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Peripheral neuropathy - Dr Shirley Wong
Chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 38% of patients undergoing treatment, particularly with agents like paclitaxel and docetaxel, leading to symptoms that can severely impact daily activities. CIPN can start weeks after chemotherapy begins and may be reversible, though treatment options remain limited and preventative strategies lack solid evidence. Overall, there is no proven association between CIPN and cancer treatment outcomes, highlighting the need for increased focus on prevention and management strategies.
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Peripheral neuropathy - Dr Shirley Wong
- 1. Neuropathy Complication of Chemotherapy inWomens’ Cancers Dr Shirley Wong Consultant Medical Oncologist Breast Unit Western Health
- 2. Chemotherapy- Induced Peripheral Neuropathy(CIPN) • Not all chemotherapy induced neuropathy • Platinum compounds • Taxanes • Vinca Alkaloids • Thalidomide and Lenalidomide • Bortezomib • Ixabepilone
- 3. Chemotherapy- Induced Peripheral Neuropathy(CIPN) • Overall incidence 38% • Grading of severity – Grade1 – reported symptoms – Grade2 – interference with function – Grade3 – interference with ADLs – Grade4 – permanent and debilitating • Observed in 60% of patients 1 month after treatment and 30% of patients 6 months after the treatment
- 4. MicroTubule-Stabilizing Agents – Paclitaxel/Docetaxol •“Unique” complication associated with microtubule-stabilizing drugs – paclitaxel and docetaxol • Uses commonly in breast/ovary/lung /Head & Neck cancers • Reported to some degree in up to 70% of patients (Pachman 2011) • Reported up to 30% of patients experience severe symptoms at high cumulative doses (Carlson 2011) • 3% patients discontinued drug • Median days for improvement 22 days to 13 weeks
- 5. MicroTubule-Stabilizing Agents – Paclitaxel/Docetaxol •More frequent in paclitaxel- than docetaxol- based chemotherapy • Therapeutic effect by binding to microtubules in dividing cells, suppress dynamic instability, lead to arrest of mitosis and ultimately apoptosis (Cell Death) • Not cross blood-brain barrier so no effect on CNS • Not affect autonomic nervous system • Affects peripheral nervous system, predominatly sensory nerve fibres (larger fibres than motor fibres)
- 6. MicroTubule-Stabilizing Agents – Paclitaxel/Docetaxol •Pathology of axonal degeneration, demyelination and nerve fibres losses • Irreversible damage if nerve fibres death • Exact sites of damages not clear ?nerve sheaths ? axons ? cell bodies ? multiple sites of injury
- 7. MicroTubule-Stabilizing Agents – Paclitaxel/Docetaxol •Mechanism of nerve damage – Multifactorial / not entirely clear • If the damage related to direct effect of taxane binding to neurons, maybe impossible to prevent neuropathy while preserving the chemotherapeutic effectiveness • Otherwise ?indirect toxicity from drug-induced metabolic derangements
- 8. Paclitaxel-Acute Pain Syndrome (P-APS) •Paclitaxel –induced arthralgias and myalgias, described in up to almost 60% patients, develops within 1-3 days of drug administration largely resolved within 1 week • Related to sensitization of mechanical pain reception neurons, rather from musculoskeletal or joint pathology • Unpredictable with subsequent cycles • Increased incidence of subsequent sensory neuropathy • Not associated with rate of infusion and dose of paclitaxel • ?gabapentin useful
- 9. Risk Factors • Pre-existingneuropathy eg, diabetic neuropathy, alcoholism • Genetic makeup • Dose and schedule of the chemotherapies
- 10. Natural History ofCIPN • May begin weeks to months after the initiation of chemotherapy • Often totally reversible sometimes only partially reversible, can remained for years • Dose limiting toxicity • Potential confusion symptoms with met disease, paraneoplastic symptoms or co-morbidity
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- 12. Clinical Presentations • LooksNORMAL • sensory > motor neuropathy • Sensory neuropathy – tingling, numbness, paresthesias, hyperalgesia and pain in the feet and hands – more on plantar surfaces • Motor neuropathy – proximal weakness like difficulty getting up from chair or climbing up stairs – distal weakness like impaired fine motor skills • Interference of daily activities
- 13. Clinical Presentations • acuteonset, tingling in fingertips and toes may be within 24 hours after paclitaxel infusion • late onset, pain involves muscles and joints of lower limbs can occur up to 2-4 days after paclitaxel infusion • most intermittently • Loss of vibration and proprioception senses first
- 14. Prevention • Amifostine – IVbinding agent to neurotoxic metabolites from platinum compounds – No consistent convincing supportive data – Limited by nausea, vomiting and light-headedness – Not available in PBS Australia
- 15. Prevention • Anticonvulsants – Smallsized clinical trials in patients received oxaliplatin based chemotherapy – One study reported 58% reduction in CIPNs but uncertain – Not used as prevention in clinical practices
- 16. Prevention • Serotonin-Norepinephrine reuptakeInhibitors (SSRIs) – Analgesic effect – Randomised-placebo-controlled trial of 54 cancer patients receiving oxaliplatin based chemotherapy – Venlafaxine (Effexor) 50mg 1 hr before chemo then extended release Venlafaxine 37.5mg twice daily Day 2-11 – Significantly better in venlafaxine arm even 3 months after the end of treatment – Reported adverse events of nausea, vomiting and somnolence – – No reported influences of venlafaxine on the anticancer effect of oxaliplatin
- 17. Prevention • Vitamin E –Antioxidant effect – Benefit not shown in phase III trial of >200 patients • Calcium and Magnesium – Increase extracellular Ca and hence reduce the hyperexcitability of neurons – In 2007, CONcePT trial of prevention of CIPN by FOLFOX, terminated prematurely after 140 patients, related to unexpected low tumour response rates in patients receiving IV Ca + Mg then those receiving placebo – ??use cautiously
- 18. Treatment • Opioids noteffective in treating pain by CIPN • Adjuvant analgesics – Topical agents – Antidepressants – Anticonvulsants • Modification of chemotherapy – Reducing the dose of chemotherapy – Changing the chemotherapy
- 19. Treatment • Topical Agents –Localised anesthetic properties – Lignocaine, NSAIDs, amitriptyline and ketamine in various combinations and concentrations – Short temporary relief – Minimal systemic absorption
- 20. Treatment • Tricyclic Antidepressant –Few small studies not powerful enough to show the benefit – Intolerable side effects – dry mouth, drowsiness, weight gain and hypotension – Not much use in clinical settings
- 21. Treatment • Duloxetine – Fortreatment of depression PBS in Australia – Daily dose of 30mg then escalated to 60mg daily after one week – Moderate side effects with high 1% dropout rate • Dzziness,nausea, somnolence, restlessness, insomnia, urinary hesistancy – Reported improvement in pain scores, improvement in daily activities and QoL in numerous clinical trials (Yang 2012, Matsuoka 2012, Smith 2013 )
- 22. Treatment • Anticonvulsants – Gabapentin,Pregablin • Numerious studies failed to show beneficial effects to pain by CIPN • Intolerable side effects – drowsiness, dizziness, peripheral edema, weight gain, dry mouths • Increasingly used
- 23. Association of CIPNwith Clinical Outcomes • An analysis of 4500 women treated with taxanes in early stage breast Ca • Grade 2-4 peripheral neuropathy reported 13-20% of patients • Matching all other factors including age, race, obesity, menopausal status, tumour size, nodal status, treatment and hyperglycaemia • No association between taxane-induced neuropathy and survival (OS and DFS)
- 24. Conclusion • Increasing complaintsdue to increased use of taxanes and platinum- based chemotherapies in multiple cancers • Spectrum of clinical severity – Mild intermittent to debilitating in ADLs • Fully reversible in most cases if reported early • Treatment options improving • Increasing focus on prevention options • No proven association between CIPN and clinical outcome of cancer treatment
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