title: Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials.
abstract: OBJECTIVE
  Dose-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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Rates 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.
  
  
  CONCLUSIONS
  PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays.
authors.affiliation: Weill Cornell Breast Center, Weill Cornell Medical College, New York, NY, USA. ltv2001@med.cornell.edu
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.forename: Eva S
authors.initials: ES
authors.lastname: Thomas
authors.forename: Henri H
authors.initials: HH
authors.lastname: Roché
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: Louise
authors.initials: L
authors.lastname: Yelle
authors.forename: Monica N
authors.initials: MN
authors.lastname: Fornier
authors.forename: Miguel
authors.initials: M
authors.lastname: Martín
authors.forename: Craig A
authors.initials: CA
authors.lastname: Bunnell
authors.forename: Pralay
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Peck
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000069287:Capecitabine; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D016208:Databases, Factual; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D016016:Proportional Hazards Models; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D034261:Epothilones; D050257:Tubulin Modulators; D003841:Deoxycytidine; D000069287:Capecitabine; C430592:ixabepilone; D005472:Fluorouracil