1. Chemotherapy Induced Nausea and Vomiting
Haley Gill, BSP
VCH-PHC Pharmacy Resident

2. Outline
Review the pathophysiology of chemotherapy induced nausea and vomiting (CINV)
Review the different categories of CINV
Review the pharmacologic agents indicated for CINV
Review the current guidelines for CINV

3. Consequences of CINV medical complications quality of life
electrolyte imbalances
dehydration
quality of life
impact daily functioning
compliance with chemotherapy

4. Pathophysiology of CINV
Chemotherapy agents directly activate the CTZ which in turn releases neurotransmitters that stimulates the vomiting center in the medulla.
Chemotherapy agents can irritate GI mucosa, resulting in release of neurotransmitters which activates receptors to send signals to the vomiting center in the medulla

5. Pathophysiology of CINV
This slide depicts some of the neurotransmitters involved in vomiting: dopamine, acetylcholine, histamine, substance P, and serotonin.1
Substance P works by binding to NK 1 receptors in the midbrain which activates the vomiting center

6. Classification of CINV
Acute
within 24 hours of chemotherapy
Delayed
occurs > 24 hours after chemotherapy
Anticipatory
prior to chemotherapy
Breakthrough
while receiving prophylactic antiemetics
Refractory
Not responsive to therapy
Delayed – specific chemo known to cxs (carboplatin, doxorubicin, cyclophosphamide). More common in pts who develop acute
Anticipatory can be triggered by smell, taste, anxiety, etc. Conditioned response, memory of bad reaction to last chemo cycles

7. Neurotransmitter Involvement

8. Risk Factors Young age Female History of low alcohol intake
Experience of emesis during pregnancy
Emetogenic potential of chemotherapeutic agent
History of motion sickness

9. Antiemetic Agents Serotonin 5-HT3 Receptor Antagonists (5-HT3 RA)
Corticosteroids
Dopamine-Serotonin Receptor Antagonists
Dopamine Receptor Antagonists
Neurokinin-1 Receptor Antagonists (NK-1 RA)
Benzodiazepines
Cannabinoids

10. Serotonin 5-HT3 RA’s Block 5-HT3 receptors in the CNS and GI tract
Equivalent in efficacy and toxicities
More effective for acute CINV
AE’s: headache, constipation, QTc interval prolongation

11. Serotonin 5-HT3 RA’s Available Agents Recommended Dose
Ondansetron (Zofran®)
IV: 8 mg or 0.15 mg/kg
PO: mg
dolasetron (Anzemet®)
IV: 100 mg or 1.8 mg/kg
PO: 100 mg
granisetron (Kytril®)
IV: 1 mg or 0.01 mg/kg
PO: mg
At approved doses, the oral formulation is therapeutically equivalent to the IV dosage form.
**single-daily dose schedules are similar in efficacy to multiple-daily dosing**

12. Corticosteroids Dexamethasone (Decadron®) Dose: 8 - 20 mg IV or PO
Effective for both acute and delayed CINV
MOA: unknown
AE’s: Insomnia, hyperglycemia, heartburn
Dexamethasone most commonly used. Methylprednisolone mentioned in some guidelines

13. Dopamine-Serotonin Receptor Antagonists
Metoclopramide (Maxeran®)
10-30 mg IV/PO Q4-6H ac
Domperidone (Motilium®)
10-20 mg PO Q4-6H ac
 doses = dopamine antagonist effects
 doses = serotonin antagonist effects
AE’s: sedation, EPS, diarrhea
Diphenhydramine (Benadryl®) may  EPS
May see greater efficacy with higher doses b/c then get Serotonin blocking effects as well.
EPS, Akasthesia (restlessness)

14. Dopamine Receptor Antagonists
prochlorperazine (Stemetil®)
5 -10 mg IV/PO Q6H
haloperidol (Haldol®)
0.5 – 2 mg PO/SC Q6-12H
MOA: block dopamine receptors in the CTZ
AE’s: EPS, disorientation, sedation

15. Neurokinin-1 Receptor Antagonists
Aprepitant (Emend®), Fosaprepitant (IV)
Dose: 125 mg PO on day 1 then 80 mg PO daily on days 2 & 3
MOA: blocks NK-1 receptor in brainstem emetic center & GI tract
AE’s: fatigue, asthenia, hiccups
Drug interactions:  dose of dexamethasone by 50%
Can give the day 1 dose IV. Asthenia = lack of strength, malaise, fatigue
Not on formulary at VGH, not a benefit for pharmacare.

16. Other Agents Agent Dose Use Lorazepam (Ativan ®) 0.5 - 2 mg IV/PO/SL
Anticipatory N&V
Cannabinoids
dronabinol (Marinol®)
nabilone (Cesamet®)
2.5 – 10 mg PO TID - QID
Refractory & Breakthrough N&V
Olanzapine (Zyprexa®)
2.5 – 10mg PO hs
Acute, Delayed & Refractory N&V
Gabapentin (Neurontin®)
Delayed
Cannabinoids role yet to be determined. Approved for refractory suggested for breakthrough. Do have some beneficial Se’s such as sedation and euphoria.
Very little evidence for gabapentin

17. Chemotherapy Emetic Risk Groups
High
Risk in nearly all patients (>90%)
Cyclophosphamide (high dose), cisplatin
Moderate
Risk in 30% to 90% of patients
Daunorubicin, cytarabine (high dose), melphalan (high dose), azacitadine
Low
Risk in 10% to 30% of patients
fludarabine, cytarabine (low dose)
Minimal
Fewer than 10% at risk
bortezomib, vincristine, hydroxyurea
Some literature suggests that all SCT conditioning regimens are high risk.

18. Guidelines
Multinational Association of Supportive Care in Cancer (MASCC)
American Society of Clinical Oncology (ASCO)
National Comprehensive Cancer Network (NCCN)

19. Highly Emetogenic Chemotherapy
Acute
Delayed
MASCC
5-HT3RA + dexamethasone + aprepitant
Dexamethasone + aprepitant
ASCO
NCCN
5-HT3RA + dexamethasone + aprepitant ± lorazepam
Dexamethasone + aprepitant ± lorazepam
Antiemetics for delayed CINV given on days 2&3 (aprepitant) and 2-4 dexameth
Conflicting results for the use of 5Ht3 RA’s for delayed. Monotx not as great as 5HT3RA + dex. Continuing a 5HT3 RA beyond 24 hrs along with dex did not confer any additional benefit compared to corticosteroids alone.
Metoclop an option for delayed. Shown to be as effective as 5HT3RA when combined with dex.

20. Moderately Emetogenic Chemotherapy
Acute
Delayed
MASCC
5-HT3RA + dexamethasone
Dexamethasone or
5-HT3RA
ASCO
NCCN
5-HT3RA + dexamethasone ± lorazepam
± lorazepam
Anthracycline + cyclophosphamide treated like high risk melphalan

21. Low Emetogenic Chemotherapy
Acute
Delayed
MASCC
dexamethasone
No Routine Prophylaxis
ASCO
NCCN
dexamethasone ± lorazepam or
prochlorperazine ± lorazepam or
metoclopramide ± lorazepam
Anthracycline + cyclophosphamide treated like high risk

22. Minimal Emetogenic Chemotherapy
Acute
Delayed
MASCC
No Routine Prophylaxis
ASCO
NCCN
Anthracycline + cyclophosphamide treated like high risk

23. Rescue Therapy Add an agent from another class
phenothiazine, metoclopramide, or dexamethasone
5-HT3 RA unlikely to be beneficial if N & V developed with 5-HT3 RA prophylaxis
Aprepitant NOT for established N & V
Consider non-chemo causes
Very unlikely that established N & V will respond to an agent in the same drug class after unsuccessful prophylaxis with an agent with the same mechanism of action
Other causes: opiods, hypocalcemia, antibiotics, etc.

24. Refractory Therapy Consider adjusting pre and post chemo regimen
Little data
Some evidence for aprepitant & palonosetron (not in Canada)

25. Patient Education Very important!!
Instruct patients to take their rescue drugs when nausea first begins
May need to use regularly scheduled rescue drugs
Additional doses of 5-HT3 RA not more effective than other rescue drugs

26. Cost Drug Cost/day Aprepitant ~$33.00, $99.60 (tri-pack) Ondansetron
IV $1.80
PO $8.70
Dexamethasone
IV $1.52
PO $1.64
Lorazepam
IV $0.48
PO $0.05
Metoclopramide
IV $11.60
PO $0.72
Prochlorperizine
IV $4.68
PO $0.56
Ondansetron IV is 8mg dose
Ondansetron PO is 8mg po bid or 16mg daily
Dexa 8mg IV daily or 8mg po daily
Lorazepam 1mg IV daily or 1mg po daily
Maxeran 30mg IV q6h, 30mg po q6h
Stemetil 10mg IV q6h, 10mg PO q6h

27. Questions?

28. References
Kris MG, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update J Clin Oncol 2006;24(18):
Hesketh PJ. Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2008;358:
Baker PD, et al. The Pathophysiology of Chemotherapy-Induced Nausea and Vomiting. Gastroenterology Nursing 2005;28(6):469-80
Navari RM. Pharmacological Management of Chemotherapy-induced Nausea and Vomiting: Focus on Recent Developments. Drugs 2009;69(5):515-33
Jordan K, et al. Guidelines for Antiemetic Treatment of Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future Recommendations Oncologist 2007;12;
Multinational Association of Supportive Care in Cancer Antiemetic Guidelines (last update: March 2008). Available at
National Comprehensive Cancer Network Antiemetic Guidelines Available at

29. Emetic Risk
Prophylaxis of acute CINV on day of chemo administration
Prophylaxis of delayed CINV
High
5-HT3RA + dexamethasone + aprepitant
Days 2 & 3 after Chemotherapy: dexamethasone + aprepitant
Moderate
Anthracycline + Cyclophosphamide:
Days 2 & 3 after chemotherapy: aprepitant
All other regimens of moderate emetic risk:
5-HT3RA + dexamethasone
Days 2-4 after chemotherapy: dexamethasone or 5-HT3RA
Low
Dexamethasone
None
Minimal