Antimicrotubular agents

Mechanism and Class Overview

• Class mechanism: Both classes disrupt the mitotic spindle and arrest cells in M phase, but by opposite actions on tubulin. Taxanes bind microtubules and ↑ tubulin polymerization (stabilize), while vinca alkaloids prevent polymerization of tubulin dimers and ↓ microtubule formation.
• Resistance: Altered tubulin and the MDR phenotype (P170 glycoprotein ↑ drug efflux; cabazitaxel has low P170 affinity, so largely retains activity).

Taxanes

• Class handling: Metabolized in the liver via P450, so dose reduce with hepatic dysfunction. Cisplatin before paclitaxel lowers paclitaxel clearance (~33%) and raises myelosuppression, so give paclitaxel first; this interaction is not a class effect (carboplatin and docetaxel not similarly affected), but by convention paclitaxel before the platinum is used for all combinations. All taxanes cause alopecia and are low emetogenic.

Paclitaxel (Taxol)

• Mechanism: Binds beta-tubulin, ↑ polymerization and stabilizes microtubules, M-phase arrest.
• Indications: Ovarian, breast, lung, Kaposi sarcoma, and other solid tumors.
• Hypersensitivity: From the cremophor solvent/vehicle; premedicate with dexamethasone plus H1 and H2 antagonists.
• Toxicities: Delayed myelosuppression (~10 d), cardiotoxicity (bradycardia and other arrhythmias; caution in CHF, prior arrhythmia, or MI within 6 months), and dose-dependent peripheral sensory neuropathy (higher risk with diabetes, alcohol use, low folate, low B12). Reduce dose ~20% for severe neuropathy or myelosuppression.

Nab-paclitaxel (Abraxane)

• Mechanism: Albumin-bound nanoparticle paclitaxel with albumin-bound, cremophor-free; proposed enhanced delivery via gp60/caveolae endothelial transport (not tumor-cell albumin receptors) (no cremophor).
• Indications: Breast, lung, and pancreatic cancers.
• Toxicities: ↓ myelosuppression and little or no hypersensitivity versus solvent-based paclitaxel, but more peripheral neuropathy.

Docetaxel (Taxotere)

• Mechanism: Semisynthetic paclitaxel derivative; more potent (poor CNS penetration, like paclitaxel). Vehicle is polysorbate 80; premedicate with dexamethasone 8 mg BID for 3 days starting the day before (mCRPC with prednisone: 8 mg at 12, 3, and 1 h before). Consider dose adjustment if AST/ALT > 1.5x.
• Indications: Breast, lung, prostate, gastric, and head and neck cancers.
• Fluid retention: Distinctive toxicity, with peripheral edema, pleural effusion, ascites, and pericardial effusion from ↑ capillary permeability. Glucocorticoid premedication dexamethasone 8 mg BID for 3 days (day before, day of, day after) reduces the rate.
• Toxicities: Delayed myelosuppression, maculopapular rash, hand-foot syndrome, nail changes, GI symptoms, excessive tearing (lacrimal duct obstruction), with much less neurotoxicity and hypersensitivity than paclitaxel.

Cabazitaxel (Jevtana)

• Mechanism: Taxane with low affinity for P170 (P-gp): active in docetaxel-resistant disease, but still a P-gp substrate.
• Indications: Metastatic castration-resistant prostate cancer after docetaxel.
• Toxicities: Myelosuppression, severe diarrhea, and hypersensitivity from the polysorbate 80 vehicle (premedicate with dexamethasone plus H1 and H2 antagonists).

Vinca Alkaloids

• Class handling: Metabolized in the liver via P450, so dose reduce with hepatic dysfunction (especially biliary obstruction). All can cause SIADH.

Vincristine (Oncovin)

• Mechanism: Prevents tubulin polymerization; high affinity for axonal microtubules.
• Never intrathecal: Intrathecal administration is almost always fatal (rare survival after immediate CSF drainage/irrigation, with severe sequelae); IV route only, a classic never-event (ascending encephalomyelopathy). Vincristine is given by the IV route only; this is a classic never-event.
• Toxicities: Dominant dose-limiting neuropathy, usually sensory but can include cranial palsies, hoarseness, facial droop, ileus/small-bowel obstruction, urinary retention, and constipation (start a bowel regimen). Also SIADH; vesicant; myelosuppression is mild.

Vinblastine (Velban)

• Indications: Hodgkin lymphoma (ABVD), testicular cancer.
• Toxicities: Myelosuppression (more than vincristine), less neurotoxicity, SIADH, alopecia, mucositis. Vesicant.

Vinorelbine (Navelbine)

• Indications: NSCLC, breast cancer.
• Toxicities: Myelosuppression (dose-limiting), much less neurotoxicity, SIADH, alopecia, mucositis. Vesicant.

Others

Eribulin (Halaven)

• Mechanism: Inhibits microtubule growth, ↓ microtubule function, G2/M arrest.
• Indications: Metastatic breast cancer, liposarcoma.
• Toxicities: Myelosuppression, peripheral neuropathy, and QTc prolongation (monitor EKG).

Ixabepilone (Ixempra)

• Mechanism: Epothilone that binds the beta-tubulin subunit; low (not absent) susceptibility to P170/efflux and some tubulin alterations; remains a P-gp substrate, retaining activity after many taxane failures, so it is used after taxane progression. Metabolized by liver P450 (attention to inhibitors and inducers).
• Indications: Relapsed/refractory metastatic breast cancer.
• Toxicities: Delayed myelosuppression (~10 d), hypersensitivity from the cremophor vehicle (premedicate with H1 and H2 antagonists ~1 h before; add a corticosteroid only after a prior hypersensitivity reaction), and peripheral neuropathy.

MMAE (vedotin)

• Mechanism: Monomethyl auristatin E (the "vedotin" payload) ↓ microtubule networks; delivered as the cytotoxic payload of antibody-drug conjugates such as brentuximab vedotin and polatuzumab vedotin.