Chemotherapy-induced nausea and vomiting

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Chemotherapy-induced nausea and vomiting

• By
• Alan OKane
• Specialist Pharmacist
• Oncology and Aseptic
• Ninewells Hospital

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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

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Emetogenic Risk categories for chemotherapy in
untreated patients (See Figure 1) Primary Risk
Factor
 
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Patient risk factors

• Age lt50 years
• Female
• Alcohol intake
• Prone to N V

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

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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.
200339(8)10741080. 2. Grunberg SM, Hesketh
PJ. N Engl J Med. 1993329(24)17901796.
Illustration by Kirk Moldoff.
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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
200525152523. Illustration by Kirk Moldoff.
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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
200525152523. 2. Hesketh PJ et al. Eur J
Cancer. 200339(8)10741080.
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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

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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

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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

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Multi-Association of Supportive Cancer Care
(MASCC) (See Handout)
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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 BMs (all manageable in most
  instances)

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

• Conditional response
• Sights and smells
• Involves higher cortical centres of brain
• Occurs in 30 of patients
• Lorazepam is an effective treatment

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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.

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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.

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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 LFTs. 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.
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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 BMs Tailor dose if agitated/ aggresive. Nausea started when dex course finished?
Levomepromazine 3-6mg bd (oral) 3.125mg SC prn 6.25-12.5mg 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
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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.

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Any Questions?