Peripheral neuropathy is a side effect of some cancer treatments and can result in pain, tingling or numbness in the area affected. Consultant Medical Oncologist Shirley Wong presented on why it happens, risk factors and what can be done to help. A BreaCan presentation held at Sunshine Hospital on 25 August 2016.

1. Neuropathy
Complication of Chemotherapy
in Womens’ 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-existing neuropathy eg, diabetic
neuropathy, alcoholism
• Genetic makeup
• Dose and schedule of the chemotherapies

10. Natural History of CIPN
• 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

11. Clinical Presentations

12. Clinical Presentations
• Looks NORMAL
• 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
• acute onset, 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
– IV binding 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
– Small sized 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 reuptake Inhibitors (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 not effective 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
– For treatment 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 CIPN with 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 complaints due 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

25. Thank you!