Description

• Chemotherapy-induced neuropathies (CIN) have a variety of presentations depending on the chemotherapy agents use.
• Most neuropathies are peripheral and sensory but may include motor and autonomic dysfunction.
• CIN can be reversible or permanent, depending on the treatment regimen, cumulative dose, and length of treatment.
• These symptoms may result in worsening quality of life (QOL) for patients necessitating reductions in dose or discontinuation of therapy.

Epidemiology

Incidence
CIN is one of the most common nonhematologic side effects of many chemotherapy agents. Incidence and severity is often underestimated because grading is subjective and based on patient reporting as opposed to formal neurologic testing (1).

• Cisplatin related: sensory 60% for any grade; 10% for grades 3 and 4 neuropathy (1)
• Oxaliplatin related: Nearly all patients will have some sensory symptoms. Acute neuropathy associated with cold temperatures. Chronic toxicity occurs in 60–75% (1).
• Vinca alkaloids related: sensorimotor and some autonomic dysfunction; up to 60% (1)
• Taxanes related: sensorimotor. 60% for paclitaxel, 15% for docetaxel. Reduced toxicity is seen with nanoparticle albumin-bound (nab) paclitaxel (1).
• Bortezomib related: sensory. Mild toxicity in up to 75% with 12% grades 3 and 4. Toxicity is reduced when administered subcutaneously (1).
• Immunomodulator related: sensory. Up to 44%. Thalidomide is associated with more toxicity than lenalidomide or pomalidomide (1).

Etiology and Pathophysiology

The mechanism of action is varied among chemotherapy agents that generally result in DNA damage and microtubule dysfunction leading to apoptosis. Proposed mechanisms of neurotoxicity include:

• Oxidative stress
• Mitochondrial toxicity
• Dysregulation of ion channels and calcium homeostasis
• Altered retrograde and anterograde transport
• Immune system activation (2)

Genetics
Genetic risk factors for neurotoxicity have been an active area of research. Certain gene polymorphisms may result in increased or decreased susceptibility to CIN via alterations in the ability to absorb, distribute, metabolize, and excrete the chemotherapy. These include:

• Glutathione transferases
• Cytochrome P450 enzymes
• ATP binding cassette transporters (2)

Risk Factors

• Prior chemotherapy
• Coadministration of other neurotoxic therapies
• Preexisting neuropathy related to alcohol consumption, diabetes mellitus, high serum creatinine levels, age-related axonal loss
• Other comorbid conditions such as HIV, amyloidosis, peripheral vascular disease, nonalcoholic liver disease, and nutritional deficiency (3)

General Prevention

CIN risk may be reduced with modification of treatment regimens, dosing schedules, and type of administration. Although numerous studies have looked into preventative agents, none have shown a consistent benefit. Additional research is needed for further recommendations. The following treatments have been investigated:

• Treatments that show no benefit, may worsen neuropathy, or potentially worsen chemotherapy efficacy: vitamin E, glutathione, acetyl-L-carnitine, amifostine, alpha-lipoic acid, calcium/magnesium, amitriptyline, nimodipine, all-transretinoic acid (3,4)[A]
• Treatments that may have some benefit but require further investigation: venlafaxine, omega fatty acid, N-acetylcysteine, carbamazepine, glutamate, goshajinkigan, oxcarbazepine (3,4)[A]