Dexamethasone Sparing Regimen

To determine the effectiveness of dexamethasone against delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC)

This reanalysis consisted of of two cohorts of chemotherapy-naïve patients who were included in two phase 3, randomized, controlled trails investigating a dexamethasone-sparing regimen. Participants were randomized to receive palonosetron (0.25 mg IV) plus dexamethasone (8 mg IV) on day 1 of chemotherapy or the same regimen followed by oral dexamethasone on days 2 and 3 in the MEC and AC regimens. Patients were divided according to the effectiveness of prophylaxis against acute CINV as either high- (experienced neither vomiting nor moderate-to-severe nausea) or low-risk (experienced vomiting or moderate to severe CINV).

• N = 624 (237 received MEC and 380 received AC)  
• MEDIAN AGE RANGE = 50–60 years
• MALES: 50.4%, 45.5%, FEMALES: 49.6%, 54.5%
• KEY DISEASE CHARACTERISTICS: Various primary cancers; breast (380); solid tumors, colorectal, and lung most common
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve patients who were included in two randomized clinical studies investigating a dexamethasone-sparing regimen; received either MEC for a solid tumor or AC-containing chemotherapy for breast cancer

• SITE: Multi-site    
• SETTING TYPE: Outpatient

• PHASE OF CARE: Active antitumor treatment

Secondary analysis of two phase 3, randomized, controlled trials

• Patients used a daily diary for five days. Nausea was assessed using a Visual Analog Scale (VAS) or verbal category scale (no nausea; mild = did not interfere with normal daily life; moderate = interfered with normal daily life; and severe = required the patient to be bedridden).
• The primary efficacy endpoint was the proportion of patients with protection against both vomiting and moderate-to-severe nausea.
• The secondary endpoints were protection against delayed vomiting, protection against delayed moderate-to-severe nausea, duration of delayed symptoms (i.e., number of delayed days phase when patients experienced either vomiting or nausea), and maximum severity of delayed nausea (two or more out of the four days was considered severe). The patient’s satisfaction with antiemetic coverage was assessed on day 6 by a satisfaction VAS (a 100 mm line marked “not at all satisfied” at the left-hand end and “totally satisfied” at the right-hand end). 

• Low-risk patients who received MEC: There were no statistically significant differences between the one-day and three-day regimens.  
• Low-risk patients who received AC: The one-day regimen was significantly less effective than the three-day regimen.
• High-risk patients who received AC: The one-day regimen experienced less control than the three-day regimen (statistically significant for no full protection against chronic CINV and moderate-to-severe nausea alone). This improvement was of greater magnitude. Additional dexamethasone doses improved the protection rates against moderate-to-severe nausea on days 2 (p = 0.083), 3 (p = 0.003), and 4 (p = 0.024) postchemotherapy.
• There were no significant differences in the duration of delayed vomiting or nausea in patients receiving MEC who were at a high or low risk. 
• Acute vomiting was an independent predictor for delayed vomiting (p = 0.045), and acute moderate-to-severe nausea independently predicted delayed nausea (p = 0.0007).

The dexamethasone-sparing regimen (three-day) achieved excellent control of delayed symptoms in patients with no acute CINV and for low-risk patients receiving AC, but it was less effective in patients receiving HEC. Additional dexamethasone doses could be offered selectively.

• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement validity/reliability questionable
• Findings not generalizable
• Other limitations/explanation:  

Patients receiving AC regimens are at an increased risk of experiencing delayed CINV. Some patients might not benefit from a dexamethasone-sparing antiemetic regimen. In this study, the reduction of dexamethasone was less effective for patients at a high risk. Extending the use of dexamethasone could produce adverse effects, so selective dexamethasone prescriptions should be individualized.

To evaluate the efficacy and toxicity of palonosetron (PAL) and dexamethasone (DEX) on day 1 versus 3 of Decadron in patients with gynecologic cancer receiving carboplatin and paclitaxel (TC); to evaluate the efficacy of a one-day versus three-day Decadron regimen (primary endpoint was complete response in the delayed phase)

All patients received an intravenous prophylactic of Decadron at 20 mg within 15 minutes of a PAL dose of 0.75 mg 30 minutes before chemotherapy. Patients in the DEX1 arn received no further Decadron. Patients in the DEX3 arm received Decadron on days 2 and 3 at 8 mg.

• N = 88  
• AVERAGE AGE = 59 years (DEX1), 62 years (DEX3)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Ovarian, cervical, and endometrial cancers
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were receiving paclitaxel and carboplatin. All participants were chemotherapy-naïve.

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

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

Single-institution, prospective, randomized, open-label study

• Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT) for data collection in the first cycle
• The primary endpoint was complete response (CR) defined as no emetic episodes and no rescue medication in the delayed phase of the first cycle.
• The secondary endpoint was CR in the acute and in all phases of chemotherapy-induced nausea and vomiting (CINV). Complete control (CC) defined as no emetic episodes, no use of rescue medications, and no significant nausea defined as a MAT score less than 3.

The authors noted that there was no significant difference between groups in complete response, complete control, or total CINV in the acute and delayed phases. There was no significant difference between groups in the rate of severe nausea. The CR rates in the delayed phase were not statistically different in the three-day group (76.9%) versus the one-day group (69.8%). The use of palonosetron and Decadron appears to be equally effective in treatment of delayed CINV for patients receiving paclitaxel and carboplatin.

The use of Decadron was effective with one-day use compared to three-day use. The side effect profile of steroids is very robust, meaning that fewer days of their usage with good control could improve patients' quality of life.

• Small sample (< 100)
• Baseline sample/group differences of import
• Risk of bias (no control group)
• Risk of bias (no blinding) 
• Risk of bias(sample characteristics)
• Findings not generalizable
• Other limitations/explanation: The homogenous population in Japan would affect drug metabolism.

Based on the results of this study, dexamethasone is effective after only one day of use compared to three days of use. The side effect profile of steroids is robust, so fewer days of their use with adequate CINV control could improve patients' quality of life.

To evaluate chemotherapy-induced nausea and vomiting and adverse events when dexamethasone is eliminated on days 2 and 3 of moderately emetogenic chemotherapy (not including anthracyclines or cyclophosphamide) in combination with palonosetron or another 5HT3 receptor antagonist

The control group received 9.9 mg of dexamethasone IV then 0.75 mg of palonosetron IV before moderately emetogenic chemotherapy then either 8 mg of oral dexamethasone or 6.6 mg of IV dexamethasone on days 2 and 3 of chemotherapy. The treatment group received only 9.9 mg of dexamethasone IV then 0.75 mg of palonosetron IV before moderately emetogenic chemotherapy and no additional prophylactic antiemetics. Rescue antiemetic drugs (excluding dexamethasone, NK1 receptor antagonists, serotonin reuptake inhibitors, and serotonin–norepinephrine reuptake inhibitors) were allowed for both the treatment and control groups. 

• N = 305 (151 in treatment group and 154 in control group)  
• MEAN AGE = 64 years (range = 23–88 years)
• MALES: 173 (57%), FEMALES: 132 (43%)
• KEY DISEASE CHARACTERISTICS: Not specified (inclusion criteria was just malignant tumor)
• OTHER KEY SAMPLE CHARACTERISTICS: Received primarily oxaliplatin-based chemotherapy then irinotecan- and carboplatin-based chemotherapy in a one-day administration; 45% (n = 138) consumed alcohol within 180 days of chemotherapy

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

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

Open-label, noninferiority, randomized, comparative, phase 3 study

• Gastrointestinal symptom diary of number of vomiting events and nausea rated on a four-point Likert scale that was completed by patient every 24 hours for five days after chemotherapy administration.
• Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), but no indication of how the data were gathered was given.
• The exacerbation of symptoms by one grade level or higher compared to baseline was considered an adverse event.
• Complete control and complete response rates in acute and delayed phases 

The noninferiority of the experimental group in regard to complete response rate (acute and delayed phases) and complete control rate (overall, acute, and delayed phases) was demonstrated. There was no difference between the treatment and control groups. A subgroup analysis according to age, sex, and chemotherapy showed no statistical differences in complete response rates. No significant difference in adverse events was found between the treatment and control group with primary events in both groups being constipation, hiccups, anorexia, and elevated alanine transaminase.

There was no difference in chemotherapy-induced nausea and vomiting (acute and delayed) or adverse events between one-day dexamethasone plus palonosetron versus three-day dexamethasone plus palonosetron among patients receiving moderately emetogenic chemotherapy (not including anthracyclines or cyclophosphamide).

• Measurement/methods not well described
• Measurement validity/reliability questionable

The one-day administration of dexamethasone (with palonosetron) was adequate in controlling acute and delayed nausea and vomiting in patients receiving moderately emetogenic chemotherapy when the chemotherapy did not include anthracyclines or cyclophosphamide.

To investigate if the use of a second-generation 5-HT3 receptor antagonist (palonosetron) and a NK1 receptor agonist (aprepitant) could allow a decreased dose of dexamethasone based on nausea and vomiting in patients with breast cancer receiving highly emetogenic chemotherapy

Randomization was to Group A: palonosetron IV plus dexamethasone IV with oral aprepitant on day 1 followed by 8 mg dexamethasone IV and 80 mg aprepitant PO on days 2 and 3. Group B received a placebo instead of dexamethasone on days 2 and 3. Patients were treated in the hospital.

• N = 80   
• MEAN AGE = Group A: 53.5 years, Group B: 52.6 years
• AGE RANGE = 35–76 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Chemotherapy naïve patients with breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Six patients who were included had metastatic disease. Patients were chemotherapy naïve with confirmed breast cancer and older than 19 years. Patients received chemotherapy that included an anthracycline-cyclophosphamide combination.

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

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

Phase-II, single-center, single-blind, placebo-controlled, parallel, randomized trial. Randomization was done on a one to one ratio using a minimization method.

• Self-report diary of nausea and vomiting
• Chart extractions measuring emetic episodes and use of rescue medications
• Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE), version 4.0.
• Patients were classified as having complete control if they used no rescue medications and had no emetic episodes and only mild nausea.
• Complete response (CR) was defined as no emetic episodes and no rescue medication.  
• Nausea was measured as none, mild, moderate, or severe, based on subjective patient reports.

This study showed that complete control and CR revealed equivalent findings in acute and delayed chemotherapy-induced nausea and vomiting (CINV) with 1 day or 3 days of dexamethasone. No statistical differences were noted between both groups. Subgroup analysis looked at patients younger than 50 years. This also did not show any differences.

Using one dose of dexamethasone is feasible in treating CINV.

• Small sample (< 100)
• Measurement validity/reliability questionable
• Findings not generalizable
• Uncertainty as to how patients were hospitalized for the duration of the study, but this certainly added to purer date 
• The researchers relied on self-reports of nausea and vomiting and medical records of emesis, which can lead to underestimation if the nausea and/or vomiting was not documented.

Reducing the use of dexamethasone may be possible in treating CINV prospectively. This may be critical in uncontrolled diabetics.

To examine the proportion of patients who achieve a complete response (no emetic episodes and no rescue medication during the overall phase in each arm) with the treatment

Patients were receiving chemotherapy with carboplatin and paclitaxel for a gynecologic malignancy. All patients received a single IV dose of palonosetron (0.75 mg) on day 1 as a bolus given 30 minutes prior to chemotherapy, dexamethasone at 9.9 mg if patients were on dose-dense chemotherapy, and 20 mg for traditional carboplatin paclitaxel within 45 minutes prior to chemotherapy. Patients were then randomly assigned to two groups. Dexamethasone 8 mg was given on days 2 and 3, but no additional dexamethasone. Rescue medication was allowed. Evaluation of emetic events and nausea were measured using a diary and a 4-stage Likert-type scale. Randomization was done at a registration center with a minimization method with stratification according to institution, cancer type, age, and chemotherapy regimen.

• N = 109   
• AGE = 45–68 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Ovarian, endometrial, or cervical cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Type of regimen, either conventional paclitaxel 175 mg/m²/carboplatin AUC 6 every three weeks or dose dense with carboplatin AUC 6 on day 1, taxol 80 mg/m² on days 1, 8, and 15; alcohol consumption, motion sickness, and age; patients were chemotherapy naïve or had received single-agent low emetogenic potential therapy

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

PHASE OF CARE: Active antitumor treatment

Randomized, controlled, non-placebo trial

• Used a patient diary to evaluate emetic events and nausea
• Nausea was measured using a 4-stage Likert-type scale.
• Multivariate logistic regression analysis showed relationships to other variables, such as motion sickness.
• Complete control was measured as no emetic episodes, no rescue medications, and mild nausea.
• Total control was defined as no emetic episodes, no rescue medications, and no nausea.

In the overall period, total control was 49.1% in the three-day dexamethasone group and 37.5% of the one-day dexamethasone group. In the acute phase, it was 90.6% in the three-day group and 92.9% in the one-day group. For delayed, it was 50.9% in the three-day group and 39.3% in the one-day group. Complete control in the overall period was 67.9% in the three-day group and 58.9% in the one-day group. In the acute phase, it was 98.1% in the three-day group and 96.4% of the one-day group. When looking at the responses, there were differences with motion sickness (p = 0.037), favoring the three-day dexamethasone regimen.

The authors concluded that one day of dexamethasone is as effective as three days of dexamethasone, except in special populations, such as those with motion sickness or severe hyperemesis gravidarum. Differences in efficacy were not found in patients with other risk factors, such as alcohol use and age.

Findings not generalizable

Nurses play a key role in assessing patient risk for chemotherapy-induced nausea and vomiting. Knowing past history of morning sickness or motion sickness should clue nurses into collaborating with providers to consider three days of dexamethasone as opposed to one day.

To examine the effects of a dexamethasone-sparing antiemetic regimen for women receiving highly emetogenic chemotherapy (HEC)

Data were obtained from medical records for women treated with anthracycline and cyclophosphamide regimens who were given antiemetic regimens not containing dexamethasone. Complete control (CC) and complete response (CR) rates were calculated and compared to reported rates. Varied medications were used for rescue, including aprepitant.

• N = 97   
• MEAN AGE = 57.6 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All had breast cancer and were receiving HEC regimens.
• OTHER KEY SAMPLE CHARACTERISTICS: Dexamethasone was not used because of a Hepatitis B or diabetes mellitus diagnosis. Most were chemotherapy naive.

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

• PHASE OF CARE: Active antitumor treatment

• Retrospective

• Patients completed questionnaires of when seen in the clinic for time and chemotherapy-induced nausea and vomiting (CINV) events during treatment.
• CR was defined as no vomiting and no use of rescue medication.
• CC was defined as no vomiting, no use of rescue, and no more than mild nausea.

Patients received one of three regimens: granisetron only, aprepitant and granisetron, or aprepitant and palonosetron. In the acute phase, the CR rates ranged from 44.8%–76.9% with the highest CR rates in aprepitant-containing regimens. The CC rates ranged from 31%–46.2%. In the delayed phase, the CR rates ranged from 44.8%–74.4%, again, with the highest rates in aprepitant-containing regimens. The CC rates in the delayed phase ranged from 27.6%–51.7%. Comparisons showed that the CR and CC rates were about 20% higher with the dexamethasone-containing regimens.

Dexamethasone-sparing regimens were less effective than standard triple drug antiemetics for CINV prophylaxis in patients receiving HEC. The best antiemetic control in dexamethasone-sparing regimens in this study was seen with the use of aprepitant.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Specific timing and questionnaire information for CINV measure not well described

Some patients may require dexamethasone-sparing antiemetic regimens while on chemotherapy because of other chronic health conditions. The findings suggest that steroid-sparing regimens are less effective for CINV control in patients receiving HEC. Further research is needed to determine the most effective alternatives to triple drug antiemetics in these cases.