Prevention of chemotherapy-induced nausea and vomiting in adults

INTRODUCTION — Few side effects of cancer treatment are more feared by patients than nausea and vomiting. Although nausea and emesis (vomiting and/or retching) can result from surgery or radiation therapy, chemotherapy-induced nausea and vomiting (CINV) is potentially the most severe and most distressing. Significant progress has been made, but 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 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.

Prevention of CINV in adult patients receiving cancer chemotherapy will be reviewed here. The management of breakthrough and poorly controlled CINV and the pathophysiology of CINV are discussed separately, as are the characteristics of antiemetic drugs, and nausea and vomiting associated with radiation therapy and opioid analgesics. (See "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults" and "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting" and "Characteristics of antiemetic drugs" and "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment" and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Nausea and vomiting'.)

OVERVIEW OF THE APPROACH TO PROPHYLAXIS

Estimating the risk of nausea and vomiting — The most important factor determining the likelihood of acute or delayed emesis developing during chemotherapy is the intrinsic emetogenicity of the particular agent. Although other factors may be important, such as patient age, sex, and history of alcohol consumption, these factors are not currently used to select the antiemetic strategy. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Chemotherapy agent' and "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Prediction models'.)

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 [1]. A modification of this schema was proposed at the 2004 Perugia Antiemetic Consensus Guideline meeting [2] and is still relevant, although many more chemotherapy agents are now available. Chemotherapy agents were divided into four categories based upon the risk of emesis in the absence of antiemetic prophylaxis:

●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)/European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) [3-8]. A classification of specific agents according to their emetogenic potential is provided separately for parenteral and oral agents (table 1 and table 2).

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 [1]. In updated antiemetic guidelines from ASCO, MASCC/ESMO, and the National Comprehensive Cancer Network (NCCN) [8], combined anthracycline and cyclophosphamide (AC) regimens have been reclassified as highly emetic [3,5-8]. It should be noted that the studies defining the AC regimens as highly emetogenic were conducted almost exclusively in women with breast cancer. It is unclear whether AC used as a component of combination regimens in other diseases with more diverse populations (eg, doxorubicin plus cyclophosphamide, vincristine, and prednisone [CHOP] in non-Hodgkin lymphoma) is also highly emetic. For example, an open-label, single-arm trial in patients with non-Hodgkin lymphoma (75 percent receiving CHOP + rituximab) evaluated a single dose of palonosetron (0.25 mg intravenously) prior to chemotherapy, achieving an overall complete response rate of 86 percent [9]. Many clinicians consider CHOP and related regimens to be moderately rather than highly emetogenic. (See 'Palonosetron' below.)

Choosing the prophylactic strategy — 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 receptor (NK1R) antagonists, and glucocorticoids (especially dexamethasone). In addition, more recent data have demonstrated substantial antiemetic activity for the antipsychotic medication olanzapine when used in combination with other antiemetics. (See '5-HT3 receptor antagonists' below and 'Neurokinin-1 receptor antagonists' below and 'Glucocorticoids' below and 'Olanzapine' below.)

These agents are used alone and in specific combinations, depending on the emetogenicity of the specific chemotherapy regimen being administered and its tendency to produce not only acute but also delayed emesis. In general, most of the regimens that are associated with delayed emesis are those that are highly emetogenic, although there are some moderately emetogenic agents that also fit into this category.

An important point is that virtually all of the clinical trials evaluating CINV have focused on intravenously delivered chemotherapy. Therefore, evidenced-based guidelines for antiemetic prophylaxis with oral chemotherapy agents are not currently possible. The following recommendations, unless indicated otherwise, pertain to intravenously administered chemotherapy agents. Management of antiemetics for patients receiving oral chemotherapy is discussed below. (See 'Oral chemotherapy' below.)

Recommendations for specific groups — Guidelines for antiemetic therapy for intravenously administered chemotherapy according to the estimated risk of CINV are available from ASCO and NCCN [8] and in a year 2016 update of recommendations from MASCC/ESMO [5-8]. Our approach to prophylaxis, which largely parallels recommendations from MASCC/ESMO and ASCO, is summarized in the following sections and outlined in the accompanying table (table 3).

Highly emetogenic chemotherapy

Cisplatin and other highly emetogenic single agents

●Day 1 – We recommend antiemetic therapy with a combination of an NK1R antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. (See '5-HT3 receptor antagonists' below and 'Neurokinin-1 receptor antagonists' below and 'Combination with a 5-HT3 antagonist' below and 'Olanzapine' below.)

●Days 2 to 4 – We recommend continuing dexamethasone (days 2 to 4) and continuing olanzapine (days 2 to 4).

If aprepitant is used on day 1, we recommend continuing aprepitant on days 2 and 3 (table 3). All other NK1R antagonists (ie, fosaprepitant, rolapitant, netupitant) are administered on day 1 only.

Anthracycline combined with cyclophosphamide

Breast cancer

●Day 1 – We recommend a combination of an NK1R antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine.

●Days 2 to 4 – We recommend continuing olanzapine on days 2 to 4. We suggest not using dexamethasone on days 2 to 4 because of the limited data supporting dexamethasone beyond day 1 when an NK1R antagonist is used with AC. (See 'NK1R antagonist plus dexamethasone and 5-HT3 antagonist' below.)

If aprepitant is used on day 1, we recommend continuing aprepitant on days 2 and 3. All other NK1R antagonists are administered on day 1 only.

Other diseases — For non-breast cancer populations (eg, non-Hodgkin lymphoma) receiving combination AC with treatment regimens incorporating corticosteroids, the use of the 5-HT3 antagonist palonosetron without the use of an NK1R antagonist or olanzapine is an acceptable option. (See 'Palonosetron' below.)

Moderately emetogenic chemotherapy

Carboplatin-based regimens — The NCCN classifies carboplatin doses of area under the curve of concentration X time (AUC) 4 or higher as highly emetogenic, but both ASCO and MASCC classify all doses of carboplatin as being moderately emetogenic [5,7,8]. However, despite the classification of carboplatin-containing regimens as moderately emetogenic at many institutions, the benefit of adding an NK1R antagonist on day 1 has been shown in many studies; for most patients, prophylaxis for delayed emesis beyond day 1 is not needed.

●Day 1 – We recommend the combination of an NK1R antagonist, a 5-HT3 receptor antagonist, and dexamethasone on day 1.

●No additional prophylaxis beyond day 1 for delayed emesis is recommended. (See 'Moderate-risk regimens' below.)

Non-carboplatin-based regimens

●Day 1 – We recommend the combination of a 5-HT3 receptor antagonist plus dexamethasone on day 1.

●Days 2 to 3 – To prevent delayed emesis if the regimen contains agents with known potential to induce delayed emesis (eg, oxaliplatin), we suggest single-agent treatment with dexamethasone on days 2 and 3. If a first-generation 5-HT3 receptor antagonist is used rather than palonosetron on day 1, then treatment with a first-generation 5-HT3 receptor antagonist alone on days 2 and 3 is a reasonable alternative. If palonosetron is used on day 1, no additional prophylaxis beyond day 1 is needed for most patients. (See 'Moderate-risk regimens' below and 'Dexamethasone duration in patients receiving moderately emetogenic chemotherapy' below.)

Low emetogenic chemotherapy

●For patients receiving low-emetic-risk agents, we suggest treatment with dexamethasone (4 to 8 mg, oral or IV) as a single agent or a 5-HT3 receptor antagonist. Other alternative approaches for patients in whom glucocorticoid use is contraindicated or undesirable (such as with the use of long-term weekly chemotherapy) are a single oral or IV dose of a drug such as prochlorperazine (5 to 10 mg, oral or IV) [8], or metoclopramide (10 mg, oral or IV). This patient population generally does not require prophylaxis against delayed emesis. (See 'Glucocorticoids' below.)

Minimally emetogenic chemotherapy

●For most patients receiving chemotherapy agents with a minimal risk of causing emesis, we suggest that antiemetic therapy not be routinely administered to prevent either acute or delayed CINV. Prophylactic antiemetics (dexamethasone 4 to 8 mg, oral or IV; prochlorperazine 5 or 10 mg, oral or IV; or metoclopramide 10 mg, oral or IV) may be administered to patients who have had emesis with prior low-risk regimens, or on an "as needed" basis. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Chemotherapy agent'.)

Immune checkpoint inhibitor immunotherapy

●For adult patients, the addition of an immune checkpoint inhibitor (ICI) to cytotoxic chemotherapy does not change the guideline recommendation for an antiemetic regimen based on the emetogenicity of the agents administered, including the use of dexamethasone [7]. Despite a prior guideline that classified atezolizumab and ipilimumab as low-emetic-risk agents [6], the updated 2020 antiemetic guidelines from ASCO classify all ICIs administered either alone or in combination with other checkpoint inhibitors as minimally emetogenic and do not require the use of a prophylactic antiemetic [7]. (See 'Patients receiving immune checkpoint inhibitors' below.)

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 and/or benzodiazepines. (See 'Anticipatory emesis' below.)

High-dose chemotherapy

●For patients receiving high-dose chemotherapy with hematopoietic cell transplantation, we recommend a combination of dexamethasone, a 5-HT3 receptor antagonist, and an NK1R antagonist. The most recent ASCO guideline update suggests a four-drug combination of dexamethasone, a 5-HT3 receptor antagonist, an NK1R antagonist, and olanzapine as an additional option. (See 'High-dose chemotherapy regimens' below.)

Multiday regimens

●Adults treated with multiday antineoplastic agents should be offered antiemetics before treatment that are appropriate for the emetic risk of the agent given on each day or the treatment, and for two days after completion of the regimen.

●For patients receiving four- or five-consecutive-day cisplatin regimens, we suggest a daily dose of a first-generation 5-HT3 receptor antagonist, or a single application of a granisetron transdermal patch or palonosetron on days 1, 3, and 5 plus daily dexamethasone, with the addition of aprepitant (days 1, 2, and 3), fosaprepitant (day 1), or another NK1R antagonist (eg, netupitant plus palonosetron [NEPA] or rolapitant) on day 1. (See 'Consecutive-day intravenous therapy with highly emetogenic agents' below.)

ANTIEMETIC EFFICACY OF INDIVIDUAL AGENTS — Extensive clinical trials have evaluated the type three 5-hydroxytryptamine (5-HT3) receptor antagonists, the neurokinin-1 receptor (NK1R) antagonists, glucocorticoids, and more recently, olanzapine in patients with acute and delayed CINV. These trials have focused primarily on patients receiving either highly or moderately emetic, intravenously (IV) administered 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 [10].

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 [11-14]. In addition to increased efficacy, these agents are easier to administer and are associated with significantly less serious side effects than the less-specific serotonin inhibitor metoclopramide.

Six first-generation 5-HT3 receptor antagonists (azasetron [15], dolasetron, granisetron, ondansetron, ramosetron, and tropisetron) and one second-generation agent (palonosetron) are approved for use with varying regional availability; azasetron, ramosetron, and tropisetron are not available in the United States. An orally disintegrating formulation of ondansetron also is available, which disperses rapidly when placed on the tongue and does not need to be swallowed with water [16]. This formulation may be particularly useful for patients with dysphagia or anorexia. A granisetron transdermal system is also available, as is an extended-release subcutaneous formulation of granisetron (Sustol), which was approved by the US Food and Drug Administration (FDA) in August 2016 for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, or combination anthracycline and cyclophosphamide chemotherapy regimens. (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. A meta-analysis has shown no clear advantage for either ondansetron or granisetron in the prophylaxis of acute or delayed emesis [17].

●There is a plateau in therapeutic efficacy at a definable dose level for each drug, and further dose escalation does not improve outcome [18].

●A single dose of a 5-HT3 receptor antagonist prior to chemotherapy is therapeutically equivalent to a multiple-dose schedule for control of acute nausea and emesis [19-23].

●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 IV formulations [18,24,25].

Cardiac issues — Electrocardiogram (ECG) interval changes are a class effect of the first-generation 5-HT3 antagonists, including ondansetron, granisetron, and dolasetron, although they have not been reported with transdermal granisetron or extended-release subcutaneous granisetron [26,27]. (See 'Granisetron transdermal patch' below.)

ECG interval changes 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 [28-30]. However, potentially fatal cardiac arrhythmias, including torsade de pointes (TdP), have been reported in association with QTc prolongation [28,30-32].

In addition to ECG interval changes, myocardial ischemia has been reported in patients treated with ondansetron; coronary artery spasm appears to be the most common underlying cause [33].

The following sections describe the warnings/precautions regarding cardiotoxicity of these agents from the FDA.

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 [34]. 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 FDA recommends the following precautions in patients receiving oral dolasetron [34]:

●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, or underlying cardiac disease, in older adults, and in patients with renal impairment.

●Use of dolasetron should be avoided in patients with congenital long QT syndrome (table 4).

●Drugs known to prolong the PR (eg, verapamil) or QRS interval (eg, flecainide, quinidine) should be avoided in patients taking dolasetron.

Because of these risks, dolasetron (both oral and IV) has been removed from the market in Canada, but it remains available elsewhere.

Ondansetron — The FDA has issued a warning about QTc prolongation and potentially fatal cardiac arrhythmias in patients treated with ondansetron [32]. QT prolongation occurs in a dose-dependent manner and, specifically, at a single IV dose of 32 mg. QT interval prolongation is expected to be greater with a faster rate of infusion and larger doses for IV administration.

Revised labeling in the United States includes a recommendation to limit single IV doses to no more than 16 mg, avoid use of ondansetron in patients with congenital long QT syndrome, and to use ECG monitoring in certain patients, including those with hypokalemia or hypomagnesemia, heart failure, and bradyarrhythmias, and in patients taking other medications that increase the risk of QTc prolongation (table 4).

Canadian guidelines that took effect in June 2014 place additional dosing restrictions on IV ondansetron to mitigate the risk of QT prolongation in older adults [35]:

●In patients ≥75 years of age, the initial IV dose should not exceed 8 mg.

●For patients age <75, the initial IV dose should not exceed 16 mg.

●Subsequent IV doses must not exceed 8 mg and may be given four and eight hours after the initial dose.

●All IV doses must be diluted in 50 to 100 mL of saline or other compatible fluid.

●All IV doses must be infused over no less than 15 minutes.

The FDA-approved label for oral ondansetron and IV ondansetron also recommend advising and monitoring patients for signs and symptoms of myocardial ischemia after oral administration of the drug, and during as well as after IV administration. Most of the cases have occurred immediately after IV administration; symptoms typically resolve with prompt treatment.

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 with first-generation 5-HT3 receptor antagonists. In contrast to first-generation 5-HT3 antagonists, QTc prolongation has not been described with palonosetron [36,37].

As a single agent, palonosetron is more effective than ondansetron or dolasetron at preventing emesis due to chemotherapy agents of varying emetogenicity [38-40]. This was illustrated by a multicenter trial in 592 patients, the majority of whom received doxorubicin and cyclophosphamide for breast cancer; a minority received cisplatin- and carboplatin-based chemotherapy regimens [38]. 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). More patients treated with palonosetron (0.25 mg) had complete control of both acute (63 versus 53 percent) and delayed emesis (54 versus 39 percent) compared with dolasetron. The dose of 0.75 mg was not significantly superior compared with 0.25 mg. A similarly designed trial also demonstrated superiority for palonosetron compared with ondansetron [39].

When used in combination with glucocorticoids, palonosetron provides superior control of delayed emesis compared with first-generation 5-HT3 receptor antagonists combined with glucocorticoids [41-43]. As examples:

●In a phase III, double-blind, double-dummy trial, 1143 patients receiving highly emetogenic chemotherapy (cisplatin or an anthracycline/cyclophosphamide combination for breast cancer) were randomly assigned to dexamethasone plus either palonosetron or granisetron on day 1 prior to chemotherapy; all patients received dexamethasone on days 2 and 3 [41]. 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).

●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 [42]. Approximately two-thirds of patients received concomitant dexamethasone. In this subset of patients, complete response rates were numerically higher in both palonosetron arms compared with ondansetron during the first 24 hours. During the delayed (24 to 120 hours) phase, complete response was significantly higher in the 0.25 mg palonosetron arm compared with the ondansetron arm (42 versus 29 percent, p = 0.021).

Two questions arising from the design of these studies are whether the efficacy differences noted would have persisted with protracted dosing (days 2 and 3) of the first-generation 5-HT3 receptor antagonists, which have a much shorter half-life than palonosetron, or with the addition of an NK1R antagonist, which all evidence-based guidelines recommend in this setting. At least one phase III study has failed to demonstrate the superiority of palonosetron over granisetron in patients also receiving an NK1R antagonist for the primary endpoint of complete response for the 0 to 120 hour period following cisplatin-based chemotherapy; however, the palonosetron arm was superior for multiple secondary endpoints [44].

Updated antiemetic guidelines from the National Comprehensive Cancer Network (NCCN) recommend palonosetron as the preferred 5-HT3 antagonist for patients who receive moderately emetogenic chemotherapy [8].

By contrast, updated guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) do not specify a preferred 5-HT3 antagonist for patients receiving moderately emetogenic chemotherapy [5,7].

A noninferiority trial documented similarity between the oral and IV formulations and validated the correct palonosetron dose (0.5 mg oral). The oral formulation of palonosetron, which was approved by the FDA in 2008, is not marketed in the United States but is available in a number of European countries.

Dexamethasone duration in patients receiving moderately emetogenic chemotherapy — A number of studies have addressed the issue of whether single day dexamethasone is comparable in efficacy to multiple day dexamethasone when combined with palonosetron in patients receiving moderately emetogenic chemotherapy [45]. These have included both anthracycline and cyclophosphamide (AC) and non-AC chemotherapy regimens. This question has been previously resolved for patients receiving AC, which is now considered highly emetogenic; in this situation, a single day 1 dose of dexamethasone in combination with a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and olanzapine has been defined as the preferred regimen. (See 'Anthracycline combined with cyclophosphamide' above.)

With carboplatin-containing moderately emetogenic regimens, single day 1 dexamethasone combined with a 5-HT3 receptor antagonist and an NK1 receptor antagonist is recommended. (See 'Carboplatin-based regimens' above.)

For non-AC, non-carboplatin moderately emetogenic chemotherapy regimens, support for a one-day dexamethasone regimen when palonosetron is employed as the 5-HT3 receptor is provided by a randomized trial conducted in Japan [46]. Three hundred and five patients receiving a variety of moderately emetogenic regimens were randomized to receive palonosetron on day 1 combined with either dexamethasone on day 1 only versus dexamethasone administered on days 1 through 3. No patients received AC, and only 12 percent of patients received carboplatin. Antiemetic control was comparable between the two study arms.

Adverse effects — 5-HT3 receptor antagonists are generally safe, with a favorable side effect profile (predominantly low-grade headache, malaise, and constipation).

A few reports have appeared suggesting a potential link between 5-HT3 receptor antagonists and the serotonin syndrome [47], which is caused when serotonin accumulates to high levels in vivo. Symptoms include confusion, agitation, restlessness, muscle twitching or stiffness, fever, sweating, fluctuations in heart rate and blood pressure, as well as nausea and/or vomiting, loss of consciousness, and coma; the syndrome can be fatal if not treated. (See "Serotonin syndrome (serotonin toxicity)".)

However, in nearly all cases, the use of concomitant medications with a 5-HT3 receptor antagonist has limited the ability to establish a definitive association. Nevertheless, caution is advised when using 5-HT3 receptor antagonists in combination with other drugs that affect serotonin levels (table 5).

Neurokinin-1 receptor antagonists — The introduction of the NK1R antagonists aprepitant and fosaprepitant (a parenteral water-soluble prodrug of aprepitant that is effective as a one-day treatment (see 'One- versus three-day administration' below)) has significantly improved the ability to prevent both acute and delayed CINV in patients receiving highly emetic, IV-administered chemotherapy (table 1). Randomized trials also support a role for NK1R antagonists with the moderately emetogenic agent carboplatin as well [48-51]. These studies demonstrated that the rate of complete response (no emesis, no rescue) increased by 10 to 15 percent with the addition of an NK1R antagonist to dexamethasone and a 5-HT3 receptor antagonist compared with the combination of dexamethasone and a 5-HT3 receptor antagonist. On the other hand, the value of an NK1R antagonist is less certain for oxaliplatin; two large randomized trials have come to opposite conclusions [52,53].

Rolapitant is a potent selective NK1R antagonist with a longer plasma half-life (approximately seven days) than aprepitant. Netupitant plus palonosetron (NEPA) is a novel, oral fixed-dose combination containing 300 mg of netupitant (a highly selective NK1R antagonist) and 0.5 mg of the 5-HT3 receptor antagonist palonosetron. Casopitant is another NK1R antagonist that can be given as a single day 1 oral dose or in a mixed IV plus oral three-day schedule in conjunction with dexamethasone and ondansetron; commercial development of this agent is not being pursued.

Although few studies have directly compared these agents head to head, the available evidence suggests that they have similar efficacy for control of acute and delayed emesis, at least in the setting of highly emetogenic chemotherapy [54].

Aprepitant and fosaprepitant

Efficacy — The benefit of combining an NK1R antagonist (aprepitant, fosaprepitant, or casopitant) with an 5-HT3 receptor antagonist plus a glucocorticoid for the prevention of acute CINV was addressed in a meta-analysis of 17 trials, totaling 8740 patients who were receiving highly or moderately emetogenic chemotherapy [55]. The addition of an NK1R antagonist to standard antiemetic therapy significantly improved the rate of complete response (absence of emesis and no need for rescue antiemetics) in the overall (during the first 120 hours of chemotherapy, 72 versus 54 percent, odds ratio [OR] 0.51, 95% CI 0.46-0.57), acute (first 24 hours, OR 0.56, 95% CI 0.48-0.65), as well as delayed phase (OR 0.48, 95% CI 0.42-0.56). For other secondary outcomes (rate of emesis, absence of nausea), the addition of an NK1R antagonist was also superior to the control arm.

In subgroup analyses, benefit was seen for both highly emetogenic (complete response 73 versus 54 percent, OR 0.46, 95% CI 0.40-0.53) and moderately emetogenic chemotherapy (complete response 71 versus 54 percent, OR 0.59, 95% CI 0.61-0.67). There appeared to be no differences in treatment efficacy for aprepitant/fosaprepitant and casopitant. The use of an NK1R antagonist did not increase the risk of diarrhea, although the rates of hiccups and fatigue/asthenia were significantly higher. There was a suggestion that use of an NK1R antagonist increased the risk of a severe infection (6 versus 2 percent in a pooled analysis of three trials); however, this was not associated with an increased rate of neutropenia or febrile neutropenia.

Need for a 5-HT3 agent — Aprepitant and fosaprepitant improve control of CINV when combined with a type three 5-hydroxytryptamine (5-HT3) receptor antagonist and dexamethasone. Aprepitant plus dexamethasone alone is not as effective as the three-drug combination regimen. A 5-HT3 receptor antagonist remains necessary, at least 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) [56]. 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 was effective in only 57 and 43 to 46 percent of cases, respectively.

One- versus three-day administration — In the United States, both aprepitant and fosaprepitant are approved for use in three-day schedules. However, 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 [57]. The control group received aprepitant administered in the standard three-day schedule along with ondansetron plus dexamethasone; this was compared with 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).

IV aprepitant has been FDA approved based solely on bioequivalence studies in human volunteers. There are different recommendations for dosing in patients receiving highly emetogenic chemotherapy (130 mg IV on day 1 only) and carboplatin-containing moderately emetogenic chemotherapy (100 mg IV on day 1 followed by 80 mg of oral aprepitant on days 2 and 3, or 130 mg IV on day 1 only) in conjunction with other agents. The data to support these different recommendations are not evident, as only bioequivalence studies are available and studies in actual patients receiving chemotherapy have not been conducted.

Netupitant plus palonosetron and fosnetupitant

●Oral NEPA – Oral NEPA is a novel, oral fixed-dose combination containing 300 mg of netupitant (a highly selective NK1R antagonist) and 0.5 mg of palonosetron, a pharmacologically and clinically distinct 5-HT3 receptor antagonist. (See 'Palonosetron' above.)

Single-dose oral NEPA in conjunction with dexamethasone for control of both acute and delayed nausea and emesis has been compared with aprepitant plus a 5-HT3 receptor antagonist and dexamethasone [58-61] in several randomized phase II and III trials conducted in populations receiving either moderately or highly emetogenic chemotherapy, all of which showed superiority or at least noninferiority for oral NEPA over the control arm. As examples:

•Efficacy of oral NEPA over multiple cycles of chemotherapy was evaluated in a phase III randomized trial in which 413 patients receiving a variety of moderately (carboplatin, oxaliplatin, doxorubicin, cyclophosphamide, irinotecan, epirubicin, daunorubicin) or highly emetogenic (cisplatin, dacarbazine, carmustine) chemotherapy were randomly assigned to oral NEPA given on day 1 with oral dexamethasone versus a three-day regimen of aprepitant plus palonosetron and dexamethasone [59]. In both groups, dexamethasone was administered on days 1 through 4 for highly emetogenic chemotherapy and on day 1 only for moderately emetogenic chemotherapy. During cycle 1, complete response rates (no emesis and no need for rescue medication through hour 120) were 81 and 76 percent for oral NEPA and aprepitant/palonosetron, respectively, and antiemetic efficacy was maintained over multiple cycles.

•Another trial compared oral NEPA with palonosetron in 1455 patients receiving cyclophosphamide plus an anthracycline (either doxorubicin or epirubicin); all patients also received dexamethasone on day 1 only [61]. The percentage of patients with a complete response (through hour 120) was significantly higher with oral NEPA (74 versus 67 percent, p = 0.001). Oral NEPA was well tolerated and had a similar safety profile to palonosetron.

Based on several of these trials, oral NEPA was approved in the United States for prevention of chemotherapy-related nausea and vomiting in October 2014. An important point is that, if oral NEPA is used in the setting of anthracycline plus cyclophosphamide chemotherapy and non-highly emetogenic regimens, routine maintenance antiemetic therapy is not recommended after day 1. If used with a cisplatin-containing regimen, dexamethasone is recommended on days 1 through 4.

●Fosnetupitant and IV NEPA – Fosnetupitant is an injectable phosphorylated prodrug of netupitant that appears similarly efficacious as fosaprepitant when combined with palonosetron and dexamethasone for prevention of CINV with cisplatin-based chemotherapy, but with a lower frequency of injection site reactions [62,63]. It is available primarily in Japan.

However, an IV equivalent to oral NEPA (IV NEPA) that consists of 235 mg of fosnetupitant plus 0.25 mg of palonosetron is approved in the United States and European Union for prevention of CINV in patients receiving highly emetogenic chemotherapy, largely based upon a phase III safety study comparing oral versus IV NEPA [64]. IV NEPA has been studied for prevention of nausea and vomiting associated with a cisplatin-containing regimen [65] but not anthracycline plus cyclophosphamide regimens.

If IV NEPA is used, the United States Prescribing Information recommends that all patients receive dexamethasone 8 mg once daily on days 1 through 4. Similar to aprepitant and fosaprepitant, netupitant is also an inhibitor of CYP3A4, and a reduced dose of concurrently administered glucocorticoids is needed. (See 'Inhibition of CYP3A4 and implications for concurrently used drugs' below.)

Rolapitant — Rolapitant is a potent selective NK1R antagonist with a longer plasma half-life (approximately seven days) than either aprepitant or fosaprepitant. Safety and efficacy were established in three randomized, double-blind trials in which rolapitant (180 mg orally, one to two hours before chemotherapy administration) in combination with IV granisetron on day 1 and dexamethasone (20 mg on day 1 followed by 8 mg twice daily on days 2 to 4 of cycle 1) was compared with a control therapy (placebo with the same dose and schedule of granisetron and dexamethasone) in patients receiving highly emetogenic (eg, cisplatin or anthracycline plus cyclophosphamide) or moderately emetogenic chemotherapy agents [66,67]. Patients treated with rolapitant had a significantly greater protection from delayed emesis, but there was less consistency in the acute phase of CINV, with the moderately emetogenic trial and one of the highly emetogenic studies failing to show a significant improvement in emesis control within 24 hours of chemotherapy.

Unlike aprepitant and fosaprepitant, which are moderate inhibitors of CYP3A4, rolapitant does not inhibit this metabolic pathway, and therefore, no adjustment of dexamethasone dose is required. Rolapitant does inhibit the cytochrome P450 2D6 (CYP2D6) enzyme, which is responsible for metabolizing certain drugs, such as thioridazine; the use of both drugs together is not recommended.

Rolapitant is approved in adults, in combination with other antiemetic agents, to prevent delayed nausea and vomiting associated with the initial and repeat courses of emetogenic cancer chemotherapy. No clinical trials have yet reported a definitive direct comparison of any of the available NK1R antagonists.

Rolapitant was originally available for use orally or through IV. Postmarketing reports surfaced about anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions in patients receiving IV rolapitant emulsion, some requiring hospitalization [68]. The intravenous preparation was subsequently removed from the market in August 2020. (See "Food allergens: Clinical aspects of cross-reactivity", section on 'Legumes: Peanut, soy, and others'.)

Inhibition of CYP3A4 and implications for concurrently used drugs — NK1R antagonists such as aprepitant, fosaprepitant, and netupitant (but not rolapitant) are moderate inhibitors of the cytochrome P450 3A4 enzyme (CYP3A4), which is particularly important in drug metabolism [69]. CYP3A4 is responsible for the metabolism of glucocorticoids, and these agents result in higher exposure for any given dose of dexamethasone. Thus, for patients treated with aprepitant, the dose of dexamethasone was reduced in clinical trials from 20 to 12 mg on day 1, and from 8 mg twice daily to 8 mg daily on days 2 through 4 [70-72]. With a single dose of fosaprepitant on day 1, the impaired metabolism of dexamethasone is on days 1 and 2 only, and the dexamethasone dose on days 1 and 2 must be reduced. On days 3 and 4, the dexamethasone dose is 8 mg twice daily [57].

Importantly, this dose reduction applies only when glucocorticoids are used as antiemetics in conjunction with NK1R antagonists, not when given as an antitumor component of a chemotherapy regimen.

Theoretically, aprepitant, fosaprepitant and netupitant 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 [72,73].

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 NK1R 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 with 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 [74]. 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 [7].

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 type three 5-hydroxytryptamine (5-HT3) receptor antagonists is significantly enhanced by the addition of a glucocorticoid [11,75-79].

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 [74]. The pooled RR for emesis protection was 1.25, indicating that the addition of dexamethasone increased the chance of no acute vomiting by 25 percent.

Patients receiving immune checkpoint inhibitors — Systemic glucocorticoids may be avoided in patients receiving immune checkpoint inhibitors (ICIs) due to concerns that they might attenuate the benefit of ICI immunotherapy, but clinical practice is variable and clinical trials have variably allowed versus disallowed the use of dexamethasone as an antiemetic. The available data from randomized trials do not support inferior outcomes in patients who receive dexamethasone as a component of the antiemetic regimen in patients receiving combination therapy with cytotoxic chemotherapy plus an ICI [80-82]. Given these findings, updated 2020 antiemetic guidelines from ASCO specifically state that the addition of an ICI to chemotherapy does not change the guideline recommendation for an antiemetic regimen that is based on the emetogenicity of the agents administered [7].

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 IV doses of dexamethasone administered by a 15-minute infusion prior to cisplatin administration [83]. 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 [84]. In this trial, all patients received IV ondansetron and were randomized to one of three schedules of dexamethasone (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 specific NK1R antagonists (aprepitant, fosaprepitant, netupitant). (See 'Inhibition of CYP3A4 and implications for concurrently used drugs' above.)

Olanzapine — Conventional antiemetics are more successful at preventing emesis than at preventing nausea, particularly delayed nausea. Olanzapine, a second-generation antipsychotic that blocks serotonin 5-hydroxytryptamine (5-HT2) receptors and dopamine D2 receptors, may be a particularly useful agent for the prevention of both acute and delayed nausea and vomiting.

The superiority of a prophylactic regimen including olanzapine over other antiemetic regimens not including olanzapine was addressed in a meta-analysis of 14 randomized trials in patients receiving highly or moderately emetogenic chemotherapy [85]. Compared with placebo, the addition of olanzapine to standard antiemetic therapy doubled the likelihood of no nausea or vomiting during chemotherapy from 25 to 50 percent (RR 1.98, 95% CI 1.59-2.47). Olanzapine also reduced delayed nausea (RR for being free of delayed nausea 1.71, 95% CI 1.40-2.09) and vomiting (RR 1.28, 95% CI 1.14-1.42), but the impact on acute nausea and vomiting was uncertain. Olanzapine also may increase adverse effects and probably increases somnolence and fatigue during treatment compared with no treatment or placebo. A subsequent network meta-analysis of antiemetic regimens for highly emetogenic chemotherapy also concluded that olanzapine-containing regimens were the most efficacious for preventing CINV in this setting [86].

In the most influential trial, 380 patients receiving highly emetogenic chemotherapy (cisplatin ≥70 mg/m² or cyclophosphamide/doxorubicin) were randomly assigned to dexamethasone, aprepitant or fosaprepitant, and a 5-HT3 receptor antagonist with either olanzapine (10 mg daily, orally, on days 1 through 4) or placebo [87]. The proportion of no patients with chemotherapy-induced nausea (the primary endpoint) was significantly higher with olanzapine, both in the first 24 hours after chemotherapy (74 versus 45 percent) and in the delayed period (42 versus 25 percent, p = 0.002). Rates of complete response (no emesis and no use of rescue medication) were also higher with olanzapine in the acute phase (86 versus 65 percent), delayed phase (67 versus 52 percent), and over the 120-hour period (64 versus 41 percent). The 41 percent complete response rate over the entire 120-hour period for the placebo group is very low by modern standards. Although not reported in the full manuscript, superiority for the olanzapine-containing arm was demonstrated in a subset analysis of both the cisplatin- and anthracycline/cyclophosphamide-treated patients [88]. The addition of olanzapine resulted in more sedation on day 2 (severe in 5 percent), which resolved thereafter, despite the continued use of olanzapine.

●Dose – The optimal dose of prophylactic olanzapine is not yet established. Although the phase III study described above used 10 mg daily, 5 mg, rather than 10 mg, may be a more appropriate dose for most patients, given the potential for excess sedation with the 10 mg dose. The following data inform this debate:

•A relatively small randomized phase II trial in 153 patients receiving cisplatin-based chemotherapy showed similar activity for the 5 mg as compared with the 10 mg dose of olanzapine, with a more favorable somnolence profile [89].

•The two doses were directly compared in a trial conducted in a broader population of patients receiving highly emetogenic chemotherapy (37 cisplatin-based and 104 doxorubicin plus cyclophosphamide); patients were randomized to oral aprepitant (daily on days 1 through 3) or 10 mg or 5 mg of olanzapine (both administered daily on days 1 through 4); all received ondansetron and dexamethasone [90]. The primary endpoint was a no nausea rate through the entire five-day assessment period. A nonsignificantly higher proportion of patients given olanzapine 10 mg (43 percent) or 5 mg (37 percent) experienced no nausea compared with aprepitant (33 percent) during the 5-day period, but a significantly lower proportion of those receiving 10 mg olanzapine had moderate to severe delayed nausea compared with aprepitant (9 versus 28 percent); the difference with olanzapine 5 mg (19 percent) was not significant. Other efficacy measures (including complete control of CINV and the need for rescue antiemetics) were similar among the three groups. Lower-dose olanzapine was not associated with a lesser proportion of patients who reported sleepiness (42 versus 41 percent).

•Additional information is available from a placebo-controlled phase III trial of lower dose olanzapine (5 mg daily on days 1 through 4) versus placebo, both in conjunction with standard antiemetic therapy in 710 patients receiving cisplatin-based chemotherapy [91]. There was a statistically and clinically significant improvement in complete control of nausea and vomiting in both the acute and delayed phases with olanzapine, and a minimal impact on daytime sleepiness compared with standard antiemetics without olanzapine.

Two separate meta-analyses of these and other trials have concluded that prophylactic regimens utilizing 5 mg olanzapine may be as efficacious as 10 mg regimens [92,93]. However, in our view, these data support the use of the 5 mg olanzapine dose over the 10 mg dose in the setting of cisplatin-based highly emetogenic chemotherapy. For patients receiving an anthracycline plus cyclophosphamide, there are insufficient data to exclude the possibility that a lower olanzapine dose may not be as effective as the higher 10 mg dose for prevention of CINV.

●Prevention of delayed emesis – A separate issue is whether olanzapine can replace an NK1R antagonist for prevention of delayed emesis in patients receiving highly emetogenic chemotherapy. This issue was addressed in the following trials:

•In one phase III trial 247 patients receiving cisplatin or doxorubicin plus cyclophosphamide 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 [94]. 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. This trial was not included in the Cochrane review of olanzapine cited above [85].

•Similar results were noted in the small randomized Thai trial described above, in which patients receiving highly emetogenic chemotherapy were randomized to oral aprepitant (daily on days 1 through 3) or 10 mg or 5 mg of olanzapine (both administered daily on days 1 through 4); all received ondansetron and dexamethasone [90]. A significantly higher proportion of patients given olanzapine 10 mg (43 percent) or 5 mg (37 percent) experienced no nausea compared with aprepitant (33 percent) during the five-day period, and a significantly lower proportion of those receiving 10 mg olanzapine had moderate to severe delayed nausea compared with aprepitant (9 versus 28 percent). Other efficacy measures (including complete control of CINV and the need for rescue antiemetics) were similar between olanzapine and aprepitant.

The benefit of olanzapine for management of breakthrough emesis is addressed elsewhere. (See "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults".)

Thalidomide — NK1R antagonists effectively prevent delayed emesis from highly emetogenic chemotherapy, but they are not available worldwide, including in China.

The benefit of thalidomide in this setting was addressed in a trial in which 656 patients scheduled to receive highly emetogenic chemotherapy that included cisplatin or a cyclophosphamide/anthracycline combination were randomly assigned to thalidomide 100 mg twice daily on days 1 to 5 versus placebo; all patients received palonosetron on day 1 and dexamethasone on days 2 through 4 [95]. The primary endpoint was no emesis or use of rescue medication in the delayed phase (25 to 120 hours) or overall (0 to 120 hours) after a single treatment cycle. Compared with placebo, delayed and overall complete response rates with thalidomide were significantly higher (77 versus 62 and 66 versus 53 percent, respectively). Rates of no nausea were also higher with thalidomide. The thalidomide group had higher rates of sedation, dizziness, constipation, and dry mouth. Given these toxicities, the association of neuropathy and thromboembolism with this agent (which is not well assessed in a trial only evaluating a single treatment cycle), its expense, and restricted access because of a history of causing fetal anomalies, thalidomide is not preferred over an NK1R antagonist for prevention of delayed emesis. However, the combination of thalidomide plus palonosetron and dexamethasone is an option for prevention of delayed emesis in patients who lack access to NK1R antagonists.

Other agents — Other agents that have been used in the treatment or prevention of CINV include dopaminergic antagonists such as phenothiazines (eg, prochlorperazine, levomepromazine outside of the United States), metoclopramide, and butyrophenones, as well as cannabinoids such as dronabinol. These agents have a lower therapeutic index than the 5-HT3 receptor antagonists, NK1R antagonists, 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 [96-100]. 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 [7]. (See "Characteristics of antiemetic drugs".)

Another drug that may be useful as an adjunct to conventional antiemetic agents is lorazepam, but it is not recommended as a single-agent antiemetic [7].

PREVENTION OF DELAYED EMESIS — Delayed emesis is defined by its occurrence more than 24 hours after chemotherapy. Although it is most common following high-dose cisplatin [101-103], delayed emesis may occur with other agents as well [23].

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 (AC) [104].

Although the risk of delayed emesis has been best studied with high-dose cisplatin and the combination of doxorubicin plus cyclophosphamide (in patients treated for breast cancer), several 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 (especially cyclophosphamide), 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 with other drugs, carboplatin ≥300 mg/m², and oxaliplatin (as used in the FOLFOX [oxaliplatin plus short-term infusional fluorouracil and leucovorin] regimen for advanced colorectal cancer) [23,105-108]. One study found that, among 68 patients treated with one of these regimens who had no postchemotherapy 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 [23]. This frequency was reduced to 15 of 75 (20 percent) when ondansetron was continued.

Management — A variety of antiemetic agents have demonstrated value in the prevention of delayed emesis. The most important classes of agents have been the neurokinin-1 receptor (NK1R) antagonists [55], corticosteroids [101,103], and more recently, olanzapine [87]. The data supporting the latter agents in delayed emesis are reviewed in the sections above. Additional agents that may have some value in some delayed emesis settings include metoclopramide and the type three 5-hydroxytryptamine (5-HT3) receptor antagonists.

NK1R antagonist plus dexamethasone and 5-HT3 antagonist — For most patients undergoing treatment with cisplatin or other (non-AC) highly emetogenic chemotherapy agents the recommended regimen to prevent delayed emesis is an NK1R antagonist combined with dexamethasone, a type three 5-hydroxytryptamine (5-HT3) antagonist, and olanzapine on day 1, followed by a combination of dexamethasone on days 2 to 4 and olanzapine on days 2 to 4. (See 'Cisplatin and other highly emetogenic single agents' above.)

The optimal way to prevent delayed emesis in patients receiving AC for breast cancer is controversial. Data supporting dexamethasone beyond day 1 when an NK1R antagonist is used are very limited:

●Phase III trials using the new NK1R antagonists netupitant and rolapitant used dexamethasone on day 1 only and achieved high rates of total control of CINV [66,109]. (See 'Netupitant plus palonosetron and fosnetupitant' above and 'Rolapitant' above.)

●Another randomized trial conducted exclusively in this population that used aprepitant or ondansetron on days 2 and 3, and gave dexamethasone on day 1 only also reported high rates of total control of CINV [72]. (See 'Efficacy' above.)

●Another trial comparing aprepitant versus dexamethasone on days 2 and 3 for preventing delayed emesis after AC, with all patients receiving aprepitant, palonosetron, and dexamethasone on day 1, showed no significant difference in outcomes [110].

Whether there is benefit for continuing dexamethasone on days 2 and 3 after a long-acting NK1R antagonist on day 1 (eg, fosaprepitant, rolapitant) or days 1 to 3 (aprepitant) plus a 5-HT3 antagonist on day 1 is better than just the long-acting NK1R antagonist plus a 5-HT3 antagonist with dexamethasone on day 1 was directly addressed in a placebo-controlled double-blind phase III trial conducted in 396 patients receiving highly emetogenic regimens (cisplatin ≥50 mg/m² or AC) [111]. All patients received palonosetron on day 1, and approximately 80 percent received a three-day aprepitant-containing regimen; the remainder had fosaprepitant on day 1. Complete response rates, defined as no emesis and no rescue medications during the overall acute and delayed phase (to 120 hours), were similar in both the three-day and one-day dexamethasone groups (46.9 versus 44 percent). The authors concluded that dexamethasone administration on days 2 and 3 can be spared when combined with an NK1R antagonist plus palonosetron. This conclusion appears most valid for patients receiving AC, as these patients comprised the majority (77 percent) of study participants. For the 23 percent of patients receiving cisplatin, a clear trend favoring the three-day dexamethasone arm was noted.

What has not been studied is if aprepitant used on day 1 followed by dexamethasone and aprepitant on days 2 to 3 is better than aprepitant alone continued on days 2 and 3, and whether day 2 and 3 dexamethasone is needed in patients receiving other 5-HT3 antagonists on day 1 plus an NK1R antagonist. Until these studies are done, it is difficult to conclude that there is benefit for adding dexamethasone on days 2 and 3 in patients receiving AC who have received a long-acting NK1R antagonist on day 1.

Metoclopramide in patients receiving cisplatin — All of the trials examining the benefit of aprepitant to prevent delayed CINV used a three-day schedule of administration in conjunction with oral glucocorticoids. Single-day administration is approved for fosaprepitant but not aprepitant. (See 'Efficacy' above.)

The use of metoclopramide as a substitute for aprepitant on days 2 and 3 was addressed in a randomized trial in which 303 previously untreated patients received a cisplatin-based chemotherapy regimen [112]. All patients received the same regimen to prevent acute emesis on day 1 (aprepitant 125 mg, dexamethasone 8 mg, and palonosetron 0.25 mg) and were randomly assigned to dexamethasone 8 mg daily on days 2 to 4 plus aprepitant 80 mg daily on days 2 and 3 or to dexamethasone 8 mg twice daily plus metoclopramide 20 mg four times a day on days 2 to 4. The primary endpoint was complete response (no vomiting or rescue medication on days 2 through 5 after chemotherapy). The complete response rate was not significantly different (80.3 versus 82.5 for aprepitant and metoclopramide, respectively), as were all secondary endpoints, including no nausea, and adverse events were not significantly different. The authors concluded that aprepitant was not superior to metoclopramide for control of delayed emesis after cisplatin when used in conjunction with dexamethasone after day 1 of chemotherapy.

Given that many institutions have switched over to day 1 single-dose fosaprepitant followed by dexamethasone alone on days 2 to 3, rather than three-day aprepitant plus dexamethasone, to prevent delayed emesis, the relevance of these results to current clinical practice is unclear.

5-HT3 antagonists alone — Conflicting results have been described with the use of first-generation type three 5-hydroxytryptamine (5-HT3) receptor antagonists as single agents for protection against delayed emesis [101,113-117]. Although some benefit has been seen when these agents are used as monotherapy, the benefit has not been as great as that seen with glucocorticoids. Furthermore, continuing a 5-HT3 receptor antagonist beyond 24 hours along with glucocorticoids did not confer additional benefit compared with corticosteroids alone. Thus, the use of 5-HT3 receptor antagonists as a sole maneuver to prevent delayed emesis in patients receiving cisplatin is not recommended.

The second-generation 5-HT3 receptor antagonist palonosetron seems to be 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 with ondansetron in preventing delayed emesis (complete response rates of 45 and 48 versus 39 percent, respectively), although the results were not statistically significant [42]. 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 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 [41]. 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).

●A third phase III trial also supports superiority of palonosetron over granisetron in patients also receiving an NK1R antagonist for prevention of delayed emesis [44].

Thalidomide — Another option for prevention of delayed emesis with highly emetogenic chemotherapy, particularly in countries where NK1R antagonists are not available, is thalidomide in combination with palonosetron and dexamethasone. (See 'Thalidomide' above.)

Moderate-risk regimens — The incidence of delayed emesis following treatment with moderate-risk regimens is not well characterized. Cyclophosphamide- or doxorubicin-based regimens used for diseases other than breast cancer, as well as carboplatin- and oxaliplatin-containing regimens, can cause delayed emesis. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Delayed emesis'.)

Carboplatin-containing regimens — There are clear supportive data for the benefit of NK1R antagonists in patients receiving moderately emetogenic carboplatin-containing chemotherapy [48-51,118,119]. (See 'Neurokinin-1 receptor antagonists' above.)

Non-carboplatin-containing regimens

●Aprepitant – In contrast to carboplatin-containing regimens, there are conflicting data on the benefit of adding an NK1R antagonist for moderately emetogenic non-carboplatin-based regimens:

•The relative roles of palonosetron and aprepitant in controlling delayed nausea were studied in a randomized trial of 944 evaluable patients receiving primarily (95 percent) moderately emetogenic chemotherapy (doxorubicin, epirubicin, cisplatin, carboplatin, or oxaliplatin) [120]. Palonosetron did not provide superior control of delayed nausea compared with granisetron when both were provided on day 1 with dexamethasone and when prochlorperazine was administered on days 2 and 3. In addition, aprepitant was not more effective than prochlorperazine when both were combined with dexamethasone on days 2 and 3.

•On the other hand, a benefit for adding aprepitant (125 mg day 1, 80 mg daily on days 2 and 3) to palonosetron and dexamethasone was shown in a randomized Chinese trial limited to a population of patients with multiple risk factors for emesis (exclusively female, all <50 years of age, history of limited ethanol consumption, and two-thirds nonchemotherapy naïve). The trial included 248 patients receiving short-term infusional fluorouracil plus leucovorin, and either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) chemotherapy for gastrointestinal cancer [121]. The complete response rate was significantly higher in the aprepitant group (87 versus 67 percent), and the benefits were seen both in the acute and delayed phases of the trial. Given the unique nature of the patient population with regards to risk factors for emesis, it is difficult to extrapolate the findings to a general population receiving these chemotherapy regimens.

•A year 2018 meta-analysis of 16 trials of moderately emetogenic chemotherapy (that did not include the Chinese trial) concluded that there was clear benefit for the addition of a NK1R antagonist for carboplatin-based chemotherapy but not globally for all moderately emetogenic regimens, including those containing oxaliplatin [119].

●Other strategies – For patients receiving other moderately emetogenic regimens with a risk of delayed emesis, glucocorticoids are consistently useful agents:

•The value of maintenance dexamethasone was demonstrated in a randomized, placebo-controlled trial of patients undergoing cyclophosphamide-based chemotherapy [102]. In this trial, 98 patients were given granisetron and dexamethasone before chemotherapy and randomized to receive oral dexamethasone 4 mg twice daily either as maintenance or no maintenance. Maintenance dexamethasone was associated with a higher rate of complete (57 versus 33 percent) and major control (33 versus 15 percent) of delayed emesis. No trials have examined the benefit of maintenance dexamethasone in patients treated with carboplatin who have received an NK1R antagonist.

•The 5-HT3 receptor antagonists also have activity as single agents for delayed emesis with cyclophosphamide-based chemotherapy [23]. However, there is no evidence that they are superior to dexamethasone alone or that combination therapy with dexamethasone is superior to dexamethasone alone [104,105].

•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 [104]:

-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. Results according to the different moderately emetogenic agents were not provided.

-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 nausea was achieved in only 41 and 23 percent of patients treated with the combination and dexamethasone, respectively.

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 and/or benzodiazepines. These recommendations are in keeping with guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC) [4,7,122].

Anticipatory nausea and emesis are conditioned responses that occur in patients who experienced severe nausea and vomiting during prior cycles of chemotherapy [123], and that appear 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 [124]. Anticipatory nausea is more commonly reported than is anticipatory emesis (14 versus 1 to 2 percent in one study [125]).

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 3). Once anticipatory emesis has been established, nonpharmacologic methods (eg, hypnosis, behavioral therapy with systemic desensitization) may be effective [126-128]. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm".)

Although few formal trials have been carried out, benzodiazepines before and during chemotherapy may be useful [129-131]. 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 to 2 mg/day) to a psychologic support program including progressive relaxation training was associated with a significantly reduced rate of anticipatory nausea compared with placebo (0 versus 18 percent) [130].

SPECIAL SITUATIONS

Consecutive-day intravenous therapy with highly emetogenic agents — For patients receiving four to five days of cisplatin, such as in regimens for testicular or ovarian germ cell cancer, we suggest the use of a daily dose of a first-generation type three 5-hydroxytryptamine (5-HT3) receptor antagonist, or a single application of a granisetron transdermal patch or palonosetron on days 1, 3, and 5 plus daily dexamethasone, with the addition of aprepitant (days 1, 2, and 3) or another neurokinin-1 receptor (NK1R) antagonist (fosaprepitant, netupitant plus palonosetron [NEPA], or rolapitant) on day 1 for highly emetogenic regimens.

When moderately emetogenic chemotherapy agents are administered on several consecutive days, 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. American Society of Clinical Oncology (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 afterward, if appropriate [7].

Trials conducted before the availability of NK1R antagonists suggested that repetitive daily dosing with a 5-HT3 receptor antagonist combined with dexamethasone was the best approach [132,133]. However, the benefit of adding aprepitant to a 5-HT3 antagonist and dexamethasone was shown in small trial of patients receiving a five consecutive day cisplatin-containing chemotherapy regimen for germ cell cancer [134]. All patients received a 5-HT3 antagonist (other than palonosetron) once daily on days 1 through 5 plus dexamethasone 20 mg once daily on days 1 and 2, and were randomly assigned to aprepitant (125 mg on day 3, 80 mg on days 4 and 5) or no aprepitant. The group receiving aprepitant also received dexamethasone 4 mg twice daily on days 6, 7, and 8, while the placebo group received dexamethasone 8 mg twice daily on days 6 and 7, and 4 mg twice daily on day 8. A complete response (no emetic episodes and no use of rescue medication) was noted in significantly more patients receiving aprepitant (42 versus 13 percent), and the visual analog scale (VAS) score for nausea was numerically lower for aprepitant, although the difference compared with placebo was not statistically significant.

Whether a similar degree of protection can be gained by substituting one day of fosaprepitant for three days of aprepitant is not clear. A phase II study conducted by the Hoosier Oncology Group in 65 patients receiving a five-day chemotherapy regimen for germ cell cancer reported a lower than expected rate of complete response (13 of 51 assessable patients, 24 percent) [135]. Although the authors provided a rationale for starting the NK1R on day 3 rather than on day 1, the optimal schedule for NK1R antagonists for patients receiving consecutive-day therapy with highly emetogenic chemotherapy is unknown, given the lack of comparative trials addressing this question.

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 has been addressed in three trials [136-138], all of which showed no significant inferiority of transdermal administration.

The largest trial was 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 [136]. Concurrent glucocorticoids, which were administered at the investigator's discretion, were given to approximately 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 significantly 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 United States for the prevention of CINV in patients receiving multiday, moderately or highly emetogenic, intravenous chemotherapy for up to five consecutive 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 [139,140].

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 [38,141,142]. 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 — For patients receiving high-dose chemotherapy with hematopoietic cell transplantation (HCT), we recommend a combination of dexamethasone, a 5-HT3 receptor antagonist, and an NK1R antagonist. A four-drug combination of dexamethasone, a 5-HT3 receptor antagonist, an NK1R antagonist, and olanzapine is another option for patients undergoing high-dose chemotherapy with HCT.

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 a limited number of randomized trials specifically studying the issue of emesis in the high-dose chemotherapy setting with HCT [143-147]. Most studies have focused on the combination of a 5-HT3 receptor antagonist and dexamethasone [148-151]. However, a role for aprepitant in this setting is supported by two phase III trials:

●In one trial, 181 patients undergoing a preparative regimen for hematopoietic stem cell transplantation were randomly assigned to ondansetron plus dexamethasone and either aprepitant or placebo [152]. Significantly better emetic control was noted in patients who received aprepitant (no emesis for the entire study period in 73 versus 23 percent of the placebo group), although there were no differences between the groups in use of rescue antiemetics.

●Benefit for aprepitant was also noted in a second phase III trial in which 362 patients with multiple myeloma undergoing autologous HCT after high-dose melphalan were randomly assigned to granisetron plus dexamethasone and either aprepitant or placebo [153]. Significantly more patients receiving aprepitant achieved the primary endpoint (no emesis and no need for rescue therapy within 120 hours of administration of high-dose melphalan, 58 versus 41 percent, p = 0.00042). Absence of major nausea (94 versus 88 percent) and emesis (78 versus 65 percent) within 120 hours also favored the aprepitant group.

Additional benefit for the addition of olanzapine to this three-drug regimen was suggested in a randomized placebo-controlled trial conducted in a trial of 98 patients undergoing high-dose chemotherapy plus HCT for a hematologic malignancy. Olanzapine 10 mg or a matching placebo was administered on each chemotherapy day and for three days after [147]. Rates of complete antiemetic response were significantly higher with olanzapine in overall (55 versus 26 percent) and delayed (61 versus 30 percent) phases, but not in the acute phase. Furthermore, significantly more patients receiving olanzapine achieved no more than minimal nausea in the overall and delayed phases. Results were significant in the autologous but not the allogeneic cohorts. None of the patients receiving olanzapine discontinued therapy for adverse events.

The updated 2020 antiemetic guidelines from ASCO and the 2016 Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO) guidelines recommend a 5-HT3 receptor antagonist plus dexamethasone with consideration of aprepitant in this setting [7,154]. However, updated 2020 ASCO guidelines suggest that clinicians may also offer a four-drug regimen in this setting, with a 5-HT3 receptor antagonist plus dexamethasone, an NK1R antagonist, and olanzapine [7].

Oral chemotherapy — A severe limitation of current recommendations for prevention and treatment of CINV is the lack of guidance for patients receiving oral chemotherapy agents, which vary in their emetogenicity potential (table 2). Virtually all of the clinical trials evaluating prevention and treatment of CINV have focused on intravenously delivered chemotherapy. Therefore, evidenced-based guidelines for antiemetic prophylaxis with oral chemotherapy agents are not currently possible. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend the following approach:

●High/moderate emetic risk agents – An orally administered 5-HT3 antagonist starting before chemotherapy and continuing daily. Options include:

•Dolasetron 100 mg daily

•Ondansetron 8 to 16 mg daily

•Granisetron 1 to 2 mg orally daily or a granisetron transdermal patch every seven days

●Low/minimal emetic risk agents – Treat only on an "as needed" basis. For patients who develop nausea/emesis during treatment, options include metoclopramide (10 to 20 mg orally, every six hours), prochlorperazine (10 mg orally, every six hours), haloperidol (1 to 2 mg orally, every four to six hours), or a daily dose of a 5-HT3 antagonist (eg, ondansetron 8 to 16 mg, dolasetron 100 mg, or granisetron 1 to 2 mg), as needed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chemotherapy-induced nausea and vomiting in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Nausea and vomiting with cancer treatment (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General aspects

•Chemotherapy-induced nausea and vomiting (CINV) is an important adverse effect of treatment. 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 four 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 receptor (NK1R) antagonists, glucocorticoids (especially dexamethasone), and the antipsychotic medication olanzapine when used in combination with other antiemetics. (See '5-HT3 receptor antagonists' above and 'Neurokinin-1 receptor antagonists' above and 'Glucocorticoids' above and 'Olanzapine' above.)

These agents are used alone and/or in combinations, depending on the specific chemotherapy regimen being administered, as recommended in the American Society of Clinical Oncology (ASCO) and Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical oncology (ESMO) guidelines. (See 'Antiemetic efficacy of individual agents' above.)

Electrocardiogram (ECG) interval changes are a class effect of the first-generation 5-HT3 receptor antagonists; avoid use in patients with congenital long QT syndrome. Abnormal potassium and magnesium levels should be corrected before initiation of treatment. ECG monitoring is recommended in patients with underlying cardiac disease, and with concurrent use of other medications that predispose to QTc prolongation (table 4). (See 'Cardiac issues' above.)

•Our recommendations for antiemetic prophylaxis for intravenously administered chemotherapy agents, which largely parallel those of MASCC/ESMO and ASCO, are outlined in the table (table 3) and summarized in the following bullets:

●Highly emetogenic regimens

•For patients receiving cisplatin and other highly emetogenic agents (table 1), we recommend antiemetic therapy with a combination of a 5-HT3 receptor antagonist, dexamethasone, and an NK1R antagonist (Grade 1A). We also suggest the addition of olanzapine (Grade 2B). (See 'Highly emetogenic chemotherapy' above and 'Need for a 5-HT3 agent' above and 'Olanzapine' above.)

Details of the regimen are described above. (See 'Highly emetogenic chemotherapy' above.)

•For patients receiving an anthracycline plus cyclophosphamide for breast cancer, we use a similar regimen except we suggest not using dexamethasone on days 2 to 4 (Grade 2B). (See 'NK1R antagonist plus dexamethasone and 5-HT3 antagonist' above and 'Olanzapine' above.)

•For non-breast cancer populations receiving an anthracycline plus cyclophosphamide regimen, this prophylactic regimen is also reasonable. However, for patients who are receiving anthracycline/cyclophosphamide regimens that incorporate glucocorticoids (eg, for non-Hodgkin lymphoma), day 1 palonosetron alone, without the use of an NK1R antagonist or olanzapine, is an acceptable option. (See 'Other diseases' above and 'Palonosetron' above.)

●Moderately emetogenic regimens

•For patients receiving carboplatin-based regimens, we recommend the combination of an NK1R antagonist, a 5-HT3 receptor antagonist, and dexamethasone on day 1 (Grade 1B). (See 'Moderately emetogenic chemotherapy' above and 'Neurokinin-1 receptor antagonists' above.)

Additional prophylaxis beyond day 1 for delayed emesis is not needed for most patients.

•For patients receiving non-carboplatin-based regimens with a moderate risk for CINV (table 1), we recommend a 5-HT3 receptor antagonist plus dexamethasone on day 1 (Grade 1A).

To prevent delayed emesis, we suggest single-agent dexamethasone on days 2 and 3 (Grade 2B) if a first-generation 5-HT3 receptor antagonist is used on day 1. Treatment with a first-generation 5-HT3 receptor antagonist alone on days 2 and 3 is a reasonable alternative. If palonosetron is used on day 1, additional prophylaxis beyond day 1 is not needed for most patients. (See 'Moderate-risk regimens' above.)

●Low and minimal risk regimens

•For patients receiving low emetic risk agents (table 1), we suggest dexamethasone (4 to 8 mg) as a single agent (Grade 2C). If glucocorticoid use is contraindicated or undesirable (eg, with the use of long-term weekly chemotherapy) alternative approaches include a single dose of a phenothiazine-type drug, such as prochlorperazine or levomepromazine; a single dose of a 5-HT3 antagonist; or metoclopramide. (See 'Glucocorticoids' above and 'Other agents' above.)

•For most patients receiving chemotherapy agents with a minimal risk of causing emesis (table 1), we suggest that antiemetic therapy not be routinely administered to prevent either acute or delayed CINV (Grade 2B). Prophylactic antiemetics (dexamethasone 4 to 8 mg, prochlorperazine, levomepromazine, or metoclopramide) may be administered to patients who have had emesis with prior low-risk regimens, or on an "as needed" basis. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting", section on 'Chemotherapy agent'.)

•For adult patients, the addition of an immune checkpoint inhibitor (ICI) to cytotoxic chemotherapy does not change the principle of choosing the antiemetic regimen based on the emetogenicity of the agents administered, including the use of dexamethasone. ICIs administered either alone or in combination with other ICIs are minimally emetogenic and do not require the use of a prophylactic antiemetic. (See 'Immune checkpoint inhibitor immunotherapy' above and 'Patients receiving immune checkpoint inhibitors' above.)

●Special situations

•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 and/or benzodiazepines (Grade 2B). (See 'Anticipatory emesis' above.)

•Patients undergoing hematopoietic cell transplantation – For patients receiving high-dose intravenous chemotherapy with hematopoietic cell transplantation, we suggest a combination of dexamethasone, a 5-HT3 receptor antagonist, and an NK1R antagonist (Grade 2A). The addition of olanzapine to this regimen is another option. (See 'High-dose chemotherapy regimens' above.)

•Multiday regimens – For patients receiving four or five consecutive days of cisplatin in regimens for testicular or ovarian germ cell cancer, we suggest a daily dose of an oral 5-HT3 receptor antagonist or a granisetron transdermal patch plus daily dexamethasone, with the addition of an NK1R antagonist on day 1 (Grade 2C). (See 'Multiday regimens' above and 'Consecutive-day intravenous therapy with highly emetogenic agents' above.)

Prophylaxis is more difficult for moderately emetogenic chemotherapy agents administered on several consecutive days. We agree with ASCO guidelines, which suggest antiemetics appropriate for the emetogenic risk class of the chemotherapy on each day of the chemotherapy and for two days after, if appropriate. (See 'Consecutive-day intravenous therapy with highly emetogenic agents' above.)

•Oral agents – Oral chemotherapy agents have a variable emetogenicity potential (table 2), and there is no consensus as to the appropriate prophylactic antiemetic strategy. We agree with consensus-based guidelines from NCCN (see 'Oral chemotherapy' above):

-High/moderate-risk agents – A 5-HT3 antagonist starting before chemotherapy and continuing daily.

-Low/minimal-risk agents – Treat only on an "as needed" basis.