Antiemetic Therapy for Chemotherapy

Chemotherapy-induced nausea and vomiting results from serotonin release from gut enterochromaffin cells, which acts on 5HT3 receptors on vagal afferents, and from substance P acting on NK1 receptors in the brainstem. Delayed vomiting (24 to 120 hours) is largely substance P mediated. Prophylaxis chosen by the emetic risk of the regimen prevents most vomiting.

Classification. 5HT3 receptor antagonists (ondansetron, granisetron, palonosetron), NK1 receptor antagonists (aprepitant, fosaprepitant, netupitant), corticosteroids (dexamethasone), dopamine antagonists (metoclopramide, haloperidol, prochlorperazine), olanzapine, and benzodiazepines (lorazepam).

Pharmacokinetics. Ondansetron is cleared by CYP3A4, CYP1A2 and CYP2D6 (ultra-rapid metabolisers respond poorly); aprepitant is a CYP3A4 substrate, moderate inhibitor and inducer of CYP2C9; palonosetron has a half life of 40 hours.

• Ondansetron 8 mg intravenously or 16 mg orally once daily on day 1 (maximum single intravenous dose 16 mg).
• Granisetron 1 mg intravenously or 2 mg orally once daily.
• Palonosetron 0.25 mg intravenously once on day 1 (0.5 mg orally).
• Aprepitant 125 mg orally on day 1, then 80 mg on days 2 and 3; fosaprepitant 150 mg intravenously on day 1.
• Dexamethasone 12 mg on day 1 with an NK1 antagonist (20 mg without; 8 mg for moderate risk), then 8 mg daily on days 2 to 4 for high risk.
• Olanzapine 5 to 10 mg orally at night on days 1 to 4.
• Metoclopramide 10 mg orally or intravenously three times daily (maximum 30 mg daily, 5 days).
• Lorazepam 0.5 to 2 mg orally or sublingually for anticipatory nausea.

Differences. Palonosetron is more effective against delayed nausea than ondansetron; aprepitant raises dexamethasone levels, so the dexamethasone dose is reduced.

• High emetic risk (cisplatin, anthracycline with cyclophosphamide, dacarbazine, high-dose cyclophosphamide): 4-drug regimen: 5HT3 antagonist, dexamethasone, NK1 antagonist and olanzapine; or 3-drug regimen where olanzapine or NK1 antagonists are unavailable.
• Moderate risk (carboplatin, oxaliplatin, doxorubicin, cyclophosphamide, irinotecan): 5HT3 antagonist with dexamethasone 8 mg; add an NK1 antagonist for carboplatin with area under the curve of 4 or more.
• Low risk (paclitaxel, docetaxel, gemcitabine, fluorouracil, etoposide): a single agent: dexamethasone 8 mg, a 5HT3 antagonist or metoclopramide.
• Minimal risk: no routine prophylaxis.
• Breakthrough: add a drug from a different class: olanzapine 5 to 10 mg, metoclopramide 10 mg, haloperidol 0.5 to 2 mg, or prochlorperazine 10 mg; do not repeat the same 5HT3 antagonist; use intravenous or rectal routes if vomiting.
• Anticipatory: optimise prophylaxis from the first cycle; lorazepam 0.5 to 2 mg the night before and morning of chemotherapy.
• Oral chemotherapy and multi-day regimens: match prophylaxis to the emetic risk of the agent; give throughout and for 1 to 2 days after.
• Regional: where NK1 antagonists and palonosetron are unavailable or costly, use ondansetron or granisetron with dexamethasone and add olanzapine or metoclopramide.

Selection. Prefer once-daily oral dosing; check QT, constipation and CYP interactions; choose olanzapine 5 mg in older adults to limit sedation.

Contraindications. Metoclopramide in bowel obstruction, phaeochromocytoma and untreated seizures; ondansetron with congenital long QT syndrome or apomorphine; olanzapine with severe liver impairment and with dementia-related psychosis (caution); hypersensitivity.

Adverse effects. Constipation, headache, QT prolongation (ondansetron, especially intravenous 16 mg, with hypokalaemia or hypomagnesaemia), sedation (olanzapine, lorazepam), extrapyramidal reactions and akathisia (metoclopramide, haloperidol), hiccups, insomnia and hyperglycaemia (dexamethasone), and fatigue.

Interactions. Aprepitant inhibits CYP3A4 and induces CYP2C9: it reduces warfarin and hormonal contraceptive effect, raises dexamethasone, and affects many drugs; rifampicin and phenytoin lower aprepitant levels; ritonavir and azoles raise it; serotonergic drugs with ondansetron risk serotonin syndrome; olanzapine with benzodiazepines (sedation).

Special groups.

• Pregnancy: ondansetron has small possible risk in the first trimester; metoclopramide and doxylamine-based drugs are used when needed.
• Breastfeeding: ondansetron and dexamethasone are acceptable in short use.
• Children: ondansetron 0.15 mg/kg intravenously (maximum 16 mg); dexamethasone dose by surface area; aprepitant by weight band.
• Older adults: reduce olanzapine dose; avoid metoclopramide at high doses.
• Kidney impairment: no adjustment for most.
• Liver impairment: ondansetron maximum 8 mg daily in severe disease.

Monitoring. Frequency of vomiting and nausea scores, hydration, electrolytes, QT in at-risk patients, and bowel habit.

Referral and escalation. Persistent vomiting that prevents oral intake, dehydration, electrolyte disturbance, severe constipation or obstruction, and extrapyramidal reactions need review.