Dr. Weimer of Columbia University has received consulting fees from Roche.)
The taxanes (paclitaxel, docetaxel, cabazitaxel) are antineoplastic drugs that commonly cause a predominantly sensory axonal neuropathy, which may be reversible. Because myelosuppression is now treatable, neuropathy is often the dose-limiting factor in taxane-based chemotherapy regimens. Accumulating experience with the taxanes suggests that at equivalent antineoplastic doses, paclitaxel may be more likely to cause neuropathy than docetaxel. It has proven difficult to define a taxane dose below which neuropathy will not occur. There is some evidence that a preexisting neuropathy increases the risk of nerve injury with taxanes, and pharmacogenomic approaches to predict the risk of taxane neuropathy are being developed. The author reviews the current knowledge of taxane-associated peripheral neuropathy.
Historical note and terminology
The taxanes (paclitaxel, docetaxel, cabazitaxel) are antineoplastic agents derived from yew trees (genus Taxus). Paclitaxel is prepared from the bark of the Pacific yew (Taxus brevifolia), whereas docetaxel is produced by chemical modification of a molecule obtained from the needles of the European yew (Taxus baccata). Both compounds are used in the treatment of breast, ovarian, lung, and head and neck cancers. The combination of paclitaxel with cisplatin or carboplatin is now considered the standard treatment for advanced ovarian cancer (Rowinsky et al 1991a; Gelmon 1994; McGuire et al 1996; Ozols and Vermorken 1997; Vasey et al 2004). Taxane-anthracycline-cyclophosphamide combinations are now widely used for treatment of metastatic breast cancer (Ellis 2010). Docetaxel is now the front-line agent for castration-resistant prostate cancer (Figg 2010). Cabazitaxel is a new taxane that shows promise in tumors no longer responsive to docetaxel (Michielsen 2011). Another application of paclitaxel's antiproliferative properties is in coronary artery stents. Some studies have found that stents coated with microgram quantities of paclitaxel have reduced rates of coronary artery stenosis compared to conventional stents (Park et al 2003), although this finding was not confirmed subsequently (Laarman et al 2006).
The taxanes inhibit tubulin depolymerization, resulting in extremely large, stable, and dysfunctional microtubules (Schiff et al 1979; Debrabander et al 1981; Mole-Bajar and Bajar 1983). Because of the importance of microtubules in axonal transport and because of the experience with vincristine, another antimicrotubule drug, peripheral neuropathy was anticipated to be one of the major toxicities of the taxanes. Neurotoxicity was not apparent, however, in preclinical toxicology studies in mice, rats, and dogs; this may have been caused by the limitations of animal models in detecting a neuropathy. Paclitaxel was the first taxane to be used in phase I and II studies in humans (Lipton et al 1989; Holmes et al 1991; Rowinsky et al 1991a; Chaudhry et al 1994; Schiller et al 1994). Neuropathy has been observed regularly in patients treated with docetaxel (Hilkens et al 1996; New et al 1996). Since the advent of hematopoietic growth factors that ameliorate the neutropenia associated with taxane use, peripheral neuropathy has become the principal nonhematological toxicity limiting the use of high single and cumulative doses of paclitaxel or docetaxel (Rowinsky et al 1993; Chaudhry et al 1994; Apfel 1996; Argyriou et al 2008).
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