Nausea and vomiting in patients with cancer

Dr Charlotte LeachConsultant in Palliative Medicine

Royal Surrey County Hospital, Guildford

Overview

■ The burden of N&V

■ Good level evidence for effectiveness – “what works?”

■ Some/low quality evidence for effectiveness – “what might work?”

■ Future challenges

BURDEN OF N&V

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)

Cumulative incidence of adverse symptom events over time

Basch, 2010

WHAT WORKS?Chemotherapy induced N&V: acute and delayed

Radiotherapy induced N&V

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

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

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)

Corticosteroids

■ Exact mechanism in

CINV/N&V unknown

■ Reduce peripheral 5HT

release

■ Central action via activation

of glucocorticoid receptors in

the medulla

Emetogenicity of anti-cancer therapies

Level of emetogenicity Risk of emesis

High (HEC) >90%

Moderate (MEC) 30-90%

Low 10-30%

Minimal <10%

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

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

■ 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

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

■ 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

WHAT MIGHT WORK?Patients with advanced cancer

Refractory nausea: cannabinoids and olanzapine

Corticosteroids for patients with cancer

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

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

■ 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.

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)

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

Patients with advanced cancer

Walsh et al, 2017

Cannabinoids

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

■ 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

■ 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

■ 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

FUTURE CHALLENGES

Long term toxicities

Cannabinoid hyperemesis syndrome

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

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

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)

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

Cannabinoid hyperemesis syndrome

■ Cyclical severe N&V over months

■ Weekly cannabis use

■ Cannabis use >1year

■ Compulsive hot baths and showers

■ Abdominal pain

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

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