BURDEN OF N&V - Guildford Advanced Courses · The burden of N&V Inadequate symptom management is...
Transcript of BURDEN OF N&V - Guildford Advanced Courses · The burden of N&V Inadequate symptom management is...
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Nausea and vomiting in patients with cancer
Dr Charlotte LeachConsultant in Palliative Medicine
Royal Surrey County Hospital, Guildford
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Overview
■ The burden of N&V
■ Good level evidence for effectiveness – “what works?”
■ Some/low quality evidence for effectiveness – “what might work?”
■ Future challenges
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BURDEN OF N&V
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The burden of N&V
■ Inadequate symptom management is the second most common
reason for hospital readmission in patients with advanced cancer
(Johnson et al, 2019)
■ 25% of patients do not believe that CINV is a high priority in
comparison to other problems (Salsman et al, 2012)
■ Significant physical, social, psychological and financial burden (Childs
et al, 2019)
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Cumulative incidence of adverse symptom events over time
Basch, 2010
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WHAT WORKS?Chemotherapy induced N&V: acute and delayed
Radiotherapy induced N&V
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CINV: acute and delayed
■ CINV is preventable
■ Acute phase: 5HT3 released from enterochromaffin cells of GI tract via peripheral pathways
■ Delayed phase: Substance P released via central pathways
Rapoport et al, 2017
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5HT3 receptor antagonists
■ “Gold standard” for acute
CINV
■ First-generation
(ondansetron) and second-
generation (granisetron,
palonesetron)
■ No evidence to support use in
patients with cancer outside
of CINV or post-operative N&V
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NK1 receptor antagonists
■ Substance P is a key emetogenic neurotransmitter in the CINV response
■ NK1-RAs block the sensitisation of NK1 receptors by substance P
■ Enhance the efficacy of steroids and 5HT3-RAs in CINV
■ Second-generation NK1-RAs (Netupitant)
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Corticosteroids
■ Exact mechanism in
CINV/N&V unknown
■ Reduce peripheral 5HT
release
■ Central action via activation
of glucocorticoid receptors in
the medulla
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Emetogenicity of anti-cancer therapies
Level of emetogenicity Risk of emesis
High (HEC) >90%
Moderate (MEC) 30-90%
Low 10-30%
Minimal <10%
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Summary of CINV guidelines
Level of emetogenicity Acute CINV Delayed CINV
High 5HT3-RA + Dex + NK1-
RA +/- Olanz
Dex + NK1-RA +/- Olanz
Moderate 5HT3-RA + Dex No routine prophylaxis
(except carboplatin/
oxaliplatin/anthracycline)
Low 5HT3-RA or Dex or D2-RA No routine prophylaxis
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Olanzapine
■ Potent D1-D4 and 5HT receptor antagonist, with some activity at α-1, H1 and muscarinic receptors
■ Consider need for glucose, lipid, and weight monitoring at baseline and every 3 months
■ Uncertainty re: optimum dose
■ No marketing authorisation for antiemesis
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■ 380 patients receiving HEC
■ Randomized, double-blind,
phase III trial
■ 5HT3-RA + Dex + NK1-RA
plus placebo or 10mg
olanzapine
■ 5% of patients in olanzapine
group reported “severe”
sedation
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Radiotherapy-induced N&V
Emetic risk Body area Recommended therapy
High Total body irradiation 5HT3-RA and Dexamethasone
Moderate Upper abdomen, craniospinal 5HT3-RA +/-Dexamethasone
Low
Cranial
Head and neck, thorax, pelvis
Prophylactic Dexamethasone
Prophylactic/rescue
Dexamethasone or 5HT3-RA or
D2-RA
Minimal Extremities, breast Rescue Dexamethasone or
5HT3-RA or D2-RA
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■ 136 patients receiving either radiotherapy to low or moderate areas
■ FLIE (Functional Living Index-Emesis) scores: 18 questions on days 5
and 10, or 3 and 7 depending on antiemetic regimen
■ Nausea has a significant impact on patients; vomiting has a more
significant impact on relatives than patients
■ RINV may last for weeks after treatment completion
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WHAT MIGHT WORK?Patients with advanced cancer
Refractory nausea: cannabinoids and olanzapine
Corticosteroids for patients with cancer
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Mechanistic versus empirical approach
Mechanistic:
Blocking the relevant emetogenic pathway through selecting an
appropriate anti-emetic
Empirical:
Use of antiemetic based on efficacy and tolerability
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Emetogenic pathways
Ach = Acetylcholine receptor; CTZ = chemoreceptor trigger zone, D2 = dopamine type 2 receptor; GABA = gamma-aminobutyric acid receptor; H1 = histamine type 1 receptor; ICP = intracranial pressure; NK1 = neurokinin 1 receptor; 5HT2 = serotonin type 2 receptor; 5HT3 = serotonin type 3 receptor; 5HT4 = serotonin type 4 receptor
Leach, 2019
Vomiting centre
H1, Ach, 5HT2
Vestibular system;
Ach, H1
Opioids, base of skull tumour
GI tract (impaired gastric empyting):
D2, 5HT4
Drugs, tumour infiltration
CTZ:
D2, 5HT3, NK1
Drugs, metabolic disturbance
Cortical:
GABA, H1
Pain, anxiety
Visceral/serosal:
Ach, 5HT3
Bowel obstruction, stretched liver
capsule
Cranial:
Raised ICP
H1
Space occupying mass, intracranial
haemorrhage
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■ Intention To Treat analysis - 185 patients (4 patients removed)
■ Multi-centre study
■ Patients randomized to either mechanistic (using national clinical
guidelines) or empirical approach (haloperidol)
■ Primary outcome: at least 2 point reduction in average nausea score
and score <3 for average nausea over preceding 24 hours using
numerical rating scale of 0-11.
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Mechanistic versus empirical approach
■ Mechanistic approach may offer a more rapid benefit at 24 hours (49% vs. 32%), but is no different to haloperidol at 72 hours (65% vs. 62%)
BUT…
■ 72 hour study
■ “Like for like” comparison (D2-RAs commonly used as first-line therapies)
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Patients with advanced cancer
■ Aetiology is often multi-factorial
■ Mechanistic approach is most common
■ Lack of RCTs and high-quality evidence
■ N&V is a chronic syndrome:
-consider reversibility
-consider long-term toxicities
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Patients with advanced cancer
Walsh et al, 2017
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Cannabinoids
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Cannabinoids
■ Cannabinoids are active chemical compounds in flowers, seeds and
stalks of cannabis plants
■ Phytocannibinoids (plants) and endocannibinoids (neurotransmitters)
■ >100 types of cannabinoid: cannabidiol (CBD) does not have
psychoactive properties, tetrahydrocannabinol (THC) does have
psychoactive properties
■ 2 main cannabinoid receptors; CB1 and CB2
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■ 23 RCTs between 1975-1991
■ Compared with placebo – more likely to report absence of vomiting
and nausea and vomiting
■ Compared with antiemetics – no evidence of difference for nausea,
vomiting, or nausea and vomiting
BUT…
■ Higher rate of adverse events – dizziness, euphoria, sedation
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■ 40 patients with cancer not
receiving anticancer
treatments
■ 10mg olanzapine nocte for 5
days
■ Primary endpoint – does
olanzapine reduce patient-
reported nausea and vomiting
at 24 hours and 7 days?
■ 38% (n=15) patients reported
increased dizziness or
sedation
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■ 3 RCTs
■ Baseline to 8 days
■ No evidence to support or refute the use of corticosteroids
■ Insufficient data to recommend optimum drug, route, or dosage
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FUTURE CHALLENGES
Long term toxicities
Cannabinoid hyperemesis syndrome
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Antiemetic toxicities: Metoclopramide
■ MHRA maximum
recommended dose of 30mg
in 24 hours
■ Risk of tardive dyskinesia
■ MHRA maximum
recommended duration of
use is 5 days
■ Informed discussion with
patient about risks vs.
benefits
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Antiemetic toxicities: Ondansetron■ Risk of arrhythmias is
proportionate to number of
causative drugs and other risk
factors
■ Informed discussion with
patient about risks vs.
benefits
■ Consider need for ECGs +/-
electrolyte replacement
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Antiemetic toxicities: corticosteroids
■ Multi-system toxicities may occur as early as one week
■ Risk of all toxicities is proportionate to dose
■ Many toxicities are reversible upon stopping steroids
■ Evening glucose monitoring initiated at the commencement of corticosteroids for in-patients (Joint British Diabetes Society, 2014)
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Cannabinoid hyperemesis syndrome
In certain individuals, chronic cannabis can cause a paradoxical reaction:
■ CB1 receptor stimulation = impaired gastric and intestinal motility
■ CB1 receptor stimulation = splanchnic vasodilation
■ Cannabis disrupts hypothalamic-pituitary-adrenal axis = impaired
digestive functioning
■ Genetic variability in hepatic metabolism of cannabinoids = excessive
levels of pro-emetic cannabinoid metabolites
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Cannabinoid hyperemesis syndrome
■ Cyclical severe N&V over months
■ Weekly cannabis use
■ Cannabis use >1year
■ Compulsive hot baths and showers
■ Abdominal pain
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Cannabinoid hyperemesis syndrome
■ Cannabis cessation (resolution of withdrawal symptoms within 2 weeks)
■ Acute phase management; rehydration, benzodiazepines, antipyschotics (haloperidol), topical capsaicin cream applied to the abdomen
■ Consider Psychiatry referral
■ Management of the underlying symptom for which the patient was originally using cannabis
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Take home messages
■ 5HT3-RAs and NK1-RAs are the cornerstone of CINV prevention
■ D2-RAs (haloperidol or metoclopramide) appear effective first-line
therapies in patients with advanced cancer
■ Insufficient evidence to make recommendations about olanzapine,
cannabinoids or corticosteroids in patients with advanced cancer
(high toxicity profile)
■ Careful consideration of long-term toxicities