Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Original Editor - Lucinda hampton

Top Contributors - Lucinda hampton and Mason Trauger  

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) commonly occurs as an adverse event following chemotherapy.

• Typically presents as: Pain, burning, tingling, and loss of sensation in the distal extremities that spread from the hands and feet.
• Typically spreads in a “stocking-glove pattern”
• Causative agents include platinum-based medications (e.g., cisplatin), taxanes (e.g., paclitaxel), and vinca alkaloids (e.g., vincristine).

Although CIPN's predominately affects sensory nerves, there can also be motor and/or autonomic involvement.

Currently there is no gold standard for diagnosis, no proven ways to lessen or stop this condition and treatment strategies are limited.

CIPN regularly impacts chemotherapy, occasionally requiring the dose to be reduced or treatment ceased, effecting survival rates. Around 30% of patients will still have CIPN a year or more post chemotherapy.

Physiotherapy, in the form of exercise therapy, has been shown to have a role in reducing symptoms in CIPN.

Risk Factors

Chemotherapy Agents

The prescribing oncologist selects chemotherapy treatments that they deem to be most appropriate for each patient's diagnosis, prognosis, etc. However, the type, cumulative dose, number of treatment cycles (and their duration) of the selected chemotherapeutic agent can increase the risk for developing CIPN. The following drugs appear to have the highest prevalence rates of CIPN development:

• platinum-based drugs(70-100% CIPN prevalence rate)
• taxanes (11-87%)
• ixabepilone (60-65%)
• thalidomide and analogues (20-60%)

Bortezomib (a proteasome inhibitor) and vinca alkaloids are also associated with developing CIPN, but to a lesser degree.

Age

Older adults are generally more susceptible to developing CIPN.

• A prospective cohort study on 350 patients with Breast Cancer found a significant correlation with paclitaxel-induced CIPN and increasing age, particularly in individuals greater than or equal to 45 years of age. The authors propose this finding to be related to potential declines in organ function, metabolism, and circulation in the older adult population.

Existing Nerve Damage

Existing nerve damage can result from direct neurotoxic chemicals, or from changes in microvasculature which impair nerve function. Some examples include:

• Smoking
• Chronic alcohol consumption
• Diabetes mellitus
• Inherited neuropathy

Genetic Susceptibility

A series of genetic predispositions have been identified through genome-wide association studies. The genes that presently appear to be linked to CIPN are:

• nerve development and neuron extension genes
• genes for pain signaling neurotransmitters
• neurite growth during development
• genes responsible for actin regulation in filopodia/lamellipodia formation
• genes associated with nerve degeneration
• genes related to apoptosis

Pathomechanisms

The respective pathomechanics for a respective chemotherapeutic agent is dependent on its class and are often multifactorial. However, these mechanisms involve microtubule destruction, immunological processes, neuroinflammation, oxidative stress, mitochondrial damage, alterations in ion channel activity, damage to the myelin sheath, and damage to DNA.

Treatment

Pharmacological: Pharmacological treatment for peripheral neuropathic pain is not very effective and also may have serious harmful consequences. Treatment options for symptoms include:

• Steroids, to lessen inflammation
• Topical anesthetics
• Antiseizure medications, which can help relieve nerve pain
• Opioids
• Antidepressants

Non pharmacological:

• Transcutaneous electrical nerve stimulation
• Physiotherapy
• Occupational therapy. eg home safety evaluations, assistive devices.

Note. Recently published American Society of Clinical Oncology (ASCO) guidelines

• Suggest strongly that duloxetine (a serotonin–norepinephrine reuptake inhibitor) is the only currently recommended treatment.

• No recommendations for treatment of CIPN in regards to exercise therapy, acupuncture, scrambler therapy, gabapentin, pregabalin, topical gel treatment (containing baclofen/amitriptyline plus/minus ketamine), tricyclic antidepressants or oral cannabinoids.

Physiotherapy

Physiotherapy is an important therapy intervention for people with neuropathies. Through individualised treatment plans and interventions, it aims to improve movement and relieve pain and discomfort. Also these clients are at increased risk of falls and home safety evaluations and assistive device may be needed. The scope of these interventions ranges from strengthening exercises designed to address muscle weakness, to balance exercises that address fall risks. For more see here

• A United States prospective observational study of 165 subjects over a mean follow-up duration of 62 days found that:
  • > 1/3 of those with CIPN fell
  • Those with CIPN were nearly 3x more likely to have a fall event than those without
  • Individuals with CIPN who fall are more likely to pursue medical attention
  • The authors did not reach a consensus on whether individuals at risk of falling should be referred to physical therapy for fall prevention; however they did advise that all individuals who are developing CIPN should be taught fall prevention strategies, and that physical therapy interventions are effective at decreasing fall risk and reducing injury related to neuropathy in other populations.

Differential Diagnosis

Many of the differential diagnoses associated with CIPN are able to be identified through lab testing or genetic testing. A common testing battery for an individual with peripheral neuropathy includes a complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, and fasting blood glucose, Vitamin B12, and thyroid-stimulating hormone levels. Additional electrodiagnostic studies may be performed if the cause is still unknown. However, another differentiating factor can also be presentation - whether the symptoms are sensory, motor, or sensorimotor. As a provider, it is important to consider any alternatives or additional conditions which may be producing a patient's symptoms. The following are potential differential diagnoses to CIPN:

• Diabetic Peripheral Neuropathy (DPN)
  • Common differences:
    • DPN does not typically affect the upper and lower extremities simultaneously
    • DPN has a more gradual onset and progression of symptoms
    • CIPN = axonal sensorimotor neuropathy; DPN = mixed neuropathy
• Charcot-Marie-Tooth Disease
• Human Immunodeficiency Virus (HIV)
• Vitamin B12 Deficiency
• Syphillis
• Heavy metals
• Tetanus
• Diphtheria toxin
• Monoclonal gammopathy
• Hypothyroidism
• End-Stage Renal Disease
• Lyme Disease