Vincristine: vinca alkaloid mitotic inhibitor in oncology

Vincristine (brand names Oncovin, generic) is a mitotic inhibitor in the class of vinca alkaloids, originally isolated from the Madagascar periwinkle (Catharanthus roseus). It was first used clinically in 1963 in leukaemia and has been an essential building block of many chemotherapy protocols ever since, particularly in paediatrics and haematological malignancies.

Compared with its sister substance vinblastine, vincristine is markedly more neurotoxic but less myelotoxic. This property makes it especially valuable in combination protocols that already cause heavy bone marrow suppression, while at the same time limiting the maximum single dose that can be given.

Mechanism of action

Vincristine binds to tubulin and prevents its polymerisation into microtubules. Microtubules are essential components of the mitotic spindle, which separates chromosomes during cell division. If the spindle cannot be assembled correctly, mitosis arrests at metaphase and apoptosis is triggered.

Rapidly dividing cells such as tumour cells are particularly sensitive to this effect. In contrast to paclitaxel, which stabilises microtubules, vincristine destabilises them. Both routes lead to mitotic arrest but with different toxicity profiles.

Microtubules are not only essential during mitosis but also for axonal transport in nerve cells. This explains the typical vinca neurotoxicity: polyneuropathy is the dose-limiting side effect of vincristine.

Indications

• Acute lymphoblastic leukaemia (ALL): vincristine is a standard component of all paediatric and adult protocols
• Hodgkin lymphoma: in regimens such as BEACOPP or Stanford V
• Non-Hodgkin lymphomas: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is standard in aggressive B-cell lymphomas
• Multiple myeloma: formerly in VAD regimens, now rare
• Solid tumours: Wilms tumour, neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, small-cell lung cancer
• Idiopathic thrombocytopenic purpura (ITP): in rare cases as an immunomodulating reserve

Dosing and administration

Standard dose: 1.4 mg per m² body surface area weekly, intravenously as bolus or short infusion. Maximum single dose: 2 mg, regardless of body surface area, to avoid severe neurotoxicity.

Paediatrics: usually 1.5 mg per m², lower dose cap in infants.

Route of administration: intravenous only. Intrathecal administration is absolutely contraindicated and has caused fatal mix-ups in the past. The WHO and EMA therefore recommend administration in a mini-bag (50 ml NaCl 0.9 %) rather than as a bolus, to make accidental intrathecal use practically impossible.

Vesicant: vincristine causes tissue necrosis on extravasation. On suspicion of extravasation stop the infusion immediately, aspirate through the cannula, give hyaluronidase as antidote and apply warmth.

Side effects

Very common: peripheral sensorimotor polyneuropathy (paraesthesia, areflexia, weakness, loss of vibration sense), constipation up to paralytic ileus (autonomic neuropathy), alopecia, nausea, vomiting, jaw pain, mild bone marrow suppression.

Common: hyponatraemia from SIADH, hypertension or hypotension, mild hepatotoxicity, pain at the infusion site, stomatitis, diarrhoea.

Uncommon: autonomic dysfunction (bladder issues, orthostatic reactions), cranial nerve deficits (optic neuritis, vocal cord paresis), seizures, more severe than usual marrow suppression, allergic reactions.

Rare: tumour lysis syndrome, ischaemic heart damage, irreversible polyneuropathy, septic toxic shock with neutropenia, cardiomyopathy in high-dose therapy.

Notes on polyneuropathy:

• Early signs are loss of Achilles reflexes and distal paraesthesia
• With clinically relevant symptoms the dose is reduced or paused
• Full recovery can take months to years and is not always achievable
• Pre-existing neuropathies (e.g. in diabetes) increase the risk

Interactions

• Strong CYP3A4 inhibitors (itraconazole, voriconazole, posaconazole, erythromycin, HIV protease inhibitors): dramatic level rises with life-threatening neurotoxicity, avoid where possible
• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): loss of efficacy
• P-glycoprotein inhibitors (verapamil, ciclosporin, tacrolimus): raised levels, caution
• Other neurotoxic substances (cisplatin, paclitaxel, bortezomib): additive polyneuropathy
• Live vaccines: contraindicated during and for several months after therapy
• Asparaginase: increased vincristine toxicity, hence timing in protocols

Special considerations

Pregnancy: contraindicated, markedly teratogenic. Reliable contraception during and for at least 6 months after therapy in both sexes.

Breastfeeding: contraindicated.

Fertility: vincristine can impair fertility; counselling on fertility preservation (cryopreservation of sperm or oocytes) before therapy is sensible.

In hepatic impairment: dose reduction is required, since hepatic metabolism and biliary elimination dominate.

Constipation prevention: high-fibre diet, adequate fluid intake, prophylactic laxatives (e.g. macrogol, lactulose) from the start of therapy, since paralytic ileus is a serious complication.

Safety culture: because of the absolute contraindication to intrathecal use, many centres apply a four-eyes principle for mixing and giving the drug; labels carry explicit warning signs.

Related substances

• Vinblastin, sister substance with a different toxicity profile
• Paclitaxel, microtubule-stabilising mitotic inhibitor
• Methotrexat, antimetabolite standard in many regimens
• Etoposid, topoisomerase 2 inhibitor

Frequently asked questions

Sources

• EMA European Medicines Agency
• BfArM Federal Institute for Drugs and Medical Devices
• AWMF oncology guidelines
• Gelbe Liste vincristine monograph