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October 23, 2018
Journal Club
Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting
Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang HM, Baranowski V
Delayed CINV
(Chemotherapy-induced nausea and vomiting)
Nausea and/or vomiting:
- Occurring > 24 hours after chemotherapy
INTRO
- Lasting for up to 1 week
occurs in at least 50% of patients on moderately emetogenic chemotherapy
Delayed CINV
(Chemotherapy-induced nausea and vomiting)
GOAL of antiemetic therapy:
- total response or prevention
Impaired QoL imparted by CINV can affect treatment outcomes when patient refuse chemotherapy
Aprepitant
Ondansetron
Current guideline
American Society of Clinical Oncology Guideline for Antiemetics in Oncology
Chemotherapy with moderate emetic risk
- Two-drug combination: 5-HT3 receptor antagonist + dexamethasone
Chemotherapy with high emetic risk
- Three-drug combination: 5-HT3 receptor antagonist + dexamethasone + aprepitant
Methodology
Randomized, double-blinded, placebo-controlled, parallel-group, 5-day study
CRITERIA
Inclusion
Exclusion
Patient >18 years old
History of anticipatory nausea or vomiting
Malignancy that did not involve the bone marrow
Primary malignancy of the brain, spinal cord, or nervous system; mets to these sites
Chemotherapy (moderate to highly emetogenic)
History of brain surgery, brain trauma, or other neurologic disorder that affect the CNS
Radiation therapy
Marijuana use within 30 days of baseline
Not pregnant and will not be pregnant
Antiemetic and diphenhydramine use within 7 days before baseline
Estimated life expectancy of at least 6 weeks postchemotherapy
On unstable doses of opiates and benzos for 2 weeks before start
ECOG 0-2 at screening
Use of corticosteroids (other than dexa)
History of pyschotic or substance abuse disorder
METHOD
Dronabinol
Combination
P
D
O
D
O
Ondansetron
Placebo
Baseline ECOG, VS, PE, ECG, labs
Record the number of vomiting or retching episodes from the previous day
Record the daily presence or absence of nausea and its duration
Days 1 - 5
Drug doses
Study drug doses are adjusted days 2 through 5
Day 1 - chemo day
Days 2 to 5 - non-chemo days
Doses can be cut in half if not tolerating
Safety analyses: VS, PE, lab, AEs
Rescue meds: metoclopramide, prochlorperazine
Secondary outcomes
Primary outcome
MED
Dosing Schedule
TREATMENT groups
DAY 1
DAY 2
DAY 3-5
Prechemotherapy
Postchemotherapy
Dexamethasone 20mg PO
Dronabinol
Dronabinol
2.5 mg PO QID
(10 mg/day)
Ondansetron 16 mg IV
Dronabinol
2.5 mg PO
Dronabinol
2.5-5mg PO QID
(10-20 mg/day)
Dronabinol 2.5 mg PO
Dexamethasone 20mg PO
Ondansetron
4-8 mg PO BID
(8-16 mg/day)
Ondansetron
8 mg PO BID
(16 mg/day)
Ondansetron 16 mg IV
Dronabinol
2.5 mg PO
Ondansteron
Dronabinol 2.5 mg PO
Dexamethasone 20mg PO
Ondansetron 16 mg IV
Dronabinol
2.5 mg PO
Combination
Dronabinol
2.5 mg PO QID
(10 mg/day)
+
Ondansetron
8 mg PO BID
(16 mg/day)
Dronabinol
2.5-5 mg PO QID
(10-20 mg/day)
+
Ondansetron
4-8 mg PO BID
(8-16 mg/day)
Dronabinol 2.5 mg PO
Dexamethasone 20mg PO
Ondansetron 16 mg IV
Placebo
Placebo PO
Placebo PO QID
Placebo PO
outcomes
Primary outcome measure
Incidence of TOTAL RESPONSE to treatment following administration of a moderately to highly emetogenic chemotherapeutic agent
*TOTAL RESPONSE - absence of vomiting and/or retching, intensity of nausea <5mm on a 100mm VAS (0mm = no nausea, 100mm = intractable nausea), and no use of rescue medications
Secondary outcome measures
Complete response, presence or absence of nausea, episodes of vomiting and/or retching, duration of nausea and vomiting and/or retching, intensity of nausea measured by VAS, ECOG, and QoL
*COMPLETE RESPONSE - absence of vomiting and/or retching, intensity of nausea <30mm on a 100mm VAS (0mm = no nausea, 100mm = intractable nausea), and no use of rescue medications
ECOG and QoL (McCorkle Symptom Distress Scale) evaluation were conducted on day screening (ECOG)/day 1(QoL) and on day 6, 7, and 8
RESULTS
*originally designed for 464 patients (80% power)
STATS
Statistical Analyses
EFFICACY ANALYSES
Based on intention-to-treat (ITT) population
Baseline - defined as Day 1; end point - defined as Day 5
END POINT - values from premature discontinuation visit were used in a last observation carried forward (LOCF) analysis
If the value at the discontinuation visit was missing, last availble postbaseline observation was used
DIFFERENCE BETWEEN TREATMENT GROUPS
Two-sided test with 0.05 level of significance
Statistical Analyses
Logistic regression model w/ Cochran-Mantel-Haenszel (CHM)
Performed to analyze total response and for supportive analysis
ANOVA
Pair-wise comparison and on ranked not normally distributed data
STATS
INTENT-TO-TREAT POPULATION
(N=64)
Randomization
Dronabinol
n=17
Ondansetron
n=16
Placebo
n=14
Dronabinol+Ondasteron
n=17
Withdrawals
n=4
3 Adverse event
1 Other
Withdrawals
n=4
2 Adverse events
1 Protocol violations
1 Other
Withdrawals
n=4
1 Adverse event
2 Protocol violations
1 Other
Withdrawals
n=3
2 Withdrew consent
(1 for lethargy)
1 Other
Completed the trial
n=11 (79%)
Completed the trial
n=13 (76%)
Completed the trial
n=12 75%)
Completed the trial
n=13 (76%)
SECONDARY efficacy
PRIMARY efficacy
Total response
Absence of nausea
ECOG
41-69% of all patients (n=64) had a score of 0 or 1 at screening
Shift from 1 to 0 occurred after treatment with dronabinol
most patients in the dronabinol group had a baseline value of 1
changes in baseline were statistically significant in patients receiving dronabinol vs placebo (p=0.036, in favor of placebo)
Overall mean changes from screening to end point for the three groups were similar and not much different from 0
QoL
Improvement from baseline was observed only in patients receiving dronabinol
Use of rescue meds
Rescue antiemetics were used in all groups:
- Dronabinol = 4/17 (24%)
- Ondansetron = 5/16 (31%)
- Combo = 2/17 (12%)
- Placebo = 6/14 (43%)
Rescue use was low on days 1 and 2 for all
Day 5 = only 2/17(12%) used rescue in dronabinol group vs 4/16 (25%) in ondansteron group
POST HOC ANALYSES
POST HOC ANALYSES
DISCUSSION
DISCUSSION
- Efficacy of dronabinol alone was comparable with ondansetron for the treatment of delayed CINV
- Patients receiving cannabinoids might be expected to have sensorial CNS AEs
- Consistent with those reported in previous trials with THC compounds
- Highest rate of CNS-related events (dizziness, fatigue) was in patients receiving combination therapy
- Addition of dronabinol before and after chemotherapy may offer more benefit than the standard regimen alone taken before chemotherapy
- More studies are needed to validate day 1 findings
LIMITATIONS
- Low number of patients (low power)
- Variance in sex, type of cacner, and difference in previous chemotherapy status may have impacted the results
- LOCF - one method used to handle missing data by filling in values based on existing data
- Recent research shows that this method gives a biased estimate of the treatment effect and underestimates the variability of the estimated result
CONCLUSION
Dronabinol and ondansetron were similarly effective antiemetic treatments in cancer patients given moderately to highly emetogenic chemotherapy
Combination therapy with dronabinol and ondansetron was not more effective than either agent alone for the treatment of CINV.
Active treatments were well tolerated
Larger trials are needed to confirm these findings