Microtubule Inhibitors

Microtubule inhibitors bind tubulin and disrupt the mitotic spindle, arresting cells in M phase and causing apoptosis. They also disrupt axonal transport, which explains peripheral neuropathy. They are active across solid tumours and lymphoid cancers.

Classification. Vinca alkaloids (vincristine, vinblastine, vinorelbine; polymerisation inhibitors), taxanes (paclitaxel, docetaxel, cabazitaxel; stabilisers of polymerised tubulin), and others (eribulin, ixabepilone).

Pharmacokinetics. Hepatic metabolism by CYP3A4 and biliary excretion, so liver dysfunction and CYP3A4 inhibitors increase toxicity. They are substrates of P-glycoprotein, a main route of resistance.

• Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously every 1 to 3 weeks.
• Vinorelbine 25 to 30 mg/m2 intravenously weekly; oral 60 mg/m2 weekly for 3 weeks then 80 mg/m2.
• Paclitaxel 175 mg/m2 every 3 weeks, or 80 mg/m2 weekly.
• Docetaxel 75 mg/m2 every 3 weeks.
• Cabazitaxel 20 to 25 mg/m2 every 3 weeks with prednisolone.
• Eribulin 1.4 mg/m2 on days 1 and 8 every 21 days.
• Ixabepilone 40 mg/m2 every 3 weeks.

Differences. Vincristine is mainly neurotoxic and spares marrow; vinorelbine and vinblastine cause neutropenia; taxanes cause hypersensitivity (paclitaxel), fluid retention (docetaxel) and neutropenia; eribulin and ixabepilone are second-line options in breast cancer.

• Lymphoma, leukaemia, Wilms tumour, rhabdomyosarcoma, Burkitt lymphoma: vincristine in combination.
• Breast, ovarian, lung, prostate and head and neck cancer: taxanes.
• Non-small cell lung cancer and breast cancer: vinorelbine.
• Resistance: taxane and vinca resistance can be cross-resistance through P-glycoprotein; eribulin and ixabepilone partly overcome it.
• Safety rules: vinca alkaloids are fatal if given intrathecally; dispense in a minibag, never in a syringe, and label "for intravenous use only, fatal if given by other routes".

Selection. Assess baseline neuropathy; weekly taxane schedules reduce neutropenia but add cumulative neuropathy.

Contraindications. Severe marrow failure, severe neuropathy, severe liver impairment, and pregnancy.

Adverse effects. Peripheral sensory and motor neuropathy, autonomic neuropathy with constipation and ileus (vinca alkaloids), neutropenia, alopecia, myalgia and arthralgia (taxanes), hypersensitivity (paclitaxel), fluid retention and nail toxicity (docetaxel), and vesicant injury (vinca alkaloids).

Interactions. CYP3A4 inhibitors (azoles, macrolides, ritonavir- and cobicistat-boosted regimens) can cause fatal neurotoxicity with vinca alkaloids; CYP3A4 inducers lower levels.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: vincristine is dosed by weight in infants.
• Older adults: neuropathy and neutropenia are more common.
• Kidney impairment: little adjustment.
• Liver impairment: reduce all; avoid in severe impairment.

Monitoring. Neuropathy grading and bowel habit each cycle, full blood count, bilirubin and liver enzymes, and infusion reactions.

Referral and escalation. Grade 3 neuropathy, paralytic ileus, intrathecal administration (neurosurgical emergency), and extravasation need urgent care.