Neurokinin-1 Receptor Antagonist (NK1)

STUDY PURPOSE: To conduct a meta-analysis comparing the effectiveness of NK₁ inhibitors in preventing chemotherapy-induced nausea and vomiting (CINV) attributed to highly emetogenic chemotherapy (HEC)

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 19
• TOTAL PATIENTS INCLUDED IN REVIEW = 6,788
• SAMPLE RANGE ACROSS STUDIES: 16–359
• KEY SAMPLE CHARACTERISTICS: Receiving highly emetogenic chemotherapy (HEC)

PHASE OF CARE: Active antitumor treatment

Antiemetic regimens including an NK₁ inhibitor (aprepitant, fosaprepitant, rolapitant, casopitant, netupitant) prevent CINV attributed to HEC significantly more than antiemetic regimens that do not include it.

Antiemetic regimens containing an NK₁ inhibitor prevent CINV attributed to HEC better than regimens that do not contain it.

Antiemetic regimens should include an NK₁ inhibitor to maximally prevent CINV.

STUDY PURPOSE: To provide a detailed assessment of the efficacy and toxicity of regimens based on rolapitant in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV)

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 4 
• TOTAL PATIENTS INCLUDED IN REVIEW = 2,856
• SAMPLE RANGE ACROSS STUDIES: 454–1,332 patients
• KEY SAMPLE CHARACTERISTICS: Three studies included patients taking highly emetogenic chemotherapy, one study included patients administered moderately emetogenic chemotherapy. Patients ethnicities are unknown.

PHASE OF CARE: Active antitumor treatment

The pooled RR for the complete response (CR) was 1.23 (95% CI [1.18, 1.33], p < 0.00001) in the overall phase, 1.12 (95% CI [1.02, 1.24], p = 0.02) in the acute phase, and 1.19 (95% CI [1.13, 1.26], p < 0.00001) in the delayed phase. The pooled RR for no significant nausea in the overall phase was 1.17 (95% CI [1.04, 1.32], p = 0.008), and the pooled RR for no emesis in the overall phase was 1.24 (95% CI [1.18, 1.31], p < 0.00001). The efficacy analyses demonstated that rolapitant-based regimens are associated with higher rates of CR (both in overall, acute, and delayed phases). No significant nausea was present and no emesis was present compared with control regimens in highly and moderately emetogenic chemotherapy. The pooled RR of all grade constipation was 1 (95% CI [0.55, 1.82], p = 0.61), and the pooled RR of all grade headache was 1.05 (95% CI [0.57, 1.96], p = 0.87). Therefore, rolapitant-based regimens are not associated with an increased RR for constipation or headache compared with antiemetic control regimens.

This analysis demonstrated that rolapitant-based regimens are associated with higher rates of CR, no significant nausea, and no emesis compared with control regimens in highly and moderately emetogenic chemotherapy. In addition, no increased risk of toxicity with constipation or headache exists when compared with standard antiemetic control regimens. The authors concluded that rolapitant is a valid addition to other available standard antiemetic regimens for highly and moderately antiemetic chemotherapy.

• Limited number of studies included
• Low sample sizes
• Limited information on patient age, sex, diagnosis, and treatment regimens

Rolapitant is associated with higher CR rates, no significant nausea, and no emesis compared to other control regimens in highly and moderately emetogenic chemotherapy without increased toxicity. Rolapitant should be a recommended addition to control regimens that do not include a neurokinin inhibitor.

• FINAL NUMBER STUDIES INCLUDED = 4 
• TOTAL PATIENTS INCLUDED IN REVIEW = Not reported
• SAMPLE RANGE ACROSS STUDIES: Not reported
• KEY SAMPLE CHARACTERISTICS: Three studies included patients with solid tumors; one study included breast cancer only.

PHASE OF CARE: Active antitumor treatment
 
APPLICATIONS: Elder care

The relative risk of complete response for patients under 65 is 1.30 (95% CI: 1.19–1.42; p < 0.0001). It is not significantly different from patients over 65 (Q = 0.281, p = 0.596). The relative risk for a complete response for patients over 75 is 1.42 (95% CI: 1.07–1.89; p = 0.02). It is not significantly different from the relative risk for patients under the age of 75 (1.28, 95% CI: 1.19–1.37; Q = 0.49, p = 0.78). The relative risk of a complete response to regimens including aprepitant for patients over 75 is not different for patients under 65 (Q = 0.42, p = 0.81). There was no statistically significant difference in heterogeneity among studies.

Aprepitant is beneficial for patients both over and under age 65.

• Included studies did not use the same chemotherapy regimen.
• Extremely limited demographic data were presented.
• Search did not include major databases.
• No year limits were described in the study.
• Authors did not state how many studies were retrieved.

The addition of aprepitant should be considered in patients, regardless of age, for the management of chemotherapy-induced nausea and vomiting associated with moderate and highly emetogenic chemotherapy.

To evaluate the overall effectiveness and safety of neurokinin 1 (NK1) receptor antagonists (RAs) in the prevention of chemotherapy-induced nausea and vomiting (CINV) when compared to standard antiemetic regimens including a 5-HT₃ RA plus dexamethasone

Databases searched were MEDLINE, Embase, Cochrane Central Register of Controlled Trials (Central), and Latin American and Carribean Health Sciences Literature (LILACS).

Search keywords were neurokinin, aprepitant, casopitant, ezlopitant, netupitant, vestipitant, chemotherapy-induced nausea and vomiting, nausea in cancer patients, vomiting in cancer patients, and randomized trials.

Studies were included in the review if they

• Were randomized controlled trials (RCTs) that addressed the addition of an NK1 RAs to standard antiemetic therapy (dexamethasone plus 5-HT₃ RA) for the prevention of CINV.
• Provided an adequate description of outcomes that could be pooled in the meta-analysis.
• Used adequate antiemetic therapy in the control arm.

No specific exclusion criteria were identified.

A total of 4,034 references were retrieved.

Two reviewers assessed the quality of each study. Items from Delphi list and Jadad score were utilized for data extraction; however, the authors did not describe if any specific scoring system was used for quality assessment.

• The final number of studies included was 17.
• The sample range across all studies was 36–1,933.
• The total number of patients included in the review was 8,740. Data from 8,173 patients in 13 studies were used for analysis about complete response (CR), which is defined as no vomiting, no retching, and no use of rescue medication. Data from 8,376 patients from 15 studies were used for acute and delayed phase analysis.
• All patients were diagnosed with cancer and receiving either highly or moderately emetogenic chemotherapy.

All patients were in active antitumor treatment.

• The use of an NK1 RA increased the CR rate in the overall phase from 54% to 72% (overall response [OR] = 0.51, 95% confidence interval (CI) = 0.46–0.57, p < 0.001), in the acute phase (OR = 0.56, 95% CI = 0.48–0.65, p < 0.001), and in the delayed phase (OR = 0.48, 95% CI = 0.42–0.56, p < 0.001).
• The addition of an NK1 RA to standard antiemetic therapy improved CR rates in the overall phase for patients who received highly emetegenic chemotherapy (OR = 0.46, 95% CI = 0.40–0.53, p < 0.001) or moderately emetogenic chemotherapy (OR = 0.59, 95% CI = 0.51–0.67, p < 0.001).
• The addition of an NK1 RA increased CR rates in the overall phase independently depending on if ondansetron was used in the control arm beyond day 1 or not (ondansetron: OR = 0.64, 95% CI = 0.54–0.76, p < 0.001; no ondansetron: OR = 0.47, 95% CI = 0.41–0.53, p < 0.001). CR in the acute phase and delayed phase demonstrated a strong correlation (r = 0.91, p < 0.001).
• Three trials (n = 1,480) suggested a statistically significant increase (from 2% to 6%) in the risk of severe infection among patients receiving NK1 RAs (OR = 3.10. 95% CI = 1.69–5.67, p < 0.001).

The addition of an NK1 RA increased CINV control in the acute, delayed, and overall phases.

The use of an NK1 RA may be associated with a statistically significant increase in the risk of severe infection. A more comprehensive evaluation of the safety profile of NK1 RAs and additional appraisal of specific data from RCTs is needed.

• Subgroup analysis requires careful scrutinization. In this review, most patients in the moderately emetogenic chemotherapy group received an AC regimen, which is now considered highly emetogenic chemotherapy.
• Favorable ondansetron use for the delayed phase was suggested after comparing its effect with placebo control. However, current guidelines suggest the use of dexamethasone rather than ondansetron as a combination regimen for delayed CINV control. Comparison should have been between an NK1 RA plus dexamethasone versus NK1 plus ondansetron.
• Toxicity analysis was based on reports  of 3 studies (out of 17 studies included) which reported on the most prevalent adverse events. NK1 RA use did not increase the risk of febrile neutropenia or any other hematologic toxicity. OR findings are not clearly interpretable.

• This systematic review summarized the results from RCTs which investigated the effect of an NK1 RA for CINV control. Overall, the use of an NK1 RA improved the CR in acute, delayed, and overall phases.
• Further studies are warranted to determine whether adding an NK1 RA to standard antiemetics could improve CINV control in non-AC, moderately emetogenic chemotherapy as most NK1 RA RCTs were based on cases receiving highly emetogenic chemotherapy (including an AC regimen).
• Although further study is warranted, occurrence of infection with NK1 use requires special attention.

To evaluate the therapeutic efficacy and safety of aprepitant for the treatment of chemotherapy-induced nausea and vomiting (CINV) during the first five days following highly or moderately emetogenic chemotherapy

Databases searched were MEDLINE and Embase. Abstracts were searched in the American Society of Clinical Oncology, Cochrane Library, and National Cancer Institute.

Search keywords were aprepitant, MK-869, substance P receptor antagonist, NK-1 receptor antagonist, and chemotherapy-induced nausea and vomiting.

Studies were included in the review if they

• Were randomized controlled trials.
• Compared the efficacy of aprepitant with placebo or no intervention for the prophylaxis of CINV.
• Contained information regarding the complete control of vomiting or nausea during the first 24 hours or the first 24 hours after chemotherapy administration.
• Had at least 80% follow up.

Studies were excluded if they

• Involved patients receiving radiotherapy treatment.
• Only provided pharmacokinetic information.
• Included healthy people or animals.
• Involved patients with depression and other nervous system diseases.
• Had insufficient data on efficacy of aprepitant.
• Had subjects who were applied more than once.
   

• The total number of references initially identified was 327; of these, 29 were retrieved for detailed evaluation.
• The evaluation method was not specified.
• When abstracts and published articles were found on the same population, only the articles were used for analysis.
• When studies used a crossover design, only data during the first cycle was used for analysis.

• The final number of studies included was 15 representing a total of 4,798 patients (2,419 experimental and 2,379 control).
• The sample range across all studies was 45–866.
• Key sample characteristics were not specified.

All patients were in active treatment.

• Incidence of emesis was significantly reduced in the aprepitant group on the first day of chemotherapy (relative response [RR] = 1.13, 95% CI = 1.10–1.16). 
• Incidence of delayed nausea and vomiting from days 2–5 after chemotherapy was also significantly reduced (RR = 1.35, 95% CI = 1.22–1.48). 
• Aprepitant and ondansetron or granisetron demonstrated superior nausea and vomiting control compared to nonaprepitant regimens; however, aprepitant plus palonosetron did not show any superiority. 
• No significant differences were found regarding the occurrence of adverse effects in aprepitant versus control groups.

Aprepitant is effective in the prevention of delayed CINV. Aprepitant improves the antiemetic effect of ondansetron and dexamethasone in patients receiving cisplatin-based chemotherapy.

Aprepitant is effective and safe for the prevention of CINV in the acute and delayed phases of treatment.

STUDY PURPOSE: The purpose of this meta-analysis is to compile the evidence on and report the efficacy of neurokinin-1 receptor antagonists (NK1RAs) for the prevention of CINV.

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: MEDLINE (via PubMed) and OVID

YEARS INCLUDED: 1990-2014

INCLUSION CRITERIA: Randomized controlled trial, using the addition of an NK1RA in addition to standard antiemetic therapy, defined as a 5-HT₃-RA plus a glucocorticoid, in patients with cancer receiving chemotherapy, published in English.  

EXCLUSION CRITERIA: CINV prevention not examined, pharmacokinetic studies, risk factors for CINV, quality-of-life studies. Not independent data set, pooled analysis, dose finding studies.

TOTAL REFERENCES RETRIEVED: 1,987

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two authors screened for eligibility of articles to be included. Of the articles deemed eligible for inclusion, one author would review to abstract out information and this was reviewed by a second author.

FINAL NUMBER STUDIES INCLUDED: 23

TOTAL PATIENTS INCLUDED IN REVIEW: 11,814

SAMPLE RANGE ACROSS STUDIES: 36–1,449

KEY SAMPLE CHARACTERISTICS: People with cancer, receiving chemotherapy for cancer

PHASE OF CARE: Active anti-tumor treatment

Compiling the results from all eligible studies reviewed, the authors found that adding a NK1RA to a standard antiemetic regimen provided better emesis control than a standard antiemetic regimen alone in patients receiving cisplatin-based highly emetogenic chemotherapy and anthracycline/cyclophosphamide (AC)-based highly emetogenic chemotherapy (all p < 0.00001). In patients receiving moderately emetogenic chemotherapy, there were no statistically significant differences in emesis between NK1RA plus standard antiemetic regimen and standard antiemetic regimen alone. In patients receiving high-dose chemotherapy before stem cell transplantation and cisplatin-based multiple-day chemotherapy (MDC) regimens, adding a NK1RA to a standard antiemetic regimen provided better emesis control (all p < 0.05).

Adding an NK1RA to standard antiemetic regimens can reduce CINV in patients receiving highly emetogenic chemotherapy. Adding an NK1RA to standard antiemetic regimens with moderately emetogenic therapy did not demonstrate an added benefit to preventing CINV.

Adding an NK1RA to standard antiemetic regimens in people receiving a chemotherapy regimen classified as highly emetogenic can reduce CINV.

STUDY PURPOSE: Define whether the addition of NK1Ras provides a clinically meaningful benefit for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: MEDLINE (via Pubmed and Ovid) Central databases 

YEARS INCLUDED: January 1990 to October 2016.

INCLUSION CRITERIA: English language, randomized trials evaluating efficacy of NK1 for prevention of CINV in MEC

EXCLUSION CRITERIA: MEC multiple days, combine MEC and HEC, AC based, reviews with pooled analysis, design, retrospective, no randomization.

TOTAL REFERENCES RETRIEVED: 626 

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Initial evaluation done by one member of team, but two others then reviewed the results, and agreement was reached using consensus.

FINAL NUMBER STUDIES INCLUDED: 16 per literature, 15 evaluated in table.

TOTAL PATIENTS INCLUDED IN REVIEW: 3,848

SAMPLE RANGE ACROSS STUDIES: 23-707

KEY SAMPLE CHARACTERISTICS: Studies evaluating the efficacy of NK-1 in chemotherapy with moderately emetogenic chemotherapy, multiple types of cancer, lung, gynecologic, colorectal, and head and neck cancers

PHASE OF CARE: Active anti-tumor treatment     

APPLICATIONS: Elder care, palliative care

Overall, a total of 626 published articles or abstracts were pulled for this systemic review. Based on the inclusion and exclusion criteria, the final review included 13 trials and three abstracts. Only two trials evaluated use of NK-1 in pure MEC regimens. The authors categorized trials as pure MEC (excluding regimens with carboplatin or oxaliplatin), regimens containing carboplatin, and regimens containing oxaliplatin. In the pure MEC group, the addition of an NK-1-RA significantly improved CINV complete response (p = 0.02). In the carboplatin group, the addition of an NK-1-RA significantly improved CINV complete response (p < 0.001). In the oxaliplatin group, the addition of an NK-1-RA did not significantly improved CINV complete response (p = 0.17).

The authors discuss that the addition of NK-1 does improve CINV in carboplatin regimens with moderate emetogenicity, but the benefit is not clear for other moderately emetogenic chemotherapy regimens. This use of NK-1 in moderately emetogenic chemotherapy is not reported in guidelines, but there is still a need to answer the question of benefit in this patient population. With carboplatin, there was evidence of usefulness in patients receiving carboplatin with doses at AUC 4 and above. In mixed regimens, it is difficult as emetogenicity ranges from 30%-90%. Only two trials were evaluated in oxaliplatin containing regimens.

• High heterogeneity

Consideration of adding NK-1 in carboplatin containing regimens is supported by results. Ongoing research is needed to further define patients who would benefit from NK-1 medications.

To determine the effects of treatments for nausea and vomiting either as a result of the disease or its treatment in adults with cancer and other chronic diseases

Databases reviewed searched were MEDLINE, Embase, and the Cochrane database. Harm alerts from the Food and Drug Administration (FDA) and the United Kingdom regulatory agency also were reviewed.

No separate description of the volume of literature evaluated or the specific evaluation process was provided. The Grading of Recommendations Assessment, Development and Evaluation (GRADES) system was used for rating the evidence, and these results were provided. The literature review was completed as of April 2008.

The study reported on 13 randomized, controlled trials (RCTs), representing more than 14,000 patients with cancer. These included studies of nausea and vomiting as a result of disease or treatment.

Results indicated that 5-HT₃ RAs + dexamethasone was beneficial.

The following were identified as likely to be beneficial.

• 5-HT₃ RAs + corticosteroid with radiotherapy-induced nausea and vomiting
• Aprepitant added to conventional regimens
• Haloperidol
• Metoclopramide for chemotherapy-induced nausea and vomiting (CINV)
• Phenothiazines
• Venting gastrostomies

Cannabinoids were identified as being a tradeoff between benefit and harm.

The following were determined to have unknown effectiveness.

• 5-HT₃ receptor antagonists (RAs) for radiation-induced nausea and vomiting
• Antihistamines
• Antimuscarinics
• Antipsychotics
• Benzodiazepines for CINV

• Although no evidence was identified, and, at this writing, there was a stated drug safety alert on haloperidol, this review identified haloperidol as likely to be beneficial. It is unclear how this can meet this category.
• Results cited tended to focus on vomiting episodes and did not address the symptom of nausea.
• Results were a mix of symptoms from the disease itself or treatment, so differentiation of applicability was not always clear.
• Some aspects of the search strategy were unclear.
• Some interventions stated that no RCTs or systematic reviews were found, so no evidence was provided; however, in other areas, observational studies and consensus opinions were cited as supporting evidence.
• Inclusion and exclusions were not stated.
• No information was included on nonpharmacologic interventions in combination with antiemetic regimens.

To investigate the efficacy and safety of aprepitant as a three-day antiemetic regimen for patients receiving single-dose cyclophosphamide 4 g/m² for peripheral blood stem cell mobilization

Baseline nausea and vomiting was recorded pretreatment, then patients received granisetron, dexamethasone, and 125 mg oral aprepitant followed by cyclophosphamide on day 1. Patients received 80 mg oral aprepitant on days 2 and 3. No rescue medication use was allowed. Nausea, vomiting, and use of antiemetics were monitored daily for 5 days, then 7 and 30 days after initiation of chemotherapy. Toxicity was monitored using the National Cancer Institute's (NCI's) Common Toxicity Criteria (CTC), version 3.0.

• The study reported on 35 patients.
• Median age was 48 years with a range of 23–64 years.
• The sample was 57% male and 43% female.
• Patients had been diagnosed with multiple myeloma (n = 19), non-Hodgkin lymphoma (n = 11), Hodgkin disease (n = 4), and acute promyelocytic leukemia (n = 1).
• The sample included 30 Caucasians, 4 African Americans, and 1 other. 
• All patients had Southwest Oncology Group (SWOG) performance statuses of 2 or lower, history of fewer than five alcohol drinks per day for the last year, and no use of chronic systemic steroids or antiemetics.

This was a single site study conducted in Detroit, MI. The setting type was not specified.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability for peripheral blood stem cell mobilization.

This was a phase 2, clinical trial.

• Nausea was recorded using a visual analog scale with 5-25 mm = mild nausea and more than 25 mm = severe nausea.
• Each emesis episode was defined as expulsion of stomach contents through the mouth separated by at least one minute.
• A retching episode was defined as an unproductive attempt to vomit stomach contents separated by at least one minute.
• NCI CTC v. 3 was used to record adverse events.

• Just over half of patients (57%, n = 20) reported no acute vomiting (0–24 hours postchemotherapy) and no acute use of rescue medication; 63% (n = 22) patients experienced no delayed vomiting (25–120 hours postchemotherapy); and 43% (n = 15) patients reported no more than mild nausea during the first five days. 
• No grade 3 or higher toxicities were found to be related to aprepitant. Common adverse events (less than grade 3) were nausea, vomiting, fatigue, diarrhea, febrile neutropenia, headache, and hiccups. No patient discontinued aprepitant due to adverse events; no treatment-related mortality was reported.

Aprepitant provides protection of acute and delayed vomiting following cyclophosphamide administration during stem cell mobilization. Aprepitant does not adequately control nausea following cyclophosphamide administration during stem cell mobilization.

• The sample size was small with fewer than 100 patients.
• No control group was included. 
• No pharmacokinetic assessment of the medication was included. 
• The authors did not specify who evaluated toxicities or how monitoring was done.

Patients receiving cyclophosphamide for stem cell mobilization can experience nausea and vomiting requiring interventions.  The addition of aprepitant to an antiemetic regimen of 5-HT₃ antagonist plus dexamethasone improved control of acute and delayed vomiting following cyclophosphamide administration during stem cell mobilization. Aprepitant was associated with few toxicities.

To assess the efficacy and safety of fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving multiday cisplatin combination chemotherapy

Germ cell tumor patients receiving a five-day cisplatin combination chemotherapy were enrolled. Fosaprepitant 150 mg was given intravenously on days 3 and 5. A 5HT3 receptor antagonist was administered on days 1–2 (on days 1, 3, and 5, if palonosetron), plus 20 mg dexamethasone on days 1–2 and 4 mg twice a day on days 6–8. Patients were asked to keep a diary of the chemotherapy cycle on days 1–8.

• N = 54   
• MEDIAN AGE = 33 years
• MALES: 100%  
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Germ cell tumors
• OTHER KEY SAMPLE CHARACTERISTICS: Caucasian, mostly chemotherapy naïve, stage I–II

• SITE: Not stated/unknown   
• SETTING TYPE: Not specified    
• LOCATION: Not stated

PHASE OF CARE: Active antitumor treatment

• Single-arm, phase-II trial

• 100 mm visual analog scale (VAS)
• Acute phase CINV defined as days 1–5 and delayed phase defined as days 6–8

The primary objective was to determine the complete response (CR) rate as no emetic episodes or use of antiemetic medications. The CR was observed in 12 (24.1%) patients.

The reported CR rate was much lower than that generally reported, suggesting a much lower efficacy for CINV with a five-day cisplatin regimen.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no appropriate attentional control condition)
• Key sample group differences that could influence results
• Measurement validity/reliability questionable

Whether substituting fosaprepitant for aprepitant provides the same benefit in a multiday cisplatin regimen is unknown.

To evaluate the effect of an increased duration of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV)

Women scheduled to receive AC regimens (doxorubicin and cyclophosphamide) enrolled in the study were randomly assigned to two groups. One group received a three-day aprepitant regimen in the first course of chemotherapy and six days in the second course. The other group received six days of aprepitant in the first course and three days in the second course of chemotherapy. All patients also received 8 mg dexamethasone IV on day 1 followed by 80 mg dexamethasone daily. During the six day course, dexamethasone was given for six days, and on the three-day regimen, it was given for three days. A 30-day washout existed between courses. Study measures were done at baseline for both chemotherapy cycles and seven days later.

• N = 49
• MEAN AGE = 38.7 years (SD = 6.5)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All had breast cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: No indication of patients being chemotherapy naive

• SITE: Single site  
• SETTING TYPE: Outpatient  
• LOCATION: Iran

• PHASE OF CARE: Active antitumor treatment

• Randomized, controlled, crossover trial

• Eastern Cooperative Oncology Group (ECOG) toxicity questionnaire 
• Complete response (CR) defined as no nausea and no episodes of vomiting

Sixty-three percent had CR with the six-day regimen compared to 39% with the three-day regimen (p < 0.001). The order of treatment regimens did not affect results.

The use of aprepitant and dexamethasone for six days was more effective than a three-day regimen for the prevention of CINV.

• Small sample (< 100)
• Risk of bias (no blinding)
• Measurement validity/reliability questionable
• The ECOG questions for nausea have questionable validity for symptom measurement.
• No 5-HT₃ was administered, which is recommended for AC regimens.

Findings suggest that the provision of an antiemetic regimen for a longer duration in patients receiving highly emetogenic chemotherapy may be more beneficial to prevent CINV than current three-day regimens. Further well designed research in this area would be helpful.

To compare the five-day administration of aprepitant with a single administration of fosaprepitant meglumine to prevent chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy regimens containing cisplatin

Participants were randomly assigned to receive a five-day course of aprepitant or a single administration of fosaprepitant meglumine. CINV was monitored for seven days after the first administration of chemotherapy.

• N = 93
• MEAN AGE = 63.6 years (range not specified)
• MALES: 80%, FEMALES: 20%
• KEY DISEASE CHARACTERISTICS: Gastric cancer, esophageal cancer, lung cancer, or head and neck cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Highly emetogenic chemotherapy regimens containing cisplatin

• SITE: Single site    
• SETTING TYPE: Not specified    
• LOCATION: University hospital in Japan

• PHASE OF CARE: Active antitumor treatment

Randomized, controlled trial

• The Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT) was used to measure the occurrence of nausea and vomiting. It consisted of a daily review of nausea and vomiting symptoms over seven days.
• Nausea was measured on a 0–10 scale.
• Vomiting was measured by the number of vomiting episodes per day.

When CINV was compared, five days of aprepitant versus a single administration of fosaprepitant meglumine did not yield statistically significant results.

Five days of aprepitant for five days and a single administration of fosaprepitant meglumine had similar outcomes in regard to the prevention of CINV.

• Small sample (< 100)

In this study, one dose of fosaprepitant meglumine had similar effects on CINV as five-day aprepitant. One dose of a medication is more cost effective and reduces patient medication burden, so this may be a preferable treatment alternative.

To study the efficacy of aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) for colorectal cancer

Patients with advanced or recurrent colorectal cancer were treated with standard MEC regimens including FOLFOX, XELOX, OR FOLFIRI and received either standard antiemetic therapy with 5-HT₃ receptor antagonist (RA) plus dexamethasone or aprepitant regimen including 5-HT₃ RA plus reduced-dose dexamethasone plus aprepitant. Patients were followed from the initiation of chemotherapy through day 5 using patient diaries to record emetic episodes, nausea, or rescue antiemetics in 24-hour intervals.

• N = 117 Japanese and Australian adults with recurrent or advanced colorectal cancer stratified based on Performance status 
• MEAN AGE = 63.48 years in standard group, 66.46 years in aprepitant group
• MALES: 56%, FEMALES: 44%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Patients with dvanced or recurrent colorectal cancer receiving MEC

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Japan

PHASE OF CARE: Active antitumor treatment

Multicenter, phase II, open-label, randomized, parallel, comparative study

The outcomes in both groups were analyzed using chi-squared tests for primary end points, secondary end points, and patients characteristics by treatment group. Two-sided sample t tests were used when appropriate. P < 0.05 was considered to be a statistically significant difference.

The percentage of patients with complete response in the overall phase was 79.6% in the standard group versus 79.7% in the aprepitant group. The acute phase was 94.9% complete response in both groups, and the delayed phase was 79.6% versus 79.7%. The overall incidence of adverse events were similar in both groups.

No significant differences existed between the standard treatment and aprepitant regimen in terms of complete suppression of vomiting, nausea, and time to treatment failure. This study demonstrates that aprepitant in combination with a 5-HT₃ RA and reduced dose of dexamethasone is well tolerated and effective for preventing CINV associated with MEC in patients with colorectal cancer.

The addition of aprepitant to standard antiemetic therapy for MEC in patients with colorectal cancer is well tolerated and effective for control of CINV, but the lack of significant difference suggests that the added cost of an additional medication is not warranted.

To compare the effectiveness of antiemetic regimens including ondansetron with and without aprepitant to prevent chemotherpy-induced nausea and vomiting (CINV)

Patients were randomized to receive (a) an antiemetic regimen consisting of ondansetron 8 mg IV 30 minutes before chemotherapy followed by 24 mg IV in a continuous infusion daily till 6–12 hours after the last dose of chemotherapy or (b) the same ondansetron regimen with the addition of oral aprepitant 125 mg 6–12 hours before chemotherapy and 80 mg daily till one day after the last dose of chemotherapy. Data were collected for six days following chemotherapy administration.

• N = 83
• AVERAGE AGE = 51 years
• MALES: 56%, FEMALES: 44%
• KEY DISEASE CHARACTERISTICS: Acute myeloid leukemia, high-risk myelodysplastic syndrome, or chronic myeloid leukemia in blast phase
• OTHER KEY SAMPLE CHARACTERISTICS: Receiving cytarabine-based chemotherapy at a dose ≥ 1 g/m² per day for at least three days

• SITE: Not stated  
• SETTING TYPE: Not specified    
• LOCATION: Not described

• PHASE OF CARE: Active antitumor treatment

Randomized, controlled trial

• Not well described
• Daily diary to record episodes of nausea or vomiting and any rescue medications needed

There were no statistically significant differences in the prevention of CINV or use of rescue medications between the two arms.

There was no difference in CINV prevention between antiemetic regimens of ondansetron with or without aprepitant.

• Small sample (< 100)
• Risk of bias (no blinding)
• Measurement/methods not well described
• Measurement validity/reliability questionable

There was no significant difference between antiemetic regimens of ondansetron with or without aprepitant in the prevention of CINV. There may not be a benefit to adding aprepitant to standard antiemetic therapy in this population of patients.

To evaluate the efficacy of adding aprepitant to an antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV)

Participants received aprepitant at 125 mg orally on day 1 followed by 80 mg orally at 24 and 48 hours after the initial dose of aprepitant. Ondansetron was given at 16 mg orally on day 1, and dexamethasone was given at at 12 mg orally on day 1 and at 8 mg orally on days 2–4. Breakthrough medications were used as needed. There was no comparison or control group. To evaluate nausea and vomiting, patients were assessed four to six times per day for the presence or absence of vomiting, the frequency of emetic episodes, the need for breakthrough antiemetic medication, and a nausea score provided by the nurse. Mean nausea scores were assessed every 24 hours beginning 24 hours after chemotherapy and continuing 120 hours after chemotherapy.

• N = 26  
• MEAN AGE = 59.3 years (no range given)
• MALES: 65%, FEMALES: 35%
• KEY DISEASE CHARACTERISTICS: Multiple myeloma and autologous stem cell transplant
• OTHER KEY SAMPLE CHARACTERISTICS: High-dose melphalan

• SITE: Not specified
• SETTING TYPE: Not specified    
• LOCATION: Not specified

• PHASE OF CARE: Active antitumor treatment

Prospective, single-arm study

• Nausea scores were determined using a linear analog scale (0–10).

Complete response was defined as no more than one emetic episode during the evaluation period. Of the 26 participants, 25 (96%) completely responded and needed no additional breakthrough medication. Twenty-four (92%) had no documented emetic episodes during the study period. Some degree of nausea was reported by 23 out of 26 (88%) patients, and the mean nausea score for the entire group during the study period was 0.7 (range = 0–10).

Adding aprepitant to a standard antiemetic regimen may result in lower rates of CINV associated with high-dose melphalan and stem cell transplant.

• Small sample (< 30)
• Risk of bias (no control group)

Adding aprepitant to standard antiemetic regimens may result in better controlled CINV. However, with such a small sample size and no comparison group, attributing these results to the intervention is difficult.

To determine the efficacy of aprepitant added to standard antiemetic therapy for the control of CINV in patients with colorectal cancer receiving FOLFOX (fluorouracil, oxaliplatin, and leucovorin) chemotherapy.

Patients with colorectal cancer receiving FOLFOX chemotherapy were given standard antiemetic therapy (palonosetron 0.25 mg IV on day 1, dexamethasone 12 mg PO day 1, dexamethasone 8 mg PO day 2-4) plus aprepitant 125 mg PO day 1 and 80 mg PO day 2 and day 3 after chemotherapy. No comparison group.

• N: 50   
• AGE: Mean age = 57 years, range = 27-80
• MALES: 47%  
• FEMALES: 53%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Colorectal cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy naïve, life expectancy greater than four months, ECOG < 2

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: USA

PHASE OF CARE: Active anti-tumor treatment

One-group pre-/post-test design

Complete response (no emesis or rescue medications used), major response (no emesis but nauseated with or without rescue medication use), treatment failure (emesis within five days of chemotherapy using daily diary recording emetic events, nausea (0-100 mm visual analog scale), rescue medication use, as well as appetite and nutritional intake.

Overall CINV remained low throughout the chemotherapy cycles (CR = 74%, major response = 23%, failure = 4%). Appetite and nutritional status did not significantly change throughout treatment. Few adverse events were reported (diarrhea, 13.6%, fatigue, 12.6%, and neutropenia, 11%).

Aprepitant added to standard antiemetic therapy results in low CINV and has few adverse events. This regimen appears to be safe and effective for prevention of CINV in patients with colorectal cancer receiving FOLFOX. However, without a comparison group it is unclear if this antiemetic regimen is equal to or better than standard antiemetic therapy.

• Small sample (< 100)
• Risk of bias (no control group)

Aprepitant added to standard antiemetic therapy is safe and effective for preventing CINV in patients with colorectal cancer receiving FOLFOX, but may or may not be an improvement over standard antiemetic therapy alone.

To assess the impact of adding rolapitant to standard antiemetics (5-HT₃ receptor antagonists and dexamethasone) on the daily lives of patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC)

This is a secondary analysis study of three clinical trials (phase III experimental studies). Patients were stratified by sex and randomly assigned (1:1) to either single oral dose rolapitant 180 mg or placebo 1–2 hours prior to chemotherapy. All patients received 5-HT₃ receptor antagonists and dexamethasone. Quality of life was assessed by patients by completing the 18-item Functional Living Index-Emesis (FLI-E) questionnaire on day 6 of cycle 1.

• N = 2,402 (1,070 patients in the pooled HEC studies and 1,332 patients in the MEC/AC)   
• AGE: Between 18–90 years
• MALES: 39.1% (938 patients), FEMALES: 60.9% (1,464 patients)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Various malignancies; a Karnofsky performance score of 60 or greater; a predicted life expectancy of four months or greater; and adequate bone marrow, kidney, and liver function
• OTHER KEY SAMPLE CHARACTERISTICS: Aged older than 18 years, naïve to their scheduled HEC/MEC

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Canada

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

Three double-blind, phase III, randomized, controlled longitudinal trials (specified analyses [MEC/AC study]), and pooled post hoc analyses (HEC studies)

Treatment comparisons were performed between the FLI-E questionnaire total score and nausea and vomiting domain scores, in addition to the end point of no impact on daily life.

Data were analyzed for all randomized patients in the modified intent-to-treat population. Patients in the rolapitant group reported a significantly higher FLI-E total score than patients in the control group in the pooled HEC studies (confidence interval [CI] [2.6, 7.9], p < 0.001) and in the MEC/AC study (CI [1.7, 6.5], p < 0.001). A significant improvement in the nausea domain score was observed with rolapitant versus control in the pooled HEC studies (CI [0.2, 3.4], p = 0.02) and the MEC/AC study (CI [0.3, 3.3], p = 0.019), as well as the vomiting domain score in the pooled HEC studies (CI [2.1, 4.7], p < 0.001) and the MEC/AC study (CI [1.1, 3.4], p < 0.001).

This secondary analysis study demonstrated the efficacy of adding rolapitant to standard antiemetics in reducing the negative delayed impact of CINV on the daily lives of patients receiving HEC or MEC.

• Baseline sample/group differences of import
• Secondary analysis data from three experimental clinical trials
• Included patient with various cancers

Nurses should be aware of the additional benefit of adding an NK₁ receptor antagonist to the treatment of patients with cancer receiving HEC and MEC.

To evaluate the effectiveness of a single dose of fosaprepitant in combination with dexamethasone and 5-HT₃ for chemotherapy-induced nausea and vomiting (CINV)

• Patients who were to receive cisplatin were randomly assigned to the experimental group or the control group. The experimental group received a single, 150-mg dose of IV fosaprepitant administered with a 5-HT₃ receptor antagonist and a corticosteroid prior to cisplatin-based chemotherapy. The control group received matched placebos for the experimental regimen and the currently recommended three-day oral regimen of aprepitant for five days after treatment.
• Ondansetron and dexamethasone were administered at current dosing recommendations.
• Patients kept diaries of episodes of vomiting, daily nausea assessment, and use of rescue mediation.
• Adverse effects were assessed at each clinic visit.

• The study consisted of 2,322 participants.
• The median age was 56 years in the experimental group and 57 years old in the control group.
• The study group was 36.7% female and 63.3% male.
• The most frequent diagnosis was lung cancer. Other cancers were GI, reproductive or genitourinary, renal and urinary tract, and breast cancer.
• The study group was 56% white and 29% Asian.
• All patients were scheduled to receive their first course of cisplatin ≥ 70 mg/m².

The study was conducted at multiple outpatient settings in 27 different countries.

All patients were in active treatment.

The study was a double-blind, randomized-controlled, parallel group.

The following measurement tools were used.

• Visual analogue scale (VAS) 100 mm for assessment of nausea
• Daily diary to record vomiting or retching episodes
• Use of rescue therapy (Common Terminology for Adverse Events [CTAE v3.0])

• No significant differences were found between groups for the primary endpoint of no vomiting or retching episodes with no use of rescue medication or episodes during the delayed phase.
• No significant differences were found between groups for the proportion of subjects who reported no significant nausea (defined as < 25 on the VAS).
• Overall, in both groups, slightly more than 74% reported no episodes of vomiting or use of rescue therapy in the delayed phase for nausea.
• Overall, the adverse events seen with the fosaprepitant regimen was similar to that seen with the three-day aprepitant regimen.

• The fosaprepitant regimen as used was as effective for the prevention of acute and delayed nausea associated with cisplatin-based chemotherapy as the currently recommended oral aprepitant regimen.
• A single dose of 150 mg of fosaprepitant was sufficient to suppress delayed CINV for 2–5 days after therapy.

• Findings demonstrated that a single, IV-dose regimen with this agent is an effective alternative to oral neurokinin 1 (NK1) receptor antagonists used as currently recommended for prevention of delayed onset CINV.
• Nurses should be aware of potential infusion-site reactions.
• About one-fourth of patients were refractory to this regimen, indicating the continued need to explore individualized alternatives for maximum symptom control.
• The most effective timing of these treatments for prevention of delayed onset CINV is not yet fully clear.

To evaluate the safety and efficacy of aprepitant, dexamethasone, and palonosetron as an antiemetic regimen for prevention of acute and delayed nausea and vomiting

Patients received one oral dose of 285 mg aprepitant and 20 mg dexamethasone one hour prior to cyclophosphamide and/or doxorubicin chemotherapy and 25 mg IV palonosetron 30 minutes prior to chemotherapy. Patients completed study diaries prior to the start of the single-day chemotherapy and then daily for five days.

• The sample consisted of 41 participants.
• Median age was 51, with a range of 33–74 years.
• Forty of the patients were female (97.5%), and one was male (2.5%). 
• Patients were diagnosed with solid tumors (no other information provided). The majority (n = 41) had performance statuses of 0 or 1.
• All patients received cyclophosphamide; 90% received doxorubicin and cyclophosphamide combination therapy.
• Patients could not receive corticosteroids or antiemetic agents other than the study drug doses immediately before or during the study period.

The study was conducted at multiple outpatient settings in Vermont and Maine.

All patients were in active treatment.

The study was a prospective trial.

• Patients recorded frequency and intensity of nausea and vomiting in study diaries.
• Nausea and vomiting was also measured based on the use of rescue antiemetic medication.

• Overall
  • 51% had a complete response (no vomiting and no rescue therapy)
  • 95% had no emesis
  • 32% had no nausea
• Acute phase (0–24 hours post chemotherapy)
  • 76% had complete response
  • 100% had no emesis
  • 59% had no nausea
• Delayed phase (24–100 hours post chemotherapy)
  • 66% had complete response
  • 95% had no emesis
  • 41% had no nausea
• Only 27% of patients had more than 1 day of significant nausea.
• No major adverse effects from medications were noted.

The single-day, three-drug (aprepitant, dexamethasone, palonosetron) antiemetic regimen is a safe and effective antiemetic regimen for patients receiving mildly or minimally emetogenic chemotherapy.

• No control group or comparison was provided.
• Only patients with low potential for nausea and vomiting were included in the study.
• Potential for bias exists, as patients may have underestimated their symptoms or rescue medications because they were a part of a study.

Identifying effective single-day antiemetic regimens may improve adherence to supportive care guidelines and reduce nausea and vomiting symptoms in patients receiving chemotherapy.

To evaluate the efficacy of one-day versus three-day administration of aprepitant in combination with palonosetron and dexamethasone for the prevention of acute and delayed nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC)

• Patients were randomization to three arms.
  • Arm A—A single dose of 0.25 mg palonosetron and 12 mg dexamethasone before receiving HEC and 3-day regimen of aprepitant.
  • Arm B—Aprepitant at 125 mg on day 1 followed by a placebo on days 2 and 3.
  • Arm C—Palonosetron at 0.25 mg 30 minutes before chemotherapy and 18 mg dexamethasone, then placebo resembling aprepitant on days 1–3.
• All patients received 8 mg dexamethasone daily on days 2–4, and all received palonosetron 30 minutes before chemotherapy and aprepitant or placebo 60 minutes before treatment.

• The sample consisted of 75 participants.
• Age: (mean age ± SD)
  • Arm A (n = 29)—59.6 years (SD = 10.7 years)
  • Arm B (n = 30)—58.3 years (SD = 10.5 years)
  • Arm C (n = 16)—56.1 years (SD = 12.6 years)
• The percentage of female patients in arm A was 69%, in arm B was 70%, and in arm C was 87.5%; the percentage of male patients in arm A was 31%, in arm B was 30%, and in arm C was 12.5%. 
• Patients' diagnoses were breast (55%), lung (13%), head and neck (19%), and other (13%).
• The median doses of chemotherapy were similar among groups except for cyclophosphamide. Median dose of cyclophosphamide in arm A was 500 mg/m², in arm B was 600 mg/m², and in arm C was 600 mg/m² (p = 0.04).
• No differences existed between groups in terms of history of motion sickness or pregnancy-induced vomiting.

The study was conducted in a single site.

All patients were in active treatment.

This was a randomized, double-blind, placebo-controlled, comparative pilot study.

• Patients defined nausea on a 100-mm visual analog scale (VAS) ranging from 0 = no nausea to 100 = worst nausea possible.
• Patients documented, via patient diaries, the number of emetic episodes, breakthrough nausea mediation, and nausea severity during the 120-hour observation period after infusion of chemotherapy.

• Initially the study had 3 arms; however, analysis displayed severe emesis with and halted arm C (n = 16).
• Those without emesis during the first 24 hours were similar between arms A and B.
• No significant differences were found in the incidence of overall nausea and severity of nausea.
• During the acute phase, complete response was similar (67% arm A and 70% arm B; p = 0.77).
• In the delayed phase, 63% arm A and 59% arm B (p = 78) had no emesis or use of breakthrough medications.
• A complete response during both phases was observed in 56% of arm A and 52% of arm B (p = 0.78).

This study suggested that a single, 125-mg dose of aprepitant provides similar effectiveness compared to the 3-day regimen. The addition of palonosetron and dexamethasone provided protection against emesis in more than 90% of patients during the 5-day study period.

• Sample size was small with fewer than 100 subjects. 
• The potential for bias was reduced by using study methods.
• No information was provided on how often patients were rating their nausea; patients may have had nausea that was not captured in diaries.

The use of aprepitant has shown to be effective in preventing acute and delayed emesis in patients who are receiving cisplatin- and anthracycline-containing therapies.

To assess the effect of gender on treatment response for aprepitant plus a 5-HT₃ antagonist and corticosteroid for the prevention of chemotherapy-induced nausea and vomiting (CINV) 

The data from two phase III studies of aprepitant plus a 5-HT₃ antagonist and corticosteroid for the prevention of CINV were pooled. The two trials were of patients receiving more than 70 mg/m² of cisplatin randomly assigned to control regimen or aprepitant regimen. Patients were randomized to one of the treatment groups and stratified by gender. Patients used a diary to document emetic episodes, severity ratings of nausea (on a 100-mm horizontal visual analogue scale), and any use of rescue medications.

The study reported on 1,044 patients older than 18 years with a Karnofsky score greater than 60 and who were scheduled for first their cycle of chemotherapy, including cisplatin.

The studies were conducted in the United States and the Netherlands, predominately in university cancer centers.

Two identically designed, randomized, double-blind parallel group, placebo-controlled trials were reviewed.

Visual analogue scales (VASs) and patient diaries were used.

• In the control group, 41% of women had an overall complete response (CR) compared with 53% of men.
• In the aprepitant group, 66% of women had an overall CR compared with 69% of men.
• The enhanced efficacy of aprepitant regimen in women occurred during acute and delayed phases and resulted in similar rates of antiemetic control for men and women.
• The aprepitant regimen partly maintained improvement over multiple cycles for men and women.

The addition of aprepitant may reverse the risk of gender for CINV in women receiving highly emetogenic chemotherapy.

Details of design, primary efficacy, and tolerability are not included, but the results of the studies are published elsewhere.

To evaluate the efficacy of the addition of rolapitant to prevent chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin

Patients were randomly assigned to receive a single oral dose of 180 mg rolapitant or a matching placebo 1–2 hours before chemotherapy administration on day 1. All patients received granisetron on days 2 and 3. Patients receiving taxanes also were given dexamethasone. For five days, patients recorded vomiting, use of rescue medication, and nausea daily in a diary. Additional study assessment was obtained on day 6 of cycle 1 of chemotherapy. This report is a subset of a larger phase-III trial focusing on individuals receiving the first course of chemotherapy with a carboplatin-based regimen.

• N = 401   
• MEDIAN AGE = 63 years
• AGE RANGE = 23–88 years
• MALES: 54.9%, FEMALES: 45.1%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Multiple tumor types—lung was most prevalent
• OTHER KEY SAMPLE CHARACTERISTICS: All were receiving a moderately emetogenic chemotherapy (MEC) regimen.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Multiple countries

• PHASE OF CARE: Active antitumor treatment

• Double-blind, randomized, placebo-controlled trial

• Visual analog scale (VAS) for nausea
• Functional Living Index-Emesis (FLIE)

Those receiving rolapitant had a higher prevalence of complete response (CR) for antiemetics in the overall phase (p < 0.001) and delayed phase (p < 0.001). No differences existed between groups for the response in the acute phase; 88%–91% across study groups had CR in the acute phase. No difference existed between groups in FLIE results. Nausea was also better controlled in the rolapitant group in the overall (p = 0.023) and delayed phases (p = 0.034) (patients reporting no nausea). No differences existed between groups in adverse events, and no serious adverse events occurred.

Rolapitant was shown to be effective for the prevention of emesis in patients receiving MEC. The proportion of patients reporting no nausea was also higher with rolapitant; however, only 62.5% had no nausea in the overall phase.

The findings support the use of rolapitant as part of a triple-drug regimen with a 5-HT₃ and dexamethasone for patients receiving carboplatin. NK1s are not routinely recommended for patients receiving MEC; however, this study showed significantly better control with the addition of an NK₁. A substantial proportion of patients continued to experience nausea, though this was also improved with use of rolapitant.

To confirm the differential time course of action noted with a neurokinin 1 (NK1) receptor antagonist (RA) compared to a 5-HT₃ RA in the setting of cisplatin-based chemotherapy using the database from three large, phase III trials

Multivariate logistic regression models were used to assess the impact of the first emesis at different time intervals of aprepitant regimens compared to control regimens using a modified intent-to-treat approach. The endpoint was the frequency of first emesis during distinct time intervals from administration of chemotherapy through 120 hours postadministration.

The trials reported on a total of 2,383 patients.

The mean age range of patients was 52–59 years.

• In the Aprepitant group, the mean age of patients in study 1 was 56 years, the mean age of patients in study 2 was 59 years, and the mean age of patients in study 3 was 53 years.
• In the Control group, the mean age of patients in study 1 was 56 years, the mean age of patients in study 2 was 59 years, and the mean age of patients in study 3 was 52 years.

The percentage of the sample that was male was not reported but assumed to range from 0%–65%. The percentage of females ranged from 35%–100%.

• In the Aprepitant group, study 1 was 42% female, study 2 was 39% female, and study 3 was 99.5% female.
• In the Control group, study 1 was 43% female, study 2 was 35% female, and study 3 was 100% female.

In study 1 and study 2, primary cancer diagnoses were respiratory, urogenital, digestive, and other. In study 3, primary diagnosis was breast cancer.

The majority (59%–80%) were Caucasian.

A total of 1,527 patients were receiving cisplatin-based HEC and 856 were receiving anthracycline plus cyclophosphamide-based moderately emetogenic chemotherapy (MEC).

All patients were in active treatment.

This was a post-hoc analysis.

Measurement instruments and methods were not specified in this article.

With cisplatin-based, highly emetogenic chemotherapy (HEC), the aprepitant regimen was associated with a lower incidence of first vomiting compared to the standard regimen beginning at the 15–18 hour interval and beyond. This lowered incidence was maintained until the 48–60 hour interval, with the first vomiting incidence reduced by 38%–77%.

With anthracycline-cyclophosphamide-based MEC, the first vomiting incidence was markedly lower, as early as the 3–6 hour interval. This effect was maintained up to the 9–12 hour interval, with the first vomiting incidence reduced by 38%–61%.

Emesis induced by cisplatin is biphasic with the initial peak within 2 hours of cisplatin and the second peak starting 16–18 hours and lasting 48 hours after cisplatin. 5-HT₃ medications appear to be most effective in the first 12 hours after cisplatin while NK1-sensitive mechanisms appear to be more effective up to 60 hours after cisplatin.

Anthracycline and cyclophosphamide agents display a monophasic emesis pattern; therefore, better emetic control is noted with NK1-dependent medications much earlier in the treatment cycle.

No discussion was included on how data was collected within each study.

Cisplatin-based regimens require 5-HT₃-dependent medications within the first 12 hours and NK1-dependent medications thereafter.  Anthracycline- and cyclophosphamide-based regimens appear to be sensitive to both 5-HT₃- and NK1-dependent medications.

To determine if a single 90-mg dose of casopitant added to ondansetron and dexamethasone would improve control of chemotherapy-induced nausea and vomiting (CINV) over 0–120 hours following initiation of oxaliplatin-based, moderately emetic chemotherapy (MEC) compared to ondansetron and dexamethasone alone and, as an optional component of the study, to measure the plasma concentration of 90 mg IV casopitant in patients enrolled in trials at various centers

Patients received 90 mg IV casopitant or IV placebo 30 minutes prior to oxaliplatin on day 1. All subjects received 8 mg IV dexamethasone and 8 mg ondansetron hydrochloride prior to starting the oxaiplatin on day 1, followed by five separate 8-mg doses at approximately 12-hour intervals on study days 1 to 3. Patients recorded efficacy data for the subsequent 120 hours.

To assess PK profiles, blood samples were obtained during cycle 1 of chemotherapy at the following times: predose, end of infusion, and 0.5, 1, 3, 5, 8, 12, 16, and 24 hours after infusion. A final sample was taken between 30 and 48 hours after infusion.

• The study reported on 707 patients.
• Mean age was 61 years old.
• The placebo arm was 59% male and 41% female.
• The casopitant arm was 51% male and 49% female.
• Patients had been diagnosed with colorectal cancer and were receiving oxaliplatin doses between 85 and 130 mg/m² in their first cycle of therapy.

This was a multi-site study conducted at multiple settings at 89 centers (hospitals or outpatient clinics) in 11 countries.

• All patients were in active antitumor treatment.
• This study has application to elder care.

This was a phase III, multicenter, randomized, double-blind, active-controlled, two-arm, parallel-group study.

• Patients recorded the number of emetic episodes, the number of nausea episodes, and use of rescue medication in study diaries during the 120-hour assessment phase.
• Patients completed the Functional Living Index–Emesis (FLIE) and used a visual analog scale (VAS) to rate nausea.
• Blood samples were used to assess PK profiles.

No difference in the rate of CR was noted in the casopitant group compared to the placebo group for the overall (placebo 85%, casopitant 86%, p = 0.7273), acute (placebo 96%, casopitant 97%), or delayed phases (placebo 85%, casopitant 86%). At 24 hours after 90 mg IV casopitant administration, the plasma casopitant concentration was 24% lower than the values noted in prior studies with 150 mg oral administration. Casopitant was well tolerated by patients.

The addition of single, 90-mg, IV dose of casopitant did not improve control of CINV at any time during 120 hours following initiation of oxaliplatin-based MEC. Excellent control of CINV was achieved in this study population with the combination of ondansetron and dexamethasone alone.

• Important differences existed in the baseline sample and groups.
• Key sample group differences could influence results.
• Findings are not generalizable.
• A difference in nausea was reported between the groups at baseline.

The results of this study indicate that ondansetron and dexamethasone are sufficient enough to control CINV associated with oxaliplatin chemotherapy in the treatment of patients with colorectal cancer. This finding is contrary to other studies, and the explanation is somewhat unclear. The PK concentration of the 90 mg IV casopitant was lower than that seen in the oral casopitant. A direct comparison of the IV regimen and the oral regimen in combination with ondansetron and dexamethasone in this patient population is warranted, as this is a large oncology patient population.

To determine the efficacy of aprepitant on patients in Asian countries receiving highly emetogenic chemotherapy (HEC)

Patients receiving HEC were stratified by gender and randomized to receive either aprepitant or a standard therapy with a placebo. Placebo medications were matched to aprepitant capsules. Data were collected from the time of chemotherapy (0 hours) to six days (120 hours). Patients recorded vomiting episodes, daily nausea, and rescue medications.

• N = 411
• AGE = > 18 years
• MALES: 66 %, FEMALES: 34% 
• KEY DISEASE CHARACTERISTICS: Solid tumors, cisplatin-naïve, and Karnofsky Performance Status Scale score > 60
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were excluded for current illicit drug use; evidence of alcohol abuse; symptomatic primary or metastatic CNS malignancy; administration of chemotherapy of moderate or high emetogenicity within the prior six days; scheduled administration of abdomen/pelvis radiation therapy within one week; scheduled administration of multiple-day chemotherapy with cisplatin in a single cycle or stem cell rescue therapy with cisplatin chemotherapy; active infection or other uncontrolled disease; or concurrent medical conditions precluding Decadron use.

• SITE: Multi-site  
• SETTING TYPE: Outpatient  
• LOCATION: China, 16 independent centers

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care 

A phase III, randomized, double-blind, placebo-controlled, parallel-group trial

Patients self-reported the times and dates of vomiting or retching episode(s), use of rescue therapy, and daily nausea assessments during the first chemotherapy cycle along with Visual Analog Scale (VAS) overall nausea ratings. Patients were contacted on the mornings of days 2–6 to ensure compliance. Functional Living Index-Emesis (FLIE) questionnaire scoring was self-administered early on day 6 directly following completion of final self-reports.

The addition of aprepitant to standard antiemetic treatment regimens for Chinese patients undergoing HEC provided superior chemotherapy-induced nausea and vomiting prevention and was very well tolerated.

The efficacy and tolerability of aprepitant were studied only for one or two cycles of chemotherapy; further study will be required for multi-cycle treatment. 56.4% of patients in the aprepitant arm used Chinese medicine versus 49% in the control arm.

Aprepitant is well-tolerated and effective in the treatment of CINV in Chinese patients receiving HEC. This is the first study in Chinese chemotherapy patients. Based on nursing knowledge of drug metabolism, this is an important study to assess that aprepitant provides efficacy in this group of chemotherapy patients.

To evaluate whether all patients undergoing highly emetogenic chemotherapy (HEC) need an NK₁ and to evaluate the effects of aprepitant on patients who experience chemotherapy-induced nausea and vomiting (CINV) in the first course of therapy

Patients received standard antiemetics consisting of IV granisetron on day 1 and dexamethasone on days 1–3 when given highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Patients who needed aprepitant experienced CINV and received aprepitant prophylactically for the subsequent courses of chemotherapy. Other agents for rescue antiemesis were allowed. Pharmacists visited patients on days 1–6 to assist them with completing diaries to record symptoms.

• N = 77
• MEAN AGE = 67 years
• AGE RANGE = 38–85 years
• MALES: 83.1%, FEMALES: 16.9%
• KEY DISEASE CHARACTERISTICS: Of the patients, 93.5% had lung cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Of the patients, 36.4% were receiving HEC and the rest were receiving MEC.

• SITE: Single site  
• SETTING TYPE: Not specified  
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

• Retrospective, descriptive

• Eleven-point numeric rating scale for nausea
• Functional Living Index-Emesis (FLIE)

Eighteen patients (23%) needed aprepitant after the first course of chemotherapy. Those receiving HEC who needed aprepitant experienced a significant improvement in the prevention of CINV (p = 0.018) and had less need for rescue medications (p = 0.001). Those receiving MEC also experienced an improvement in CINV after the use of aprepitant, although the difference was not statistically significant. Most improvement was seen in the delayed phase. Though vomiting was reduced, no significant improvement in nausea was observed. About 50% of patients required rescue antiemetics with the first course of chemotherapy.

Not all patients receiving HEC or MEC need an NK₁ to prevent CINV. Aprepitant was effective in preventing vomiting in patients who had CINV during the first course of chemotherapy.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• No information regarding rescue medications used is provided.

The findings suggest that all patients may not need NK₁s for complete control of CINV; however, no evidence predicts which patients will or will not experience CINV without an NK₁. Current guidelines recommend triplet antiemetics for HEC. Further work to identify the factors that would predict the patients who need NK₁s would be helpful to potentially provide control of CINV without the high cost of NK₁s.

To evaluate the efficacy and safety of triple antiemetic therapy with aprepitant, a 5-HT3 receptor antagonist, and dexamethasone compared to standard therapy with a 5-HT3 receptor antagonist and dexamethasone

Chemotherapy-naïve patients receiving a carboplatin-based therapy were randomized to standard antiemetic regimens of a 5-HT3 receptor antagonist plus dexamethasone or a triple antiemetic regimen of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant.  

• N = 134  
• AGE = ≥ 20 years
• MALES: 82%, FEMALES: 18%
• KEY DISEASE CHARACTERISTICS: Chemotherapy-naïve patients with stage IIIB or IV ​non-small-cell lung cancer (NSCLC) who received moderately emetogenic, carboplatin-based chemotherapy (either carboplatin/taxol or carboplatin/pemetrexed)
• OTHER KEY SAMPLE CHARACTERISTICS: Exclusion criteria: nausea and vomiting within 24 hours or use of antiemetic agents within 48 hours before administration of chemotherapy; use of pimozide; uncontrolled diabetes mellitus; asymptomatic brain metastasis; GI obstruction; or an active gastric ulcer

• SITE: Multi-site    
• SETTING TYPE: Outpatient  
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care, palliative care 

Multi-center, randomized, open-label, parallel-group, phase-II trial

Daily questionnaire regarding the frequency of vomiting and scoring of nausea during five days. Physicians recorded any additional antiemetic therapies used during the study period.

The aprepitant group had a better overall complete response (CR) of 80% (95% CI 69%–88%); the control group had a CR rate of 67% (95% CI 55%–77%). The difference is not significant. Rescue antiemetics were given to 15% of the aprepitant group and 28% of the control group. Adding aprepitant to patients receiving carboplatin/pemetrexed (with or without bevacizumab) had an overall CR of 84% in the aprepitant group versus 57% in the control group and a 87% CR in the aprepitant group versus 59% in the control group in the delayed phase of chemotherapy. The aprepitant group had a reduced need for rescue antiemetics compared to the control group (16% versus 36%, p = 0.04). Adding aprepitant to patients receiving carboplatin/paclitaxel did not reduce the use of rescue antiemetics.

Triple antiemetic therapy did not demonstrate a significant improvement in CR and decrease in chemotherapy-induced nausea and vomiting events in the overall and delayed phases of therapy when compared to standard use of 5-HT3 and dexamethasone as an antiemetic regimen in patients with stage IIIB–IV NSCLC being treated with carboplatin-based chemotherapy (considered moderately emetogenic chemotherapy). The addition of aprepitant to the regimen of carboplatin/pemetrexed (with or without bevacizumab) improved the overall response rate and delayed phase response in addition to decreasing use of rescue antiemetics.

• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions are not described that would influence results.
• Key sample group differences that could influence results
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Other limitations/explanation: High percentage of male to female study participants overall may reduce generalizability to general population. Patients on carboplatin/paclitaxel regimen received a high-dose steroid (12 mg) IV to prevent anaphylaxis; this may influence the effectiveness of the antiemetic regimen.

There may be benefit to adding aprepitant to antiemetic regimens for patients with NSCLC being treated with carboplatin/pemetrexed. This benefit was not demonstrated when aprepitant was added to carboplatin/paclitaxel regimens.

To determine the role of an neurokinin 1 (NK1) antagonist in multiple-day chemotherapy, in addition to standard of a 5-HT₃ receptor antagonists and dexamethasone

Oral aprepitant 125 mg was given 1 hour before chemotherapy on day 1 and 80 mg oral aprepitant was given daily during chemotherapy and for 2 days after completion of the treatment course. Patients also received 1 mg IV granisetron and 8 mg IV dexamethasone daily prior to chemotherapy. Use and choice of rescue medication was at the discretion of the physician.

• The study reported on 78 participants.
• Mean age was 40, with a range of 18–71 years.
• The sample was 18% female and 82% male.
• The most frequent diagnoses were germ cell cancer and sarcoma. Other diagnoses were myeloma, lymphoma, and thymus cancer.

The setting was a single site in Germany.

Patients were in active treatment.

The study design was a prospective trial.

• The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 for toxicity assessment was used with nausea rated as yes or no.
• Complete response (CR) was defined as no nausea or vomiting and no use of rescue medication.

• 65.8% had CR in the acute phase.
• 68.4% had CR in the delayed phase.
• 57.9% had CR in the overall phase.
• Preexisting nausea (p < 0.05), pretreatment anxiety (p = 0.0001), and patients with brain metastases (p = 0.04) were associated with lower CR rates.
• No patients discontinued because of adverse events.
• Most common events were hiccups (7.7%), diarrhea, and constipation.

Aprepitant appears to be well-tolerated. CR rates were only slightly above those commonly seen with 5-HT₃ receptor antagonists and dexamethasone.

• No control comparison or blinding with associated risk of bias was used.
• Methods of nausea and vomiting measurement were not clearly stated.
• Use of rescue medications was not stated.
• Definition of nausea as a single yes or no measure is questionable.
• Timing of measures was not stated.

Further well-defined research to fully evaluate multiple drug chemotherapy-induced nausea and vomiting regimens is warranted.

The purpose was to evaluate the efficacy of a three-day aprepitant regimen to manage CINV during cycle one of moderately emetogenic chemotherapy.

Three-day regimen of aprepitant plus ondansetron and dexamethasone compared to three-day regimen of placebo plus ondansetron and dexamethasone.

• N = 480   
• AGE: Overall mean = 60.3, range = 23-85 years 
• MALES: 55%
• FEMALES: 45%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Any cancer type
• OTHER KEY SAMPLE CHARACTERISTICS: Receiving cycle one of non-anthracycline plus cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC), aged 20 years and older, Eastern Cooperative Oncology Group (ECOG) performance status 0–2 or Karnofsky score of 60 or greater, predicted life expectancy of 4 months or greater. 

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Korea

PHASE OF CARE: Active anti-tumor treatment

Randomized, controlled trial, double-blind.

Measures of nausea and vomiting were not specifically described but aspects measured were vomiting during the overall phase (0-120 hours), use of rescue therapy during the overall phase, time to first vomiting event during the overall phase, vomiting during the acute (0–24 hours following initiation of chemotherapy) and delayed (25–120 hours following initiation of chemotherapy) phases.

Participants who received the three-day aprepitant regimen did not have statistically significant fewer episode of vomiting or use of rescue medications in the overall phase (0-120 hours after chemotherapy) as compared with those who received the placebo regimen.

The addition of aprepitant to a standard antiemetic regimen for moderately emetogenic chemotherapy did not result in significant improvement in CINV.

Measurement/methods not well described

For patients receiving moderately emetogenic chemotherapy, adding aprepitant to antiemetic therapy may not provide additional prevention of CINV.

To investigate the incidence of CINV among chemotherapy naïve patients with breast cancer receiving docetaxel-cyclophosphamide chemotherapy regimen (MEC). To investigate the prophylactic efficacy of aprepitant on CINV for the patients who experienced CINV in their first chemotherapy cycle

Phase 1: involved 212 breast cancer naïve patients receiving TC and detected the incidence of CINV. Antiemetic therapy on the first cycle consisted of dexamethasone 8 mg (x 3) for day 1 and then dexamethasone 8 mg (x 2) on days 2 and 3 plus 5-hydroxytryptamine (5-HT₃) antagonists (gransetron 1 mg [x 2], or tropisetron 5 mg [x 1]) on day 1. Patient also received 8 mg dexamethasone on day 0. 

Phase 2: for the patient who experienced vomiting and requested rescue antiemetic in the first 120 hours were involved during their second chemotherapy cycle. Patients received same antiemetic regimen prescribed in cycle 1 in addition to aprepitatnt 125 mg orally (x 1) on day 1, and aprepitant 80 mg and dexamethasone 4 mg (x 2) in days 2 and 3 Patients’ diaries and Functional Living Index Emesis (FLIE) questionnaires were collected in cycles 1 and 2.

• N = 185 patient in the observational phase; 32 patient in the efficacy phase (24 evaluable)  
• AGE: Median = 57 years (range = 34-82)
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage I to III breast cancer, chemotherapy naive patients, receiving T-75 mg/m² and C-600 mg/m²
• OTHER KEY SAMPLE CHARACTERISTICS: No anticipatory nausea and vomiting, no radiotherapy, no receiving systemic cortisone, had Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1; and had a life expectancy ≥ 4 months and adequate bone marrow, liver, and renal functions

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: 12 sites in Spain

PHASE OF CARE: Active anti-tumor treatment

Open-label, non-comparative, observational clinical trial

FLIE questionnaire on day 1 before chemotherapy and day 6. Patient diary for nausea and vomiting episodes and severity (VAS) and need of rescue antiemetics day 1-6.

On cycle 1, 87% achieved a complete response (no vomiting and no rescue antiemetic). On cycle 2, 23 patients reached a CR (52.2%). The absence of CR significant affected the patients QOL on cycle 1 (p = 0.0124) and 2 (p = 0.0059). No AEs related to aprepitant were observed in cycle 2.

Antiemetic guidelines of dexamethasone for 3 d plus 5-hydroxytryptamine (5-HT₃) antagonists on day 1 is associated with low incidence of CINV for patient receiving MEC. Aprepitant is effective as a secondary treatment line for patients who do not response to the first-line antiemetic.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Even with the use of standard antiemetics (steroid, %HT3 RAs) with patient receiving MEC, some patients still experience CINV. Failing to be free of nausea and vomiting negatively affect patients’ quality of life and therefore required additional therapy (aprepitant).

To compare the safety and efficacy of fosaprepitant with the safety and efficacy of aprepitant

Patients on cisplatin-based chemotherapy were randomly assigned to receive a single IV dose of fosaprepitant or a three-day dosing regimen of aprepitant. All also were given a dexamethasone regimen and ondansetron on day 1. Both groups could receive rescue therapy. Patients recorded nausea and vomiting episodes for the first 120 hours after chemotherapy.

• N = 272
• MEAN AGE =  50.5 years
• AGE RANGE = 19–79 years
• MALES: 73.5%, FEMALES: 24.5%
• KEY DISEASE CHARACTERISTICS: Patients had varied tumor types; lung and gastrointestinal cancers were most prevalent.

• SITE: Multi-site  
• LOCATION: India 

• PHASE OF CARE: Active antitumor treatment

• Subgroup analysis of a double-blind, randomized controlled trial

• Patient diary

No significant differences occurred between groups in complete response (CR) during the acute phase. In the delayed phase, 77.7% of patients on fosaprepitant had CR compared to 73.9% in the aprepitant group. This difference was not statistically significant. No differences existed in need for rescue medication. None of the patients experienced infusion site reactions with fosaprepitant.

The findings showed essentially equivalent efficacy of single dose fosaprepitant and a three-day aprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic chemotherapy.

• Risk of bias (no blinding)
• The study states a double-blind design and refers to a placebo, but the use of a placebo is not described in the report.

A single dose of fosaprepitant can provide the same essential prevention of CINV as a multiday aprepitant regimen as part of triple-drug therapy. Infusion site reactions have been described with fosaprepitant but were not shown in this particular analysis. Selection of the type of NK₁ use can be planned according to individual patient situations.

• N = 1,014 (HEC), 848 (MEC)
• MEAN AGE = 58–59 years (Study 1 HEC, SD = 12 years), 53–54 years (Study 2 HEC, SD = 13–14 years). Demographic results of the HEC studies were reported. Data only about females participants were reported.  
• MALES: Study I = 62%, Study II = 61% (both for HEC studies), FEMALES: Study 1 = 38%, Study 2 = 39%. All results are related to the HEC studies.
• KEY DISEASE CHARACTERISTICS: Respiratory, urogenital, and others (not specified)

• SITE: Multi-site  
• SETTING TYPE: Not specified  
• LOCATION: Not specified

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care 

Phase III clinical trial program; included data from two HEC trials and one MEC trial

• Modified version of the Functional Living Index–Emesis (FLIE)

More patients who received the aprepitant regimen in the HEC trials achieved overall complete response compared with those on standard antiemetic therapy in cycle one adjusted for gender, region, and use of concomitant chemotherapy (67.7% versus 47.8%, p < 0.01). A significantly higher number of patients who received aprepitant reported NIDL (74.4%) as compared with those on the standard antiemetic regimen (63.9%, p < 0.01). In the HEC group, when compared to standard therapy, patients who received aprepitant reported significantly lower nausea (70.2% versus 60.9%) and vomiting (84.6% versus 68.7%, p < 0.01). In the MEC trial, reports of no emesis were significantly lower in the aprepitant group (76.2%) than in the standard regimen (61.1%, p < 0.001) after the first cycle of chemotherapy. Patients receiving aprepitant in the MEC trial had a significantly higher percentage of complete response (68.7%) than the patients in the standard regimen (56.3%, p < 0.001). Aprepitant also had a significant impact on patient report of NIDL with 73.4% reporting no impact compared to 66.3% in the standard regimen group (p < 0.05).

Aprepitant, when given with HEC, led to higher overall complete response rates than the standard regimen. Patients who received aprepitant and MEC also reported lower levels of nausea and vomiting. For patients receiving both HEC and MEC, aprepitant improved outcomes on activities of daily living (ADL).

• Patients may not be able to detect the effect of chemotherapy on their daily function.
• Recall bias could be considered as a limitation.

Aprepitant, in addition to standard CINV prophylactic medications, reduces nausea and vomiting associated with chemotherapy and decreases the impact of CINV on ADLs. This is true for patients receiving HEC and MEC. Nurses should spend time educating patients on how CINV can impact ADLs and work with patients to create patient-centered, nurse-led interventions to ease the influence of CINV on patient quality of life.

To assess the additional effects of aprepitant in combination with conventional 5HT3 blocker-based prophylaxis for chemotherapy-induced nausea and vomiting (CINV) during highly or moderately emetic chemotherapy for hematologic malignancies

Patients were divided into two arms. Patients in the conventional antiemetic therapy arm received 5HT3 receptor antagonists (RAs) alone (19 patients, control arm), and patients in the treatment group received 5HT3 RAs plus aprepitant (22 patients, aprepitant arm). The incidence of CINV and the use of rescue medications were analyzed and compared between the two groups over the total period of 10 days from the start of chemotherapy. Oral food intake also was appraised by patients and sorted into four levels: (1) not impaired, (2) slightly impaired, (3) moderately impaired to about half of the usual amount, or (4) severely impaired.

• N = 41  
• AGE = ≥ 20
• MALES: 65.85%, FEMALES: 34.14%
• KEY DISEASE CHARACTERISTICS: Hematologic malignancies 
• OTHER KEY SAMPLE CHARACTERISTICS: The eligible chemotherapies were limited to the following: (a) preparative regimens for autologous hematopoietic stem cell transplantation for multiple myeloma or malignant lymphoma, (b) platinum-containing regimens for resistant or refractory malignant lymphoma mainly consisting of etoposide, methylprednisolone, cytarabine, and cisplatin or its modified variant, which substitutes carboplatin for cisplatin, or (c) induction or consolidation therapies for acute leukemia, which contain either anthracyclines, high-dose methotrexate, or high-dose cytarabine. Patients with poor performance statuses or with an estimated life expectancy of less than three months were disqualified. Patients had to have sufficient cognitive capacity, adequate blood counts, no significant hepatic or renal dysfunctions at the start of chemotherapy. Patients who had had a previous history of aprepitant administration also were excluded.

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: The University of Tokyo Hospital

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care 

Randomized, controlled study

• Vomiting was measured daily by the number of vomiting episode the patient reported.
• Nausea was measured by Visual Analog Scale (VAS).
• The amount of oral food intake was recorded daily on days 1–10 of chemotherapy administration. 
• Rescue medication use was recorded by the physicians.

This study revealed the benefit of adding aprepitant to highly emetic chemotherapy regimens for various hematologic malignancies. Sufficient antiemetic effects were achieved without obvious adverse events, and additional aprepitant use is recommended for patients who received chemotherapy for a hematologic malignancy. The additional research of individual chemotherapies that specifically prefer antiemetic intensification with aprepitant is warranted.

• Small sample (< 100)
• Measurement/methods not well described

Aprepitant is a good option for nurses to recommend for patients receiving chemotherapy for hematologic malignancies. NK1s such as aprepitant are recommended in relevant guidelines.

To evaluate the efficacy of aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) for in patients with colorectal cancer receiving oxaliplatin

• N = 413 for full analysis set; however, because of either refusal of chemotherapy (10 patients) or ineligibility on review, only 370 patients were evaluated for the first cycle protocol set. The number lowered further to 338 for second cycle protocol set because of deletion of oxaliplatin from the chemotherapy regimen or lack of data (i.e., not recording in the patient diary).  
• MEAN AGE = 64.2 years
• MALES: 61%, FEMALES: 39%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Colorectal cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Oxaliplatin-based chemotherapy, adults

• SITE: Multisite
• SETTING TYPE: Hospitals
• LOCATION: Japan

PHASE OF CARE: Active anti-tumor treatment

This was a double-blind, randomized, placebo-controlled trial.

Patients used a diary on days 1–6 to record the use of rescue antiemetics, severity of nausea, and episodes of vomiting. The severity of nausea was recorded on a four-grade scale. Tolerability, or other adverse effects, were monitored through laboratory tests and a physical examination.

For patients receiving oxaliplatin for the treatment of colorectal cancer, CINV prophylaxis with aprepitant or fosaprepitant significantly reduced the rate of vomiting in the acute and delayed phases and significantly reduced the rate of nausea in the delayed phase.

Aprepritant and fosaprepitant are safe and effective for the prevention of CINV in patients with colorectal cancer who receive oxaliplatin.

To evaluate the safety and efficacy of four different doses of rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with cisplatin-based, highly emetogenic chemotherapy

Eligible patients were randomized to receive rolapitant at 9, 22.5, 90 or 180 mg or no rolapitant (active control) administered two hours before the first dose of chemotherapy on day 1 of cycle 1 with cisplatin greater than 70 mg/m². Patients also received Zofran^® at 32 mg IV and Decadron^® at 20 mg orally 30 minutes before chemotherapy. Dexamethasone was administered at 8 mg orally twice daily on days 2, 3, and 4.

• N = 454  
• MEDIAN AGE = 55 years (range = 18–86 years)
• MALES: 244 (54%), FEMALES: 210 (46%)
• KEY DISEASE CHARACTERISTICS: No disease characteristics were provided. Patients were receiving highly-emetogenic chemotherapy at 70 mg/m².
• OTHER KEY SAMPLE CHARACTERISTICS: Exclusions included patients who had previously received cisplatin, 5HT3 antagonists, NK1 antagonists, or other drugs that may interfere with the study five days prior to treatment. Patients who had abdominal or pelvis radiation scheduled on day 5 or 6 or were receiving systemic corticosteroids also were excluded.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: Seventy-five sites in 21 countries

• PHASE OF CARE: Active antitumor treatment

Phase 2, randomized, double-blinded, active-controlled, parallel-group, dose-ranging study

• Patient diary with Visual Analog Scale (VAS) for nausea, emesis episodes, and use of rescue medication
• Functional Living Index-Emesis (FLIE) for quality of life
• Laboratory values, vital signs, electrocardiograms, and physical examinations for safety and tolerability

Rolapitant was well tolerated and was associated with greater complete response rates than the placebo group. Rolapitant at 180 mg achieved a statistically significant improvement compared to the active control group in the acute (87.6% and 66.7%, respectively, p = 0.001) and delayed (63.6% and 48.9%, respectively, p = 0.045) phases. Complete response rates across all phases of CINV were consistently higher for all other rolapitant dose groups compared to the active control group except the 9 mg group in the acute phase. However, this did not achieve statistical significance. Rolapitant also was statistically superior to the active control in other key secondary efficacy variables including less emesis in the acute and delayed phases and less nausea in the acute and delayed phases. Rolapitant at 90 and 180 mg doses significantly improved quality of life compared to the control group. The incidence of serious adverse events was similar in all treatment groups.

All doses of rolapitant were well tolerated and were associated with greater compete response rates than the active control (except 9 mg in the acute phase). Rolapitant at 180 mg demonstrated a clinical statistically significant effect in preventing CINV in the overall, acute, and delayed phases for patients receiving highly emetogenic chemotherapy.

In this study, rolapitant at 180 mg was safe, well tolerated, and effective in controlling CINV in all phases when given in combination with dexamethasone and a 5HT3 receptor antagonist for patients receiving highly emetogenic chemotherapy.

To assess the safety and efficacy of 180 mg rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer who receive moderately or highly emetogenic chemotherapy (HEC)

Patients who had a KPS of 60 or higher, were expected to live at least four months, and had adequate bone marrow and liver and kidney function were randomly assigned to receive 180 mg of rolapitant versus placebo, which looked exactly like the rolapitant.

• N = 1,087 (from two identically designed global studies)
• MEAN AGE = 58.8 years
• MALES: 63%, FEMALES: 37%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS Most common primary tumor was lung (44%), followed by head and neck (18%)
• OTHER KEY SAMPLE CHARACTERISTICS: Patients who had a KPS of 60 or higher, were expected to live at least four months, and had adequate bone marrow and liver and kidney function

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: International study

PHASE OF CARE: Active antitumor treatment

This article describes two randomized, double-blind, active-control studies.

In both studies (and in the pooled results), treatment with rolapitant resulted in a significantly increased number of patients experiencing a complete response in the delayed phase. The pooled studies found significant difference in the acute phase (first 24 hours). In the overall phase, complete response was significantly more frequent in the first study and in the results of the pooled studies. No significant differences were observed between study groups with respect to daily living as measured by the FLI-E questionnaire.

Oral rolapitant taken once daily before chemotherapy in combination with a 5-HT₃ receptor antagonist and dexamethasone is superior to 5-HT₃ receptor antagonist and corticosteroid alone.

The study participants were enrolled prior to recommendations for the addition of an NK₁ receptor antagonist to standard care and the use of dexamethasone to HEC.

As now accepted, the addition of an NK₁ receptor antagonist reduces CINV experienced by patients receiving HEC. Patient education regarding adherence to medications and correct timing can help them prevent what is often the most worrisome side effect.

To determine the efficacy, safety, and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) regimens and to determine if aprepitant would provide a complete response at preventing CINV in the first 5 days (120 hours) following chemotherapy

Patients naïve to moderately or highly emetogenic chemotherapy (HEC) and scheduled to receive a single dose of MEC agent, were enrolled in the study. Group one received an aprepitant triple-therapy regimen; group two received a control regimen that included a placebo 1 hour prior to chemotherapy, ondansetron (same dosing as aprepitant group), and dexamethasone on day 1, and, on days 2 and 3, placebo once daily and ondansetron twice daily (by mouth).

• The study looked at 848 participants.
• The mean age in years for patients receiving the aprepitant regimen was 57.1 (SD = 11.8 years); the mean age for patients receiving the control regimen was 55.9 (SD = 12.6 years).
• Diagnoses were 52% breast, 20% colon, 13% lung, and 4.6% ovarian.
• Chemotherapy regimens were 52% nonanthracycline/cyclophosphamide (n = 441) and 48% anthracycline/ cyclophosphamide (n = 407).
• More than two-thirds (69%) of participants were white.
• History of motion sickness was present in 5.6% of the aprepitant group and 9.8% of the control group.
• History of vomiting during pregnancy was present in 14.2% of the aprepitant group and 17.9% of the control group.

Studies were conducted at multiple sites in the United States, Mexico, Canada, Chile, Brazil, Peru, Colombia, Panama, Hong Kong, Australia, South Africa, France, Germany, Israel, and Russia.

Patients were in active treatment.

The study was a phase III, prospective, randomized, gender-stratified, double-blind trial.

Patients recorded the time and date of nausea, retching, and vomiting episodes in diaries. Nausea was assessed daily using a 100-mm horizontal visual analogue scale (VAS). If a rescue drug was used, the drug name and date and time of administration was recorded. Common Terminology of Adverse Events, version 3.0 (CTAE v 3.0) was used to assign toxicity grades to all laboratory test results and adverse events.

• The proportion of patients reporting no vomiting during the five days (0–120 hours) following initiation of chemotherapy was significantly higher in the aprepitant group (p < 0.001).
• In both the acute and delayed phases, significantly more patients in the aprepitant group reported no vomiting compared to the control group (p < 0.001).
• More patients in the aprepitant group reported a complete response in both the acute and delayed phases (p < 0.001), and time to first vomit was longer.
• No significant differences in the reporting of adverse events were found between groups.

The aprepitant regimen provided significantly more vomiting-free time. Better control with an aprepitant–containing, triple antiemetic regimen was seen for those receiving MEC (nonanthracycline and cyclophosphamide [AC] or AC).

• Results presented were for cycle one only.
• Limited generalizability is possible because the majority of the sample was female (77%) and Caucasian (69%).

Aprepitant was effective in preventing chemotherapy-associated vomiting in patients receiving a broad range of MEC and should be considered as part of a standard antiemetic regimen.

To explore the efficacy and safety of rolapitant in preventing chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC)

Patients were stratified by gender to receive either 180 mg oral rolapitant or placebo approximately 1–2 hours before receiving either MEC or HEC. All patients received a 5-HT₃ antiemetic and dexamethasone. Patients receiving MEC were given 2 mg oral granisetron on days 1–3 and 20 mg dexamethasone on day 1. Patients receiving HEC (e.g., cisplatin-based chemotherapy) were given 10 mc/kg granisetron intravenously and oral 20 mg dexamethasone on day 1 and 8 mg twice daily on days 2–4. Patients receiving taxanes were given dexamethasone per the package insert.

• N = 1,998   
• AGE RANGE = 18–90 years
• MEAN AGE = 57 years
• MALES: 38.4% (intervention arm), 36.9% (control arm); FEMALES: 61.6% (intervention arm), 63.1% (control arm)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Patients were not recruited or stratified by specific tumor type. More than half of the patients (67%) had breast cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria required that patients be aged 18 or older, have a Karnofsky score of 60 or better, have a life expectancy of four months or longer, and have adequate bone marrow, liver, and kidney functions. Patients in the MEC group were required to be naïve to MEC or HEC and scheduled to receive their first course of IV cyclophosphamide (< 1500 mg/m²), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, and/or IV cytarabine (> 1 g/m²). At least 50% of the patients were to receive an AC-based (doxorubicin and cyclophosphamide) regimen. Patients in the HEC arm were required to be naïve to cisplatin and scheduled to receive their first course of cisplatin-based chemotherapy.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Multinational—North, Central, and South America; Europe; Asia; and Africa

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Global, randomized, double-blind, placebo-controlled studies

Patients were given a diary to record all episodes of nausea, vomiting, and use of rescue drugs for five days post chemotherapy administration during cycle 1. For subsequent cycles, patients were asked two CINV assessment questions on days 6–8: (a) Have you had any episodes of vomiting or retching since your chemotherapy started in this cycle? and (b) Have you had any nausea since your chemotherapy started in this cycle that interfered with normal daily life? Assessments of safety variables, such as adverse events, vital signs, physical and neurological exams, electrocardiograms, and clinical lab values, were assessed during all cycles.

Compared to the control group, more patients receiving rolapitant reported no emesis or interfering nausea in cycles 2 (p = 0.006), 3 (p < 0.001), 4 (p = 0.001), and 5 (p = 0.021) when compared to the control group. Time to first emesis was significantly longer for the rolapitant group in cycles 1–6 (p < 0.001). The incidence of treatment-related adverse events were only slightly lower in the rolapitant (5.5%) than the control group (6.8%) during cycles 2–6.

Oral rolapitant was effective in protecting against CINV over multiple cycles of MEC and HEC. Rolapitant was well tolerated and demonstrated no increased frequency of adverse effects and no cumulative toxicity over multiple cycles.

Women were disproportionately high in the MEC study largely because of the high number of patients with breast cancer receiving AC chemotherapy.

The findings support the possible benefits of adding rolapitant to the therapy of patients receiving MEC and HEC.

The purpose of the study was to compare the combination of aprepitant and decadron versus metoclopramide and decadron for delayed emesis in patients receiving the same combination of aprepiant, palonosetron, and dexamethasone for the prophylaxis of cisplatin-induced acute emesis.

All patients received on day 1 a combination of 0.25 mg of palonosetron administered IV 30 minutes before the beginning of chemotherapy followed by 12 mg of decadron. Aprepitant was orally administered one hour before chemotherapy. Patients were randomized to receive delayed antiemetics with decadron 8 mg once daily day 2 to 4 plus aprepitant 80 mg daily on day 2 and 3, or decadron 8 mg twice daily on days 2 to 4 plus metoclopramide 20 mg four times a day on days 2 to 4. Patients recorded a diary card days 1 to 6 with reports of nausea, vomiting, adverse events and any rescue treatments using FLIE, and nausea intensity on a visual analog scale.

• N: 284   
• AGE: Adult (categorized as less than 50, 50 to 64, and 65 and up.
• MALES: MTC + Dex arm 71.5%, APR + Dex 71.4%  
• FEMALES: MTC + Dex 28.5%, Apr + Dex 28.6%
• CURRENT TREATMENT: Chemotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy naïve cancer patients scheduled to receive cisplatin containing chemotherapy at doses 50 mg/m² or above

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Italy

PHASE OF CARE: Active anti-tumor treatment

Multicenter, double-blind, parallel, randomized 1:1 study aimed to evaluate the efficacy of aprepitant versus metoclopramide

Fisher’s exact test was used to compare the two groups with respect to the endpoints expressed by a binary variable, as well as to evaluate the differential safety. FLIE was used for patient diary and symptom reporting, as well as a visual analog scale for nausea.

During days 2 to 5, complete response was similar in both antiemetic prophylaxes (82.5% with M + D, and 80.3% with A + D).

The effectiveness and safety of the two combinations in the treatment of cisplatin induced CINV in the delayed phase are similar. However, they have very different cost profiles. These are important considerations for treatment-related decisions.

• Self reported lack of power
• May not detect small differences

Both aprepitant + decadron and metoclopramide + decadron are effective for delayed emesis for patients receiving cisplatin. Because of the substantial cost difference, consideration should be given to metoclopramide + decadron for delayed nausea.

To determine if dexamethasone is superior to aprepitant in the prevention of delayed emesis in patients with breast cancer receiving chemotherapy that includes anthracyclines and cyclophosphamide

Patients were randomized using computer generated numbers, and blinding was performed by a special company. On day 1, 30 minutes prior to chemotherapy, all patients received palonosetron at 0.25 mg IV in a 30-second bolus and dexamethasone at 8 mg IV diluted in 100 ml of saline IV over 15 minutes. Aprepitant at 125 mg was administered orally one hour prior to chemotherapy. On days 2 and 3, patients randomly received either dexamethasone at 4 mg twice daily or aprepitant at 80 mg daily. Patients receiving aprepitant took a placebo in the evenings, and all pills were placed in identical capsules. On days 1–5, patients could receive either prochlorperazine at 10 mg via a suppository or metoclopramide at 10 mg intramuscularly as rescue medication. Adherence to medications on days 2 and 3 was checked by counting the remaining pills. Data were collected on days 1–6 after chemotherapy.

• N = 551  
• MEAN AGE = 53 years (median = 50 years)
• MALES: < 1%, FEMALES: > 99%
• KEY DISEASE CHARACTERISTICS: Breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve patients with breast cancer receiving anthracyclines plus cyclophosphamide

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: Italy

• PHASE OF CARE: Active antitumor treatment

Randomized, double-blinded, parallel study

• Daily diary to record the number of vomiting episodes, adverse events, rescue medications, and the presence, intensity, and duration of nausea
• Functional Living Index–Emesis (FLIE)
• Visual Analog Scale (VAS) for nausea

There was no significant difference in complete responses between the two groups in the acute (p = 0.39) or delayed phases (p = 1). There were no statistically significant differences in total control (p = 0.27), vomiting (p = 0.39), nausea (p = 0.24), significant nausea (p = 0.10), number of emetic episodes (p = 0.07), maximum severity of nausea (p = 0.26), or duration of nausea (p = 0.13) between the two groups in the delayed phase. Patients receiving dexamethasone experienced more insomnia (p = 0.02) and heartburn (p = 0.03) than those in the aprepitant group. More patients in the aprepitant group reported sedation and anorexia, but these results were not statistically significant.

In patients with breast cancer receiving chemotherapy containing anthracyclines and cyclophosphamide, dexamethasone and aprepitant have similar efficacy for the management of delayed chemotherpy-induced nausea and vomiting (CINV) when the optimal prophylactic treatment for acute CINV is administered. Patients who receive dexamethasone may experience a slight increase in adverse events compared to those taking aprepitant.

Nurses can help patients consider the differences in efficacy, safety, and cost of dexamethasone versus aprepitant when selecting an appropriate pharmacologic intervention for delayed CINV. In addition, nurses can help ensure that patients receive the optimal prophylactic treatment recommended for CINV with chemotherapy regimes that contain anthracyclines and cyclophosphamides.

To investigate the efficacy and safety of fosaprepitant in combination with palonosetron and dexamethasone in the prevention of nausea and vomiting during five weeks of fractionated radiotherapy and concomitant weekly cisplatin in patients with cervical cancer

Patients received fractionated radiotherapy and concomitant weekly cisplatin 40 mg/m² for five weeks. Patients were randomly assigned to receive either single doses of 150 mg fosaprepitant IV or placebo (saline) in combination with 0.25 mg palonosetron IV and 16 mg dexamethasone orally before cisplatin administration. All patients received 8 mg dexamethasone orally twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once a day on day 4. The treatment was repeated for five weeks. Patients kept daily logs of their symptoms, which were reviewed weekly to determine continued eligibility.

• N = 234   
• MEAN AGE = 47–48 years
• FEMALES: 100%
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Cervical cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Patients who were chemotherapy and radiation therapy naïve, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, who were able to read, understand, and complete questionnaires and daily records in a patient diary throughout the study period

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: Recruited from eight centers in four countries

• PHASE OF CARE: Active antitumor treatment

• Multinational, randomized, double-blind, placebo-controlled, phase-III trial

• Functional Living Index-Emesis (FLIE)
• Common Terminology Criteria for Adverse Events (CTCAE), version 4.02 
• Pearson X2, modified intention to treat approach
• Fine and Gray’s proportional subhazard model (competing risk regression)
• Schoenfeld Residuals Test

Of the patients, 48.7% of the placebo group and 65.7% of the control group with fosaprepitant sustained no emesis at five weeks. A significantly lower cumulative risk of emesis was seen in the fosaprepitant group compared to the placebo group (p + 0.008).

Patients receiving concomitant chemo/radiation therapy for cervical cancer who received fosaprepitant in addition to palonosetron and dexamethasone were less likely to experience emesis and nausea compared to those receiving palonosetron and dexamethasone alone.

Neurokinin 1 receptor antagonists (NK₁s) use should be considered in the prevention of radiation-induced nausea and vomiting.

To evaluate the efficacy and safety of single-dose fosaprepitant in combination with IV granisetron and dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC) containing cisplatin at 70 mg/m² or higher

Patients receiving high-dose cisplatin were randomized to one of two groups (fosaprepitant or placebo). On day 1, one hour before antineoplastic treatment, both groups received IV granisetron 40 µg/kg and an IV infusion over 20-30 minutes of either fosaprepitant 150 mg or placebo. Dexamethasone also was given on day 1 (10 mg given to the fosaprepitant group and 20 mg given to the placebo group). Aprepitant is known to increase plasma dexamethasone concentrations when used in combination with dexamethasone; therefore, to achieve comparable plasma levels of dexamethasone, the fosaprepitant group received a half dose of dexamethasone on days 1 and 2 only. On day 2, both groups received dexamethasone 4 mg and 8 mg, respectively. On day 3, both groups received dexamethasone 8 mg IV, administered in the morning.

• The study consisted of 340 participants.
• Participants' ages ranged from 25-86.
• The majority of patients were male (74%), and 26% were female.
• Diagnoses were respiratory (71%), genitourinary (10%), digestive (8%), head and neck (7%), and other (4%).
• In the standard (placebo) group, 64% of the participants did not consume alcohol whereas, in the fosaprepitant group, 50% had no alcohol intake.
   

This was a multisite study conducted at 68 institutions in Japan.

All patients were in active antitumor treatment.

This was a multicenter, placebo-controlled, double-blind, randomized, parallel study.

Patients kept self-assessment symptom diaries. Vomiting was defined as one episode of emesis or retching; nausea was assessed on most intense during a 24 hour-period of time.

• The percentage of patients who achieved a complete response (CR) in the overall phase (1-120 hours) was significantly higher in the fosaprepitant group than in the control group (64%, 95% confidence interval [CI] 16%-46%) versus 47% (95% CI, 10%-36%, p = 0.0015).
• CR rates in the acute and delayed phases were significantly higher in the fosaprepitant group than in the control group (acute phase: 94% versus 81%, P = 0.0006; delayed phase: 65% versus 49%, p  = 0.0025).
• Although the prevalence of a CR was decreased in the delayed phase, the difference between the two groups was higher in the delayed phase than in the acute phase (16% versus 13%).
• In patients who had received cisplatin and experienced vomiting, CR rates in the overall phase were higher in the fosaprepitant group than in the control group (60% versus 30.3%).
• Significant nausea in all phases and percentages of those with no rescue therapy in the overall phase did not differ significantly.

A single-dose administration of fosaprepitant (150 mg), used in combination with granisetron and dexamethasone, was found to be well-tolerated and effective in preventing CINV in patients receiving HEC, including high-dose cisplatin.

• A risk of bias exists because of the sample characteristics.
• Although the two groups had comparable numbers of individuals with a history of vomiting during pregnancy and previous treatment with cisplatin, the fosaprepitant group had slightly more individuals with a history of motion sickness, which is associated with higher susceptibility to nausea and vomiting. 
• The fosaprepitant group had slightly more individuals with alcohol use, which is associated with slightly less nausea.  
• Women are known to experience more acute nausea and vomiting than do men. In this study, 76% of the population was men.

The use of single-dose fosaprepitant (150 mg) in combination with granisetron and dexamethasone has shown effectiveness in preventing nausea and vomiting in patients receiving highly emetogenic antineoplastic therapies, such as cisplatin.

To evaluate the efficacy of aprepitant in addition to standard antiemetic therapy with ondansetron and methylprednisolone in the prevention of chemotherapy-induced nausea and vomiting (CINV) caused by high-dose melphalan given as part of conditioning for allogeneic ​hematopoietic stem cell transplantation (HSCT)

• N = 60 (20 in the treatment arm, 40 in the control arm)
• MEDIAN AGE = 47 years (control), 52 years (treatment)
• MALES: 50% (control); 52.5% (treatment), FEMALES: 50% (control), 47.5% (treatment)
• KEY DISEASE CHARACTERISTICS: Lymphoma and multiple myeloma
• OTHER KEY SAMPLE CHARACTERISTICS: Patients received fludarabine and high-dose melphalan conditioning were included. Patients receiving TBI for graft-versus-host disease prophylaxis also were enrolled.

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: Tokyo, Japan

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care 

Retrospective, single-center analysis

Medical records during the period were analyzed to extract data about CINV and food information. Adverse events were monitored during the observation period, and there were no statistically significant differences in the incidence of grade 2 or greater adverse events between the two groups.

Aprepitant was well tolerated and positively affected the rates of delayed vomiting in this population. The ability to consume food more quickly after the conditioning regimen was improved with aprepitant.

• Small sample (< 100)
• Risk of bias (no random assignment)
• Selective outcomes reporting
• Measurement validity/reliability questionable
• Other limitations/explanation: Retrospective design instead of a prospective, randomized, controlled trial

This retrospective study did not indicate how the data were categorized from the records. There was no specific information regarding the rescue antiemetics used, and the rescue medications were chosen by the physicians. This impact on CINV was not discussed in the manuscript. The results are intriguing and demonstrate the safety of adding aprepitant, but a prospective, randomized, controlled trial will be needed to change clinical practice.

To compare the effectiveness of adding an aprepitant regimen to an ondansetron and dexamethasone regimen for chemotherapy-induced nausea and vomiting (CINV)

Patients were randomized to receive the treatment arm (aprepitant, ondansetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2–3; dexamethasone on day 4) or the control arm (ondansetron plus dexamethasone on days 1–4).

The study looked at 489 patients with solid malignancies receiving chemotherapy (patients were cisplatin-naïve). The treatment arm had 231 participants, and the comparison group had 229 participants.

The study was a prospective, randomized, double-blind trial with sponsor blinding.

Measurement instruments were

• Patient diaries used to record number of episodes of vomiting
• Use of rescue medication
• Nausea visual analogue scale (VAS).

Patients were considered treatment failures if they needed to take rescue medication.

• Complete response (CR) was defined as no vomiting and no rescue medication in the overall period (days 1-5 after cisplatin infusion).
• The aprepitant regimen was superior to the control arm in the overall treatment period (CR = 72% versus 61%, p = 0.003).
• No significant difference was observed among groups in control of nausea.
• The aprepitant group had higher rates of drug-related adverse events.

Efficacy might be further improved if ondansetron is given on days 1-4 as well (as per guidelines), rather than only on day 1 as done in this study.

The addition of aprepitant to prevention of CINV provides an objective improvement in control of vomiting as compared to ondansetron and dexamethasone alone; however, the triple-drug combination is recommended for practice.

To assess rolapitant in combination with a serotonin receptor antagonist and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with cancer after the administration of moderately emetogenic chemotherapy (MEC) or regimens containing an anthracycline and cyclophosphamide

Patients received either one oral dose of 180 mg rolapitant or a placebo 1–2 hours before chemotherapy on day 1. All patients received 2 mg granisetron plus 20 mg dexamethasone approximately 30 minutes prior to chemotherapy. Granisetron (2 mg) was also given once daily on days 2 and 3. Additional medications, such as dexamethasone for taxanes, were administered as needed and according to package instructions. Cycles were a minimum of 14 days, and patients received the same regimen (rolapitant or placebo) for up to five subsequent cycles during the study.

• N = 1,333
• AGE RANGE = 22–86 years (rolapitant group), 22–88 years (control group)
• MEDIAN AGE = 58 years (rolapitant group), 56 years (control group)
• MALES: 20% (rolapitant group), 20% (placebo group); FEMALES: 80% (rolapitant group), 80% (placebo group)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: No specific tumor type was recruited; however, the majority of patients had breast cancer or lung cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria required that patients be older than 18 years, have a Karnofsky score of 60 or better, have a life expectancy of four months or greater, and have adequate bone marrow, liver, and kidney functions. Patients with a history of receiving moderately or highly emetogenic chemotherapy or with a contraindication to any of the study drugs were excluded. Also, patients with histories of alcohol misuse, seizure disorders, or psychiatric conditions were excluded.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: Data were collected from 170 study sites in 23 countries located in North, Central, and South Americas; Europe; Asia; and Africa.

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Global, multicenter, randomized, double-blind, active-controlled, phase-III trial

Efficacy was measured as a complete response (CR) or no emesis or use of rescue medications as reported in a daily patient journal for up to 120 hours post chemotherapy. Responses were stratified into acute (< 24 hours) and delayed (> 24 hours) phases. Also, the Functional Living Index-Emesis (FLIE) survey was used to measure the effect of nausea or vomiting on daily living. The FLIE uses a seven-point visual analog scale (VAS) on nine questions to assess patients on day 6 of cycle 1. Finally, safety variables (e.g., adverse reactions) were assessed and reported.

The findings showed that a significantly greater proportion of patients receiving rolapitant had CRs in the delayed phase than those who received the active control (95% CI [1.2, 2.0], p = 0.0002). No significance was found in the acute phase between patients receiving rolapitant and the control. Adverse events were similar between groups with the most frequent events being fatigue, constipation, and headache. In cycle 1, grade 3–4 neutropenia was 5% in the rolapitant group and 3% in the active control group.

The findings showed that rolapitant in combination with a 5-HT₃ and dexamethasone was well tolerated and showed superiority over active control for the prevention of CINV during the five-day (0–120 hour) at-risk period after the administration of MEC or drug regimens containing an anthracycline.

• Risk of bias (sample characteristics)
• Sample was disproportionately female.
• The authors referred to both a placebo control and an active control—control condition unclear.

Rolapitant in combination with a 5-HT₃ receptor antagonist and dexamethasone was well tolerated by this sample and demonstrated acceptable extended (0–120 hours) control of CINV associated with MEC regimens and regimens containing an anthracycline and cyclophosphamide.

To evaluate the safety and efficacy of oral aprepitant in combination with ondansetron and dexamethasone in the prevention of acute and delayed nausea and vomiting compared to ondansetron and dexamethasone alone in patients receiving highly emetogenic preparative regimens before autologous or allogeneic stem cell transplant (SCT).

Patients were stratified by gender and randomized to one of two treatments. The aprepitant group received 125 mg oral aprepitant on day one then 80 mg daily during the preparative regimen + 3 days, 7.5 mg dexamethasone IV, and 8 mg ondansetron by mouth every eight hours daily during preparative regimen + 1 day. The placebo group received an oral placebo daily during the preparative regimen + 3 days, 10 mg IV dexamethasone, and 8 mg oral ondansetron every eight hours daily during the preparative regimen +1  day. Lorazepam was used for breakthrough nausea or vomiting. Prochlorperazine was allowed only for repeated episodes of vomiting (defined as more than four episodes in any 12-hour period). The primary objective was complete response (CR) rate, defined as no emesis with no or mild nausea.

• The study was initiated with 181 randomized participants, of which 179 were eligible for analysis.
• The median age was 50 years with a range of 19-79.
• The sample was 57% male and 33% female.
• Cancer diagnoses were non-Hodgkin lymphoma (32%), acute myeloid leukemia (26%), multiple myeloma (19%), acute lymphoblastic leukemia (7%), Hodgkin lymphoma (7%), chronic myeloid leukemia (3%), and other (6%).
• Treatment groups were stratified based on gender and were balanced with respect to age, weight, and history of nausea and vomiting with prior chemotherapy. Graft type was comparable, however, autoperipheral blood progenitor cell transplantation (PBPCT) represented 53% in the placebo group and 44% in the aprepitant group.

The study was conducted at Loyola University Medical Center Cardinal Bernardin Cancer Center in Maywood, IL.

All patients were in active antitumor treatment.

This study was a single center, comparative (placebo controlled), randomized, double-blind, phase III trial.

Patients rated the number of emetic episodes and nausea severity on a 100-mm visual analog scale (VAS).

• Patients who received aprepitant had significantly higher CR rates (81.9% versus 65.8%; p < 0.001) and significantly better complete control (CC) of vomiting  (73.3% versus 22.5%; p = 0.001) compared to the standard ondansetron plus dexamethasone treatment.
• The percentage of days with one episode of emesis with major efficacy and less than grade 4 nausea was significantly higher in the aprepitant arm (p < 0.001), while those with a minor response or failed was significantly higher in the control arm.
• Fewer total rescue doses were given in the aprepitant arm than in the control arm (594 versus 852; p = 0.033).
• The majority of patients, in both arms, used lorazepam for breakthrough therapy (p = 0.979).
• Aprepitant did not have a negative effect on engraftment. Median time for engraftment and platelet recovery was similar (p =  0.778 and p = 0.8206, respectively).
• A nonsignificant, higher tacrolimus level was noted in the aprepitant group; however, this was not enough to recommend adjustment of standard dosing (p = 0.5858).

Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, without an increase in regimen-related toxicities. The regimen did not affect short-term survival and had no significant impact on the use of as-needed antiemetics or overall nausea scores. It did not negatively affect patient outcomes.

Five myeloablative high-dose cyclophosphamide preparative regimens were used. Only two regimens included total body irradiation (TBI), which is thought to cause more nausea.

Similar to standard-dose chemotherapy regimens, aprepitant demonstrated a much higher impact on emesis than it did on nausea. Aprepitant in combination with dexamethasone and ondansetron significantly decreased emesis and significant nausea, without increasing toxicities or affecting short-term survival; the regimen had no significant impact on the use of as-needed antiemetics or overall nausea scores.  Findings suggest that aprepitant assisted in control of nausea as well as emesis.

To evaluate the safety and efficacy of the addition of aprepitant in patients receiving carboplatin-based chemotherapy after initial doublet-based antiemetics in the first chemotherapy cycle

In the first cycle of chemotherapy, patients were receiving doublet therapy, consisting of a 5-HT₃ and dexamethasone. In the second cycle, patients received aprepitant and reduced dexamethasone, as in standard triplet regimens. Patients completed daily questionnaires regarding vomiting frequency, nausea scoring, and food intake for five days of each cycle.

• N = 63   
• MEAN AGE = 66 years
• AGE RANGE = 44–81 years
• MALES: 79.4%, FEMALES: 20.6%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Tumor types were not stated, but 11.1% had brain metastases and 71.4% had a stage IV disease.

• SITE: Single site   
• SETTING TYPE: Not specified    
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

• Observational

• Evaluation of complete response (CR) rates (no vomiting and no rescue antiemetics)
• Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

The overall (p < 0.001) and delayed phase (p < 0.001) CR rates were better in the second cycle with the addition of aprepitant. No difference existed in the CR rates in the acute phase. Fewer patients in the second cycle required rescue antiemetics (p = 0.006). The proportion of patients who had grade 2 or higher nausea was less in the cycle with aprepitant (p = 0.013).

The addition of aprepitant significantly improved CINV control.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Experience of CINV in the first cycle could have influenced experiences in cycle 2 and beyond.

This study showed that the addition of an NK₁ as salvage for patients on MEC who did not have complete control in initial chemotherapy cycles was associated with improved CINV control, particularly in the delayed phase.

To evaluate the effectiveness of adding aprepitant to standard antiemetic treatment in patients receiving high-dose chemotherapy prior to stem cell transplantation

• N = 96  
• MEAN AGE = 58.1 years (experimental), 56.5 years (control)
• MALES: 70%, FEMALES: 30%
• KEY DISEASE CHARACTERISTICS: Lymphoma (38 patients) and myeloma (58 patients)
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy regimens, high-dose melphelan, BEAM, BEAC, and BBM

• SITE: Single site
• SETTING TYPE: Inpatient    
• LOCATION: Sweden

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care

This was a randomized, blinded study.

Patient diaries were used to record nausea and vomiting. An analysis was made on an intention-to-treat basis, and differences between the groups were then analyzed. Days at the hospital, weight, and use of total parenteral nutrition also were analyzed.

Thirty-eight patients (83%) in the experimental group experienced no vomiting compared to 16 patients (36%) in the control group. This finding was statistically significant. The number of vomiting episodes was also significantly lower in the experimental arm compared to the control arm up to 17 days post chemotherapy. There were no significant differences regarding days of nausea or use of antiemetic rescue medications between the two groups. There were no significant differences noted in days at the hospital, weight and use of TPN between the two groups.

The results also showed that there was a significant difference between patients who expected nausea and those who did not. Patients who did not expect nausea had lower rates of vomiting as well as fewer days of nausea.

The addition of aprepitant to the antiemetic regimen in this patient population was well-tolerated and demonstrated a statistically significant reduction in the rate of delayed vomiting.

• Small sample (< 100)

Delayed CINV is an issue of critical importance for this patient population, and ongoing research to identify and improve symptom control and quality of life is necessary. These findings provide a springboard to conduct additional research with a larger sample size to confirm the positive impact of aprepitant on delayed vomiting.

To evaluate the efficacy and safety of aprepitant plus standard therapy (granisetron and dexamethasone) in the prevention of chemotherapy-induced nausea and vomiting (CINV) in Japanese patients with cancer undergoing treatment with chemotherapy including a highly emetogenic cisplatin-based regimen (≥ 70 mg/m²)

Patients were allocated to three groups.

• The aprepitant 125/80 mg group received 125 mg on day 1 and a dose of 80 mg on days 2–5.
• The aprepitant 40/25 mg group received of 40 mg on day 1 and a dose of 25 mg on days 2–5.
• The standard therapy group received an oral administration of placebo on days 1–5.

All patients received standard therapy consisting of 40 µg/kg IV granisetron on day 1 and dexamethasone. Concomitant use of other antiemetics was prohibited from 48 hours before day 1 to the morning of day 6, except for rescue therapy for CINV.

• The study looked at 439 participants.
• Mean age for the 125/80 group was 60.5 years (SD = 9.7 years); for the 40/25 group, 63.3 years (SD = 9.4); and for the standard group, 62.2 years (SD = 9.8).
• Gender of patients was 24% female and 76% male.
• Patient diagnoses were
  • 72% respiratory
  • 15% urogenital
  • 5% digestive
  • 5% eyes/ears/nose/throat
  • 3% other
• Mean cisplatin dose (mg/m²) for the 125/80 group was 76.9; for the 40/25 group, 76.9; and for the standard group, 76.2.
• Percentage of patients with a history of morning sickness was 42%; 8% of patients had a history of motion sickness.
• Patients receiving cisplatin chemotherapy was 17%; chemotherapy except cisplatin, 21%, and CINV except cisplatin chemotherapy, 40%.

The study was conducted at multiple sites in Japan.

Study participants were in active treatment.

This was a phase II, placebo-controlled, double-blind, randomized parallel comparative study.

• Patients recorded in a symptom diary the onset of vomiting and nausea intensity on a 4-point scale, and the name and dose of any rescue therapy used along with the date and time from day 1 to the morning of day 6.
• Safety was evaluated based on physical examination findings (vital signs, weight, general lab tests, lab values).
• Toxicity was evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTAE).

In the three study groups, the percentage of patients with complete response (no emesis and no rescue therapy) was 50.3% (standard therapy), 66.4% (aprepitant 40/25 mg), and 70.5% (aprepitant 125/80 mg). Efficacy was significantly higher in the aprepitant 40⁄25 mg and 125/80 mg groups than in the standard therapy group (p = 0.0053 and p = 0.0004, respectively), and efficacy was the highest is the aprepitant 125/80 mg group. The delayed phase efficacy was similar to the overall phase efficacy, indicating that aprepitant is effective in the delayed phase when standard therapy is not very effective. Aprepitant was generally well tolerated.

Aprepitant was shown to be more effective in the overall phase, including both acute and delayed, when compared to the standard group, irrespective of sex, age, or previous treatment with cisplatin.

• Limited information was provided regarding measurement tools.
• The potential for anticipatory nausea was not addressed, especially in patients who had received previous emetogenic therapies.

Aprepitant used in combination with 5-HT₃ receptor antagonists and a corticosteroid is effective in preventing CINV associated with highly emetogenic agents.

To determine the effectiveness and safety of aprepitant in Japanese patients with hematologic malignancy receiving multiday chemotherapy

All patients were given 3 mg IV granisetron 30 minutes before chemotherapy. Corticosteroids were administered as part of the chemotherapy regimen.  In the aprepitant group, 125 mg was given orally on day 1; on following days, patients received 80 mg aprepitant daily. 

Data were collected via retrospective electronic medical records review for comparison of outcomes between those who received aprepitant versus those who did not. Nausea, vomiting, and adverse events were monitored daily and recorded in the medical record.

• The study consisted of 82 patients.
• The mean age was 47.5.
• The sample was 42.7% male and 57.3% female.
• All participants had hematologic malignancies.  Stem cell transplant patients were excluded.  All patients were receiving moderately or highly emetogenic chemotherapy in multiday regimens.

The study was conducted at a single inpatient site in Japan.

All patients were in active antitumor treatment.

This was a retrospective comparison.

Measurement tools were the Common Terminology for Adverse Events version 4.0 and complete response calculation.

• With aprepitant, the complete response (CR) rate for chemotherapy-induced nausea and vomiting (CINV) control was 76%, compared to 50% in those who did not receive aprepitant (p = 0.013). 
• The percentage of patients without any vomiting was significantly higher with aprepitant (p = 0.002).
• No significant differences were found between groups in prevalence of nausea. 
• Patients treated with regimens containing cytarabine had more CINV (p = 0.028).  In those patients receiving cytarabine 4 g/m² or more per day, CINV was poorly controlled for all patients. 
• Few adverse effects were found with aprepitant with the most common being malaise.

The study showed aprepitant to be safe and effective for CINV prophylaxis in this group of Japanese patients. Analysis suggested that cytarabine at a dosage of 4 g/m² or more per day should be considered highly emetogenic.

• The study had a small sample of fewer than 100 patients.
• A risk of bias exists because no blinding or random assignment was done.

This study adds to the body of evidence that demonstrates the safety and effectiveness of aprepitant for multiday chemotherapy by demonstrating effects in Japanese patients.

To evaluate the antiemetic effect and safety of aprepitant in combination with 5-HT3 receptor antagonist in patients undergoing autologous peripheral blood stem cell transplantation (auto-PBSCT)

This was a retrospective evaluation of patients who received conditioning high-dose chemotherapies prior to auto-PBSCT for hematologic malignancies comparing 26 consecutive patients who received antiemetic therapy that included both aprepitant and granisetron (the aprepitant group) between April 1, 2010, and January 31, 2010, and 22 patients who received granisetron alone (control group) between January 1, 2008, and March 31, 2010, before the introduction of aprepitant. In both groups, IV granisetron 3 mg was started 30 minutes prechemotherapy on day 1 and then repeated every 12 hours while receiving chemotherapy. In the aprepitant group, 125 mg of aprepitant was administered orally 60–90 minutes preadministration of the first moderately to highly emetogenic anticancer drug on day 1 and aprepitant 80 mg PO was given the following two days. Rescue medication including metoclopramide or hydroxyzine was used for breakthrough nausea or vomiting. A corticosteroid was not administered in either group for emetic control.

• N = 48              
• MEDIAN AGE = 52 years (range = 20–66 years)
• MALES:  58%, FEMALES:  42%
• KEY DISEASE CHARACTERISTICS: Patients with non-hodgkin lymphoma, multiple myeloma, hodgkin lymphoma, and leukemia. Conditioning regimens: MCEC (ranimustine 200 mg/m², carboplatin 300 mg/m², etoposide 500 mg/m², cyclophosphamide 50 mg/m²) or melphalan (100 mg/m²) +/– bortezomibor; LEED (etoposide 500 mg/m², cyclophosphamide 60 mg/m², melphalan 130 mg/m²). 
• OTHER KEY SAMPLE CHARACTERISTICS: Japanese descent

• SITE: Single-site  
• SETTING TYPE: Not specified  
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

Retrospective study design with a historical control.

Nausea, vomiting, and other adverse events (ADEs) were monitored twice daily (morning and evening), mainly by nurses, and recorded into EMRs. Primary endpoint was achievement of complete response (CR, defined as no emesis with only grades 1–2 nausea using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) during and until five days after the last chemotherapy dose was administered. Secondary endpoints included percent of patients without vomiting, percent without severe nausea, and the frequency of other ADEs. Severity of ADEs was classified by CTCAE version 4.0.

The percentage of patients who achieved CR in the aprepitant group was significantly higher than in the control group (42% versus 4.5%, p = 0.003). The percentage of patients without vomiting was higher in the aprepitant group (57%) versus the control group (4.5%; p < 0.001), and the percentage of patients without severe nausea was higher in the aprepitant group (58% versus 23%, p = 0.02) in the control group. There was no significant increase in ADEs when adding aprepitant to the antiemetic regimen.

The prophylactic administration of aprepitant significantly enhanced the effectiveness of antiemetic therapy without increasing the frequency and severity of ADEs in Japanese patients receiving high-dose chemotherapy prior to auto-PBSCT for hematologic malignancies.

• Small sample (< 100)
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions that would influence results are not described.
• Measurement/methods not well described
• Other limitations/explanation: The study design is limited in that it is a purely retrospective comparison of a very small group. There is limited of description of data collection. There was no report on the use of rescue medication in any of the analyses.

This study suggests that the addition of aprepitant to a 5-HT3 as prophylaxis for CINV in HEC regimens results in significant improvement in the control of CINV. This comparison of treatment regimens before and after the availability of aprepitant validates the added benefit of including a neurokinin 1 receptor antagonist to 5-HT3 in HEC regimens for improved CINV prophylaxis. Also, this antiemetic regimen did not incorporate the use of steroids, demonstrating a good level of efficacy with a 5-HT3 in addition to neurokinin 1 receptor antagonist.

To evaluate the efficacy and safety of aprepitant added to standard antiemetic regimens in high-dose chemotherapy for allogeneic hematopoietic stem cell transplantation

• N = 88  
• AVERAGE AGE = 47 years (control), 53 years (aprepitant)
• MALES: 57.1% (control); 60.9% (aprepitant), FEMALES: 42.9% (control); 39.1% (aprepitant)
• KEY DISEASE CHARACTERISTICS: Acute myeloid leukemia, acute lymphoblastic leukemia, T-cell leukemia, lymphoma, myelodysplastic syndrome; sources of stem cells were related donors, placenta stem cells, bone marrow, unrelated donors, and cord blood
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapies included cyclophosphamide, busulfan, fludarabine, and melphan as well as total body irradiation.

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: Kyushu University Hospital in Japan

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care and palliative care 

Retrospective medical record review of electronic medical records

• Adverse effects were recorded by nurses in the medical records.

The use of aprepitant with granisetron was highly effective in decreasing vomiting and nausea in patients receiving hematopoietic stem cell transplantations. There was no increase in adverse events. There were therapeutic outcomes.

• Small sample (< 100)
• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Selective outcomes reporting

The combination of granisetron and aprepitant was highly effective for chemotherapy-induced nausea and vomiting in patients receiving hematopoietic stem cell transplantations. Nurses should know that the combination did not increase side effects or affect engraftment.

To evaluate the efficacy of aprepitant combined with conventional antiemetic therapy in patients receiving moderately emetogenic chemotherapy

5-HT₃ receptor antagonists were given 30 minutes prior to chemotherapy. Aprepitant was given orally at 125 mg on day 1 and 80 mg on days 2 and 3. Dexamethasone was given by infusion 30 minutes prior to chemotherapy. Patients were followed for five days. Results in these patients were compared to a control group that received only 5-HT₃ and dexamethasone.

• The study consisted of 52 patients.
• The mean age was 68.2, with a range of 34-83.
• The majority of the sample (73%) was male, and 27% was female.
• All patients had lung cancer.
   

The study was conducted at a single inpatient site in Japan.

All patients were in active antitumor treatment.

This was a retrospective study.

• The Common Terminology Criteria for Adverse Events was used.
• Complete response (CR) was defined as complete suppression of vomiting and no rescue medication.
• Food intake was measured.
• Chemotherapy completion rate was monitored.

• The CR for control of vomiting was 96% in controls and 100% in the group that was given aprepitant. 
• Complete suppression of nausea was reported as 89% among controls and 96% in the aprepitant group (p = 0.0043). 
• The amount of food intake was greater in the aprepitant group. 
• Completion of planned chemotherapy was higher in the aprepitant group (73.3% versus 88.2%, p = 0.042).

The addition of aprepitant to standard antiemtic therapy in patients receiving moderately emetogenic chemotherapy was associated with less nausea and vomiting and better food intake.

• The study had a small sample of fewer than 100 patients.
• A risk of bias exists because no control group, blinding, or random assignment was included.
• Rescue medications used were not described.  
• Whether differences in completion of the planned chemotherapy were related to chemotherapy-induced nausea and vomiting (CINV) or other toxicities was not clear.

Neurokinin 1 (NK1) receptor antagonists have been recommended for highly emetogenic chemotherapy (HEC); however, less evidence is available regarding their use with moderately emetogenic regimens (MEC).  This study suggests that the addition of NK1 to MEC is beneficial for reduction of CINV in this group of patients. Nurses can advocate for maximal symptom control to prevent CINV, one of the most severe adverse effects of chemotherapy.

Whether prognostic factors in nausea and vomiting can be used to identify a low-risk group for whom ondansetron plus dexamethasone alone would provide a high level of protection (defined as 80% or less of no emesis) and to evaluate the impact of the neurokinin 1 (NK1) receptor antagonist aprepitant on chemotherapy-induced nausea and vomiting (CINV), regardless of the antiemetic risk 

• The study reported on 866 patients.
• Mean age was 53.1 years.
• The sample was 99.5% female and 0.5% male.
• All patients had been diagnosed with breast cancer, and 99% of the sample was receiving anthrocycline-based chemotherapy.
• To be included in the study, patients had to provide Informed consent, be naïve to emetogenic chemotherapy, have a predicted life expectancy of at least four months, and have a Karnofsky score of 60 or greater.

This was a multisite study.

All patients were in active treatment.

This was a phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial evaluating women with breast cancer who were receiving their first anthracycline plus cyclophosphamide-based chemotherapy regimen.

• Patients used diaries to record occurrence of emetic episodes, use of rescue therapy, and daily ratings of nausea severity using a visual analog scale.
• The authors used logistical regression models to evaluate the impact of the number of risk factors on treatment outcomes.

The most significant factor that had an impact on incidence of vomiting was treatment with aprepitant (p = 0.0001). Age over 55 years (p = 0.006), alcohol use (p = 0.005), and no history of morning sickness (p = 0.0007) were all associated with decreased risk. Motion sickness was not predictive of emesis.

The study's overall recommendation was to use the best available antiemetic regimen from the first cycle to maximize control of CINV and minimize anticipatory nausea and vomiting in subsequent cycles.

Aprepitant use ameliorated the risk of emesis associated with age, alcohol use, and previous history of morning sickness. 

The study only looked at patients with breast cancer receiving anthrocycline-containing chemotherapy regimens with cyclophosphamide. Only two men were included in the study. The results are not generalizable to all patients with cancer.

Expansion of this study to include all cancer types and evaluate emetogenic potential with consideration of risk factors would be useful. This study demonstrates the importance of risk analysis when choosing antiemetics, but it also shows the clear benefit of using aprepitant in this group.

To assess the efficacy and safety of a single dose of fosaprepitant (150 mg IV) combined with a 5-HT₃ receptor antagonist and a corticosteroid versus a standard 5-HT₃ receptor antagonist and a corticosteroid for the prevention of chemotherapy-induced nausea and vomiting (CINV)

Patients received fosaprepitant versus placebo with ondansetron plus dexamethasone on day 1. Oral ondansetron and dexamethasone were used. Patients who received fosaprepitant on day 1 received placebo medication on days 2–3, while those in the control group received ondansetron every 12 hours. Rescue medications were allowed at the discretion of the provider.

• N = 1,000   
• MEAN AGE = 59.6 years
• MALES: 40.6% in experimental group, 41.2% in standard group; FEMALES: 59.4% (experimental group), 58.8% (standard group)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Multiple malignancies
• OTHER KEY SAMPLE CHARACTERISTICS: Patients who were treatment naïve and receiving moderately emetogenic chemotherapy (MEC)

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Conducted at 125 sites across 30 countries

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care, palliative care 

• Randomized, double-blind, placebo-controlled trial

• Nausea and the Functional Living Index-Emesis (FLIE)—the research does not discuss how this was administered.  
• Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
• Events of clinical interest (reactions, thrombophlebitis, infusion-site pain, erythema, and induration) were recorded.

Complete response (CR) in delayed phase met superiority for the experimental fosaprepitant group versus the control group (p < 0.001) and for the overall phase (p < 0.001). Both regimens had high CR in the acute phase with no significant differences (p = 0.184). Fosaprepitant was superior to the control group for no vomiting in the overall phase (p < 0.001) and delayed phase (p < 0.001), and the time to first vomiting (p < 0.001). Fosaprepitant group had significantly more “no significant nausea” patients than the control group (p = 0.026).

Fosaprepitant demonstrated superior CR overall to oral ondansetron and dexamethasone alone in MEC regimens. These results are similar to results seen in highly emetogenic chemotherapy. Treatment differences of 0.1% in delayed and overall phases are seen to be clinically meaningful for patients.

• Measurement/methods not well described
• How often instruments were completed is unknown.
• Industry supported trial (Merck & Co, Inc.)
• Several authors are either employed, stockholders, and/or paid consultants of Merck & Co.

Fosaprepitant may be safely used in patients receiving MEC. Further study is warranted.

To evaluate the efficacy aprepitant as an additional antiemetic among individuals who failed to obtain nausea and vomiting relief from 5-HT₃ antagonists and dexamethasone while receiving cisplatin-based chemotherapy

Physician and nurse investigators recorded patients' nausea and vomiting episodes daily while they were hospitalized. If discharged, patients their symptoms daily for up to 6 days.

• The study reported on 257 patients.
• Median age was 62 years with a range of 26–82.
• the sample was 70% male and 30% female.
• Cancer diagnoses were genitourinary (54.6%), gastrointestinal (20.2%), head and neck (13.2%), breast (3.9%), lung (3.5%), and other (6.6%).
• All patients had no prior exposure to cisplatin-based chemotherapy, and 97% of patients were chemotherapy naïve.

The study was conducted at a single inpatient site in Taiwan.

All patients were in active antitumor treatment.

This was a prospective, descriptive study.

• Vomiting was measured on a four-point scale of complete response, major response, minor response, or failure. 
• Nausea was measured on a four-point scale of none, mild, moderate, or severe.
• The acute phase was defined as day 1 of chemotherapy infusion, and the delayed phase was defined as days 2–6.

• In cycle 1, 19% of patients reported acute and delayed nausea and vomiting. 
• In cycle 2, 40 of 49 patients with CINV received aprepitant, and 98% experienced complete protection from acute vomiting, 93% from acute nausea, 65% from delayed vomiting, and 60% from delayed nausea.
• In cycle 3, 35 of 40 patients with CINV received aprepitant, and 100% experienced complete protection from acute vomiting, 100% from acute nausea, 77% from delayed vomiting, and 71% from delayed nausea.
• Adverse events associated with aprepitant for each cycle were hiccups (n = 5) and constipation (n = 4).

Aprepitant is an effective additional agent for CINV with minimal side effects; however, the medication should not routinely be used because only a small percentage of patients need an additional antiemetic.

• A risk of bias exists because no control group, blinding, or random assignment was used in this study. For example, while patients were hospitalized, the investigators collected their own data and, when patients were discharged, patients' providers were asking for the data.
• Key sample group differences could have influenced results.
• Measurement and methods were not well described, and measurement validity and reliability were questionable.
• Findings are not generalizable to other populations. The sample was primarily patients who were chemotherapy naïve, which may have influenced the overall rates of CINV.
• Although categories remained consistent for the measurement of nausea and vomiting, consistency in data collection (e.g., time of day), which may have influenced results, was not described. 
• Validity and reliability of the measurements was not described, and inter-rater evaluation was not performed to ensure consistency of measurement. 
• Delayed nausea and vomiting was defined as days 2–6 after chemotherapy, which is not typical timing for a delayed measurement.
• The generalizability of these findings is limited because it was a single institution study; furthermore, these findings are generalizable only to patients receiving cisplatin-based chemotherapy.
• Adverse events were reported in the results but the authors did not state how this information was obtained.

Nurses need to assess for CINV throughout chemotherapy and advocate for additional antiemetic therapy when needed. Aprepitant is an effective additional antiemetic medication for relief of CINV among patients receiving cisplatin-based chemotherapy.

To evaluate the efficacy of aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions in patients with gynecologic cancer who are receiving paclitaxel and carboplatin

All patients received either 1 mg of granisetron or 4 mg of ondansetron and 20 mg of dexamethasone IV on day 1. Patients in the placebo group received a placebo on days 1–3, and patients in the aprepitant group received 125 mg of aprepitant PO on day 1 and 80 mg of aprepitant PO on days 2 and 3.

• N = 297   
• MEAN AGE = 59 years
• AGE RANGE = 24–79 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Ovarian cancer, endometrial cancer, cervical cancer, peritoneal cancer, tubal cancer

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Japan

PHASE OF CARE: Active antitumor treatment

This was a randomized, double-blind, placebo-controlled study.

Hypersensitivity reactions were graded using the Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. From days 1–5, patients recorded the highest level of nausea severity each day (absent, mild, moderate, severe), number of episodes of emesis, and time of each episode. Patients also recorded the date and time of each rescue antiemetic and responses to questions about appetite. Adverse effects were graded using CTCAE, version 4.0.

The rates of hypersensitivity reactions were similar in the control and test groups. Patients who received aprepitant, when compared to the control group, had higher rates of no vomiting in the overall phase and during the acute and delayed phases (p < 0.0001, p < 0.0001, p = 0.0495). The rate of \"no significant nausea\" was also significantly higher in the aprepitant group in the overall phase and delayed phase (p = 0.0143, p = 0.0274). Complete response (no vomiting and no rescue medication) was significantly higher in the aprepitant group in the overall and delayed phases (p = 0.0073, p = 0.0072).

Aprepitant is beneficial when used in combination with a 5-HT₃ receptor antagonist and dexamethasone in patients with gynecologic cancer receiving paclitaxel and carboplatin.

Aprepitant may be given as CINV prophylaxis for patients receiving paclitaxel and carboplatin for the treatment of gynecologic cancer.

To compare the efficacy of an aprepitant-based antiemetic regimen and a standard antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in Chinese patients with breast cancer receiving a first cycle of moderately emetogenic chemotherapy (MEC) and to compare patient-reported quality of life (QOL) among all patients

Chemotherapy naïve patients with breast cancer receiving adjuvant AC chemotherapy were assigned to either an aprepitant-based regimen (day 1: 125 mg aprepitant, 8 mg ondansetron, and 12 mg dexamethasone before chemotherapy and 8 mg ondansetron 8 hours later; days 2-3: 80 mg aprepitant four times a day) or a control arm (day 1: 8 mg ondansetron and 20 mg dexamethasone before chemotherapy and 8 mg ondansetron 8 hours later; days 2-3: 8 mg ondansetron twice daily).

• The sample consisted of 124 participants.
• Mean age (range) for the aprepitant group was 46.5 years (32–66 years) and, for the control group, 48.5 years (26–68 years).
• All of the patients were female (100%).
• Diagnoses were 94% invasive ductal carcinoma, 1.6% invasive lobular carcinoma, and 5% other.
• Cancer stages were 22% stage I, 50% stage II, 18% stage IIIa, and 9% stage IIIb.
• Patients had to be ethnic Chinese females older than 18 years with a life expectancy of four months or more and a Karnofsky score of 60 or more.
• Both groups had slight differences in history of motion sickness and vomiting during pregnancy.

The study was conducted at a single site in China.

All study participants were in active treatment.

This was a randomized, double-blind placebo-controlled study.

• Patient diaries were used to monitor the antiemetic efficacy for 120 hours following chemotherapy infusion. Vomiting episodes and the use of rescue therapy were recorded on days 1–6, and daily nausea ratings (based on a visual analogue scale [VAS]) were recorded on days 2–6.
• The Functional Living Index, an emesis questionnaire (Chinese version), was completed immediately after the patients completed the diary on day 6. It contained nine items in both the nausea and vomiting domains.
• Adverse events were collected according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTAE).
• Data on nausea, vomiting, and the use of rescue medication were collected with self-report diaries, and patient QOL assessment was self-administered.

• In the overall timeframe (0–120 hours) in cycle 1, no significant differences in symptoms were found.
• The requirement of rescue medication appeared to be less in the aprepitant group than the control group (11% versus 20%; p = 0.06).
• No significant difference was found in the median time to first vomiting and nausea domain.
• Both treatment arms were generally well tolerated.

The addition of aprepitant to ondansetron and dexamethasone for CINV did not have a definitive superiority over the existing regimen in Chinese patients with breast cancer; however the addition of aprepitant reduced the requirement of rescue medication and resulted in significantly better QOL.

• Cultural and traditional Chinese medicine influences may have influenced the study outcomes.
• No reporting was given on of how often patients needed to take the rescue therapy, metoclopramide, which may have influenced outcomes.
• Limited generalizability of study findings exists because of the homogenous sample population.
• The standard “control” regimen only included dexamethasone on day 1.

The addition of aprepitant to ondansetron and dexamethasone for CINV in Chinese patients with breast cancer receiving MEC may have some effect in improving QOL and reducing the requirement for rescue medication.

To characterize the antiemetic treatment response of aprepitant when combined with ondansetron and dexamethasone compared to ondansetron and dexamethasone alone, in multiple patient populations receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC)

Study participants had been diagnosed with lung, breast, gastrointestinal (GI), and genitourinary (GU) tumor types and were included in four previously completed randomized control trials. Authors selected the articles for review. Inclusion and exclusion criteria were outlined for each study.

All patients were in active antitumor treatment.

The results of the post hoc analysis of the pooled data demonstrated that complete antiemetic responses were observed in a higher proportion of both HEC and MEC treated patients for all tumor types. For HEC treated patients, significant differences were found in GU (61% versus 44.7%, p = 0.001), GI (68% versus 45%, p = 0.013), and lung cancers (73% versus 53%, p = 0.001). In MEC-treated patients, a significant difference was found in breast cancer (54.9% versus 43.9%, p = 0.0001). Complete response (no vomiting and no rescue medications) following MEC ranged from 54.9% in the breast cancer group to 76% in the lung cancer group.

This analysis demonstrates the consistent efficacy of aprepitant as part of an antiemetic regimen across different tumor types and chemotherapy regimens. The authors recommend the use of an antiemetic regimen that includes aprepitant prior to the first cycle, noting that it will prevent anticipatory chemotherapy-induced nausea and vomiting (CINV) in those patients who respond to the preventative measures.

• This was not a systematic review but, rather, a report of four pooled studies examined by post hoc analysis. 
• The sample size for some of the tumor types was small. 
• This article did not address nausea but, instead, focused on vomiting and use of rescue antiemetic medications.
• The studies were believed to be from randomized trials sponsored by Merck to test efficacy of Amend.

Evidence supports the use of aprepitant in combination with other antiemetic medications for patients receiving MEC and HEC. This supports current understanding of multiple pathways leading to CINV.

To review the pathophysiology of cancer-related nausea and vomiting and the research regarding various medications for management of this symptom, as well as similarities and differences among guidelines of various professional groups

Multinational Association of Supportive Care in Cancer (MASCC) guidelines are based on consensus via surveys and a consensus conference.

High emetic risk (e.g., cisplatin, dacarbazine, high-dose cyclophosphamide)

• Acute: Serotonin antagonist plus dexamethasone plus aprepitant
• Delayed: Aprepitant days 2–3 plus dexamethasone day 2–3 or 2–4

Moderate emetic risk (e.g., cyclophosphamide at more than 100 mg/m², anthracyclines, oxaliplatin, carboplatin)

• Acute: Serotonin antagonist plus dexamethasone
• Delayed: Dexamethasone days 2–3
• Patients receiving cyclophosphamide plus an anthracycline should receive acute protection for high emetic risk and delayed emesis protection with aprepitant or dexamethasone days 2–3.

Low emetic risk (e.g., topotecan, gemcitabine, taxanes, capecitabine, trastuzumab)

• Acute: Low-dose dexamethasone
• Delayed: No routine prophylaxis

Minimal emetic risk (e.g., bleomycin, vinca-alkaloids, bevacizumab): No routine prophylaxis

No approach to anticipatory nausea was provided.

New medications are highly effective in prophylaxis of emesis, but prevention of nausea remains challenging.

To provide guidance to clinicians for the prevention and management of chemotherapy-induced nausea and vomiting in patients receiving cancer chemotherapy of varying emetogenic potential

The evidence-based process was not fully described. Specific research was not stated. Literature cited were the antiemetic resource center at www.mascc.org and the Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer 2004 consensus conference, cited in Annals of Oncology 2006, 17, 20–28.

Levels of evidence and grades of recommendation as used by the American Society of Clinical Oncology (ASCO) were applied to specific recommendations and considered by the authors and European Society for Medical Oncology (ESMO) faculty. This was approved by the ESMO guidelines working group.

This reference provides definitions of nausea and vomiting; relative emetogenic potential of oral and IV drugs; recommended drugs, dosing, and schedules for antiemetic drugs; and recommendations for management of nausea and vomiting based on emetogenic potential.

Specific regimens are outlined below. Stated level (I–V) and grade of evidence assessed are shown in parentheses.

• Acute nausea and vomiting
  • High-emetogenic potential: Serotonin antagonists + corticosteroid + aprepitant (I, A)
  • Anthracycline + cyclophosphamide: Serotonin antagonist + dexamethasone + aprepitant (II, A)
  • Moderate potential: Serotonin antagonist + corticosteroid (I, A)
  • Low potential: Single agent such as corticosteroid (III, IV, D)
  • Minimal potential: No prophylaxis (V, D)

• Delayed nausea and vomiting
  • High-emetogenic potential: Corticosteroid + aprepitant (II, A)
  • Anthracycline +cyclophosphamide: Dexamethasone or aprepitant (II, A)
  • Moderate potential: Corticosteroid (I, A) or serotonin antagonist (II, B)
  • Low potential: No routine prophylaxis
  • Minimal potential: No routine prophylaxis

• Specific issue recommendations
  • Multiple-day chemotherapy: As for acute on chemotherapy days and as delayed 1–2 days after chemotherapy
  • Refractory nausea and vomiting: Consider aprepitant if not already used or add dopamine antagonists to serotonin antagonists and corticosteroids (V, D)
  • Anticipatory nausea and vomiting: Lorazepam or similar drugs, behavioral techniques (V, D)
  • High-dose chemotherapy: Corticosteroids, serotonin and dopamine antagonists in full doses (III, C)

• The principal author performed ad hoc advisory board activity for multiple pharmaceutical companies and was conducting research sponsored by Merck.
• The secondary author was a member of advisory boards on palonosetron and aprepitant, had been a sponsored speaker, and had conducted research on casopitant and fosaprepitant.
• Recommended timing of interventions for delayed nausea and vomiting prophylaxis was unclear.
• The authors were not clear if the recommendation was to use these medications prophylactically interventionally for delayed symptoms.
• No discussion was provided regarding dosage titration approaches to individualize management.

• This guideline provides a good reference for classification of chemotherapeutic agents according to emetogenic potential and a good reference for initial dosing of medications used.
• The recommendations are based on patients who are chemotherapy-naïve.
• The recommendations focus on pharmaceutical management, except for consideration of behavioral techniques for anticipatory nausea and vomiting.

This Perugia consensus panel was composed of 10 committees that reported findings to a 23-member expert panel from 10 different countries. The panel determined level of evidence and made changes in 2004 guidelines if evidence supported a greater than 10% increase in benefit. Updates were approved by the European Society of Medical Oncology (ESMO) Guidelines Working Group. All author relationships were reported. The panel used MEDLINE and other databases, which were not specified.

Emetogenicity of agents:

• As new agents are developed, often limited recording of common toxicities is provided in order to accurately reflect emetogenic potential.
• Increased use of oral agents and chronic oral administration creates issues regarding whether emetogenicity is defined by a single dose or a full course, and chronic use has blurred the lines between acute and delayed chemotherapy-induced nausea and vomiting (CINV).
• The authors provided an updated list of chemotherapy agents and levels of emetogenicity. Classification of oral agents was provided on the basis of a full course of treatment.

Prevention of acute CINV:

• Minimal risk: No routine prophylaxis
• Low risk: Day 1—dexamethasone or 5-HT₃ receptor antagonists or dopamine receptor antagonist
• Moderate emetogenic chemotherapy (MEC)
  • With anthracycline: Day 1—5-HT₃ receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—aprepitant
  • Without anthracycline: Day 1—palonosetron + dexamethasone; days 2 and 3—dexamethasone
• Highly emetogenic chemotherapy (HEC): Day 1—5-HT₃ receptor antagonist + dexamethasone + aprepitant or fosaprepitant; days 2 and 3—dexamethasone + aprepitant; day 4—dexamethasone
• Although studies have shown effectiveness of casopitant, the producer discontinued regulatory filings, so this was not recommended for use.
• All 5-HT₃ receptor antagonists were found to show the same efficacy. More studies are needed to determine if palonosetron is more effective with cisplatin-based therapies.

Prevention of delayed CINV:

• Aprepitant should be used to prevent delayed CINV.
• Whether dexamethasone is as effective or if the combination of dexamethasone and aprepitant would be more effective is not known. The optimal dose and duration of dexamethasone is not defined.
• Prevention with multiple-day cisplatin was not clear. Aprepitant + dexamethasone for acute and dexamethasone for delayed CINV was recommended. The possible role of ​neurokinin 1 (NK1) was not clear.

Refractory CINV and rescue:

• Maximally effective prophylaxis should be used.
• The addition of cannabinoids, olanzapine, and nonpharmacologic interventions could be considered.

Prevention of anticipatory CINV:

• The best way to prevent this learned response is maximum effective control of acute and delayed CINV.
• Anticipatory CINV is difficult to control with medication.
• Benzodiazepines are the only drugs identified as effective, but efficacy tends to decrease as chemotherapy continues.

Prevention of CINV with high-dose chemotherapy:

• Complete protection is currently only achieved in a minority of patients.
• Current standard is dexamethasone + 5-HT₃ receptor antagonists.
• Evaluation of the addition of aprepitant is needed.

Radiation-induced nausea and vomiting:

• Risk level and antiemetic guidelines are provided.
• Generally, prophylaxis with 5-HT₃ receptor antagonists + dexamethasone and rescue with 5-HT₃ receptor antagonists are recommended.

Antiemetics in children:

• All pediatric patients receiving MEC or HEC should receive prophylaxis with 5-HT₃ and dexamethasone. Optimal dosing requires further study.
• No studies have evaluated approaches for prevention of anticipatory CINV.
• Metoclopramide, phenothiazines, and cannabinoids have shown only moderate efficacy.

The guidelines provide a clear set of recommendations and review of the relevant evidence strength assessed for various cancer treatment scenarios.

A complete listing of databases used for evidence retrieval was not provided.

Control of emesis has markedly improved in recent years; however, nausea remains a challenge and future research should shift attention to this aspect. Current trials generally define complete response end points that exclude consideration of the experience of nausea rather than vomiting. Trials suggest that some agents are more effective for acute vomiting, others are more effective for delayed vomiting, and some may be more effective for nausea. Identification of these differences and incorporation into the rationale for treatment needs to continue.

Further research is needed in the areas of prevention with high-dose chemotherapy and stem cell support, combined chemotherapy and radiation therapy, and anticipatory nausea and antiemetic use in children. Practitioners need to be aware of the impact of oral therapy and chronic oral chemotherapy treatment on current approaches to antiemetic treatment, timing, and definitions of acute and delayed CINV. Practitioners also need to be aware that current chemotherapy risk determination does not apply to combined radiotherapy and chemotherapy.