  • Patients without acute nausea or vomiting (the low-risk group) were randomized to receive dexamethasone (4 mg orally twice daily on days 2 through 5) plus ondansetron (8 mg orally twice daily on days 2 through 5), dexamethasone alone on the same schedule, or a placebo. Among these 618 patients, there was a complete absence of delayed nausea and vomiting in 92, 87, and 77 percent of patients in the combined therapy, dexamethasone, and placebo groups, respectively. Protection with dexamethasone alone or with dexamethasone plus ondansetron was better than that with placebo; however, the combination was not statistically superior to dexamethasone alone.
  • The key factor in preventing delayed emesis was the control of acute symptoms following chemotherapy. Patients who had either vomiting or moderate to severe nausea in the 24 hours following chemotherapy constituted a high-risk group. These 87 patients were randomly assigned to oral dexamethasone alone or in combination with ondansetron, at the same doses and schedules as in the low-risk group. Despite treatment, complete protection from delayed emesis or moderate to severe was achieved in only 41 and 23 percent of patients treated with the combination and dexamethasone, respectively.

ANTICIPATORY EMESIS — Anticipatory emesis is a conditioned response that occurs in patients who experienced severe nausea and vomiting during prior cycles of chemotherapy [75]. It appears to be induced by sensory cues and cognitive anticipation of subsequent chemotherapy. Anticipatory nausea has also been described among patients who have a high expectation of developing nausea despite never having received chemotherapy [76].

The most effective means to prevent anticipatory nausea or emesis is to ensure good control of acute and delayed emesis, starting from the initial chemotherapy cycle (table 6). Once anticipatory emesis has been established, nonpharmacologic methods (eg, hypnosis, behavioral therapy with systemic desensitization) may be effective [77-79]. (See "Complementary and alternative therapies for cancer".)

Although few formal trials have been carried out, benzodiazepines before and during chemotherapy may be useful [80,81]. In one double-blind trial of 57 women undergoing adjuvant chemotherapy for primary breast cancer for example, the addition of low-dose alprazolam (0.5 mg to 2 mg/day) to a psychologic support program including progressive relaxation training was associated with a significantly reduced rate of anticipatory nausea compared to placebo (0 versus 18 percent) [81].

SPECIAL SITUATIONS

Consecutive day therapy with highly emetogenic agents — When moderately or highly emetogenic chemotherapy is administered on several consecutive days (cisplatin, dacarbazine), prophylaxis is more difficult. This may be due to anticipatory emesis on the subsequent days of therapy or to the compounding of acute and delayed effects of treatment.

The optimal approach in this setting is uncertain. Trials conducted before the availability of aprepitant suggested that repetitive daily dosing with a 5-HT3 receptor antagonist combined with dexamethasone was the best approach [82,83]. Despite the absence of data from trials evaluating aprepitant for multi-day chemotherapy regimens, the addition of aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) could be considered in instances where highly emetogenic chemotherapy agents (cisplatin, dacarbazine) are administered over multiple consecutive days.

Updated ASCO antiemetic guidelines suggest that antiemetics appropriate for the emetogenic risk class of the chemotherapy be administered for each day of the chemotherapy and for two days after, if appropriate [5]. For patients receiving a five-day cisplatin-containing regimen, a 5-HT3 receptor antagonist in combination with dexamethasone and aprepitant (or fosaprepitant) is appropriate. For regimens containing five days of cisplatin (eg, for testicular germ cell cancer), we suggest a daily dose of an oral 5-HT3 receptor antagonist (or granisetron transdermal patch, see below) plus dexamethasone, with the addition of aprepitant or fosaprepitant.

Granisetron transdermal patch — A transdermal preparation of granisetron is available (Sancuso®) that contains 34.3 mg of granisetron and is designed to deliver 3.1 mg of the drug every 24 hours for up to seven days. The efficacy of the granisetron patch relative to daily oral administration of granisetron was shown in a multinational randomized, double-blind, double-dummy controlled trial in which 641 patients receiving the first cycle of a multiday regimen of either moderately or highly emetogenic chemotherapy were randomly assigned to the patch (applied 24 to 48 hours before the first day of chemotherapy) plus a placebo capsule or to oral granisetron (2 mg daily, one hour prior to chemotherapy on each day of chemotherapy administration) plus a placebo patch [84]. Concurrent glucocorticoids, which were administered at the investigator's discretion, were given to about 70 percent of the patients in each arm.

The percentage of patients who had complete control of nausea and vomiting until 24 hours after the last chemotherapy dose was not worse with the transdermal patch (60 versus 65 percent with oral granisetron). Fewer than 1 percent of the patches became detached during treatment. In both groups, the most commonly reported toxicities were constipation and headache.

Based upon this trial, the granisetron transdermal system was approved in the US for the prevention of CINV in patients receiving moderately or highly emetogenic chemotherapy for up to five days. It is recommended that the patch be applied to the upper outer arm a minimum of 24 hours before chemotherapy and removed 24 hours or more after the last chemotherapy dose is administered. It can be worn for up to seven days, depending on the duration of the chemotherapy regimen.

Induction therapy for acute leukemia — High-dose cytarabine regimens (in which cytarabine is administered daily for five or seven days, often with an anthracycline) are the cornerstone of treatment for acute myeloid leukemia (AML). Few studies have addressed the issue of CINV and optimal prophylaxis in this setting [29,85,86]. Although data are lacking, a daily dose of a 5-HT3 receptor antagonist (eg, ondansetron 16 mg) with or without dexamethasone appears to be a reasonable option in this setting.

High-dose chemotherapy regimens — The use of high dose chemotherapy in association with a bone marrow or peripheral blood stem cell transplant presents a special challenge to achieving good antiemetic control. The chemotherapy agents employed are often of moderate to high emetogenic risk.

In addition, there are a number of potential factors that can contribute to an increased incidence and severity of CINV in this setting:

  • Higher doses of chemotherapy
  • Consecutive day administration
  • Prior treatment with chemotherapy
  • Inclusion of radiation therapy (especially total body irradiation), which has high emetogenic risk
  • Associated other medical conditions or medications that may cause emesis

There are few randomized trials specifically studying the issue of emesis in the high dose setting [87-90]. Most studies have focused on the combination of an 5-HT3 receptor antagonist and dexamethasone [91-93]. However, a role for aprepitant in this setting was suggested in a phase III trial in which 181 patients undergoing a preparative regimen for hematopoietic stem cell transplantation were randomly assigned to ondansetron plus dexamethasone and either aprepitant or placebo [90]. Significantly better emetic control was noted in patients who received aprepitant (no emesis and no or mild nausea for the entire study period in 49 versus 15 percent of the placebo group).

The 2011 updated antiemetic guidelines from ASCO suggested a 5-HT3 receptor antagonist plus dexamethasone with consideration of aprepitant in this setting [5].

Poor control of emesis — Despite the use of appropriate antiemetic prophylaxis, many patients experience clinically significant CINV. Before considering any change in the antiemetic regimen, it is important to exclude other disease- and medication-related causes for emesis. Examples include the following:

  • The use of opiate analgesics
  • Certain antibiotics (eg, erythromycin)
  • Central nervous system metastases
  • Gastrointestinal obstruction
  • Hypercalcemia
  • Abdominopelvic radiotherapy

Assuming these factors are excluded, it is important to ensure that the patient is receiving the antiemetic appropriate for the drug(s) being given (table 1 and table 3) and the correct dose (table 3). If the patient was receiving chemotherapy with low emetic risk and is experiencing poor emesis control, it is possible to adjust the regimen to that typically used for a higher risk group. The addition of a benzodiazepine may help to counter increased patient anxiety and possible anticipatory emesis.

The majority of patients who have breakthrough emesis have derived some benefit from the original antiemetic regimen employed. One or two episodes of emesis with cisplatin is less than ideal but still reflects substantial antiemetic efficacy. Thus, the original antiemetic regimens should usually be retained. Additional agents can be added, including lorazepam or alprazolam, olanzapine [94-96], a dopaminergic antagonist (eg, prochlorperazine, thiethylperazine, haloperidol), or substituting high-dose intravenous metoclopramide for the 5-HT3 antagonist [5].

Another alternative is to switch to a different serotonin antagonist, since there may be incomplete cross-resistance between agents [97-99]. This approach was tested in a double-blind trial, in which patients who failed ondansetron plus dexamethasone in the first 24 hours following highly emetogenic chemotherapy were randomly assigned to continue the same treatment or switch to granisetron plus dexamethasone. There was a significantly higher rate of complete protection from emesis in the patients who switched to granisetron (47 versus 5 percent) [97].

In other cases, chemotherapy can be altered. Alterations could include single day instead of multiple day therapy, lengthening infusion time, or substituting a less emetogenic agent if such maneuvers do not compromise antitumor activity.

COMPLEMENTARY THERAPIES

Ginger — Conventional antiemetics are more successful at preventing emesis than in preventing nausea. The benefit of ginger (Zingiber officinale) as an aid to reduce nausea during chemotherapy was addressed in a randomized trial in which 744 patients who experienced nausea following any chemotherapy cycle were randomly assigned to placebo, or supplemental ginger (at doses of 0.5, 1.0 or 1.5 g twice daily) for six days, starting three days prior to the first day of the next two chemotherapy cycles [100]. All patients received a 5-HT3 receptor antagonist on day 1 of all cycles. Two-thirds of the enrolled patients were receiving chemotherapy for breast cancer.

All doses of ginger were associated with a significant reduction in acute nausea throughout day 1 of the chemotherapy cycles, although the largest reduction was seen with the 0.5 and 1.0 g doses. The authors concluded that ginger supplementation significantly aids in reduction of day 1 nausea during chemotherapy.

A benefit for ginger root in conjunction with ondansetron and dexamethasone was also shown in a placebo-controlled randomized trial of 57 children and young adults receiving cisplatin/doxorubicin chemotherapy for bone sarcoma [101]. Compared to conventional antiemetics, the addition of ginger (334 or 800 mg depending on the size of the patient) one hour before, and three and eight hours after the start of chemotherapy significantly reduced the incidence of both acute and delayed emesis.

However, in contrast to these results, a benefit for ginger in addition to conventional antiemetics (5-HT3 antagonists and/or aprepitant) could not be shown in a randomized, placebo-controlled phase II trial of 162 cancer patients who had suffered CINV during at least one prior cycle of chemotherapy [102]. In fact, patients who took ginger plus aprepitant had more severe acute nausea than did those who took only aprepitant.

Acupuncture and related therapies — Several techniques have been used to stimulate the pericardium 6 (P6 or neiguan) site, which is commonly thought to be useful in the management of chemotherapy-induced nausea and vomiting. These include manual stimulation with the insertion of fine needles (acupuncture), electrostimulation, and noninvasive pressure on the skin over the P6 pressure point (ie, acupressure). A 2005 systematic review of randomized trials conducted in patients receiving moderately or highly emetic chemotherapy concluded that acupuncture-point stimulation significantly reduced the proportion of patients with acute vomiting (31 versus 22 percent) [103]. However, the mean number of emetic episodes was not significantly decreased and no benefit was apparent in the control of delayed emesis. Not all studies utilized state-of-the-art antiemetics, and the role of acupuncture and acupressure remains uncertain. These data are discussed in detail elsewhere. (See "Complementary and alternative therapies for cancer", section on 'Nausea and vomiting'.)

Other nonpharmacologic strategies — Findings from randomized controlled trials of reasonable quality provide limited support for several nonpharmacologic methods to reduce CINV, including cognitive distraction (eg, playing video games during treatment), systematic desensitization (a cognitive approach using visualization and learned relaxation techniques), exercise, hypnosis, acupuncture, and transcutaneous electrical nerve stimulation [104,105]. (See "Complementary and alternative therapies for cancer" and "Acupuncture".)

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SUMMARY AND RECOMMENDATIONS

  • Chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of treatment, despite recent advances in prevention. CINV is classified as acute, delayed, and anticipatory, and these distinctions have important implications for patient management. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Types of emesis'.)
  • The most important factor determining the likelihood of acute or delayed emesis developing is the intrinsic emetogenicity of a particular chemotherapy agent (table 1 and table 2). (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Chemotherapy agent'.)
  • The three categories of drugs with the highest therapeutic index for the management of CINV are the type three 5-hydroxytryptamine (5-HT3) receptor antagonists, the neurokinin-1 (NK1) receptor antagonists (aprepitant and fosaprepitant), and the glucocorticoids (especially dexamethasone) (table 3). (See '5-HT3 receptor antagonists' above and 'Aprepitant and fosaprepitant' above and 'Glucocorticoids' above.)

    These agents are used alone (glucocorticoids) and in combinations depending on the specific chemotherapy regimen being administered, as recommended in the ASCO and MASSC/ESMO guidelines [4,5]. (See 'Acute emesis' above.)
  • All of the first-generation 5-HT3 receptor antagonists appear equally effective when used at the recommended dose. An orally disintegrating formulation of ondansetron, one that disperses rapidly when placed on the tongue and does not need to be swallowed with water, may be particularly useful for patients with dysphagia or anorexia.

    EKG interval changes appear to be a class effect of the first generation 5-HT3 antagonists. Their use should be avoided in patients with congenital long-QT syndrome. Potassium and magnesium levels should be assessed, and if abnormal, corrected before initiation of treatment. ECG monitoring is recommended in patients with underlying cardiac disease including heart failure and bradyarrhythmias, and in patients taking other medications that increase the risk of QTc prolongation (table 5). (See 'EKG interval changes and cardiac arrhythmias' above.)

    The second-generation agent palonosetron may be more effective than first generation 5-HT3 antagonists, particularly for prevention of delayed emesis, and QTc prolongation has not been described with palonosetron. In settings when aprepitant is not indicated, available evidence would support palonosetron as the preferred 5-HT3 receptor antagonist. (See '5-HT3 receptor antagonists' above.)

Recommendations — Antiemetic recommendations from ASCO according to the emetogenicity of the chemotherapy regimen are outlined in the table (table 6) [5]. In general, our recommendations parallel these guidelines.

Cisplatin and other high risk agents

  • For patients receiving cisplatin-based chemotherapy or another agent with high emetogenic risk (table 1 and table 2), we recommend therapy with a combination of a 5-HT3 receptor antagonist, dexamethasone, plus a neurokinin-1 (NK1) receptor antagonist (aprepitant or the parenteral form of aprepitant, fosaprepitant) on day 1 (table 3) (Grade 1A). (See 'Cisplatin' above.)

Anthracycline plus cyclophosphamide

  • If aprepitant is used on day 1, we recommend maintenance therapy with a combination of aprepitant on days 2 and 3 and dexamethasone on days 2 through 4 (table 3) (Grade 1B). (See 'Management' above.)

Moderate risk agents and regimens

  • For patients receiving moderately emetogenic chemotherapy (table 1 and table 2), we recommend the combination of palonosetron plus dexamethasone on day 1 (Grade 1A). If palonosetron is not available, clinicians may substitute a first-generation 5-HT3 receptor antagonist. (See 'Combination with a 5-HT3 antagonist' above.)

    To prevent delayed emesis in this population, we suggest single agent treatment with dexamethasone on days 2 and 3 (Grade 2B). If palonosetron is not employed on day 1, treatment with a first generation 5-HT3 receptor antagonist alone is a reasonable alternative. (See 'Moderate risk agents' above.)

Low risk

  • For patients receiving low emetic risk agents (table 1 and table 2), we suggest treatment with dexamethasone (8 mg) as a single agent (Grade 2C). An alternative approach for patients in whom glucocorticoid use is contraindicated or undesirable (such as with the use of long-term weekly chemotherapy) is a single dose of a drug such as prochlorperazine [106]. This patient population generally does not require prophylaxis against delayed emesis. (See 'Glucocorticoids' above.)

Minimal risk

Anticipatory emesis

  • The primary approach to the prevention of anticipatory emesis is the prevention of CINV beginning with the initial cycles of chemotherapy. For patients who do develop anticipatory emesis, we suggest behavioral therapy or benzodiazepines (Grade 2B). (See 'Anticipatory emesis' above.)

High-dose chemotherapy

Multiday regimens

Poor emesis control

  • For patients who do not achieve adequate control of CINV with their initial antiemetic regimen, the patient's management should be reviewed to ensure that there are no other factors responsible for continued emesis and that adequate antiemetic therapy actually was administered for the given chemotherapy regimen. If CINV remains an issue, the addition or substitution of a second line agent or changing from one 5-HT3 receptor antagonist to another may be useful. (See 'Poor control of emesis' above and 'Other agents' above.)

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REFERENCES

  1. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358:2482.
  2. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15:103.
  3. Roila F, Hesketh PJ, Herrstedt J, Antiemetic Subcommitte of the Multinational Association of Supportive Care in Cancer. Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 2006; 17:20.
  4. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21 Suppl 5:v232.
  5. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011; 29:4189.
  6. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) available online at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (Accessed on April 27, 2011).
  7. Heron JF, Goedhals L, Jordaan JP, et al. Oral granisetron alone and in combination with dexamethasone: a double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. The Granisetron Study Group. Ann Oncol 1994; 5:579.
  8. Chevallier B. Efficacy and safety of granisetron compared with high-dose metoclopramide plus dexamethasone in patients receiving high-dose cisplatin in a single-blind study. The Granisetron Study Group. Eur J Cancer 1990; 26 Suppl 1:S33.
  9. Warr D, Wilan A, Venner P, et al. A randomised, double-blind comparison of granisetron with high-dose metoclopramide, dexamethasone and diphenhydramine for cisplatin-induced emesis. An NCI Canada Clinical Trials Group Phase III Trial. Eur J Cancer 1992; 29A:33.
  10. Chevallier B, Cappelaere P, Splinter T, et al. A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy. Support Care Cancer 1997; 5:22.
  11. Davidson N, Rapoport B, Erikstein B, et al. Comparison of an orally disintegrating ondansetron tablet with the conventional ondansetron tablet for cyclophosphamide-induced emesis in cancer patients: a multicenter, double-masked study. Ondansetron Orally Disintegrating Tablet Emesis Study Group. Clin Ther 1999; 21:492.
  12. Billio A, Morello E, Clarke MJ. Serotonin receptor antagonists for highly emetogenic chemotherapy in adults. Cochrane Database Syst Rev 2010; :CD006272.
  13. del Giglio A, Soares HP, Caparroz C, Castro PC. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy-induced nausea and vomiting: results of a meta-analysis of randomized controlled trials. Cancer 2000; 89:2301.
  14. Gandara DR, Roila F, Warr D, et al. Consensus proposal for 5HT3 antagonists in the prevention of acute emesis related to highly emetogenic chemotherapy. Dose, schedule, and route of administration. Support Care Cancer 1998; 6:237.
  15. Seynaeve C, Schuller J, Buser K, et al. Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicentre, double-blind, randomised, parallel group study. Ondansetron Study Group. Br J Cancer 1992; 66:192.
  16. Beck TM, Hesketh PJ, Madajewicz S, et al. Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 1992; 10:1969.
  17. Ettinger DS, Eisenberg PD, Fitts D, et al. A double-blind comparison of the efficacy of two dose regimens of oral granisetron in preventing acute emesis in patients receiving moderately emetogenic chemotherapy. Cancer 1996; 78:144.
  18. Harman GS, Omura GA, Ryan K, et al. A randomized, double-blind comparison of single-dose and divided multiple-dose dolasetron for cisplatin-induced emesis. Cancer Chemother Pharmacol 1996; 38:323.
  19. Kaizer L, Warr D, Hoskins P, et al. Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: a phase III trial by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1994; 12:1050.
  20. Perez EA, Hesketh P, Sandbach J, et al. Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study. J Clin Oncol 1998; 16:754.
  21. Gralla RJ, Navari RM, Hesketh PJ, et al. Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Clin Oncol 1998; 16:1568.
  22. Navari RM, Koeller JM. Electrocardiographic and cardiovascular effects of the 5-hydroxytryptamine3 receptor antagonists. Ann Pharmacother 2003; 37:1276.
  23. Pinarli FG, Elli M, Dagdemir A, et al. Electrocardiographic findings after 5-HT3 receptor antagonists and chemotherapy in children with cancer. Pediatr Blood Cancer 2006; 47:567.
  24. Keller GA, Ponte ML, Di Girolamo G. Other drugs acting on nervous system associated with QT-interval prolongation. Curr Drug Saf 2010; 5:105.
  25. Turner S, Mathews L, Pandharipande P, Thompson R. Dolasetron-induced torsades de pointes. J Clin Anesth 2007; 19:622.
  26. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm272041.htm (Accessed on September 20, 2011).
  27. FDA safety communication available online at http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm (Accessed on December 21, 2010).
  28. Gonullu G, Demircan S, Demirag MK, et al. Electrocardiographic findings of palonosetron in cancer patients. Support Care Cancer 2011.
  29. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer 2003; 98:2473.
  30. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol 2003; 14:1570.
  31. Likun Z, Xiang J, Yi B, et al. A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults. Oncologist 2011; 16:207.
  32. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol 2009; 10:115.
  33. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 2006; 17:1441.
  34. Grunberg S, Voisin D, Zufferli M, et al. Oral palonosetron is as effective as intravenous palonosetron: A phase III dose ranging trial in patients receiving moderatelty emetogenic chemotherapy. Presented at the 14th European conference of Clinical Oncology, Barcelona, Spain, September 23-27, 2007.
  35. Navari RM. Fosaprepitant (MK-0517): a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Expert Opin Investig Drugs 2007; 16:1977.
  36. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol 2003; 21:4112.
  37. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003; 97:3090.
  38. de Wit R, Herrstedt J, Rapoport B, et al. Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol 2003; 21:4105.
  39. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 2006; 17:1000.
  40. Campos D, Pereira JR, Reinhardt RR, et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001; 19:1759.
  41. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005; 23:2822.
  42. Herrstedt J, Muss HB, Warr DG, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005; 104:1548.
  43. Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer 2010; 18:423.
  44. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol 2011; 29:1495.
  45. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003; 74:17.
  46. Nygren P, Hande K, Petty KJ, et al. Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients. Cancer Chemother Pharmacol 2005; 55:609.
  47. Grunberg SM, Rolski J, Strausz J, et al. Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10:549.
  48. Herrstedt J, Apornwirat W, Shaharyar A, et al. Phase III trial of casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy. J Clin Oncol 2009; 27:5363.
  49. Roila F, Rolski J, Ramlau R, et al. Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting. Ann Oncol 2009; 20:1867.
  50. Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol 2000; 18:3409.
  51. Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer. The Italian Group for Antiemetic Research. N Engl J Med 1995; 332:1.
  52. Roila F, Tonato M, Cognetti F, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9:675.
  53. Smyth JF, Coleman RE, Nicolson M, et al. Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron? BMJ 1991; 303:1423.
  54. Hesketh PJ, Harvey WH, Harker WG, et al. A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol 1994; 12:596.
  55. Joss RA, Bacchi M, Buser K, et al. Ondansetron plus dexamethasone is superior to ondansetron alone in the prevention of emesis in chemotherapy-naive and previously treated patients. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 1994; 5:253.
  56. Double-blind, dose-finding study of four intravenous doses of dexamethasone in the prevention of cisplatin-induced acute emesis. Italian Group for Antiemetic Research. J Clin Oncol 1998; 16:2937.
  57. Italian Group For Antiemetic Research. Randomized, double-blind, dose-finding study of dexamethasone in preventing acute emesis induced by anthracyclines, carboplatin, or cyclophosphamide:. J Clin Oncol 2004; 22:725.
  58. Pomeroy M, Fennelly JJ, Towers M. Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemother Pharmacol 1986; 17:285.
  59. Sallan SE, Zinberg NE, Frei E 3rd. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 1975; 293:795.
  60. Herman TS, Einhorn LH, Jones SE, et al. Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. N Engl J Med 1979; 300:1295.
  61. Todaro B. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw 2012; 10:487.
  62. Olver I, Paska W, Depierre A, et al. A multicentre, double-blind study comparing placebo, ondansetron and ondansetron plus dexamethasone for the control of cisplatin-induced delayed emesis. Ondansetron Delayed Emesis Study Group. Ann Oncol 1996; 7:945.
  63. Koo WH, Ang PT. Role of maintenance oral dexamethasone in prophylaxis of delayed emesis caused by moderately emetogenic chemotherapy. Ann Oncol 1996; 7:71.
  64. Kris MG, Gralla RJ, Tyson LB, et al. Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 1989; 7:108.
  65. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. The Italian Group for Antiemetic Research. N Engl J Med 2000; 342:1554.
  66. Pater JL, Lofters WS, Zee B, et al. The role of the 5-HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy. Ann Oncol 1997; 8:181.
  67. Hesketh PJ, Sanz-Altamira P, Bushey J, et al. Prospective evaluation of the incidence of nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (abstract #9645). J Clin Oncol 2008; 26:9645.
  68. Hesketh PJ, Sanz-Altamira P, Bushey J, Hesketh AM. Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. Support Care Cancer 2012; 20:1043.
  69. Navari RM, Madajewicz S, Anderson N, et al. Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo. J Clin Oncol 1995; 13:2408.
  70. Latreille J, Pater J, Johnston D, et al. Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998; 16:1174.
  71. Goedhals L, Heron JF, Kleisbauer JP, et al. Control of delayed nausea and vomiting with granisetron plus dexamethasone or dexamethasone alone in patients receiving highly emetogenic chemotherapy: a double-blind, placebo-controlled, comparative study. Ann Oncol 1998; 9:661.
  72. Tsukada H, Hirose T, Yokoyama A, Kurita Y. Randomised comparison of ondansetron plus dexamethasone with dexamethasone alone for the control of delayed cisplatin-induced emesis. Eur J Cancer 2001; 37:2398.
  73. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 2005; 23:1289.
  74. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol 2011; 9:188.
  75. Morrow GR, Roscoe JA, Kirshner JJ, et al. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 1998; 6:244.
  76. Roscoe JA, Bushunow P, Morrow GR, et al. Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer 2004; 101:2701.
  77. Morrow GR, Morrell C. Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 1982; 307:1476.
  78. Burish TG, Jenkins RA. Effectiveness of biofeedback and relaxation training in reducing the side effects of cancer chemotherapy. Health Psychol 1992; 11:17.
  79. Fallowfield LJ. Behavioural interventions and psychological aspects of care during chemotherapy. Eur J Cancer 1992; 28A Suppl 1:S39.
  80. Greenberg DB, Surman OS, Clarke J, Baer L. Alprazolam for phobic nausea and vomiting related to cancer chemotherapy. Cancer Treat Rep 1987; 71:549.
  81. Razavi D, Delvaux N, Farvacques C, et al. Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of alprazolam. J Clin Oncol 1993; 11:1384.
  82. Hainsworth JD. The use of ondansetron in patients receiving multiple-day cisplatin regimens. Semin Oncol 1992; 19:48.
  83. Räth U, Upadhyaya BK, Arechavala E, et al. Role of ondansetron plus dexamethasone in fractionated chemotherapy. Oncology 1993; 50:168.
  84. Boccia RV, Gordan LN, Clark G, et al. Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer 2011; 19:1609.
  85. Mattiuzzi GN, Cortes JE, Blamble DA, et al. Daily palonosetron is superior to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting in patients with acute myelogenous leukemia. Cancer 2010; 116:5659.
  86. López-Jiménez J, Martín-Ballesteros E, Sureda A, et al. Chemotherapy-induced nausea and vomiting in acute leukemia and stem cell transplant patients: results of a multicenter, observational study. Haematologica 2006; 91:84.
  87. Bosi A, Guidi S, Messori A, et al. Ondansetron versus chlorpromazine for preventing emesis in bone marrow transplant recipients: a double-blind randomized study. J Chemother 1993; 5:191.
  88. Okamoto S, Takahashi S, Tanosaki R, et al. Granisetron in the prevention of vomiting induced by conditioning for stem cell transplantation: a prospective randomized study. Bone Marrow Transplant 1996; 17:679.
  89. Gilbert CJ, Ohly KV, Rosner G, Peters WP. Randomized, double-blind comparison of a prochlorperazine-based versus a metoclopramide-based antiemetic regimen in patients undergoing autologous bone marrow transplantation. Cancer 1995; 76:2330.
  90. Stiff P, Fox-Geiman M, Kiley K, et al. Aprepitant vs. placebo plus oral ondansetron and dexamethasone for the prevention of nausea and vomiting associated with highly emetogenic preparative regimens prior to hematopoietic stem cell transplantation; A prospective, randomized double-blind phase III trial. Blood (ASH Annual Meeting Abstracts) 2009; 114:2267. (Abstract available online at abstracts.hematologylibrary.org/cgi/content/abstract/114/22/2267?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=aprepitant&searchid=1&FIRSTINDEX=0&volume=114&issue=22&resourcetype=HWCIT, accessed May 6, 2010).
  91. Abbott B, Ippoliti C, Bruton J, et al. Antiemetic efficacy of granisetron plus dexamethasone in bone marrow transplant patients receiving chemotherapy and total body irradiation. Bone Marrow Transplant 1999; 23:265.
  92. Barbounis V, Koumakis G, Hatzichristou H, et al. The anti-emetic efficacy of tropisetron plus dexamethasone in patients treated with high-dose chemotherapy and stem cell transplantation. Support Care Cancer 1999; 7:79.
  93. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol 1999; 17:2971.
  94. Passik SD, Kirsh KL, Theobald DE, et al. A retrospective chart review of the use of olanzapine for the prevention of delayed emesis in cancer patients. J Pain Symptom Manage 2003; 25:485.
  95. Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 2005; 13:529.
  96. Navari RM, Einhorn LH, Loehrer PJ Sr, et al. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer 2007; 15:1285.
  97. de Wit R, de Boer AC, vd Linden GH, et al. Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy. Br J Cancer 2001; 85:1099.
  98. Harousseau JL, Zittoun R, Bonneterre J, et al. [Improvement in the control of chemotherapy induced emesis with ondansetron, methylprednisolone and lorazepam combination in patients treated by a moderate emetic treatment and uncontrolled by a previous antiemetic combination]. Bull Cancer 2000; 87:491.
  99. Sigsgaard T, Herrstedt J, Christensen P, et al. Antiemetic efficacy of combination therapy with granisetron plus prednisolone plus the dopamine D2 antagonist metopimazine during multiple cycles of moderately emetogenic chemotherapy in patients refractory to previous antiemetic therapy. Support Care Cancer 2000; 8:233.
  100. Ryan JL, Heckler CE, Roscoe JA, et al. Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients. Support Care Cancer 2011.
  101. Pillai AK, Sharma KK, Gupta YK, Bakhshi S. Anti-emetic effect of ginger powder versus placebo as an add-on therapy in children and young adults receiving high emetogenic chemotherapy. Pediatr Blood Cancer 2011; 56:234.
  102. Zick SM, Ruffin MT, Lee J, et al. Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care Cancer 2009; 17:563.
  103. Ezzo J, Vickers A, Richardson MA, et al. Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 2005; 23:7188.
  104. Lotfi-Jam K, Carey M, Jefford M, et al. Nonpharmacologic strategies for managing common chemotherapy adverse effects: a systematic review. J Clin Oncol 2008; 26:5618.
  105. Ezzo JM, Richardson MA, Vickers A, et al. Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev 2006; :CD002285.
  106. National Comprehensive Cancer Network (NCCN) guidelines. Available at: www.nccn.org (Accessed on October 13, 2011).
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