Chemotherapy Hypersensitivity

Chemotherapy hypersensitivity is an infusion related reaction to a cytotoxic drug. It includes IgE-mediated allergy, cytokine release and complement mediated reactions, and can limit treatment unless the drug is continued by desensitisation.

Pathophysiology. Taxanes (paclitaxel, docetaxel) cause reactions at the first or second exposure, from vehicle (Cremophor, polysorbate 80) activation of complement and mast cells. Platinum drugs (carboplatin, oxaliplatin, cisplatin) cause IgE-mediated allergy after repeated cycles (usually 6 or more). Others include etoposide, asparaginase, liposomal doxorubicin (complement activation related pseudoallergy), and monoclonal antibodies (cytokine release).

Reactions occur in up to 10% of patients on paclitaxel without premedication, and about 1 to 2% with premedication. Platinum allergy rises with cumulative cycles.

Reactions are graded from mild (flushing, itching) to severe (hypotension, bronchospasm, anaphylaxis).

• Flushing, itching, rash and urticaria during infusion
• Back and chest pain, dyspnoea, tightness
• Fever, rigors and headache (cytokine release)
• Hypotension, bronchospasm, wheeze
• Anaphylaxis with loss of consciousness
• Onset in minutes, usually in the first 10 to 30 minutes of infusion
• Platinum reactions late in the course, after repeated exposures

• History: drug, cycle number, time to onset, features, severity, premedication given, and infusion rate.
• Classification: immediate (within 6 hours) versus delayed; type 1 (IgE), cytokine release, or complement mediated; severity grade.
• Serum tryptase within 1 to 2 hours of the reaction, with a baseline later. Tryptase may be normal in non-IgE reactions.
• Skin testing: prick and intradermal tests with the culprit drug at non-irritant dilutions (platinum drugs, taxane vehicle) in specialist centres.
• Specific IgE is not widely available.

Differential diagnosis.

• Infusion related reaction without allergy (cytokine release)
• Anaphylaxis to a co-administered drug (antiemetic, antibiotic, contrast)
• Cardiac event or pulmonary embolism
• Tumour lysis syndrome and sepsis
• Mast cell disorder
• Vasovagal and anxiety reaction

• Stop the infusion immediately and treat by severity.
• Mild reaction: chlorphenamine 10 mg intravenously and hydrocortisone 100 mg intravenously, and when symptoms settle restart at half the rate for 15 minutes, then increase gradually.
• Severe reaction or anaphylaxis: adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) into the anterolateral thigh, repeated after 5 minutes if no improvement, plus oxygen, intravenous fluids and observation for at least 6 hours.
• Premedication for taxanes: dexamethasone 20 mg intravenously (or 20 mg orally 12 and 6 hours before), chlorphenamine 10 mg intravenously and famotidine 20 mg intravenously 30 minutes before paclitaxel. Docetaxel uses dexamethasone 8 mg orally twice daily for 3 days starting the day before.
• Platinum allergy: carboplatin and oxaliplatin reactions need testing, and then rapid drug desensitisation (a multi-step, 12-step infusion in 3 bags with stepwise concentration and rate increases, in a monitored unit with premedication) allows treatment to continue. Switching to a different platinum agent is not always safe.
• Other agents: change to an alternative formulation (for example nab paclitaxel for paclitaxel vehicle reactions) when possible.
• Complement mediated reactions (liposomal doxorubicin): slower infusion, premedication and the first infusion at a low rate.
• Document the reaction and the plan for all future cycles.

Special groups.

• Patients with a history of severe reaction: oncology and allergy teams jointly decide on desensitisation versus an alternative regimen.

Monitoring. Observe in a unit with resuscitation facilities for the first doses after reaction. Check vital signs every 15 minutes during infusion.

Referral and escalation. Refer to allergy or a drug desensitisation service for any reaction beyond mild, and for platinum reactions. Emergency for anaphylaxis.