Taxanes

Taxanes bind the beta subunit of tubulin and stabilise polymerised microtubules, which blocks mitotic spindle function and arrests cells in G2 and M phases. They are among the most active drugs in breast, ovarian, non-small cell lung, prostate, gastric and head and neck cancers.

Classification. Paclitaxel (including albumin-bound paclitaxel), docetaxel, and cabazitaxel.

Pharmacokinetics. Hepatic metabolism: paclitaxel by CYP2C8 and CYP3A4, docetaxel and cabazitaxel by CYP3A4; biliary excretion. Paclitaxel and docetaxel are given in solvent vehicles that cause hypersensitivity.

• Paclitaxel 175 mg/m2 over 3 hours every 3 weeks, or 80 mg/m2 weekly; Kaposi sarcoma 100 mg/m2 every 2 weeks.
• Albumin-bound paclitaxel 125 mg/m2 on days 1, 8 and 15 every 28 days with gemcitabine (pancreatic cancer), or 260 mg/m2 every 3 weeks (breast cancer); no solvent premedication needed.
• Docetaxel 75 mg/m2 every 3 weeks (60 to 100 mg/m2 in different regimens).
• Cabazitaxel 25 mg/m2 every 3 weeks (20 mg/m2 in frail patients) with prednisolone 10 mg daily, for metastatic castration-resistant prostate cancer after docetaxel.

Premedication.

• Paclitaxel: dexamethasone 10 to 20 mg (oral 12 and 6 hours before or intravenous 30 minutes before), an antihistamine (chlorphenamine 10 mg intravenously), and an H2 blocker; reduced premedication is used in weekly regimens after the first doses.
• Docetaxel: dexamethasone 8 mg orally twice daily for 3 days starting the day before.

Differences. Paclitaxel: hypersensitivity, neuropathy, myalgia. Docetaxel: neutropenia, fluid retention, nail changes, epiphora. Cabazitaxel: neutropenia and diarrhoea.

• Breast cancer: adjuvant and metastatic; weekly paclitaxel has less neutropenia.
• Ovarian cancer: paclitaxel with carboplatin.
• Non-small cell lung cancer: paclitaxel with a platinum drug; docetaxel in second line.
• Prostate cancer: docetaxel with prednisolone 5 mg twice daily; cabazitaxel after docetaxel.
• Kaposi sarcoma: paclitaxel as an alternative to liposomal doxorubicin where available.
• Administration: paclitaxel needs non-PVC infusion sets and an in-line filter of 0.22 micron or less.

Selection. Docetaxel is contraindicated when bilirubin is over the upper limit of normal; weekly regimens when neutropenia is a concern.

Contraindications. Neutrophils under 1.5 x 10^9/L before a cycle; severe hypersensitivity to the drug or vehicle; docetaxel with bilirubin over the upper limit of normal, or AST or ALT over 1.5 times the upper limit with alkaline phosphatase over 2.5 times; pregnancy.

Adverse effects. Febrile neutropenia, hypersensitivity (usually within the first 10 minutes of the first or second dose), peripheral neuropathy, myalgia and arthralgia (paclitaxel acute pain syndrome), alopecia, fluid retention, pleural effusion and nail changes (docetaxel), cystoid macular oedema, and cardiac conduction abnormalities.

Interactions. CYP3A4 inhibitors raise docetaxel and cabazitaxel levels (avoid strong inhibitors including ritonavir-boosted regimens); CYP2C8 inhibitors (gemfibrozil) raise paclitaxel; CYP3A4 inducers reduce effect; give paclitaxel before platinum drugs to reduce neutropenia.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: limited use.
• Older adults: neuropathy and neutropenia risk higher; weekly dosing is often used.
• Kidney impairment: no adjustment.
• Liver impairment: reduce paclitaxel (175 mg/m2 to 135 mg/m2 or less when bilirubin is raised); avoid docetaxel when bilirubin is over the upper limit of normal.

Monitoring. Full blood count before each cycle, liver function, neuropathy grade, fluid balance and weight (docetaxel), and observation during the first 30 minutes of each infusion.

Referral and escalation. Hypersensitivity (stop infusion, give adrenaline 0.5 mg intramuscularly for anaphylaxis), febrile neutropenia, and grade 3 neuropathy need urgent care.