Triple Drug Regimen

• FINAL NUMBER STUDIES INCLUDED = 26
• TOTAL PATIENTS INCLUDED IN REVIEW = Not stated
• KEY SAMPLE CHARACTERISTICS: Adults at risk for nausea related to chemotherapy or radiotherapy

PHASE OF CARE: Active antitumor treatment

The strongest evidence suggested that three-drug regimens (5HT3 antagonists plus corticosteroids and aprepitant) with mixed delivery methods (PO plus IV) offered maximal relief of chemotherapy-induced nausea and vomiting (CINV).

• The evidence combined patients receiving chemotherapy and radiotherapy, so the results may not be completely applicable to CINV.
• Many of the studies included in this review had a low strength of evidence in the AHRQ grading system.

The addition of aprepitant to standard antiemetic regimens with mixed PO and IV antiemetics can greatly improve CINV in patients with cancer.

To update the recommendations for the prophylaxis of delayed emesis induced by moderately emetogenic chemotherapy via a systematic review

The database searched was PubMed.

Search keywords were moderately, chemotherapy emesis, casopitant, aprepitant, granisetron, ondansetron, dolasetron, tropisetron, palonosetron antagonists, and dopamine receptor antagonists

Studies were included in the review if they 

• Were randomized, controlled trials (RCTs).
• Described subjects receiving moderately emetogenic chemotherapy (MEC) as defined by the Multinational Association of Supportive Care in Cancer (MASCC).

Papers were excluded if they were not in English.

The number of references retrieved was not provided. The method of study evaluation was the presence of vomiting.

• The final number of studies included in the review was nine RCTs.
• The total sample size was 4,177; however, not all numbers were included. The study sample sizes ranged from 99–1,114 participants.
• All patients were receiving MEC.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability for late effects and survivorship.

• This study of aprepitant and casopitant demonstrated that, when added to a 5-HT₃ receptor antagonist and dexamethasone, a neurokinin 1 (NK1) receptor antagonist reduces the incidence of acute and delayed emesis induced by anthracycline- and cyclophosphamide-based chemotherapy.
• For patients receiving MEC, one dose of palonosetron administered before chemotherapy was more efficacious in reducing the incidence of delayed emesis than a single dose of a 5 -HT₃ receptor antagonist with a shorter half-life.
• Weak evidence suggested that a dopamine receptor antagonist may improve the control of delayed emesis.

• Patients receiving MEC, which is known to be associated with significant incidence of delayed nausea and vomiting, should receive antiemetic prohylaxis for delayed emesis.
• In patients with breast cancer receiving a combination of anthracycline plus cyclophosphamide treated with a combination of aprepitant, a 5-HT₃ receptor antagonist, and dexamethasone to prevent acute nausea and vomiting, aprepitant should be used to prevent delayed nausea and vomiting.
• Multiday oral dexamethasone is the preferred treatment for the prevention of delayed emesis in patients receiving chemotherapy with moderate emetic risk. 
• Insurance concerns continue with 5-HT₃ as well as NK1 receptor agonsists.  Nurses need to consider this when assisting patients with nausea, and they should consider the need for precertification or prior authorization of medications.

STUDY PURPOSE: To identify the best triple drug antiemetic regimen for cisplatin-induced nausea and vomiting

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Not stated

INCLUSION CRITERIA: All were double-blind randomized controlled trials.

EXCLUSION CRITERIA: Not cisplatin-based therapy, no triple-drug regimen used, non-English language

• FINAL NUMBER STUDIES INCLUDED = 10
• TOTAL PATIENTS INCLUDED IN REVIEW = 7,317
• SAMPLE RANGE ACROSS STUDIES: 174–2,322 patients
• KEY SAMPLE CHARACTERISTICS: All were receiving cisplatin-based chemotherapy.

PHASE OF CARE: Active antitumor treatment

Pairwise meta-analysis was done to rank treatments for effectiveness in terms of complete response (CR) rate. Ranking for best results was: (a) netupitant, palonosetron, and dexamethasone (NEPA); (b) fosaprepitant, ondansetron, and dexamethasone; (c) palonosetron and dexamethasone; (d) fosaprepitant, granisetron, and dexamethasone. However, comparisons did not reach statistical significance. NEPA also ranked highest in percentage of cases with no nausea. The regimen of aprepitant, granisetron, and dexamethasone ranked highest in the side effect of constipation. The regimen of rolapitant, ondansetron, and dexamethasone ranked highest for delayed nausea control and fewest side effects. No significant differences existed across regimens in side effects.

Findings suggest that triple drug regimens, including NEPA, may be most effective in chemotherapy-induced nausea and vomiting (CINV) prevention and the prevention of delayed nausea, though actual differences across all triple drug regimens were not statistically significant.

The authors noted that some evidence reveals that the efficacy of various triple drug regimens may depend upon the tumor type rather than the antiemetic regimen. In general, all triple drug antiemetic regimens are shown to be effective for CINV management, and variation across regimens exists regarding their efficacy for nausea and response in the delayed phase, in particular. Further research is needed to identify comparative effectiveness for various regimens with analysis by tumor type as well as type of chemotherapy. In practice, given potential differences in effect, regimens for individual patients should be planned according to individual patient responses and risks.

STUDY PURPOSE: To compare the effects of different regimens of NK₁-based antiemetic treatment for patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC)

TYPE OF STUDY: Meta-analysis and systematic review

TOTAL REFERENCES RETRIEVED: 1,796

• FINAL NUMBER STUDIES INCLUDED = 35 
• TOTAL PATIENTS INCLUDED IN REVIEW = 18, 889
• SAMPLE RANGE ACROSS STUDIES: 16–1438
• KEY SAMPLE CHARACTERISTICS: All were receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) treatment regimens.

PHASE OF CARE: Active antitumor treatment

Regimens using various NK₁s showed equivalent antiemetic effect in the overall, acute, and delayed phases. In patients receiving HEC, almost all triple-drug regimens showed significantly higher complete response rates when compared to duplex antiemetic regimens. In patients with MEC, the only NK₁ that showed better antiemetic effect than duplex regimens was aprepitant. Palonosetron-based regimens did not show any difference from first generation 5-HT₃s for CINV complete response rate. No differences in outcomes were observed with differing doses of dexamethasone as part of a triple-drug regimen.

This analysis provides some key information regarding the specific selection of agents and regimens used for CINV control among patients receiving MEC and HEC. Consistent with other evidence, CINV was best controlled with a triple-drug regimen rather than a duplex regimen. The findings suggest that varied doses of dexamethasone do not reduce efficacy.

No quality evaluation

The findings suggest that a standard triple drug regimen is more effective for CINV control with HEC regimens compared to duplex regimens. The findings also suggest that differences in dexamethasone dosing does not appear to alter antiemetic effectiveness. Regimens with reduced use of corticosteroid may be needed for patients with diabetes or low tolerance for side effects of steroids.

To evaluate the efficacy of aprepitant, ramosetron, and dexamethasone 20 mg on chemotherapy-induced nausea and vomiting (CINV) in women with ovarian cancer receiving paclitaxel/carboplatin

On day 1, one hour before chemotherapy, patients received 125 mg oral aprepitant, 0.6 mg IV ramosetron, and 20 mg IV dexamethasone (over 30 minutes). On days 2 and 3, patients received 80 mg aprepitant. Vomiting episodes and use of rescue therapy were recorded for 120 hours after chemotherapy was administered. A daily Visual Analog Scale was completed on the first five mornings after chemotherapy. Rescue medications were permitted throughout the study, and type of medication was at the treating physicians' discretion.

• N = 85  
• MEDIAN AGE = 55 years (range = 28–88 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Ovarian cancer

• SITE: Single-site    
• SETTING TYPE: Outpatient    
• LOCATION: South Korea

• PHASE OF CARE: Active antitumor treatment

Prospective, nonrandomized trial

• Visual Analog Scale (VAS, 0–100) of nausea
• Number of emetic episodes
• Number of rescue medications
• Complete response (CR, defined as no vomiting or emesis for five days)

98.8% of patients had CR in the acute phase, 89.4% in the delayed phase, and 89.4% overall. Patients over age 55 had a significantly higher rate of CR (97.8%) than those younger than 55 (80%) (p = 0.011). 95.3% of patients experienced no vomiting in the overall phase, and 91.8% took no rescue medications in the overall phase. Overall CR (89.4%) achieved in cycle 1 was maintained in cycles 2–6. Four hundred and sixty cycles were analyzed for adverse events. Results are as follows: ≥ 1 adverse event occurred in 179 (38.9%) cycles, drug-related adverse events occurred in 35 (7.6%) cycles, and serious adverse events occurred in 10 (2.2%) cycles. No patients discontinued therapy due to adverse events.

The combination of aprepitant, ramosetron, and dexamethasone for CINV is highly effective in the acute and delayed phases after chemotherapy administration. CR is achieved by a high number of patients for the six days following chemotherapy.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Findings not generalizable
• Other limitations/explanation: All subjects were women with ovarian cancer.

Nurses can educate patients on the available pharmacologic options to control CINV, including the combination of aprepitant, ramosetron, and dexamethasone.

To assess emetic responses to multiday palonosetron, aprepitant, and low-dose dexamethasone among patients treated with pretransplant regimens for multiple myeloma and lymphoma prior to undergoing stem cell transplantation

Oral aprepitant with IV dexamethasone and palonosetron was administered on days -3, -2, -1 for multiple myeloma and days -7 through -5 for patients with lymphoma. The patients with lymphoma also received IV dexamethasone and palonosetron on days -4 and -3.  Palonosetron was repeated on third post transplant day. Patients with multiple myeloma were given melphalan, and patients with lymphoma received BCNU, etoposide, cytarabine, and melphalan with or without rituximab. Patients with multiple myeloma completed questionnaires on days -2, -1, +3, and +7. Patients with lymphoma completed questionnaires on days -6 through -2 and on days +3 and +7. The Common Terminology Criteria for Adverse Events version 3 wascused to evaluate nonhematologic toxicities.

• N = 18  
• AVERAGE AGE = Multiple myeloma group: 60 years (range = 53–66 years), lymphoma group: 48 years (range = 35–60 years)
• MALES: 61%, FEMALES: 39%
• KEY DISEASE CHARACTERISTICS: Six out of nine patients with multiple myeloma reported using pain medications at time of transplantation.
• OTHER KEY SAMPLE CHARACTERISTICS: Most subjects were Caucasian with Karnofsky Performance statuses greater than 60. 

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: University of Kansas Medical Center

• PHASE OF CARE: Active antitumor treatment

Nonrandomized, prospective, descriptive cohort design

• Emetic response was assessed by daily patient diaries and the MASCC Antiemesis Tool (MAT).
• Nausea was measured by a 10-point Visual Analog Scale (VAS)
• The Osoba modules were modified by removing retching from the nausea module and adding it to the emetic module.  
• The modified Osoba modules were used to assess impact of CINV on overall quality of life.

Complete control (CC) was achieved in the acute phase by 55% of patients with multiple myeloma and 100% of patients with lymphoma for a combined acute phase CC of 78%. In the delayed phase, CC fell to 22% in the multiple myeloma group and 44% in the lymphoma group. In the extended phase, CC fell to 11% and 22%, respectively. No complete emetic response was noted in either group, and no patients experienced more than five emetic episodes with a 24-hour period. They reported no significant nausea in the acute phase although they could not report on nausea in the delayed and extended phases because of missing data. Overall nausea remained a major problem with 78% of all patients developing some level of nausea.

Nausea and vomiting continued to be problematic for both groups in the post-transplant period, and these data were correlated with worsening Osoba scores. This drug combination was safe, feasible, and effective in the acute phase of CINV. However, other strategies are needed to treat patients scheduled for stem cell transplants.

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

The results of this study were not strong enough to influence treatment protocols. However, the study did underscore the need to assess patients receiving stem cell transplantations for at least a week for CINV.

To evaluate the efficacy and safety of aprepitant in combination with palonsetron and dexamethasone in patients receiving three-day cisplatin-based chemotherapy

• Patients received three-day cisplatin-based chemotherapy and had never been treated with aprepitant. 
• All patients received the same antiemetic regimen of aprepitant 125 mg orally before chemotherapy on day 1 and 80 mg orally once daily on the following two days. 
• Palonosetron was given on days 1 and 3, and dexamethasone was given on days 1, 2, and 3. 
• The study physician evaluated efficacy and safety daily for seven days.  
• Patients were evaluated over multiple cycles of chemotherapy if applicable.

• The study consisted of 41 patients receiving a total of 89 cycles of chemotherapy.
• The median age of participants was 52.8 years (range = 21-74 years).
• Twenty-four patients (59%) were male, and 17 (41%) were female.
• Diagnoses were lung (32), nasopharyngeal (3), testicular (2), esophagus (2), stomach (1), and oropharyngeal (1).
• Eight of the patients were chemotherapy-naïve; 27 patients had a history of smoking, 16 had a history of drinking, 11 had a history of motion sickness, and 12 had a history of morning sickness.

This was a single-site study conducted in Guangzhou, China.

All patients were in active treatment.

This was a prospective, nonrandomized study.

Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute, version 3.0, was used to assess nausea and safety.

• Findings indicated that 17% of patients had no nausea, 54% had grade 1 nausea, and 29% had grade 2 nausea. 
• With regard to vomiting, 63% had no vomiting in the acute phase, 78% had no vomiting in the delayed phase, and 58.5% had no vomiting overall. The number of patients reporting no vomiting decreased from 85% on day 1 of chemotherapy to 65% on day 3. 
• The most common side effects were hiccups (37%), fatigue (17%), headache (15%), and constipation (12%).  No adverse events were grade 2 or more. No cumulative toxicities from multiple chemotherapy cycles were reported.

Triple antiemetic medications of aprepitant, palonosetron, and dexamethasone are safe and effective for multiple-day chemotherapy to prevent vomiting.  The antiemetic efficacy is maintained during multiple chemotherapy cycles. The regimen was not as effective in preventing nausea.

• This study had a small sample of fewer than 100 participants.
• No control group was included. 
• The study was conducted at a single institution. 
• This was a nonrandomized study. 
• Descriptions of how the variables were measured were poor. For example, no information was provided on how vomiting was monitored and recorded.

Using the combination of aprepitant, palonosetron, and dexamethasone is effective in decreasing the incidence of chemotherapy-induced nausea and vomiting (CINV) in multiple-day chemotherapy regimens with low incidence of toxicity. Control of the symptom of nausea remains problematic.

To determine the efficacy and safety of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor (TGCT)

Male patients being treated with cisplatin-based therapy for TGCT received a three-drug antiemetic regimen. The antiemetic therapy consisted of palonosetron 0.75 mg on day 1; aprepitant 125 mg on day 1 and 80 mg on days 2–5; and dexamethasone 12 mg on day 1 and 9 mg on days 2–8. Patients were given a diary to complete from 0–216 hours after the start of chemotherapy for a maximum of three consecutive chemotherapy courses.

• N = 30  
• MEAN AGE = 33.9 years
• MALES: 100%
• KEY DISEASE CHARACTERISTICS: TGCT, chemotherapy-naive
• OTHER KEY SAMPLE CHARACTERISTICS: All patients receiving a five-day, cisplatin-containing treatment regimen

• SITE: Single-site    
• SETTING TYPE: Outpatient    
• LOCATION: Nine hospitals in Japan

• PHASE OF CARE: Active antitumor treatment

Open-label, single-arm, multi-center prospective trial

Patients were given a diary to record nausea and vomiting events. The severity of the nausea was graded using the Common Terminology Criteria for Adverse Events (CTCAE).

This three-drug regimen resulted in a 90% complete response (CR) rate in the first course of therapy. In the second and third courses of treatment, CR rates of 82.1% and 78.3 %, respectively, were achieved. No vomiting was reported in the first course of treatment. There were six episodes of vomiting reported by three different patients during the second course of treatment in the delayed phase. One patient reported two episodes of vomiting in the acute phase, and an additional patient reported three episodes in the delayed phase of the third course.

This three-drug regimen is effective in controlling nausea and vomiting in this patient population. There is still data needed to better identify the appropriate dose and duration of dexamethasone and to determine the efficacy and tolerability of the regimen when using palonosetron 0.25 mg versus the 0.75 mg that was used in this study.

• Small sample (< 30)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)
• Different approved dose of palonosetron in Japan versus United States limits the applicability of the findings.

This small study provides continued evidence regarding the efficacy and tolerability of this three-drug combination approach with five-day cisplatin regimens. There is still data needed about the appropriate duration and dose of dexamethasone in this approach. A higher dose of palonosetron was used. There will need to be future studies assess the 0.25 mg dose used in the United States.

To evaluate the effectiveness of aprepitant, dexamethasone, and palonosetron in the prevention of nausea and vomiting in patients with breast cancer receiving an initial cycle of doxorubicin and cyclophosphamide (AC)

Patients were asked to keep a diary recording the number and timing of any episodes of vomiting or retching, frequency and timing of use of rescue antiemetics, degree of nausea using a four-point categorical scale, and notation of other medications taken. The patients were called by a study coordinator at 24, 48, 72, 96, and 120 hours after starting chemotherapy to assist the patients in the completion of the diary.

• The study consisted of 36 participants.
• The median age of patients was 53 years.
• All of the patients were female with a diagnosis of breast cancer.
• All of the patients were chemotherapy naïve with Karnofsky performance statuses of 60 or more
• Patients were scheduled to receive their first course of chemotherapy with cyclophosphamide (≥ 500 mg/m²) and doxorubicin (60 mg/m²) .

The study was conducted at a single outpatient setting at Lahey Clinic Medical Center in Burlington, MA.

• All patients were in active treatment.
• The study has clinical application to elderly care.

This was a prospective trial.

Patients recorded in diaries the number and timing of any episodes of vomiting or retching, frequency and timing of rescue antiemetic use, and degree of nausea using a four-point categorical scale.

• Eighteen patients (50%) achieved a complete response during the 120-hour study period.
• Acute (≤ 24 hours) and delayed (24–120 hours) complete response rates were 81% and 61%, respectively.
• No emesis rates for the acute, delayed, and overall study periods were 97%, 94%, and 92%, respectively.

The aprepitant, dexamethasone, and palonosetron appeared to be well tolerated and effective at preventing emesis, with no emesis rates ranging from 92%–97% during the study period. However, 50% of patients still developed some degree of nausea and took antiemetic rescue medications, highlighting the need for  further improvement in chemotherapy-induced nausea and vomiting (CINV) control in patients with breast cancer receiving AC.

• The study had a small sample size of fewer than 100 patients.
• Current guidelines suggest the use of a 5-HT₃ receptor antagonist, dexamethasone, and aprepitant prior to treatment with an anthracycline and cyclophosphamide (AC) and then aprepitant alone on days 2 and 3. According to the large, phase-III trial that supports the use of the current suggested premedication regimen, approximately half of the patients will achieve a complete response (CR). This study yielded a 50% CR rate. The authors did try to compare the regimen in this study to the regimen used in the phase-III trial. To more fully assess the combinations, a large, randomized controlled trial would need to be done to compare the regimens.

AC is a common treatment regimen for breast cancer and is highly emetogenic. Further studies exploring ways to better control nausea in this patient population, including the use of nonpharmacologic strategies, are needed.

To assess the safety and efficacy of aprepitant for chemotherapy-induced nausea and vomiting (CINV) prophylaxis with highly emetogenic cheomtherapy (HEC) or moderately emetogenic chemotherapy (MEC) regimens

Patients received 125 mg aprepitant on day 1 and 80 mg along with palonosetron and dexamethasone

• N = 75   
• AGE RANGE = 18-71 years
• MALES: 10.3%, FEMALES: 89.7%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Multiple tumor types 
• OTHER KEY SAMPLE CHARACTERISTICS: Sixty percent were receiving HEC therapy.

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

PHASE OF CARE: Active antitumor treatment

Open-label, prospective, observational

• Complete response (CR) defined as no emesis and no use of rescue medicatiton
• Common Terminology Criteria for Adverse Events (CTCAE), version 4

For all regimens, CR rates were 96.8%, 93.7%, and 92% for acute, delayed, and overall phases. Nine percent reported side effects; the most common was hiccoughs.

Triple drug antiemetic prophylaxis was effective to manage CINV in most patients.

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

This study adds to the substantial body of evidence for the efficacy of triple drug antiemetic regimens for the prevention of CINV.

To study the effectiveness of aprepitant as a secondary agent to prevent chemotherapy-induced nausea and vomiting (CINV) in patients with lung cancer for whom cisplatin-induced nausea and vomiting was poorly controlled by a conventional antiemetic regimen of granisetron and dexamethasone

Stage 1 of the study recruited patients receiving cisplatin-based chemotherapy being actively treated for lung cancer. Patients who experienced vomiting of grade 2 or higher and needed rescue antiemetics during their first cycle of chemotherapy (stage 1) were enrolled in stage 2 of the study. During stage 2, patients had oral aprepitant added on day 1 at 125 mg and on days 2 and 3 at 80 mg daily of subsequent chemotherapy cycles. Patients were asked to keep diaries during the first two chemotherapy cycles.

• N = 25 (stage 2)  
• MEDIAN AGE = 61 years (range = 32–71 years)
• MALES: 4, FEMALES: 21
• KEY DISEASE CHARACTERISTICS: All patients were being actively treated for lung cancer.
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were expected to receive at least two cycles of cisplatin-based chemotherapy.

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

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

Two-stage, prospective observation study

• Demographics and patient characteristics were collected. 
• Patients recorded the number and times they experienced vomiting or retching, the frequency and timing of rescue antiemetic use, the severity of CINV, and adverse events or additional medications taken.
• CINV was monitored for acute (0–24 hours) and delayed (25–120 hours) episodes using the Common Terminology Criteria for Adverse Events version 3 grading scale.
• Outcomes were classified as complete response (CR, no emetic episodes or use of rescue therapy) or complete control (CC, no nausea, emetic episodes, or rescue therapy).

Patients who advanced to stage 2 of the study and who had aprepitant added to subsequent chemotherapy regimens reported significantly less acute and delayed nausea and vomiting compared to their first chemotherapy cycle. During the first cycle of chemotherapy, 18.7% of the 132 patients initially recruited required rescue antiemetics, and 52% required intravenous hydration. Of the 25 patients continuing to stage 2 of the study, none required rescue antiemetics or required intravenous hydration. 64% met the criteria for CR, and 28% met the criteria for CC after round two of chemotherapy.

The findings of this study show that aprepitant was effective in preventing acute and delayed nausea after high-dose, cisplatin-based chemotherapy for patients with lung cancer at a high risk of emesis, anticipatory vomiting, and poor CINV control.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Unintended interventions or applicable interventions not described that would influence results
• Findings not generalizable
• Other limitations/explanation: The study was not blinded, the role of anticipatory nausea and vomiting was not considered, and the effects of the addition of aprepitant was only studied in cycle 2. 

Nursing care would benefit from improved strategies to manage CINV for patients with lung cancer receiving chemotherapy. However, the authors of this study acknowledged that larger randomized, controlled studies are needed before recommendations can be made. The assessment of CINV risk during all cycles of chemotherapy is an important aspect of nursing care and patient advocacy. Outcomes for CINV improve when standardized antiemetic guidelines are followed.

To gain evidence regarding which regimen should be used for the management of highly emetogenic chemotherapy (HEC) induced chemotherapy-induced nausea and vomiting (CINV)

Patients were randomly assigned to the order of receiving either palonosteron and dexamethasone (PD) or aprepitant, granisetron, and dexamethasone (AGD) prophylaxis. The PD regimen was 0.75 mg palonosetron and 13.2 mg dexamethasone IV prior to treatment and 8 mg oral dexamethasone 24 and 48 hours later. The AGD regimen was 125 mg oral aprepitant and 3 mg granisetron and 6.6 mg dexamethasone IV before treatment, followed by 80 mg aprepitant and 4 mg dexamethasone at 24 and 48 hours. During the second cycle, patients were crossed over to the alternative regimen. During cycle 1, CINV and the use of rescue antiemetics were evaluated. After crossover, patients were asked which treatment was more effective and preferred. Rescue medications were metoclopramide or prochlorperazine.

• N = 84   
• MEDIAN AGE = 64.5 years
• AGE RANGE = 30–77 years
• MALES: 79.8%, FEMALES: 20.2%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Most patients had stage IV disease
• OTHER KEY SAMPLE CHARACTERISTICS: All patients were chemotherapy naïve and were scheduled to receive two or more cycles of chemotherapy including cisplatin at 60 mg/m² or more.

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

• PHASE OF CARE: Active antitumor treatment

• Randomized crossover trial

• Common Terminology Criteria for Adverse Events (CTCAE)
• Functional Living Index-Emesis (FLIE) questionnaire
• Complete response rate for acute, delayed, and overall phases defined as no emesis and no use of rescue medications

No significant differences existed between treatment regimens for complete response in the acute phase. The complete response (CR) rate was higher in the delayed (p = 0.025) and overall phases (p = 0.025) in the regimen including aprepitant. Less than 40% with either treatment had no nausea. FLIE scores indicating impact on daily life showed that more patients in the aprepitant-based regimen group were not affected by nausea (p = 0.014). Forty-one percent indicated preference for AGD, 19.7% preferred PD, and 39.3% indicated no preference.

Findings suggest that a CINV prophylactic regimen containing an NK1—in this case, aprepitant—was more effective in preventing CINV than a regimen of palonosetron and dexamethasone alone.

• Data collection methods for response rates were not reported.

Findings support the use of a triple drug regimen of a 5HT3, NK1, and dexamethasone for patients receiving HEC. Nausea in the delayed phase continues to be an ongoing problem that is not completely relieved with these regimens. Further research is needed to identify other adjuvant medications to address nausea.

The purpose of this study was to evaluate the efficacy of triplet therapy aprepitant, palonosetron, and dexamethasone in patients receiving carboplatin and paclitaxel (CP) for gynecologic malignancy.

Seventy patients with gynecologic cancer receiving CP were enrolled into a prospective single-arm study with APR (125 mg on day 1, 80 mg on days 2–3), PALO (0.75 mg), and DEX (20 mg) before initiating chemotherapy. The primary endpoint was delayed complete response (CR) rate (i.e., no vomiting and no rescue) at 24–120 hours after chemotherapy administration.

• N = 70   
• AGE: Median age = 57 (range = 37-80) 
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Gynecologic cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve women aged 20 years or older with a confirmed diagnosis of gynecologic malignancy; scheduled to receive CP; Eastern Cooperative Oncology Group performance status of 0–1 and adequate organ function

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: Nara Medical University, Japan

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Elder care

Single-arm phase II

• MASCC Antiemetic Tool was used to evaluate the efficacy of the antiemetic used 
• The primary endpoint was the complete response (CR) rate (no emetic episodes, no rescue medication) in the delayed phase for the first cycle
• The secondary endpoints were CR rates in the acute and overall phases; complete control (CC) rates (no significant nausea, no rescue medication) in the acute, delayed, and overall phases;
• Total control (TC) rates (no emetic episodes, no rescue medication, and no nausea) in the acute, delayed, and overall phases; and adverse events.“Acute” was defined as up to 24 hours after the administration of CP, and “delayed” was defined as the 24–120 hours after administration. 
• No significant nausea was defined as a MASCC Antiemetic Tool score of 3 or lower.

• Seventy patients were enrolled as planned, and all were eligible .
• Delayed CR rate was 97.1% (68/70). CR rates in the acute and overall phases were 100% (70/70) and 97.1% (68/70), respectively. CC rates in the acute, delayed, and overall phases were 98.6% (69/70), 1.4% (64/70), and 91.4% (64/70), respectively. TC rates in the acute, delayed, and overall phases were70% (49/70), 87.1% (61/70), and 65.7% (46/70), respectively.
• Proportions of the incidence of adverse events were 42.5 and 2.5% of constipation grades 1 and 2 (17/40 and 1/40), respectively, and 5% of insomnia grade 1 (2/40). No grade 3 or 4 events were observed.
• In the univariate logistic analysis, there were no significant factors associated with the delayed CR rate.
• Only the factor of age 50 years and younger tended to be associated with a poor delayed CR rate (p = 0.096).

Adding APR to PALO and DEX combination therapy may be promising for patients with gynecologic cancer receiving CP. A phase III study comparing APR, PALO, and DEX to PALO and DEX should be conducted in order to determine if APR in addition to PALO and DEX is efficacious for female patients receiving CP.

• Small sample (< 100)
• Intervention expensive, impractical, or training needs

Encourage more studies to better determine the efficiency of APR in addition to PALO and DEX in this patient population.

To evaluate the efficacy of ramosetron, aprepitant, and dexamethasone in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving cisplatin-based chemotherapy

On day 1, all patients received intravenous 0.6 mg ramosetron and oral 12 mg dexamethasone 30 minutes before chemotherapy, and they received 125 mg aprepitant orally one hour before chemotherapy. On days 2 and 3, patients received 80 mg aprepitant and 8 mg dexamethasone orally in the morning. On day 4, patients only received 8 mg dexamethasone. Patients could take rescue antiemetic medications at any time for vomiting or severe nausea. Antiemetic rescue medications were determined by treating physicians.

• N = 39  
• MEDIAN AGE = 59 years (range = 43–74 years)
• MALES: 75.6%, FEMALES: 24.4%
• KEY DISEASE CHARACTERISTICS: Multiple types of cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Both adjuvant and palliative chemotherapy (primarily palliative)

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

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Palliative care 

Prospective, open-label study

• Complete response (no vomiting and no rescue medications divided into acute phase [0–24 hours], delayed phase [24–120 hours], and overall phase)
• Absolute complete response (no vomiting, no rescue medications, and no nausea) 
• Multinational Association of Supportive Care in Cancer Visual Analog Scale (MASCC VAS)
• Common Toxicity Criteria for Adverse Events (CTCAE) clinical and laboratory adverse events

Complete response (CR) was achieved by 94.9% of patients in the acute phase, 92.3% in the delayed phase, and 92.3% in the overall phase. Absolute CR was achieved by 74.4% in the acute phase, 51.3% in the delayed phase, and 46.2% in the overall phase. The median nausea score during the acute phase was 0 (interquartile range [IQR] 0–1), 0 in the delayed phase (IQR 0–4), and 2 during the overall phase (IQR 0–4). On the VAS, mild nausea was observed in 10% of patients in the acute phase and 13% of patients in the delayed phase. Moderate to severe nausea was observed in 15% of patients in the acute phase and 36% of patients in the delayed phase.

The combination of ramosetron, aprepitant, and dexamethasone is an effective CINV regimen. The overwhelming majority of patients in this study achieved a complete response and experienced no nausea or vomiting in both the acute and delayed phase after chemotherapy.

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

Ramosetron, aprepitant, and dexamethasone is an effective regimen to prevent CINV in patients receiving cisplatin-based therapy. Almost all of the patients were able to achieve a complete response in both the acute and delayed phase after administration of chemotherapy. In this study, the majority of patients were receiving palliative care, therefore this combination of drugs should be considered for palliative care patients.

To assess the role of an neurokinin 1 (NK1) antagonist in antimetic protection in combination with granisetron and dexamethasone in patients receiving high-dose chemotherapy (HDC)

• Patient undergoing multiple days of HDC received granisetron, dexamethasone, and aprepitant during chemotherapy and two days after the completion of chemotherapy.
• Patients were receiving two HDC regimens for at least two days.
  • Melphalan, 70 mg – 100 mg/m², days 1-4, followed by peripheral blood stem cell translant (PBSCT)
  • Paclitaxel, carboplatin, etoposide, and ifosfamide

• This study consisted of 64 patients.
• Patient mean age was 42.3 with a range of 21–67. The percentage of patients younger than age 35 was 18%.
• The study consisted of 52 male patients (81.2%) and 12 female patients (18.8%).
• Patients had been diagnosed with multiple myeloma (MM) (32.8%), thymic cancinoma (6.3%), testicular cancer (35.9%), sarcoma (23.4%), and unknown primary (1.6%).
• Additionally, 9.4% of patients had received previous gastrointestinal (GI) surgery, 7.8% had a history of alcohol abuse, 7.8% had a history of loss of appetite, 6.3% had preexisting nausea, 1.6% had preexisting dizziness, and 14.1% had anxiety.

This study was conducted at a single site at a university hospital in Halle, Germany.

• All patients were in active treatment.
• The study has clinical application for elderly care.

This was a nonrandomized, single-center, observational trial.

• Complete response (CR) was defined as no vomiting and no use of rescue medications in the overall phase (days 1 until 5 days postchemotherapy).
• Nausea and vomiting were recorded daily on a special documentary chart.  All adverse events were recorded to evaluate the tolerability and were graded according to the common terminology criteria.
• All other drugs administered to the patient during the study were recorded.

• For the overall evaluation phase, the primary endpoint of CR was achieved with 40 (63%) patients.
• For the acute phase (during days of HDC), CR was achieved in 53 patients (83%).
• For the delayed phase (days 1 through 5 after the end of HDC) CR was seen in 45 patients (70%).
• Acute nausea was observed in 13 patients (20%), delayed nausea in 24 patients (24%), and overall nausea in 30 patients (47%).
• At the day of retransfusion of stem cells (second day of delayed phase in all HDC groups), the CR rate was 84% and the rate of nausea was 19%.
• The authors concluded that randomized studies may be necessary to add aprepitant to guidelines.

The study demonstrated a good toxicity profile with the addition of aprepitant to the standard antiemetic regimen, with improvement in the prevention of chemotherapy-induced nausea and vomiting (CINV) during multiday, high-dose regimens.

• The study had a small sample with fewer than 100 patients.
• Tools or scales used to measure nausea were not reported.
• A description of how vomiting and nausea were recorded on the special documentation form was not included.
• The authors did not describe how the nurses were trained to use the form and whether it was only recorded by registered nurses.
• Methodological limitations exist with comparing the results with those only from the current literature.

• The addition of aprepitant to standard antiemetic regimens during multiday HDC administration provides additional protection for both acute and delayed CINV.
• The possible reaction between aprepitant and Ifosfamide was within the reported range of induced encephalopathy (26%, range = 10%–30%).

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.

To compare the efficacy of triplet versus doublet antiemetic therapy in patients receiving mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy

Patients were randomized to receive either palonosetron, dexamethasone, and aprepitant, or ondansetron and dexamethasone for chemotherapy-induced nausea and vomiting (CINV) control.

• N = 60
• MEAN AGE = 51 years
• AGE RANGE = 34–70 years
• MALES: 86.6%, FEMALES: 13.4%
• KEY DISEASE CHARACTERISTICS: All patients had head and neck cancer.

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

• PHASE OF CARE: Active antitumor treatment

• Open-label, randomized, prospective trial

• Count of emesis episodes
• Nausea measured on 100 mm visual analog scale (VAS)

Complete response (CR), defined as no vomiting and no rescue medications, was seen in 86.7% of those on triplet therapy and 60% of those on doublet therapy in the acute phase (p < 0.05). In the delayed phase, the CR was 83.3% and 53.3% of those on triplet and doublet therapy respectively (p < 0.05). The authors cited the WHO cost effective and strategic planning guidelines to note that because triplet therapy was more effective, it was cost-effective.

The findings showed that triplet therapy was associated with higher CR rates for CINV prevention than doublet therapy (without an NK1) for patients receiving MEC.

• Small sample (< 100)
• Risk of bias (no blinding)

A growing volume of research exists to compare antiemetic regimens with and without NK1s, likely because of the cost of NK1 medication. This study showed that triplet therapy containing NK1 was effective for the control of CINV in a greater proportion of patients than doublet therapy. CINV is a debilitation side effect of chemotherapy. Nurses can advocate for the use of the interventions that are most effective for symptom control among patients receiving MEC and HEC.

To compare palonosetron-based and first generation 5-HT3 receptor antagonist-based triple drug therapies on chemotherapy-induced nausea and vomiting (CINV) in patients receiving multiday highly emetogenic chemotherapy (HEC)

The study was open to patients who received multiday HEC. Patients were divided into two groups according to the triple-drug antiemetic therapy prescribed by the treating physician. The experimental group received 0.25 mg fixed-dose palonosetron 30 minutes prior to chemotherapy. The control group received any first-generation 5-HT3 receptor antagonist including ondansetron, granisetron, dolasetron, and ramosetron. The first-generation drug was administered at the recommended dose prior to chemotherapy either via IV or orally. All patients received 125 mg oral aprepitant and 12 mg oral dexamethasone on day 1 prior to chemotherapy and received 80 mg oral aprepitant and 8 mg oral or IV dexamethasone on both days 2 and 3 prior to chemotherapy. Either 10 mg IV metoclopramide or 1 mg lorazepam was used for breakthrough CINV. Baseline data and CINV-related data were collected from electronic medical records for 120 hours after chemotherapy began.

• N = 115  
• MEAN AGE = 54.39 years
• MALES: 63.5%, FEMALES: 36.5%
• KEY DISEASE CHARACTERISTICS: 80.9% of patients had solid tumors
• OTHER KEY SAMPLE CHARACTERISTICS: 88.7% of patients received cisplatin-based therapy

• SITE: Single-site    
• SETTING TYPE: Not specified    
• LOCATION: South Korea

• PHASE OF CARE: Active antitumor treatment

Retrospective analysis

• Number of emetic episodes
• Time to first emetic episode
• Severity of nausea (categorized by patient’s physician)
• Use of rescue medication
• Number of days with rescue medications
• Time to first administration of rescue medication

There was no statistically significant difference in complete response rates between the two study groups in any phase (acute phase 0–24 hours [p = .877]; overlap phase 24–120 hours [p = .997]; overall phase 0–120 hours [p = .723]). There was no statistically significant difference in the number of patients who achieved complete control in any phase of the study (acute phase 0–24 hours [p = .862]; overlap phase 24–120 hours [p = .838]; overall phase 0–120 hours [p = .828]). Within this sample, more women than men experienced acute nausea (p = .040) and vomiting (p = .046).

There was no significant difference in the complete response between the two groups in the acute phase (0–24 hours), overlap phase (24–120 hours), or overall phase (0–120 hours).

• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Palonosetron-based triple antiemetic therapy is not more effective than triple therapies that use older 5-HT3 receptor antagonists as part of the regimen. Both regimens should be considered when choosing a triple-drug therapy combination for the prevention and management of CINV.

To evaluate the efficacy of combination antiemetic therapy including 5HT3 receptor antagonists, neurokinin-1 (NK1) receptor antagonists, and dexamethasone for multiple highly emetogenic anticancer agents in patients with bone and soft tissue sarcoma; to compare the effectiveness of single-shot palonosetron and consecutive-day granisetron

A single randomization method was used to assign eligible patients to the palonosetron or granisetron arm. Patients in the palonosetron arm received a palonosetron regimen during the first and third chemotherapy courses and a granisetron regimen the second and fourth courses. Patients in the granisetron arm received granisetron during the first and third courses and palonosetron the second and fourth. All patients received an NK1 receptor antagonist and dexamethasone. Patients receiving the palonosetron regimen were administered 0.75 mg of palonosetron on day 1, and patients receiving the granisetron regimen received 3 mg of granisetron twice daily on days 1–4 and once on day 5. Patients were followed for 10 days during each course for efficacy and safety endpoints. On days 4 and 10, patients responded to a questionnaire about emetic experiences and rescue medication use. Nausea severity was rated from 0–10 according to subjective assessments during the acute and delayed phases.

• N = 24
• MEAN AGE = 43.4 eyars (range = 15–70 years)
• MALES: 50%, FEMALES: 50%
• KEY DISEASE CHARACTERISTICS: Nine patients with osteosarcoma; eight with malignant fibrous histiocytoma; two with leiomyosarcoma; five with other bone or soft tissue sarcomas; receiving highly emetogenic chemotherapy

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

• PHASE OF CARE: Active antitumor treatment

Randomized, single-blinded crossover study

• No specific instruments were listed for the questionnaire (which included number of emetic episodes, use of rescue therapy, nausea severity rated on scale of 0–10, and patient’s preferred regimen).
• Toxicity data were graded according to Common Terminology Criteria for Adverse Events (CTCAE)-adapted toxicity grades.

The overall complete response rate was 66 out of 96 courses (69%) for the acute phase, 38 out of 96 (40%) for the delayed phase, and 33 out of 96 (34%) overall. In the acute phase, complete responses were achieved in 34 out of 48 courses (71%) of the palonosetron regimen and 33 out of 48 courses (69%) of the granisetron regimen. In the delayed phase, complete responses were achieved in 18 courses (38%) of the palonosetron regimen and 20 courses (42%) of the granisetron regimen. There were no statistically significant differences in complete responses for either regimen. Patient preference was recorded for 15 patients. Two patients (13%) preferred palonosetron, three patients (20%) preferred granisetron, and 10 patients (67%) reported that both antiemetic regimens had similar efficacies. The amount of time till the first administration of rescue therapy tended to be longer in the granisetron regimen (5.65 days) compared to palonosetron (5.12 days), but this was not statistically significant (p = 0.115). For palonosetron, regimen rescue therapy was administered in 24 out of 48 courses compared to 17 out of 48 courses for the granisetron regimen. Nausea severity was slightly greater with granisetron (3.58 acute phase, 4.04 delayed) than palonosetron (3.40 acute phase, 3.92 delayed), but this was not statistically significant.

Antiemetic therapy with a three-drug combination was not sufficient to control chemotherapy-induced nausea and vomiting during chemotherapy with multiple highly emetogenic chemotherapy agents for bone and soft tissue sarcoma. However, consecutive-day granisetron was not inferior to single-shot palonosetron for treating chemotherpy-induced nausea and vomiting.

• Small sample (< 30)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Other limitations/explanation: Did not use National Comprehensive Cancer Network-recommended dosage of dexamethasone for highly emetogenic chemotherapy (12 mg on day 1 and 8 mg daily on subsequent days [study used 6.6 mg daily])

This study demonstrated that granisetron given in consecutive-day dosing was not inferior to single-dose palonosetron in triplet therapy for highly emetogenic chemotherapy in patients with bone or soft tissue sarcoma. However, neither combination therapy was adequate to control chemotherapy-induced nausea and vomiting in this population. The development of novel antiemetic agents, or new combination therapies with existing agents such as olanzapine, was recommended. The appropriate dosing of all agents in combination therapy is an important consideration.

To evaluate the antiemetic potential of palonosetron, aprepitant, and dexamethasone in patients with urothelial cancer receiving gemcitabine and cisplatin chemotherapy

Patients received one of two antiemetic regimens, ondansetron or granisetron plus dexamethasone, or palonosetron, aprepitant, and dexamethasone, and over one cycle of chemotherapy were evaluated for chemotherapy-induced nausea and vomiting (CINV) events, rescue medications needed, and food intake.

• N = 122   
• AGE RANGE = 36–82 years
• MEDIAN AGE = 68–70 years
• MALES: 86%, FEMALES: 13.9%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Urothelial cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Patients receiving gemcitabine and cisplatin chemotherapy

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

• PHASE OF CARE: Active antitumor treatment

• Nonrandomized, nonblinded, two-group comparison

• CINV events and anorexia were identified through review of the medical record and rated based on criteria from the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
• The rescue medications used were identified through the review of the medical record.

Patients in the palonosetron, aprepitant, and dexamethasone group had significantly fewer episodes of CINV, anorexia, and rescue medication used compared to the ondansetron or granisetron plus dexamethasone group during the first cycle of chemotherapy (p = 0.012) and overall during chemotherapy (p = 0.0019).

The use of palonosetron plus aprepitant and dexamethasone results in significantly fewer episodes of CINV, anorexia, and rescue medications used in people with urothelial cancer treated with gemcitabine and cisplatin as compared to another commonly used antiemetic regimen, ondansetron or granisetron plus dexamethasone.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Key sample group differences that could influence results
• The two groups were different sizes: ondansetron or granisetron plus dexamethasone (n = 75), and palonosetron, aprepitant, and dexamethasone (n = 47), so the intervention effect may be influenced.

Palonosetron, aprepitant, and dexamethasone may offer more relief from CINV in people being treated with gemcitabine and cisplatin chemotherapy.

To determine the best antiemetic drug combinations for patients receiving moderately emetogenic chemotherapy (MEC)

Chemotherapy-naïve patients with a mix of malignancies receiving MEC were randomized to two treatment groups. Group A received palonosetron plus one day of dexamethasone and group B received fosaprepitant, granisetron, and dexamethasone on day 1. The primary endpoint was complete response (CR, no emesis and no rescue drugs). The secondary endpoints were complete control (CC, no vomiting, no use of rescue drugs, and no more than mild nausea), total control (TC, no nausea), and therapy chosen by patients. CR, CC, and TC were measured in the acute, delayed, and overall phases for five days. Data on chemotherapy-induced nausea and vomiting (CINV) were collected on days 2 and 5 following chemotherapy.

• N = 35
• AGE RANGE = 60 ± 14 years
• MALES: 37%, FEMALES: 63%
• KEY DISEASE CHARACTERISTICS: Solid malignant tumors (majority breast and colon)
• OTHER KEY SAMPLE CHARACTERISTICS: Eastern Cooperative Oncology Group performance statuses of 0, 1, and 2

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

• PHASE OF CARE: Active antitumor treatment

Prospective, single-blinded, randomized crossover study

• Japanese version of the ​Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT)
• Patients recorded the incidence and severity of CINV on days 2 and 5. The severity of nausea was recorded using a Numeric Rating Scale (NRS).

There were no significant differences in the efficacy of the two protocols, and no significant difference in CC or TC during the acute, delayed, or overall period was found. Nausea scores were not reported although their collection was reported. These results suggest that palonosetron and dexamethasone have the same efficacy as fosaprepitant, granisetron, and dexamethasone.

The combination of palonosetron and dexamethasone was as effective as triple-drug antiemetic regimens for patients receiving MEC.

• Small sample (< 100)
• Baseline sample/group differences of import
• Key sample group differences that could influence results
• Other limitations/explanation: CINV data were only collected on days 2 and 5.

The data from this study were not strong enough to affect nursing care; however, because of the similar efficacy of the study drugs, additional studies should be investigated.

To evaluate the effectiveness of a combination of aprepitant, palonosetron, and dexamethasone during the acute and delayed phase of chemotherapy-induced nausea and vomiting (CINV) in patients with lung cancer receiving carboplatin-based, moderately emetogenic chemotherapy or cisplatin-based, highly emetogenic chemotherapy

• Day 1: Aprepitant 125 mg PO, palonosetron 0.75 mg IV, and dexamethasone 3.3 mg IV
• Days 2 and 3: Aprepitant 80 mg PO

• Day 1: Aprepitant 125 mg PO, palonosetron 0.75 mg IV, and dexamethasone 9.9 mg IV
• Days 2 and 3: Aprepitant 80 mg PO and dexamethasone 3.3 mg IV

• N = 133 courses
• MEAN AGE = 65.8 years
• MALES: 77%, FEMALES: 23%
• KEY DISEASE CHARACTERISTICS: Lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Prior experiences of CINV and motion sickness and a history of alcohol consumption

• SITE: Single site    
• SETTING TYPE: Not specified    
• LOCATION: Department of Respiratory Medicine at Sasebo City General Hospital in Japan

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

This study was a prospective trial.

• Patients completed a self-reported questionnaire on the presence of emesis (yes or no), level of nausea (four choices), and status of salvage treatment. This questionnaire was completed on days 1–5.

Patients who received carboplatin or cisplatin-based chemotherapy had CINV, even with prophylaxis including aprepitant, palonosetron, and dexamethasone. There was no difference in CINV rates between patients who received carboplatin and those who received cisplatin-based chemotherapy. This study did not compare this regimen to any other prophylaxis, so it is difficult to draw a conclusion regarding the usefulness of this regimen for CINV prophylaxis for moderately or highly emetogenic chemotherapy.

• Risk of bias (no control group)
• Findings not generalizable
• Other limitations/explanation: This study only included patients with lung cancer who received carboplatin- or cisplatin-based chemotherapy. The prospective study included only one facility. The findings of this study may not be generalizable.

The purpose of this study was to compare outcomes in patients who received aprepitant, azasetron, and dexamethasone versus patients who received a 5-HT₃ receptor antagonist and dexamethasone.

Thirty-seven women received double combination therapy on cycle 1 and then triple combination therapy on cycle 2. Forty-one women received triple combination therapy on cycles 1 and 2. Eighty-five women only received double combination therapy. Double combination therapy consisted of azasetron 10 mg IV and dexamethasone 20 mg IV prior to chemotherapy on day 1. Triple combination therapy consisted of azasetron 10 mg IV, dexamethasone 8 mg IV and aprepitant 125 mg PO prior to chemotherapy on day 1 and then aprepitant 80 mg PO on days 2 and 3.

• N = 163
• AGE: Not stated
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Endometrial cancer (n = 62), cervical cancer (n = 27), ovarian cancer (n = 74)

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

PHASE OF CARE: Active anti-tumor treatment

Prospective, non-randomized trial

Nausea, vomiting, and appetite loss were self-reported and measured on a scale of 0 (not present) to 2 (strongly present). Dietary intake was self-reported and measured on a scale of  0-10 for staple foods and 0-10 for side dishes (score of 20 = perfect score). It is unclear how the investigators collected this data, but it was collected for day 1 and day 5.

For the patients who received double combination therapy on cycle 1 and then triple combination therapy on cycle 2, there was a significant improvement in day 5 (delayed) nausea (p < 0.001), appetite loss (p < 0.0001), and dietary intake (p = 0.04) on cycle 2. There was not a significant difference in vomiting.

When comparing all cycles with double combination therapy to all cycles with triple combination therapy, patients who received double combination therapy for that cycle reported higher nausea (p = 0.002), appetite loss (p = 0.002), and vomiting (p = 0.02) on day 1. There were no significant differences between the two groups on day 5.

This study suggests that triple combination therapy (aprepitant plus dexamethasone plus azasetron) may result in less delayed nausea and less acute nausea, appetite loss, and vomiting, when compared to double combination therapy (dexamethasone plus azasetron). However, there are several limitations to this study.

• Baseline sample/group differences of import–unsure if there are baseline differences
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Measurement validity/reliability questionable

Aprepitant, when added to dexamethasone and azasetron, for patients with gynecological cancers receiving carboplatin and paclitaxel may decrease acute nausea, appetite loss, and vomiting as well as delayed nausea.

To compare the efficacy of triplet versus doublet antiemetic prophylaxis in patients receiving carboplatin-based chemotherapy

Patients were randomized to triple drug or doublet prophylaxis. Both groups received palonosetron 0.75 mg on day 1 and dexamethasone 8 mg on days 1–3. In addition, those randomized to triple drug therapy received aprepitant 125 mg on day 1 and 80 mg on days 2–3.  Physicians recorded the use of rescue therapy.

• N = 80
• KEY SAMPLE CHARACTERISTICS: Patients were chemotherapy naive.

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

PHASE OF CARE: Active antitumor treatment

Open-label, randomized, two-group trial

Complete response rate was defined as no vomiting or rescue therapy.

Aprepitant and control groups showed overall complete response rates of 80.5% and 76.9%, respectively. No significant difference existed between groups. No differences existed in patient reports of nausea.

Doublet antiemetic prophylaxis using palonosetron was as effective as triplet antiemetic treatment for the control of chemotherapy-induced nausea and vomiting (CINV).

• Measurement/methods not well described
• Method of measurement of nausea was not described.  
• Nausea apparently was not considered in the definition of complete control.

The finding suggest that antiemetics with a 5-HT₃ and dexamethasone were as effective as triplet therapy, including an NK₁, for control of CINV in patients receiving carboplatin. The 5-HT₃ used here was palonosetron. A variety of mixed evidence exists regarding the comparative efficacy of doublet versus triplet antiemetics for CINV, as well as the comparative efficacy of dexamethasone-paring regimens and olanzapine-based regimens. Ongoing research and evaluation of comparative effectiveness for various chemotherapy regimens are needed. Multiple factors need to be considered in individualization of antiemetic treatments, and nurses need to evaluate the effectiveness of interventions across cycles to provide the most effective regimen for each patient.

To evaluate whether the antiemetic efficacy of triple combination aprepitant, palonosetron, and dexamethasone could be sustained for up to six cycles of highly emetogenic chemotherapy (HEC) (cisplatin ≥ 50 mg/m²)

To be eligible, patients had to be chemotherapy-naïve adults with lung cancer, have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0–2, and be receiving 4–6 cycles platinum-based therapy (cisplatin ≥ 50 mg/m²).

All eligible patients received 125 mg oral aprepitant, 0.25 mg IV palonosetron, and 20 mg IV dexamethasone before chemotherapy on day 1, and 80 mg oral aprepitant and 4 mg oral or intramuscular dexamethasone on days 2 and 3. Patients recorded all vomiting episodes, any use of rescue medication, and the severity of nausea on 4-point Likert-type scale in diaries for 5 days (0–120 hours) after chemotherapy during all planned cycles.

• The study began with 156 patients, and 118 completed the study.
• The median age of participants was 64 with a range of 33–81.
• The sample was 77% male and 23% female.
• Cancer staging was 74% stage IV and 12% stage IIIb.
• Cisplatin dosing was 46% 75 mg/m²and 41% 80 mg/m².  Patients receiving cisplatin combined with two other drugs represented 87% of the sample.
• Number of chemotherapy cycles planned was 6 cycles (80%) and 4 cycles (18%). The majority (84%) completed their planned cycles.
• Patients were excluded if they had
  • Emesis within 24 hours before starting chemotherapy
  • Noncontrolled metastasis in the brain
  • Previous radiation to the brain, abdomen, or pelvis
  • Concomitant medication with antiemetic activity or known to induce cytochrome P450 enzymes.

The study was conducted at multiple outpatient sites in Italy.

All patients were in active antitumor treatment.

This was a prospective observational study.

• Patients maintained study-specific diaries for 5 days (120 hours) post chemotherapy (up to 6 cycles) using a 4-point Likert-type scale and reporting adverse events. 
• Complete response (CR) was defined as no emetic episodes and no use of rescue therapy during the overall phase of all planned chemotherapy.
• Complete control (CC) was defined as no emesis, no rescue therapy, and no more than mild nausea.
• No grade 3-4 adverse events reported.

• CR rates ranged rom 74.4%-82.0% per cycle, and CC ranged from 74.4%-82.0% per cycle (CI 95%).
• More than 90% of patients were emesis free during all cycles (CI 95%).
• No severe nausea was detected. More than 60% of patients were nausea free during all chemotherapy cycles.
• The authors did not report on acute versus delayed chemotherapy-induced nausea and vomiting (CINV).

The triple combination of aprepitant, palonosetron, and dexamethasone enhanced antiemetic protection during the first cycle and the efficacy was sustained for up to six cycles of cisplatin-based highly emeotgenic chemotherapy (HEC) in patients with lung cancer. The majority (84%) of patients were able to complete their planned number of chemotherapy treatment cycles.

• Study limitations include the risk of bias because the study had no control group, no blinding, and no random assignment.
• The measurement and methods were not well described.
• The measurement validity and reliability was questionable.
• Forty patients were lost to attrition by cycle 6.

Patients with advanced stage lung cancer treated with HEC who are given CINV prophylaxis according to accepted guidelines prior to each cycle maintain the benefit from the CINV prophylaxis through all cycles of treatment. Managing the distress caused by CINV may increase overall quality of life and is an important consideration when treating patients with palliative chemotherapy.

To appraise the effectiveness and safety of a three-drug antiemetic prophylaxis treatment in patients with breast cancer receiving a regimen of ​5-fluorouracil, epirubicin, and cyclophosphamide

All patients received the same antiemetic prophylaxis regimen consisting of aprepitant (oral 125 mg on day 1 and oral 80 mg on days 2 and 3), palonosetron (0.25 mg IV on day 1), and dexamethasone (12 mg IV on day 1). The acute phase was defined as the first 24 hours after chemotherapy, and the delayed phase was defined as days 2–5 following chemotherapy. Complete response (CR) was defined as no vomiting or rescue treatment, and complete protection was defined as no vomiting, no rescue treatment, and no significant nausea. Total control was defined as no vomiting, no rescue treatment, and no nausea. Data were collected for five days following the administration of chemotherapy.

• N = 92  
• MEDIAN AGE = 55 years (range = 37–72 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer

• SITE: Single site    
• SETTING TYPE: Outpatient    
• LOCATION: University of Florence, Largo

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

Cross-sectional, descriptive, single-arm design (design was not specifically mentioned in the article)

• Presence of nausea and vomiting
• Intensity of nausea
• Use of antiemetic drugs
• Additional symptoms

Only cycle 1 data were used in this study. In the acute phase, 89.1% of patients achieved CR, and 81.5% achieved CR in the delayed phase. Complete protection was achieved in 67.4% of patients in the acute phase and 62.0% of patients in the delayed phase. Total control was achieved in 52.2% of patients in the acute phase and 48.9% of patients in the delayed phase.

Prophylaxis consisting of aprepitant, palonosetron, and dexamethasone was safe, effective, and highly recommended in patients receiving anthracycline-based regimens (although it is not classified as a highly emetogenic chemotherapy by all international guidelines). Additional controlled trials are strongly needed to better define the optimal approach in emesis prophylaxis.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described

The majority of patients in this study experienced CR in the acute and delayed phases after chemotherapy administration. Triple-drug therapy was an appropriate intervention for chemotherapy-induced nausea and vomiting prophylaxis in patients with breast cancer receiving anthracycline and cyclophosphamide treatment.

To evaluate the efficacy of triple antiemetic therapy consisting of a 0.75 mg dose of palonosetron, a three-day course of aprepitant, and four days of dexamethasone in the control of chemotherapy-induced nausea and vomiting (CINV) among chemotherapy-naïve patients with lung cancer undergoing highly emetogenic chemotherapy (HEC) regimens

From September 2010 to June 2012, patients received triplet antiemetic therapy (0.75 mg palonosetron IV + 9.9 mg dexamethasone IV + 125 mg of aprepitant orally) on day 1, followed by 80 mg aprepitant on days 2 and 3, and 8 mg dexamethasone on days 2–4.

• N = 67 (later excluded 4, N = 63)              
• MEDIAN AGE: 64 years (range = 36–78 years)
• MALES: 65.7%, FEMALES: 34.3%
• KEY DISEASE CHARACTERISTICS: Chemotherapy-naïve patients with lung cancer scheduled to receive HEC [50 mg/m² or higher dose of cisplatin with concurrent agents (pemetrexed [38.8 %], vinorelbine [32.7 %], gemcitabine [9.0 %], irinotecan [7.5 %], etoposide [7.5 %], and docetaxel [4.5 %])
• OTHER KEY SAMPLE CHARACTERISTICS: No emesis within 24 hours of chemotherapy administration; no symptomatic or suspected brain metastasis; no concomitant radiotherapy; no complications that prohibited dexamethasone use; and no known hypersensitivity to palonosetron, aprepitant, or dexamethasone

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

• PHASE OF CARE: Active antitumor treatment

Single-arm, phase II prospective, multi-centered, longitudinal trial

• CR rates: 81% (overall), 96.8% (acute), and 81.0% (delayed)
• CC rates: 63.5% (overall), 92.1% (acute), and 63.5% (delayed)
• No nausea: 54% (overall), 84.1% (acute), and 54.0% (delayed)
• No significant nausea: 66.7% (overall), 93.8% (acute), and 66.7% (delayed)
• More than half of the patients suffered from appetite loss due to CINV.
• No of adverse events exceeded grade 3 of the Common Terminology Criteria for Adverse Events (CTCAE). Constipation was the most frequent adverse event.

The triplet antiemetic therapy was the most promising regimen in preventing CINV in chemotherapy-naïve patients with lung cancer treated with HEC. The dose-response relationship between palonosetron and aprepitant use needs to be further investigated. However, the experience of nausea by almost half of the patients during the overall phase highlighted the necessity of conducting further investigations to control CINV during the delayed phase.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement validity/reliability questionable
• Findings not generalizable
• No consideration about CINV risk factors such as the explanation not measuring for patients’ history of alcohol consumption; experiencing nausea and vomiting during previous radiotherapy or during pregnancy for female patients; and anxiety level. As the starting of the study was on the first cycle of chemotherapy, the investigators had no chance to determine prior experience of CINV and thus anticipatory nausea and vomiting.

Although adding palonosetron to antiemetic regimens shows improvement more impressively in the acute phase among patients, caution should be taken before interpreting the result of this study as it did not use the most robust research design (of randomization, blinding, placebo control) to detect the drug's efficacy. Constipation is a commonly reported adverse effect in this study, therefore careful management should be considered when palonosetron is used.

To assess the efficacy of triple drug antiemetic prophylaxis for patients receiving moderately emetogenic chemotherapy (MEC)

Patients receiving MEC containing carboplatin were treated with standard triple drug antiemetic therapy of palonosetron, dexamethasone, and aprepitant. Patients were assessed from the beginning of chemotherapy to day 7.

• N = 90   
• MEDIAN AGE = 69 years
• AGE RANGE = 38-82 years
• MALES: 80%, FEMALES: 20%
• KEY DISEASE CHARACTERISTICS: Not provided
• OTHER KEY SAMPLE CHARACTERISTICS: All patients were chemotherapy naïve except for patients with lung cancer receiving tyrosine kinase inhibitors.

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

PHASE OF CARE: Active antitumor treatment

Prospective, observational

• Functional Living Index-Emesis (FLI-E) questionnaire
• 100 mm visual analog scale (VAS) for quality of life and nausea severity
• Common Terminology Criteria for Adverse Events (CTCAE)

No patient vomited within the first 24 hours after chemotherapy. For the delayed and overall phases, completed response was seen in 91.9% of patients. Complete control was seen in 88.9%–97.8% across study days. The lowest rate of complete control was seen on day 3. Men tended to have a high prevalence of complete response and complete control. Hypertension of grade 3, which may have been related to the study drugs, was seen in five patients. Comparison to findings from five other studies showed high complete response rates in the present study.

Triple drug therapy for the prevention of chemotherapy-induced nausea and vomiting (CINV) was shown to be very effective for patients receiving MEC.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• No discussion of any use of rescue medication
• No direct comparison to more standard MEC regimens for antiemesis

Triple antiemetic therapy is recommended in several professional guidelines for highly emetogenic chemotherapy but not for MEC. This study showed better efficacy for CINV control compared to some other studies in CINV management for MEC. Triple drug antiemetic prophylaxis should be considered for patients receiving MEC.

To determine the effectiveness of the addition of a seven-day aprepitant dose to standard triple-drug antiemetic therapy for patients receiving multiday, highly emetogenic chemotherapy (HEC)

Patients were given 125 mg of oral apreipitant on day 1 and 80 mg of apreipitant on days 2-7, a 5-HT₃ on days 1-5, and 8 mg of dexamethasone on 1-8 for each cycle of chemotherapy.  Assessment of efficacy was performed via daily diaries, and analysis of outcomes was done for each chemotherapy cycle.  Rescue medication was lorazepam, metoclopramide, haloperideol, or prochlorperazine.

• The study consisted of 50 participants.
• The median age was 30 with a range of 19-60.
• The sample was 96% male and 4% female.
• All patients had germ cell cancer.

The study was conducted at a single outpatient site in Austalia.

This was a prospective, observational trial.

Patients recorded the number of vomiting episodes and severity of nausea and an 11-point numeric scale in diaries.

• The majority of patients (96%) reported no emesis on day 1, and an average of 82% (95% CI 68-91) had no emesis on days 1-7 in cycle 1.  This was maintained over 4 cycles, with more than 80% reporting no emesis on any day.
• Nausea was not as well controlled. In cycle 1, 71% of patients experienced no nausea on day one but only 27% reported no nausea days 1-7.  The pattern of nausea was similar for all cycles.
• Authors stated that adherence was good, but they did not report actual adherence to the medications.

This study adds to the current evidence for effectiveness of triple-drug antiemetic therapy for patients receiving HEC. The findings suggested that additional days of neurokinin 1 (NK1) may improve outcomes. The findings showed that nausea continues to be poorly controlled with current regimens.

• The sample size was small with fewer than 100 participants.
• A risk of bias exists because no control group, blinding, or random assignment was included in the study design.
• The outcomes reporting was selective.
• The measurement validity and reliability was questionable.
• No information on nausea severity or use of rescue medications was provided, so it was not clear how use may have varied and influenced results. 
• No data was provided on adherence or compliance with diary documentation of symptoms and episodes of vomiting.
• Findings cannot be directly compared to others because this study did not evaluate and define outcomes in terms of complete control per phase of chemotherapy administration.

Triple-drug antiemetic therapy for patients receiving HEC is the current established recommendation for management of chemotherapy-induced nausea and vomiting (CINV).  The addition of further NK1 may improve control. Although current therapies appear to control vomiting well, nausea continues to be a problem for patients.  Ongoing research aimed at nausea control is needed.

To examine the efficacy of palonosetron, dexamethasone, and aprepitant to prevent chemotherapy-induced nausea and vomiting (CINV) in patients with gastric cancer receiving S-1 (oral 5-fluorouracil analog) and cisplatin

• Day 1: 125 mg aprepitant PO 60 minutes prior to chemotherapy, then 9.9 mg dexamethasone IV and 0.75 mg palonosetron IV 30 minutes prior to chemotherapy
• Days 2 and 3: 80 mg aprepitant PO QAM and 8 mg dexamethasone PO BID
• Day 4: 8 mg dexamethasone PO BID
• Throughout observation: Rescue antiemetic as needed
• Vomiting, retching, changes in dietary intake, and impact on quality of life were measured for 120 hours post administration of cisplatin.

• N = 72, 70 patients completed Functional Living Index-Emesis (FLIE) questionnaires   
• AGE = 50–81 years
• MEDIAN AGE = 65 years
• MALES: 80.6%, FEMALES: 19.4%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Gastric cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Sixty-five patients had received previous chemotherapy, and no patients had a history of CINV.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

• This was a prospective, observational, noncomparative study.

Patients with gastric cancer who received S-1 and cisplatin tolerated palonosetron and dexamethasone. When compared to a previous study in a similar population who received aprepitant, granisetron, and dexamethasone, no significant differences existed in the CR rate, complete protection, dietary intake, or quality of life.

• Small sample (< 100)

The CR rate and complete protection were observed in the majority of patients with gastric cancer on S-1 and cisplatin who received antiemetic prophylaxis with palonosetron and dexamethasone. Although CINV did not significantly affect the quality of life in most patients, dietary intake decreased during the five-day observation time.

Evaluate the efficacy of new antiemetic combination (aprepitant, granisetron, and dexamethasone) in gastric cancer patients’ receiving chemotherapy regimen (cisplatin 60 mg/m² and 5-flourouracil analog (S-1) 80 mg/m²) in day 1, aprepitant and dexa on day 2 and 3, and dexa on day 4.

S-1 (80 mg/m²) orally x 2 x 3 weeks of a five-week cycle. Cisplatin 60 mg/m² IV on day 8 of each cycle. Antiemetic regimen: aprepitant 125 mg 1 hour before cisplatin plus dexamethasone 9.9 mg IV plus granisetron 3 mg IV 30 minutes before cisplatin infusion on day 1, oral aprepitant 80 mg x 1 & oral dexamethasone 8 mg bid on days 2 and 3, and oral dexamethasone 8 mg bid on day 4. Observations of the patients done 0-120 hours.

• N = 53   
• AGE: Median = 65 years
• MALES: 90.6%  
• FEMALES: 9.4%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Gastric cancer, chemotherapy naïve, receiving cisplatin and S-1 
• OTHER KEY SAMPLE CHARACTERISTICS: ECOG performance status of 0-2, not experienced ANV 24 hours before chemotherapy, did not received radiotherapy to the abdomen or pelvis before 1 week, no CNS metastasis, with other medical condition that can induce a risk for vomiting

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: 17 institutions of the digestive disease support organization; Japan

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care

Prospective observational non-comparative study

Patient self-report of number and timing of any episodes of vomiting or retching; the degree of nausea using a four-point categorical scale (0, none; 1, mild; 2, moderate; 3, severe, use of rescue therapy (frequency and timing), and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire daily on days 1-5. Safety was assessed by physical examination, toxicity used NCI-CTCAE, version 4.

88.7, 98.1, and 88.7 % achieved complete response (CR) (no emesis, and no rescue antiemetics) in the overall, acute, and delayed phases, respectively. While 67.9, 96.2, and 67.9 % achieved complete protection (CR + no significant nausea). Half of the patients had anorexia, FLIE indicated 79.5% of the patients reported minimal or no impact of CINV on QOL. About half of the patients had some degree of anorexia. 30% of the patients reported decrease volume of diet intake to half and 10% could not consume any food during the delayed phase. Antiemetics therapy was well-tolerated.

Addition of aprepitant to standard antiemetic therapy was effective in patients with gastric cancer undergoing treatment with cisplatin and S-1.

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

CINV incidence with highly emetogenic chemotherapy is a challenge. A combination of a recommended JSCO guidelines of aprepitant, granisetron, and dexamethasone was well tolerated and very effective in preventing CINV for patients with gastric cancer receiving cisplatin.

To evaluate the efficacy of a triple-drug combination (palonosetron + aprepitant + dexamethasone) to prevent acute and delayed emesis after high-dose chemotherapy with BEAM (carmustine + etoposide + cytarabine + melphalan) before hematopoietic stem cell transplantation (HSCT) by comparison with historical control of patients treated with dexamethasone + ondansetron or dexamethasone + palonosetron

Triple drug antiemetic regimen (aprepitant 1 hour before chemotherapy [125 mg on day one and 80 mg on days 2 & 3] + 0.25 mg IV palonosetron 30 minutes before chemotherapy and 20 mg IV dexamtheasone 15 minutes before chemotherapy for day 1 and 12 mg daily for rest of chemotherapy regimen) was compared to data from historical control patients that received 32 mg ondansetron and IV dexamethasone daily during chemotherapy or palonosetron and dexamethasone (dexamethasone given as 20 mg IV day 1 and 12 mg daily for rest of chemotherapy regimen in all cases). Acute phase was defined as the first 24 hours after receiving chemotherapy, and delayed phase was definied as days 2–5.

• The study consisted of 96 participants.
• The age and gender of patients was not provided.
• The study group sample consisted of 54 patients with non-Hodgkin lymphoma and 42 patients with Hodgkin lymphoma for patients receiving “triple drug regimen.” Historical controls were described as “comparable in terms of numbers, age, sex, weight and underlying diseases.\"
• Historical control patients received ondansetron (32 mg IV daily during HDC) or palonosetron (assumed to be daily). Both regimens included dexamethasone.

The study was conducted at a single inpatient setting in Warsaw, Poland.

All patients were in active treatment.

This was a descriptive study with comparison to historical controls.

• Severity of nausea was measured on a 4-point scale with none = no nausea; mild = slight nausea but no disruption to daily activities; moderate = nausea and some disruption to daily activities; and severe = extreme nausea and severe disruption to daily activities. 
• Emetic response rate was evaluated using the following criteria: complete response = no emetic episodes; major response = 1-2 episodes; minor response = 3-5 episodes; and treatment failure = more than 5 episodes.
• Response to study drugs was measured on 4-point scale based on the relief of nausea and vomiting: highly effective, moderately effective, slightly effective, and not effective.

Patients treated with the triple-drug antiemetic combination showed higher response rates than those receiving palonosetron or ondansetron (+ dexamethasone) during both the acute and delayed phases in reduction of chemotherapy-induced nausea and vomiting (CINV).

Drawing conclusions based on the information provided in the study is difficult.

• The sample size was small with fewer than 100 participants.
• The researchers did not use validated tools to measure response.
• The article does not clearly indicate whether the study was observation or self-report. 
• The authors did not provide clear descriptions of the patients in the historical controls (e.g., number of patients, diagnosis, ages, sex). 
• The authors did not describe the statistical analysis process.
• The method of describing the results was confusing and difficult to interpret.

Although the study appeared to support the use of established CINV guidelines established by the National Comprehenaive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO), the data in this study were of questionable significance because of the information provided and poor quality of the study.

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 plus a standard antiemetic regimen (granisetron plus dexamethasone) in preventing CINV for patients with multiple myeloma receiving high-dose chemotherapy and autologous stem-cell transplantation (ASCT)

Patients randomly were assigned to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2–4) plus granisetron (2 mg orally on days 1–4) and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2–3) or a placebo plus granisetron (2 mg orally on days 1–4) and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2–3). High-dose chemotherapy (melphalan 100 mg/m²) was administered on days 1–2, and ASCTs were performed on day 4.

• N = 362
• MEAN AGE = 58.1 years
• MALES: 230 (64%), FEMALES: 132 (36%)
• KEY DISEASE CHARACTERISTICS: Multiple myeloma
• OTHER KEY SAMPLE CHARACTERISTICS: High-dose chemotherapy; receiving ASCT

• SITE: Single site    
• SETTING TYPE: Inpatient  
• LOCATION: Large university hospital in Germany

• PHASE OF CARE: Active antitumor treatment

Prospective, placebo-controlled, randomized, double-blinded, parallel-group, single-center study

• Functional Living Index–Emesis (FLI-E) questionnaire to record quality of life
• Daily diary with a 100 mm Visual Analog Scale (VAS) to record episodes and severity of nausea and vomiting

Patients receiving aprepitant plus standard antiemetic therapy were significantly more likely to achieve complete response (no emesis and no rescue therapy within 120 hours of melphalan administration) (p = 0.0042), were significantly more likely to be without major nausea (p = 0.026) and emesis (p = 0.0036) within 120 hours of melphalan administration, and had a higher quality of life (p < 0.001) compared to the placebo plus standard antiemetic therapy group.

The addition of aprepitant to standard antiemetic therapy resulted in significantly less CINV and a positive effect on quality of life.

The addition of aprepitant to standard antiemetic therapy not only reduced CINV but also improved quality of life for patients receiving ASCT.

To compare the use of a three-drug antiemetic regimen to a two-drug antiemetic regimen in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with non-Hodgkin lymphoma receiving R-CEOP or CEOP, highly emetogenic regimens (HECs)

• N = 108 enrolled, 90 completed the study.  
• AGE = 40.4 years
• MALES: 68.5%, FEMALES: 31.4%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Non-Hodgkin lymphoma
• OTHER KEY SAMPLE CHARACTERISTICS: Treatment with R-CEOP or CEOP

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

PHASE OF CARE: Active antitumor treatment

Prospective, open-label, randomized, comparative clinical trial

• Diaries–patient self-report
• CTCAE, version 4, for vomiting and retching
• VAS for nausea
• FLI-E questionnaires for quality of life

Complete response (CR) was defined as no emesis and no use of rescue medications. 

• Overall study CR: Aprepitant group 77%, control group 56% (p = 0.03)
• CR acute phase: Aprepitant group 92%, control 78% (p = 0.045)
• CR delayed phase: Aprepitant group 82%, control 64% (p = 0.037)
•  Secondary end point–no emesis:  
• Acute phase: Aprepitant group 94%, control 84% (p = 0.153)
• Delayed phase: Aprepitant group 86%, control 64% (p = 0.003)
• Overall study: Aprepitant group 78%, control 60% (p = 0.02)
• No differences for nausea in the acute phase and overall phase between the groups
• In the delayed phase, 73% of the aprepitant group reported no nausea and 50% of the control group (p = 0.2).
• FLI-E scores for CINV with minimal or no effect on quality of life: Aprepitant group 84%, control 64% (p = 0.02)

CR rate was achieved significantly with the addition of aprepitant to a two-drug antiemetic in both the acute and delayed phases. There were significant differences related to no emesis between the groups but no differences in nausea. For patients taking aprepitant, CINV had less affect on quality of life throughout treatment.

• Small sample (< 100)
• Risk of bias (no blinding)

For patients receiving R-CEOP or CEOP for non-Hodgkin lymphoma, a three-drug regimen was more effective in preventing CINV  than a two-drug regimen and was generally well-tolerated.

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 efficacy of the triple therapy of aprepitant, palonosetron, and dexamethasone in patients with gynecological cancer receiving highly emetogenic chemotherapy

Women with gynecological cancer who were receiving highly emetogenic chemotherapy received 125 mg PO aprepitant before chemotherapy on day 1 and 80 mg on days 2 and 3, 0.75 mg of IV palonosetron before chemotherapy on day 1, and 9.9 mg of PO/IV dexamethasone before chemotherapy on day 1 and at 6.6 mg on days 2–4. The primary aim was to evaluate the number of patients with a complete response (CR) overall, which was defined as no vomiting and no use of rescue medication during the entire study period (0–120 hours postchemotherapy). The secondary aims were (1) to evaluate CR in the acute (0–24 hours postchemotherapy) and delayed (24–120 hours postchemotherapy) phases of treatment and (2) to evaluate complete protection (CP) defined as no vomiting, no rescue therapy, and no significant nausea overall and during the acute and delayed phases of treatment.

• N = 96  
• MEDIAN AGE = 55 years (range = 32–75 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Gynecologic cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Patients receiving highly emetogenic chemotherapy that included cisplatin ≥ 50 mg/m².

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

• PHASE OF CARE: Active antitumor treatment

Prospective, multi-center study

No information was provided on the measurement of nausea and vomiting. A Visual Analog Scale (VAS) may have been used, although this was not expressly stated and the range and timing of administration of the VAS was undefined.

For the primary aim, overall CR rate was 54.2 %. For the secondary aim, evaluating the number of patients with CR in the acute and delayed phases of treatment, CR was 87.5% in the acute phase of treatment and 56.3% in the delayed phase of treatment. For the secondary aim evaluating CP overall and during the acute and delayed phases of treatment, CP overall was 44.8%, CP during the acute phase of treatment was 82.3%, and CP during the delayed phase of treatment was 45.8%.

• Small sample (< 100)
• Risk of bias (no control group)
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Findings not generalizable
• Other limitations/explanation: No information was provided as to how the authors assessed nausea and vomiting, and as such we cannot know how valid or reliable the method of assessment was. The findings are only applicable to Japanese gynecological patients at this stage until further testing can take place in a more diverse sample.

CINV is often difficult to control and is especially prevalent in female patients. The combination of aprepitant, palonosetron, and dexamethasone has comparable rates of CR and CP when compared to other antiemetic regimens; however, the population used in this study has been shown to be at greater risk for severe CINV. This should be a recommended antiemetic regimen for gynecological patients receiving highly emetogenic chemotherapy.

To determine the effects of triple-drug therapy on chemotherapy-induced nausea and vomiting (CINV) in patients with head and neck cancer

Thirty men received 53 cycles of chemotherapy, and 11 women 18 cycles of chemotherapy consisting of cisplatin, docetaxel, and ​5-fluorouracil. Patients received concomitant radiation therapy except in the induction phase. Prior to each cycle, patients received fosaprepitant at 150 mg/kg, palonosetron at 0.75 mg/kg, and dexamethasone at 10 mg/kg. They also received dexamethasone at 6.6 mg/kg daily for three days after chemotherapy. Each patient received a diary to record their experiences of nausea and vomiting with each cycle.

• N = 41
• MEAN AGE = 59 years (range = 31–75 years)
• MALES: 73%, FEMALES: 27%
• KEY DISEASE CHARACTERISTICS: Head and neck cancers including laryngeal, oral cavity, nasopharyngeal, mesopharyngeal, and hypopharyngeal among others
• OTHER KEY SAMPLE CHARACTERISTICS: Patients received cisplatin-based regimens.

• SITE: Not stated
• SETTING TYPE: Not specified    
• LOCATION: Tokyo Medical University Hachioji Medical Center in Japan

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

Prospective, quantitative, nonrandomized, nonblinded trial

• A 0–100 mm Visual Analog Scale (VAS) was used to measure nausea (0 = no nausea, ≥ 0 and < 30 = slight nausea, ≥ 30 and < 70 = moderate nausea, ≥ 70 and < 100 = severe nausea, and 100 = very severe nausea).
• Patient diary with multiple choice questions
• Acute phase was day of administration
• The delayed phase was day of administration to day 5

A complete response (CR) was defined as no vomiting and no rescue therapy. In the overall phase, 69% (49 of 71) of courses achieved CR. The rate of no vomiting in the overall phase was 90.1%. Nausea in acute phase was reported as no nausea or slight nausea in 91.5% of patients. 87.3% of patients experienced no changes in or slightly reduced food intake, and 85.9% of patients reported good or relatively good general condition in the acute phase. In the delayed phase, no nausea to slight nausea was reported in 56.3% of patients, and 43.7% reported no changes in or slightly reduced food intake. 53.5% reported good to relatively good general condition.

In the overall phase, the majority of patients achieved a CR and reported no nausea or slight nausea. More patients experienced some nausea during the delayed phase than during the overall phase.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)
• Measurement validity/reliability questionable 
• Findings not generalizable
• Questionable protocol fidelity
• Other limitations/explanation: The diary used to measure outcomes was not validated as a research tool. The findings were not generalizable because of the variation in cisplatin dosing, postoperative status of patients, and doses of radiotherapy.

Triple-drug therapy should be considered during prophylaxis for CINV in patients with head and neck cancer receiving chemotherapy. Although the majority of patients experienced CR during the overall phase, more patients experienced nausea in the delayed phase. Additional interventions to prevent and treat CINV in the delayed phase may be necessary.

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 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.

To evaluate the efficacy of the triple drug combination of palonosetron, aprepitant, and dexamethasone for chemotherapy-induced nausea and vomiting (CINV) prevention

The antiemetic regimen was 0.25 palonosetron IV prior to chemotherapy, 125 mg aprepitant on day 1 and 80 mg on days 2–3, and 20 mg dexamethasone IV on day 1 and 5 mg dexamethasone IV every 12 hours after chemotherapy. Antiemetic rescue of either diphenhydramine or metoclopramide was used as needed. Nausea and vomiting were recorded daily during hospital stay and by patients daily after discharge. Evaluation was done across two cycles.

• N = 69   
• MEDIAN AGE = 61 years
• AGE RANGE = 32–81 years
• MALES: 61%, FEMALES: 30%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All were scheduled to receive at least 50mg/m² cisplatin. Patients had varied tumor types, of which esophageal and genitourinary were most prevalent.
• OTHER KEY SAMPLE CHARACTERISTICS: All were chemotherapy naive.

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

• PHASE OF CARE: Active antitumor treatment

• Observational

• Complete response (CR) defined as no emesis and no rescue
• Nausea reported on four-point scale from none to severe (bedridden because of nausea)

The CR rate was 100% in the acute phase and 96.7% in the delayed phase. During the first cycle, the CR rate of no nausea was 98.6% during the acute phase and 87% in the delayed phase. The CR rate reported was exactly the same in the acute phase for the second cycle, and rates for no nausea were similar to those in cycle 1.

The triple drug antiemetic regimen used here was shown to be effective. The CR rates reported here are higher than seen in other studies, and during the acute phase, dexamethasone was given IV rather than PO, as done in most outpatient studies.

• Small sample (< 100)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement validity/reliability questionable
• Nausea rating and timing not well described

This study aligns with a significant volume of evidence showing the effectiveness of a standard triple drug regimen for CINV prophylaxis in patients receiving highly emetogenic chemotherapy.

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.

RESOURCE TYPE: Evidence-based guideline

Not provided

Nothing has been listed regarding the updated antiemetic guidelines and the used databases.

Nurses should know about pharmaceutical antiemetics advancement, assess patients' nausea and vomiting, and discuss the efficacy of the antiemetics with physicians if it is not within the recommended guidelines. Although some differences across guidelines exist, evidence and most guidelines support triplet therapy for HEC. It is unclear in these guidelines why multiday HEC recommendations do not include an NK₁.

Table of antiemetic recommendations and strength of evidence of recommendations

1. Children ≥ 12 years, high emetogenicity, no known interaction with aprepitant-ondansetron or granisetron and dexamethasone and aprepitant, if interaction with aprepitant–ondansetron or granisetron and dexamethasone 
2. Children < 12 years, high emetogenicity: Ondansetron or granisetron and dexamethasone
3. No age restriction, moderate emetogenicity: Ondansetron or granisetron and dexamethasone
4. No age restriction, low emetogenicity: Ondansetron or granisetron
5. No age restriction,  minimal emetogenic risk: No routine prophylaxis
6. Aprepitant should be restricted to children 12 years of age and older who are about to receive highly emetogenic chemotherapy, which is not known to interact with aprepitant. There is no evidence to support the safe and effective use of aprepitant in younger children.
7. Aprepitant dose recommendations: Day 1, 125 mg PO x 1; Days 2 and 3, 80 mg PO once daily
8. Chlorpromazine dose recommendations: 0.5 mg/kg/dose IV q6h
9. Dexamethasone dose recommendations: ≤ 0.6 m2, 2 mg/dose IV/PO q12h; > 0.6 m2, 4 mg/dose IV/PO q12h. If given concurrently with aprepitant, reduce dexamethasone dose by half. 
10. Granisetron dose recommendations: High emetogenicity, 40 mcg/kg/dose IV as a single daily dose; moderate emetogenicity, 40 mcg/kg/dose IV as a single daily dose; low emetogenicity, 40 mcg/kg/dose IV as a single daily dose 
11. Metoclopramide dose recommendations: Moderate emetogenicity, 1 mg/kg/dose IV pretherapy x 1 and then 0.0375 mg/kg/dose PO q6h. Give diphenhydramine or benztropine concurrently. 
12. Ondansetron dose recommendations: High emetogenicity, 5 mg/m2/dose (0.15 mg/kg/dose) IV/PO pretherapy x 1 and then q8h; moderate emetogenicity, 5 mg/m2/dose (0.15 mg/kg/dose, maximum 8 mg/dose) IV/PO pre-therapy x 1 and then q12h; low emetogenicity, 10 mg/m2/dose (0.3 mg/kg/dose, maximum 16 mg/dose IV or 24 mg/dose PO) pretherapy x 1   

Limited evidence exists for the prevention of CINV in pediatric populations making conclusions and guidelines difficult to establish.

When managing acute CINV in pediatric patients, nurses can make informed decisions by consulting evidence-based guidelines.

RESOURCE TYPE: Consensus-based guideline

PROCESS OF DEVELOPMENT: A literature search for papers published between January 1, 2009, and January 6, 2015, related to high-dose chemotherapy, multiple-day chemotherapy regimens, and breakthrough nausea and vomiting

DATABASES USED: PubMed

INCLUSION CRITERIA: Clinical trials, systematic reviews, stem cell transplantations (SCTs), patients with germ cell tumors

EXCLUSION CRITERIA: Other studies

PHASE OF CARE: Active antitumor treatment

Few studies related to the prevention of acute and delayed CINV in patients receiving high-dose and multiple-day chemotherapy regimens and for breakthrough nausea and vomiting. Little evidence related to the control of nausea exists.

Aprepitant should be added to two-drug antiemetic regimens in patients receiving high-dose and multiple-day cisplatin regimens to prevent acute and delayed CINV. Olanzapine is recommended for breakthrough CINV.

To update the 2005 Spanish Society of Medical Oncology (SEOM) clinical guidelines for the treatment of chemotherapy-induced emesis and to continue to improve the supportive care of patients with cancer

The Clinical Guideline Working Group, on behalf of the Spanish Society of Medical Oncology (SEOM) Executive Committee, provided expert opinion based on a review of the literature covering patients with cancer receiving chemotherapy.

All patients were in active treatment. This paper has application to antiemetic drugs.

• For highly emetogenic chemotherapy, one-day regimen, the following is recommended.
  • Day 1:  5-HT₃ receptor antagonist (preferably palonosetron); 125 mg oral aprepitant; and 12 mg IV or oral dexamethasone
  • Days 2-3: 80 mg oral aprepitant per day
  • Days 2-4: 4 mg oral dexamethasone every 12 hours
• For moderately emetogenic chemotherapy, one-day regimen, the following is recommended.
  • Day 1:  5-HT₃ receptor antagonist and 8 mg IV or oral dexamethasone
  • Days 2-3: 4 mg oral dexamethasone every 12 hours
• For low-emetogenic chemotherapy, the recommendation is day 1, 12 mg IV or oral dexamethasone or, alternatively, 0.5 mg/kg IV or oral metochlopromide.
• For minimally emetogenic chemotherapy, no prophylactic antiemetics are recommended.
• For multiple-day chemotherapy, the recommendation is day 1, 5-HT₃ receptor antagonist (palonosetron) and dexamethasone.
• For delayed emesis, dexamethasone is recommended.
• For refractory emesis and rescue treatment, metoclopromide, benzodiazepines, and/or phenothiazines, butyrophenones, or olanzapine are recommended.
• For acute and delayed emesis, three recommendations are made.
  • Palonosetron, a second-generation serotonin receptor antagonist, has been shown to be at least equally effective as first-generation antagonists when controlling acute emesis and more effective than first-generation antagonists when controlling delayed emesis.
  • Aprepitant, a neurokinin 1 receptor antagonist, with serotonin receptor antagonists and steroids are recommended.
  • Combining dexamethasone with other antiemetics is more effective at controlling chemotherapy-induced nausea and vomiting (CINV) than using dexamethasone alone. 
• For anticipatory nausea and emesis, use benzodiazepines, such as lorazepam.
• The authors cautioned that the use of metoclopramide as an antiemetic is limited by the presence of serious side effects such as akathisia, extrapyramidal reactions, and dose dependency.
   

Prevention of CINV can be accomplished through pharmacologic interventions, increasing patients' quality of life. The use of 5-HT₃, along with dexamethasone and aprepitant, seems to be the most effective regimen. Although these recommendations are helpful, no insight into cost implications and little discussion of potential side effects of antiemetic treatment were provided. Additionally, the recommendations offered are purely pharmacologic and, thus, only aimed at those with prescriptive authority.

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.

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Active antitumor treatment

One thousand three hundred and thirty articles were initially retrieved, and a final set of 22 were used for the update.

• Triple drug regimen for prevention of acute CINV—high level of evidence and consensus
• Triple drug regimen with dexamethasone on days 2–4 for non-AC regimens—high level of evidence, moderate consensus
• Triple drug regimen for the prevention of acute CINV with AC-based chemotherapy—high level of evidence and high consensus
• Triple drug regimen with aprepitant or dexamethasone on days 2–3 if fosaprepitant, netupitant, or rolapitant was not used on day 1 to prevent delayed CINV with the AC regimen—moderate level of evidence and moderate consensus
• Olanzapine and 5-HT₃ and dexamethasone can be considered—low evidence and low consensus

Very few studies examining olanzapine were included. More evidence is available.

This review provides guidelines regarding prophylaxis for acute and delayed CINV for patients receiving HEC or AC-based chemotherapy. Recommendations are consistent with those of other professional groups. This review does not include the consideration of dexamethasone-sparing regimens and does not include the full range of olanzapine-based regimen evidence.

To update the 1999 American Society of Clinical Oncology (ASCO) guideline for antiemetics in oncology 

The update committee reviewed studies identified through a literature search.

Databases searched were MEDLINE, the National Library of Medicine, and the Cochrane Collaboration Library (1998-Feb. 2006).

Studies were included if they were phase II and III randomized, controlled trials.

The search identified the following studies.

• Systematic reviews and meta-analysis on neurokinin 1 (NK1) receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting (CINV) related to high-dose chemotherapy
• A meta-analysis of randomized trials assessing the efficacy of dexamethasone in controlling CINV
• Three systematic reviews and meta-analyses of 5-hydroxytryptamine 3 (5-HT₃) receptor antagonists

Additional materials provided to the committee were

• Two additional systematic reviews available prepublication from the Cancer Care Ontario Program in Evidence-Based Care
• Consensus statements and guidelines from Multinational Association of Supportive Care in Cancer (MASCC).

• The combination of 5-HT₃ receptor antagonist, dexamethasone, and aprepitant is recommended before highly emetogenic chemotherapy (HEC). This combination is recommended for patients receiving an anthracycline and cychlophosphamide. At equivalent doses for the prevention of acute emesis, 5-HT₃ receptor antagonists have equivalent safety and efficacy. 
• For patients receiving HEC, antiemetic agents of lower therapeutic index are not an appropriate first choice. Agents with lower therapeutic index should be used in patients who are unable to take to a 5-HT₃ receptor antagonist, dexamethasone, and aprepitant because of allergy or side effects or for whom these agents have been ineffective.
• For patients receiving moderately emetogenic chemotherapy (MEC), a combination of a 5-HT₃ receptor antagonist and dexamethasone is recommended.
• In patients receiving cisplatin and all other agents of high emetic risk, the combination of aprepitant and dexamethasone is recommended for the prevention of delayed emesis.
• The combination of a 5-HT₃ receptor antagonist and dexamethasone is no longer a recommendation for the prevention of delayed emesis after HEC.
• The recommendation to lower the dose of dexamethasone when administered as an antiemetic with aprepitant does not apply to corticosteroids for anticancer therapy.

Databases searched were MEDLINE, Cochrane Database of Abstracts of Reviews and Effects, Cochrane Register of Clinical Trials, hand searching from previous systematic reviews, National Guideline Clearinghouse, National Quality Measures Clearinghouse, and Web sites of professional organizations.

Search keywords were extensive and provided in an appendix. 

A panel of nine experts reviewed evidence to identify minimum standards of care. 

This report was part of the RAND Cancer Quality Assessing Symptoms Side Effects and Indicators of Supportive Treatment Project to develop evidence-based tools to evaluate aspects of supportive cancer care practice. The work was supported by a grant from Amgen to RAND.

• Assess for nausea and vomiting at each outpatient visit and within 24 hours of an inpatient visit.
• Evaluate emetogenic risk of every chemotherapy regimen for prevention.
• For highly emetogenic chemotherapy (HEC) and patients with breast cancer on anthracycline with aprepitant, use a three-drug regimen for acute and a two-drug regimen for delayed chemotherapy-induced nausea and vomiting (CINV) prevention.
• For MEC, use 5-HT₃ receptor antagonists and dexamethasone for acute and one of these for delayed CINV prevention.
• For low emetogenic chemotherapy (LEC), use dexamethasone if clinically appropriate.
• Consider electroacupuncture if the technique is available by a capable operator.
• Present alternative treatment options to patients with persistent symptoms within one month in an outpatient setting and within 48 hours in an inpatient setting.

• Minor differences are recommended here in the area of low emetogenic potential compared to some other guidelines, as prophylaxis is suggested here.
• Use of a one-month cutoff for presenting alternatives to people with persistent nausea and vomiting seems like a long time to wait for better symptom control.
• As noted, many pharmacologic options for antiemesis are available; however, in trials, often substantial proportions of patients still do not achieve symptom control. This points to the continuing need for research in this area, as well as individualization of regimens in clinical practice.
• The authors suggest that results of a 2005 systematic review of the effects and costs of 5-HT₃ receptor antagonists for delayed nausea cast doubt on the cost-effectiveness of this approach.

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Multiple phases of care

One hundred seventy-one articles were retrieved via aPubMed search. No information was provided regarding which articles were selected as relevant to these guidelines, and no discussion of any method used for rating the quality of included evidence exists.

Limited database used. Recommendations are a combination of evidence- and consensus-based suggestions, and most nonpharmacologic interventions are by consensus.

Provides multiple evidence- and consensus-based recommendations for prophylaxis and the management of nausea and vomiting due to chemotherapy or radiation therapy. Recommendations provide a list of chemotherapy agents, including oral agents and categorization as to emetic potential.

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.

RESOURCE TYPE: Consensus-based guideline

This publication has important updates for the nurse regarding the inclusion of oral antineoplastics, radiation emetogenicity, and treatments, and the addition of two new NK₁ receptor antagonists: netupitant and rolapitant. Both require further study before recommendations can be made. Although control of vomiting is markedly improved, nausea remains a challenge.