Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials.

Linda T Vahdat,Louise Yelle,Craig A Bunnell,Ronald A Peck,Monica N Fornier,Joseph A Sparano,Henri H Roché,Edith A Perez,Pralay Mukhopadhyay,Gabriel N Hortobagyi,Eva S Thomas,Miguel Martín

doi:10.1007/s00520-012-1384-0

Abstract

PurposeDose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile.MethodsWe searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies.ResultsRates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks.ConclusionsPN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays.Electronic supplementary materialThe online version of this article (doi:10.1007/s00520-012-1384-0) contains supplementary material, which is available to authorized users.

Highlights

Microtubules play a fundamental role in diverse cellular functions through a very complex dynamic process of polymerization and depolymerization
Incidences of grade 3/4 sensory Peripheral neuropathy (PN) in monotherapy studies ranged from 0% in taxane-naive patients to 14% in taxane, anthracyclines, and capecitabine-resistant patients depending on dose, schedule, and setting of administration
Grade 3 PN was reported in 20% of patients previously treated with anthracycline

Summary

Introduction

Microtubules play a fundamental role in diverse cellular functions (cell division, growth, motility) through a very complex dynamic process of polymerization and depolymerization. They have emerged as an important target for anticancer drugs. The success of the treatments with taxanes in breast cancer and in other tumor types has led to the development of new microtubule-stabilizing agents (MTSAs) as antineoplastic drugs [1]. The nature of PN may vary depending on the type of nerve fibers involved: sensory (manifested by paresthesia, numbness and pain in the feet and hands) [7, 8], motor (usually preceded by sensory neuropathy and usually mild with muscle weakness such as foot drop or difficulty in climbing stairs) [9, 10], or autonomic [rare, observed in less than 1% of patients with metastatic breast cancer (MBC)]. The incidence of grade 3/4 sensory PN in breast cancer patients treated with taxanes ranges from 0% to 33% and that of grade 3/4 motor neuropathy varies from 0% to 14% (Supplemental Table 1)

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Conclusion