1. Chemotherapy-induced nausea and vomitingBy
Alan O’Kane
Specialist Pharmacist
Oncology and Aseptic
Ninewells Hospital

2. Chemotherapy-induced nausea and vomiting
Most feared side-effect
May be more distressing than future concerns of life expectancy
Medical complications: dehydration, electrolyte imbalance, risk of aspiration pneumonia
Many treatments palliative intent = maintain QOL
Effective management of N + V is essential

3. Emetogenic Risk categories for chemotherapy in untreated patients
(See Figure 1)
Primary Risk Factor
High
Risk in nearly all patients (>90%)
Moderate
Risk in 30-90% of patients
Low
Risk in 10-30% of patients
Minimal
Risk in less than 10% of patients.

4. Patient risk factors Age <50 years Female Alcohol intake
Prone to N +V

5. Nausea Vomiting Substance P GABA Serotonin Acetylcholine Dopamine
Histamine
???????
Cannabinoid

6. Categories of CINV Acute - within 24 hours of chemotherapy Delayed
- 24 hours to 7 days post chemo
The most effective way of controlling CINV is to prevent symptoms of acute and delayed CINV by using a combination of an NK1 antagonist, 5HT3 antagonist and dexamethasone.

7. Brainstem vomiting enter1,2 GI vagal afferent nerve fibers1
Anatomy of CINV
Brainstem vomiting enter1,2
Area postrema
Chemoreceptor trigger zone (CTZ)
Nucleus tractus solitarius
Dorsal motor nucleus of the vagus nerve
Substance P/neurokinin 1 (NK1) receptors1
Serotonin/5-HT3 receptors1
GI vagal afferent nerve fibers1
Serotonin/5-HT3 receptors
Substance P/NK1 receptors
1. Hesketh PJ et al. Eur J Cancer. 2003;39(8):1074–1080.
2. Grunberg SM, Hesketh PJ. N Engl J Med. 1993;329(24):1790–1796.
Illustration by Kirk Moldoff.

8. Proposed pathways for CINV
CTZ activation
Blood
Cerebrospinal fluid
Activated vomiting center
Chemotherapy
Increased afferent input to the CTZ and vomiting center
Increased efferent output to target organs resulting in emesis
Cell damage
Release of neuroactive agents
Vagal activation
Berger AM, Clark-Snow RA. In: DeVita VT Jr et al. 7th ed. Cancer: Principles & Practice of Oncology. Lippincott Williams & Wilkins; 2005:2515–2523.
Illustration by Kirk Moldoff.

9. Serotonin and 5­HT3 receptor pathway
Introduction of 5-HT3 receptor antagonists offered an improved treatment option.2
Effective in acute vomiting; very limited efficacy for delayed events
Primary mechanism of action appears to be peripheral.2
1. Berger AM, Clark-Snow RA. In: DeVita VT Jr et al. 7th ed. Cancer: Principles & Practice of Oncology. Lippincott Williams & Wilkins; 2005:2515–2523.
2. Hesketh PJ et al. Eur J Cancer. 2003;39(8):1074–1080.

10. Substance P and NK1 receptor pathway
Substance P relays noxious sensory information to the brain
High density of substance P/NK1 receptors located in brain.
NK1 receptor blockade effective for delayed vomiting:
Less effective for acute vomiting: needs a 5HT3 antagonist
Less effective for nausea: needs dexamethasone

11. NK1 antagonists
Aprepitant 125mg 1 hour before chemotherapy on Day 1, 80mg Day 2 and Day 3
SMC approved for cisplatin containing regimens (other regimens??)
Some interactions: clinical significance

12. 5HT3 Antagonists
Block release of serotonin release from enterochromaffin cells in GI tract
Most effective for acute vomiting
All equally effective e.g ondansetron/granisetron
(?palonesetron)
Best given as a stat dose pre-chemo
Oral and IV equally effective
Side effects: constipation, abdominal spasms, headaches

13. Multi-Association of Supportive Cancer Care (MASCC) (See Handout)

14. Dexamethasone M.O.A not fully understood.
Very effective for nausea, acute and delayed vomiting
Acute: pre-dose before chemo
Delayed: 2-4 days after
Side effects: heartburn/indigestion, agitation, hiccups, abnormal BM’s (all manageable in most instances)

15. DEXAMETHASONE HIGH 20mg 8mg bd 3-4 d MODERATE 8mg 8mg od 2-3 d LOW
(12mg with aprepitant)
8mg bd 3-4 d
(8mg od 3-4d
with aprepitant)
MODERATE
8mg
8mg od 2-3 d
LOW
4-8mg
N/A
MINIMAL

16. Anticipatory N + V Conditional response Sights and smells
Involves higher cortical centres of brain
Occurs in 30% of patients
Lorazepam is an effective treatment

17. Other situations… Breakthrough symptoms
- N + V in spite of optimal preventative treatment.
Rescue therapy
- Treatment of breakthrough symptoms
Refractory
- CINV recurs in subsequent cycles of therapy when all previous preventative and rescue treatments have failed.

18. Breakthrough symptoms- which anti-emetic?
Less well-conducted trials available to guide treatment decisions.
Diagnosis of the cause of nausea and vomiting is crucial for deciding on which anti-emetic to use.
Key questions- when did symptoms start? when was last dose of chemo/XRT? When did steroid course stop? Nausea related to smells/taste of food? How many vomiting episodes? VAS to assess nausea? Appetite/food and fluid intake?
The only evidence available to rescue patients who have CINV is with the use of a D2 antagonist e.g. metoclopramide or a 5HT3 antagonist such as ondansetron.
Consider the side-effect profile of each anti-emetic. There may be more than one cause of nausea and vomiting therefore do not prescribe an anti-emetic that may worsen symptoms e.g. ondansetron and cyclizine may constipate- avoid if constipation and nausea present- use metoclopramide instead.
Severe cases- consider syringe driver for 48 hours then review.
Domperidone is supplied at a dose of 20mg qds with the majority of chemotherapy regimens. Consider if you want to add or substitute. If patient feels ineffective- consider compliance in view of low confidence in medicine.

19. Anti-emetic Dose Indication Contra-indication Other advice
Metoclopramide
10mg tds (oral) 30 minutes pre-meals
30mg via SD
Nausea or vomiting with constipation
Nausea or vomiting with reduced gastric turnover (inc. chemo or radiotherapy)
Parkinsons disease
Gastric outlet obstruction
Caution if associated diarrhoea
Higher doses can cause dyskinetic reactions.
May cause drowsiness- crosses blood barrier.
Ensure domperidone stopped
Ondansetron
8mg bd or 16mg od
(oral or IV)
Vomiting (chemo or radiotherapy induced)
Avoid if constipated
Use for minimum time- long duration can cause abdom spasms and constipation, also increase in LFT’s. Reduce to “when required” where possible.
Cyclizine
50mg tds (oral)
150mg via SD
Nausea or vomiting with diarrhoea
Nausea or vomiting in gastric outlet obstruction.
Avoid if constipated.
Avoid if reduced gastric turnover is cause.
Reduces GI effect of metoclopramide/
Domperidone.
Maximum dose by any route is 150mg in 24 hours.

20. Anti-emetic Dose Indication Contra-indication Other advice
Dexamethasone
8mg od (oral)
8mg via SD
Delayed CINV
Severe XRT
Brain mets
Liver mets
Appetite- low dose
Previous intolerance
Caution in diabetic patients (not CI)- monitor BM’s
Tailor dose if agitated/
aggresive.
Nausea started when dex course finished?
Levomepromazine
3-6mg bd (oral)
3.125mg SC prn
mg via SD
Chemotherapy
Radiotherapy
Unknown cause
Caution may cause drowsiness
May prolong QT interval.
Tailor dose to patient- frail patients 6.25mg via syringe driver.
Oral tabs unlicensed- difficult to obtain outwith hospital.
Lorazepam
0.5-1mg bd. (oral/SL/IV)
Anticipatory nausea and vomiting.
Caution if elderly and frail- increased risk of falls. If necessary- lowest dose.
Useful for anxiety issues, smells and taste of food problematic.
Triple therapy- ond/dex and lorazepam useful

21. Effective control
Give appropriate antiemetic medicines before chemo and after at correct dose, route, frequency, duration and timing
Start “prophylaxis” Cycle 1 and then throughout
“Breakthrough symptoms”- diagnosis cause and chose anti-emetic wisely (consider anti-emetic choice, dose, frequency, duration and side effect profile).
Counsel patient on diet when feeling sick or vomiting- importance of small amounts of food frequently (5-6 meals instead of 3), plenty fluid, eat easy to swallow foods with minimal smell e.g. clear broth, white toast, yoghurt, custard, crackers.

22. Any Questions?