Chemotherapy-Induced Peripheral Neuropathy

by Efstathia Tzatha, MD

Associate Professor of Neurology

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Importance of CIPN

For some patients, the side effects and deficits caused by CIPN are so severe that they impair daily function and diminish quality of life

CIPN can result in chemotherapy dose reductions or early treatment discontinuation, compromising effective cancer treatment and patient survival

Profession-specific disability: especially important for patients who are engaged in professions or activities requiring intact sensory and motor functions, as well as fine control of the hands (e.g., dentist, pianist/professional musician, carpenter, jewelry maker) or feet (e.g., professional driver)

Prevalence

In a recent meta-analysis of 31 studies of CIPN involving a total of 4,179 patients, the aggregate prevalence of CIPN was 48 percent

Within the first month after the patients completed chemotherapy, 68 percent had CIPN; the prevalence decreased to 30 percent after 6 months

Seretny M, Currie GL, Sena ES, et al  Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis  Pain  2014;155:2461-70

Prevalence assessments of CIPN must take into account:

  • chemotherapy regimen administered
  • duration of patient exposure to the neurotoxic agent(s)
  • evaluation methods used 

Causes of CIPN

Possible neurotoxic mechanisms

  • Excessive oxidative stress
  • Mitochondrial damage with energy failure
  • Interference with axonal transport
  • Lack of trophic support
  • Immune mediated response

Chemotherapy agents that can cause CIPN

  • Platinum-based (cisplatin, oxaliplatin)
  • Vinca alkaloids (vincristine, vinorelbine, vinblastine)
  • Taxanes (paclitaxel, docetaxel)
  • Eribulin
  • Ixabepilone
  • Proteasome inhibitors (bortezomib)
  • Thalidomide, lenalidomide, pomalidomide
  • Biologics (ipilimumab, nivolumab) 

Presentation of CIPN

Classic presentation

  • Symmetric
  • Predominantly sensory
  • Distal sensory loss/paresthesias (stocking-, glove-, or length-dependent)

Common presenting symptoms

  • Paresthesias/positive symptoms: burning, tingling and sharp pain
  • Numbness/negative symptoms: loss of sensation
  • Impaired balance/ataxia

Drug-specific symptoms

  • Cisplatin, oxaliplatin: ataxia, “coasting effect”
  • Vincristine: distal motor impairment (foot drop), autonomic symptoms, “coasting effect”, cranial neuropathies
  • Paclitaxel: prominent small fiber neuropathy (“burning”)        
  • Ipilimumab, nivolumab: prominent motor involvement (weakness, muscle atrophy)

There is great individual variability in the onset, severity, and duration of symptoms

Individual genetic variations or polymorphisms may explain the wide spectrum of vulnerability to CIPN from a given agent  Numerous genes have been investigated (GSTP1, CYP2C8, and AGXT) but the findings are inconclusive

National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading scale

Total Neuropathy Scores

EORTC QLQ-C30 with CIPN20 module

Patient-reported outcome measures

Preventing CIPN

No high-quality studies demonstrate effective prevention of CIPN using any agent

The latest guidelines from the American Society of Clinical Oncology (ASCO) acknowledge this limitation and recommend against offering any CIPN-preventive drug to patients undergoing neurotoxic cancer treatment

Optimize/correct co-existing risk factors for neuropathy prior to initiating neurotoxic chemotherapy (HbA1C, B12/B1 deficiency, B6 intoxication, thyroid abnormalities)

Cryotherapy is showing promising results for preventing CIPN from paclitaxel

Educate patients against unnecessary use of vitamin supplements (especially B6)

Diagnosis of CIPN

Early and accurate diagnosis of CIPN is crucial

  • Enables dose adjustment of chemotherapy to prevent worsening of peripheral neuropathy  
  • Overdiagnosis may compromise treatment with an otherwise beneficial chemotherapy regimen, negatively affecting cancer outcomes and survival

In a study of 55 breast cancer patients referred for electrodiagnostic studies due to symptoms suggesting possible taxane-related polyneuropathy, 33 percent had no electrophysiologic evidence of polyneuropathy or showed only focal entrapment neuropathy (carpal tunnel syndrome); 67 percent had a large fiber polyneuropathy

Chen X, Stubblefield M, Custodio C, et al  Electrophysiological features of taxane-induced polyneuropathy in patients with breast cancer  J Clin Neurophysiol  2013;30:199-203  

Diagnosis is based on:   

  • Timing/onset of symptoms
  • Complete neurological examination
  • Nerve conduction studies/Electromyography (NCS/EMG) for selected patients (objective predictive measurement of the severity of peripheral nerve damage and therefore can be used to prognosticate neurologic recovery) 

Is It Really CIPN?

Question the diagnosis if:

  • Progression of the symptoms does not follow the expected gradual, distal, symmetric, stocking-, glove distribution
  • Symptoms appear much earlier than expected for the particular agent and dosing schedule
  • One limb only is affected
  • One side of the body only is affected
  • Motor symptoms only are present     
  • Hands are affected more than feet
  • Coexisting neck or back pain

Treating CIPN

ASCO guidelines:

  • Clinicians may offer duloxetine to symptomatic patients
  • Should consider offering tricyclic antidepressants, gabapentin, or pregabalin
  • Educate patients about expectations and limitations of the pharmacologic treatments (only effective for positive symptoms, not for numbness)
  • Use appropriate doses and titration schedule:
  • Gabapentin: start at 300 mg at bedtime and increase by 300mg every 5-7 days, up to 600 mg every 8 hrs, maximum effective dose is usually 900 mg every 8 hrs  Warn/educate patient about fatigue, sleepiness  Better not to drive the next morning (start on a weekend)
  • Duloxetine: start at 30 mg daily for one week and then increase to 60 mg daily  Most common side effects are diarrhea and headache

Physical and occupational therapy

  • Don’t underestimate the benefits
  • Refer the patients early
  • Refer specifically for gait training and balance
  • Educate patient about falls risk/precautions
  • Prognosis and recovery depends on severity
  • Most patients improve over time but some deficits (especially numbness) can be permanent
  • Recovery is slow and depends on severity (slow improvement for up to 2 years)