Chemotherapy-induced Chemotherapy-induced nauseanausea and vomitingand vomiting

ByBy

Alan O’KaneAlan O’Kane

Specialist Pharmacist Specialist Pharmacist

Oncology and AsepticOncology and Aseptic

Ninewells HospitalNinewells Hospital

Chemotherapy-induced nausea and Chemotherapy-induced nausea and vomitingvomiting

Most feared side-effectMost feared side-effect

May be more distressing than future concerns of May be more distressing than future concerns of life expectancylife expectancy

Medical complications: dehydration, electrolyte Medical complications: dehydration, electrolyte imbalance, risk of aspiration pneumoniaimbalance, risk of aspiration pneumonia

Many treatments palliative intent = maintain QOLMany treatments palliative intent = maintain QOL

Effective management of N + V is essentialEffective management of N + V is essential

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.

 

Emetogenic Risk categories for chemotherapy in untreated patients

(See Figure 1)

Primary Risk Factor

Patient risk factors Patient risk factors

Age <50 yearsAge <50 years

FemaleFemale

Alcohol intakeAlcohol intake

Prone to N +V Prone to N +V

Substance P

Serotonin

Dopamine

Cannabinoid

Histamine

Acetylcholine

GABA

???????

Nausea

Vomiting

Categories of CINVCategories of CINV

Acute Acute

- within 24 hours of chemotherapy- within 24 hours of chemotherapy

Delayed Delayed

- 24 hours to 7 days post chemo- 24 hours to 7 days post chemo

The most effective way of controlling CINV is to The most effective way of controlling CINV is to prevent symptoms of acute and delayed CINV prevent symptoms of acute and delayed CINV by using a combination of an NK1 antagonist, by using a combination of an NK1 antagonist, 5HT3 antagonist and dexamethasone.5HT3 antagonist and dexamethasone.

Anatomy of CINVAnatomy of CINV

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.

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

Proposed pathways for CINVProposed pathways for CINV

Cell damage

• Release of neuroactive agents

• Vagal activation

Increased afferent input to the CTZ

and vomiting center

CTZ activation

• Blood• Cerebrospinal fluid

Activated vomiting center

Increased efferent output to target organs

resulting in emesis

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.

Chemotherapy

Serotonin and 5 HTSerotonin and 5 HT33 receptor receptor

pathwaypathwayIntroduction of 5Introduction of 5--HTHT33 receptor antagonists offered an receptor antagonists offered an

improved treatment option.improved treatment option.22

– Effective in acute vomiting; very limited efficacy for Effective in acute vomiting; very limited efficacy for delayed eventsdelayed events

Primary mechanism of action appears to be peripheral.Primary mechanism of action appears to be peripheral.22

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.

Substance P and NKSubstance P and NK11 receptor pathway receptor pathway

Substance P relays noxious sensory information to the Substance P relays noxious sensory information to the brain brain

High density of substance P/NKHigh density of substance P/NK11 receptors located in receptors located in

brain.brain.

NKNK11 receptor blockade effective for delayed vomiting: receptor blockade effective for delayed vomiting:

- Less effective for acute vomiting: needs a 5HTLess effective for acute vomiting: needs a 5HT33

antagonist antagonist - Less effective for nausea: needs dexamethasoneLess effective for nausea: needs dexamethasone

NK1 antagonistsNK1 antagonists

Aprepitant 125mg 1 hour before Aprepitant 125mg 1 hour before chemotherapy on Day 1, 80mg Day 2 and chemotherapy on Day 1, 80mg Day 2 and Day 3Day 3

SMC approved for cisplatin containing SMC approved for cisplatin containing regimens (other regimens??)regimens (other regimens??)

Some interactions: clinical significanceSome interactions: clinical significance

5HT3 Antagonists5HT3 Antagonists

Block release of serotonin release from enterochromaffin cells in GI Block release of serotonin release from enterochromaffin cells in GI tracttract

Most effective for acute vomitingMost effective for acute vomiting

All equally effective e.g ondansetron/granisetronAll equally effective e.g ondansetron/granisetron (?palonesetron)(?palonesetron)

Best given as a stat dose pre-chemoBest given as a stat dose pre-chemo

Oral and IV equally effectiveOral and IV equally effective

Side effects: constipation, abdominal spasms, headachesSide effects: constipation, abdominal spasms, headaches

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

DexamethasoneDexamethasone

M.O.A not fully understood.M.O.A not fully understood.

Very effective for nausea, acute and delayed Very effective for nausea, acute and delayed vomitingvomiting

Acute: pre-dose before chemoAcute: pre-dose before chemoDelayed: 2-4 days afterDelayed: 2-4 days after

Side effects: heartburn/indigestion, agitation, Side effects: heartburn/indigestion, agitation, hiccups, abnormal BM’s (all manageable in most hiccups, abnormal BM’s (all manageable in most instances)instances)

DEXAMETHASONEDEXAMETHASONE

HIGHHIGH 20mg 20mg (12mg with aprepitant)(12mg with aprepitant)

8mg bd 3-4 d8mg bd 3-4 d(8mg od 3-4d(8mg od 3-4d

with aprepitant)with aprepitant)

MODERATEMODERATE 8mg 8mg (12mg with aprepitant)(12mg with aprepitant)

8mg od 2-3 d8mg od 2-3 d

LOWLOW 4-8mg4-8mg N/AN/A

MINIMALMINIMAL N/AN/A N/AN/A

Anticipatory N + VAnticipatory N + V

Conditional responseConditional response

Sights and smellsSights and smells

Involves higher cortical centres of brainInvolves higher cortical centres of brain

Occurs in 30% of patients Occurs in 30% of patients

Lorazepam is an effective treatmentLorazepam is an effective treatment

Other situations…Other situations…

Breakthrough symptoms Breakthrough symptoms - - N + V in spite of optimal preventative treatmentN + V in spite of optimal preventative treatment. .

Rescue therapy Rescue therapy - - Treatment of breakthrough symptoms Treatment of breakthrough symptoms

Refractory Refractory - - CINV recurs in subsequent cycles of therapy when all CINV recurs in subsequent cycles of therapy when all

previous preventative and rescue treatments have previous preventative and rescue treatments have failedfailed..

Breakthrough symptoms- which anti-emetic?Breakthrough symptoms- which anti-emetic?

Less well-conducted trials available to guide treatment decisions.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.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 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 course stop? Nausea related to smells/taste of food? How many vomiting episodes? VAS to assess nausea? Appetite/food and fluid intake?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 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.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 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. 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 ondansetron and cyclizine may constipate- avoid if constipation and nausea present- use metoclopramide instead.metoclopramide instead.

Severe cases- consider syringe driver for 48 hours then review. 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. 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 Consider if you want to add or substitute. If patient feels ineffective- consider compliance in view of low confidence in medicine. of low confidence in medicine.

Anti-emeticAnti-emetic DoseDose IndicationIndication Contra-Contra-indicationindication

Other adviceOther advice

MetoclopramideMetoclopramide 10mg tds (oral) 30 10mg tds (oral) 30 minutes pre-mealsminutes pre-meals

30mg via SD30mg via SD

Nausea or vomiting Nausea or vomiting with constipationwith constipation

Nausea or vomiting Nausea or vomiting with reduced with reduced gastric turnover gastric turnover (inc. chemo or (inc. chemo or radiotherapy)radiotherapy)

Parkinsons diseaseParkinsons disease

Gastric outlet Gastric outlet obstructionobstruction

Caution if Caution if associated associated diarrhoeadiarrhoea

Higher doses can Higher doses can cause dyskinetic cause dyskinetic reactions.reactions.

May cause May cause drowsiness- drowsiness- crosses blood crosses blood barrier.barrier.

Ensure Ensure domperidone domperidone stoppedstopped

OndansetronOndansetron 8mg bd or 16mg od8mg bd or 16mg od

(oral or IV)(oral or IV)

Vomiting (chemo or Vomiting (chemo or radiotherapy radiotherapy induced)induced)

Avoid if constipatedAvoid if constipated Use for minimum Use for minimum time- long duration time- long duration can cause abdom can cause abdom spasms and spasms and constipation, also constipation, also increase in LFT’s. increase in LFT’s. Reduce to “when Reduce to “when required” where required” where possible.possible.

CyclizineCyclizine 50mg tds (oral)50mg tds (oral)

150mg via SD150mg via SD

Nausea or vomiting Nausea or vomiting with diarrhoeawith diarrhoea

Nausea or vomiting Nausea or vomiting in gastric outlet in gastric outlet obstruction.obstruction.

Avoid if Avoid if constipated. constipated.

Avoid if reduced Avoid if reduced gastric turnover is gastric turnover is cause.cause.

Reduces GI effect Reduces GI effect of metoclopramide/of metoclopramide/

Domperidone.Domperidone.

Maximum dose by Maximum dose by any route is 150mg any route is 150mg in 24 hours.in 24 hours.

Anti-emeticAnti-emetic DoseDose IndicationIndication Contra-Contra-indicationindication

Other adviceOther advice

DexamethasoneDexamethasone 8mg od (oral)8mg od (oral)

8mg via SD8mg via SD

Delayed CINVDelayed CINV

Severe XRTSevere XRT

Brain metsBrain mets

Liver metsLiver mets

Appetite- low Appetite- low dosedose

Previous Previous intoleranceintolerance

Caution in Caution in diabetic patients diabetic patients (not CI)- monitor (not CI)- monitor BM’sBM’s

Tailor dose if Tailor dose if agitated/agitated/

aggresive.aggresive.

Nausea started Nausea started when dex course when dex course finished?finished?

LevomepromazineLevomepromazine 3-6mg bd (oral)3-6mg bd (oral)

3.125mg SC prn3.125mg SC prn

6.25-12.5mg via 6.25-12.5mg via SDSD

ChemotherapyChemotherapy

RadiotherapyRadiotherapy

Unknown causeUnknown cause

Caution may Caution may cause drowsinesscause drowsiness

May prolong QT May prolong QT interval. interval.

Tailor dose to Tailor dose to patient- frail patient- frail patients 6.25mg patients 6.25mg via syringe driver.via syringe driver.

Oral tabs Oral tabs unlicensed- unlicensed- difficult to obtain difficult to obtain outwith hospital.outwith hospital.

LorazepamLorazepam 0.5-1mg bd. 0.5-1mg bd. (oral/SL/IV)(oral/SL/IV)

Anticipatory Anticipatory nausea and nausea and vomiting.vomiting.

Caution if elderly Caution if elderly and frail- and frail- increased risk of increased risk of falls. If necessary- falls. If necessary- lowest dose.lowest dose.

Useful for anxiety Useful for anxiety issues, smells issues, smells and taste of food and taste of food problematic.problematic.

Triple therapy- Triple therapy- ond/dex and ond/dex and lorazepam usefullorazepam useful

Effective controlEffective control

Give appropriate antiemetic medicines before chemo and after at Give appropriate antiemetic medicines before chemo and after at correct dose, route, frequency, duration and timingcorrect dose, route, frequency, duration and timing

Start “prophylaxis” Cycle 1 and then throughoutStart “prophylaxis” Cycle 1 and then throughout

““Breakthrough symptoms”- diagnosis cause and chose anti-emetic Breakthrough symptoms”- diagnosis cause and chose anti-emetic wisely (consider anti-emetic choice, dose, frequency, duration and wisely (consider anti-emetic choice, dose, frequency, duration and side effect profile).side effect profile).

Counsel patient on diet when feeling sick or vomiting- importance of Counsel patient on diet when feeling sick or vomiting- importance of small amounts of food frequently (5-6 meals instead of 3), plenty 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, fluid, eat easy to swallow foods with minimal smell e.g. clear broth, white toast, yoghurt, custard, crackers.white toast, yoghurt, custard, crackers.

Any Questions?Any Questions?