Taxane neuropathy: clinical features, mechanisms and methods of assessment

 Dose-dependent distal sensory neuropathy with numbness and paresthesia in extremities  Motor involvement in severe cases  Symptoms may be long-lasting  Proposed mechanisms include disruption of axonal transport

Park et al., 2008 Curr Med Chem

71% reported neuropathic symptoms Developed after mean of 6 weeks of treatment Most reported simultaneous onset UL and LL symptoms 63% reported no improvement at follow-up

NoneAsymptomatic; loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function Sensory alteration or paresthesia (including tingling), interfering with function, but not interfering with ADL Sensory alteration of paresthesia interfering with ADL Disabling National Cancer Institute – Common Toxicity Criteria for Adverse Events

Conventional nerve conduction studies (NCS) use supramaximal stimuli to assess: Conventional nerve conduction studies (NCS) use supramaximal stimuli to assess: Amplitude (= number conducting fibres) Amplitude (= number conducting fibres) Latency (= the velocity of the fastest fibres) Latency (= the velocity of the fastest fibres) demyelinating axonal

Oxaliplatin vs. Paclitaxel  Differences in time course of CSAP decline Baseline Month 1 Month 2 Month 3 Final Normalised peak CSAP Oxaliplatin Paclitaxel ‘Coasting’ Axonal transport dysfunction? Park et al Muscle & Nerve

 Novel threshold tracking techniques  Evaluates determinants of membrane potential and ion channel function in vivo  Parameters sensitive to change prior to axonal loss  Assess both motor and sensory function STIMULATING RECORDING

Initial Treatment Final Treatment Threshold reduction Delay (ms) (%) TEh ms Interstimulus interval (ms) Threshold change (%) Refractoriness Superexcitability PACLITAXEL OXALIPLATIN

Neurology  Matthew Kiernan  Susanna Park  Cindy Lin  Jenna Murray  Hannah Pickering Medical Oncology  Michael Friedlander  David Goldstein  NHMRC