STUDY PURPOSE: The primary aim of this systematic review was to compare the efficacy and safety of olanzapine with standard antiemetics.

TYPE OF STUDY: Systematic review/meta-analysis

DATABASES USED: MEDLINE, EMBASE, SCOPUS, Cochran Central Register of Controlled Trials

YEARS INCLUDED: Inception to July 15, 2016

INCLUSION CRITERIA: The studies of interest were those that reported either olanzapine as add-on treatment (dexamethasone plus 5-HT₃ antagonist, with or without NK1 antagonist) or olanzapine monotherapy compared to standard treatment. 

EXCLUSION CRITERIA: Duplicate data and non-English language studies.

TOTAL REFERENCES RETRIEVED: 573

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two independent reviewers

FINAL NUMBER STUDIES INCLUDED: 16 studies however, only 9 were pooled for statistical analysis because 1 was an observational study, and 6 clinical trials did not have a comparison group. 

TOTAL PATIENTS INCLUDED IN REVIEW 1,308 (in the 9 studies included in analysis) 

SAMPLE RANGE ACROSS STUDIES: 17-380

KEY SAMPLE CHARACTERISTICS: Multiple tumor types, focused on patients receiving olanzapine.

PHASE OF CARE: Active anti-tumor treatment

The results of the combined studies included in the meta-analysis showed that CR (defined as no emesis and no rescue drugs) was achieved more frequently for delayed CINV (RR = 1.77, 95% CI [1.07, 1.49]) and overall CINV (RR = 1.32; 95% CI [1.08, 1.62]). Olanzapine was not superior to traditional antiemetic therapy for acute CINV. The most frequently occurring adverse events were drowsiness and constipation.

• Limited number of studies included
• High heterogeneity
• Multiple measures used to determine the presence of nausea and vomiting.

Nurses caring for patients with delayed CINV can consider the use of olanzapine, but also must recognize the common occurring drowsiness and constipation with the use of the medication.

Evaluate the safety and efficacy of olanzapine for prevention and rescue of CINV

Medical records of adult patients who received one or more doses of olanzapine for prophylaxis of CINV or treatment of breakthrough CINV were reviewed. Routinely patients are phoned by a pharmacist or research assistant 72 hours after each chemotherapy cycle and an assessment of CINV is documented in the electronic record. Patients were on various chemotherapy and antiemetic regimens.

• N: 170   
• AGE: Median = 51 years (range = 20-85)
• MALES: 16.5%  
• FEMALES: 83.5%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Various tumor types–breast was most common (57%)

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

Retrospective descriptive

Olanzapine was used for breakthrough in 154 patients over 193 treatment cycles. 88.1% of patients reported that it improved nausea, and 21.8% reported it improved vomiting. Twenty patients had been given olanzapine for prophylaxis. Among these 100% reported it improved nausea, and 35% said it improved vomiting. Analysis showed that olanzapine effects were not related to cycle, emetogenicity of the chemotherapy, or antiemetic regimen used. Side effects observed were sedation with continuation of olanzapine (29.5%).

Olanzapine was shown to have been effective as a rescue medication for CINV and may be effective for CINV prophylaxis.

• Baseline sample/group differences of import         
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Other limitations/explanation: No subgroup analysis based on emetogenicity of chemotherapy and antiemetic regimen–these factors could confound results seen. No standard approach to measurement or reporting of CINV symptoms.

Olanzapine can be effective as a rescue medication for CINV and as part of a CINV prophylaxis regimen.

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 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).

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.

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.

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.

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 determine if the addition of a standard dose ginger supplement to a standard antiemetic protocol for moderately to highly emetogenic chemotherapy in patients who were chemotherapy naïve reduced the incidence of CINV and positively affected quality of life. Secondarily, to determine the effect on fatigue and malnutrition in these same study patients

The study group received 1.2 g of ginger extract in addition to standard unspecified antiemetics while the control group was given a placebo. The ginger or placebo was taken in divided doses four times per day for five days starting the day of chemotherapy and four days after for three cycles. Both the ginger and the placebo were in similar capsule forms.

• N = 34   
• AGE: 57
• MALES: 37%  
• FEMALES: 63%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Breast cancer, colon cancer, lymphoma
• OTHER KEY SAMPLE CHARACTERISTICS: Moderately- and highly-emetogenic chemotherapy, Karnofsky score of 60, aged 18 years or older, no known coexisting disease process that causes nausea, and no use of over-the-counter drugs or complementary products.

• SITE: Single site   
• SETTING TYPE: Not specified    
• LOCATION: Brisbane, Australia

PHASE OF CARE: Active anti-tumor treatment

Double blinded, randomized, placebo controlled trial

Functional Living Index Emesis 5 Day Recall (FLIE-5DR), Rhodes Inventory of Nausea, Vomiting, and Retching (INVR), Patient-Generated Subjective Global (FACT-G) assessed nutrition; Functional Assessment of Cancer Therapy-Global (FACT-G) assessed fatigue and QOL; Functional Assessment of Chronic Illness Therapy-Fatigue (FACTIT-F) and an assessment of factors that are known to increase the risk of CINV; symptom assessment using the Edmonton Symptom Assessment Scale to determine any adverse reactions to the ginger/placebo.

The group receiving ginger had better nausea-related QOL and better total CINV-related QOL, less fatigue, and better overall cancer-related QOL, although clinical significance was minimal. There was no significant improvement in CINV occurrence or intensity.

Ginger had some benefits, including better nausea-related quality of life and better total CINV-related quality of life as well as less fatigue. The overall clinical significance of these findings is minimal. No significant improvement in CINV occurrence or intensity was noted.

• Small sample (< 100)
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The group receiving ginger were able to guess they were receiving ginger due to the smell, taste, or reflux and lack of nausea.

There was no indication as to the cost or availability of this ginger extract, which may affect relevance. Also many assessment tools were used which questions validity. This manuscript suggests that ginger may be effective on nausea-related quality of life and fatigue, but a larger study would need to be done to confirm these findings.

To determine the effectiveness of a standardized low-dose ginger supplement in addition to standard antiemetic therapy decreased the incidence of acute and delayed CINV in patients with lung cancer receiving chemotherapy regimens containing cisplatin

Patient randomly allocated to receive ginger root powder taken orally in the dose of 250 mg twice daily for five days starting 30 minutes prior to the start of chemotherapy or identical placebo in addition to standard antiemetics therapy (5HT₃ RA)

• N: 140   
• AGE: 57
• MALES: 71%  
• FEMALES: 29%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Cisplatin-based regimen

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Peking, China

PHASE OF CARE: Active anti-tumor treatment

Randomized, double-blind, placebo controlled

Multinational Association of Supportive Care in Cancer (MASCC) antiemesis tool; Functional Assessment of Cancer Therapy-General (QOL)

There was no significant difference between the intervention group and the control group in the incidence and severity of acute and delayed CINV or quality of life.

The use of a standardized ginger product with standardized antiemetic protocols produced no additional benefit in improving the incidence and severity of CINV in patients with lung cancer receiving chemotherapy regimens containing cisplatin.

• Unintended interventions or applicable interventions not described that would influence results
• Other limitations/explanation: No control for at what point the intervention was initiated in each patients’ chemotherapy cycle so that patients who experienced CINV with previous cycles of chemotherapy are more likely to have CINV. No stratification for the previous experience of CINV. There was some difficulty in blinding because patients could smell the ginger. There also was no control of the among of dietary ginger that patients used during the study. Using a standardized dose of ginger which contains 5% gingerol could affect generalizability.

Although nurses have historically recommended ginger-containing products to relieve nausea, a standardized dose of ginger extract demonstrated no efficacy.