1. Taxane neuropathy: clinical features, mechanisms and methods of assessment

2.  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

3. Park et al., 2008 Curr Med Chem

8. 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

9. 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 01234 National Cancer Institute – Common Toxicity Criteria for Adverse Events

13. 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

14. Oxaliplatin vs. Paclitaxel  Differences in time course of CSAP decline 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 Baseline Month 1 Month 2 Month 3 Final Normalised peak CSAP Oxaliplatin Paclitaxel ‘Coasting’ Axonal transport dysfunction? Park et al. 2010 Muscle & Nerve

16.  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

18. Initial Treatment Final Treatment -200 -100 0 100 Threshold reduction 0100200 Delay (ms) (%) TEh 90-100ms -50 0 50 10100 Interstimulus interval (ms) Threshold change (%) Refractoriness Superexcitability PACLITAXEL OXALIPLATIN

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