Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication and dose-limiting side effect of cancer treatments, stemming from damage to the peripheral nervous system as a result of neurotoxic agents. Common medications that cause CIPN include platinum agents, vinca alkaloids, taxanes, and bortezomib, among others. Symptoms depend on the type of chemotherapy agent used, total dose, frequency, and duration in addition to patient-specific comorbidities. Sensory nerve fibers are more commonly affected, but motor and autonomic nerve fibers can also be involved. Patients can present with pain, numbness, paresthesias, and dysesthesias in a distal symmetric distribution. Electrodiagnostic studies can determine the type of nerve fiber pathophysiology as either demyelinating or axonal, and may also define the severity of damage. While there are no preventative agents for CIPN, symptomatic treatment of CIPN is possible with neuropathic pain agents, antidepressants, and other pharmacologic and nonpharmacologic treatments. Rehabilitative efforts can work on impairments including weakness, reduced proprioception, and poor balance and gait. While research is limited on procedures, trials of neurostimulation may be helpful. CIPN is a challenging medical condition, but can be treated with a comprehensive management plan.
Keywords
chemotherapy, neuropathic pain, peripheral neuropathy, platinum agents, taxanes, vinca alkaloids
| Synonyms | |
| |
| ICD-10 Codes | |
| G62.0 | Drug-induced polyneuropathy (i.e., peripheral neuropathy due to chemotherapy) |
| G62.9 | Polyneuropathy, unspecified |
| D49.9 and G63 | Polyneuropathy, Cancer related |
| T45.1X5A | Adverse effect of antineoplastic and immunosuppressive drugs |
Definition
Chemotherapy-induced peripheral neuropathy (CIPN) is defined as damage and dysfunction of the peripheral nervous system secondary to chemotherapeutic agents, including platinum agents, taxanes, vinca alkaloids, thalidomide, and bortezomib, among others ( Table 97.1 ). CIPN occurs in approximately 68% of individuals within the first month of completing chemotherapy and has a prevalence of 30% at 6 months after chemotherapy completion. The type of chemotherapy, total dose, frequency, and duration of treatment result in different degrees of neuronal damage, as CIPN is dose-dependent. Risk factors for the development of CIPN include the presence of baseline neuropathies such as diabetes, age, smoking, and reduced creatinine clearance. Other possible predictors of developing CIPN include sensory changes such as cold allodynia and hyperalgesia during chemotherapy and pharmacogenetic predisposition. The severity of neuropathy generally increases until cessation of treatment; however, symptoms associated with platinum drugs may progress for up to 3 to 4 months after treatment completion, a phenomenon called the “coasting” effect.
| Drug | Mechanism of Action |
|---|---|
| Platinum compounds (cisplatin, carboplatin, oxaliplatin) | Damages DNA via crosslinking in dorsal root ganglion causing neuronopathy/ganglionopathy with sensory axonal neuropathy resulting in apoptosis |
| Vinca alkaloids (vincristine, vinblastine, vinorelbine, vindesine) | Anti-microtubulin agents that inhibit interference with axonal transport, causing sensorimotor axonal neuropathy |
| Taxanes (paclitaxel, abraxane, docetaxel) | Increase crosslinking in microtubules, resulting in axonal transport interference |
| Epothilones (ixabepilone, sagopilone) | Microtubule-stabilizers, interfering with axonal transport |
| Thalidomide/Lenalidomide/Pomalidomide | Neuronal degeneration |
| Bortezomib | Inhibits 26S proteasome, resulting in reduced NFkB activity |
| Suramin | Axonal degeneration in the dorsal root ganglia |
| Eribulin | Binds to β-tubulin |
Many scales have been proposed to assess CIPN but lack standardization and reproducibility. Recommended scales to use with good validity and reliability for determining impairment are the National Cancer Institute Common Toxicity Criteria, the Total Neuropathy Score clinical version, and the modified Inflammatory Neuropathy Cause and Treatment group sensory sumscore. Table 97.2 shows the National Cancer Institute Common Terminology Criteria for Adverse Events, which is used for sensory and motor symptoms and is considered the standard for assessing CIPN.
| Grade | Description | Action |
|---|---|---|
| 0 | Normal | No intervention |
| 1 | Mild, asymptomatic, clinical or diagnostic observations only, weakness on exam only, loss of deep tendon reflexes or paresthesia | No intervention |
| 2 | Moderate symptoms, limiting instrumental ADLs | Decrease dosage |
| 3 | Severe symptoms, limiting self-care ADLs, assistive device indicated, assistive devices indicated | Decrease dosage or discontinue treatment |
| 4 | Life-threatening consequences, urgent intervention indicated, disabling | Discontinue treatment, urgent intervention indicated |
| 5 | Death |
Symptoms
The onset of symptoms can be acute or slowly progress over time. Symptoms vary depending on the types of nerve fibers affected. Sensory nerves are more commonly affected because their cell bodies are located in dorsal root ganglion (DRG), which lie outside the protective blood-brain barrier. Symptoms depend on the nerve fibers affected, which is modality-dependent (e.g., suramin tends to result in large fiber loss whereas bortezomib results in small fiber loss). Patients can present with a combination of numbness, paresthesia, dysesthesia, and pain in a symmetric distal length-dependent pattern. Patients may also present with pruritus, as in the case of paclitaxel. Symptoms also depend on the pathophysiology of nerve-related damage as either axonal or neurotmetic. As can be seen in Table 97.1 , agents such as taxanes and vinca alkaloids cause microtubule disruption and affect axonal transport, resulting in an axonal presentation with a “stocking-glove” distribution and an overall better prognosis. Platinum agents, on the other hand, have a predilection for DRG damage resulting in apoptosis and neuronopathy with a “glove-stocking” distribution and a poorer prognosis. Patients may also have cold sensitivity, allodynia, numbness, and tingling. Pain may occur early or late and can be chronic, and is often described as burning, stabbing, lancinating, shock-like, or electric jolts.
Motor nerve fiber cell bodies located in the spinal cord are protected within the blood-brain barrier and have the capacity for distal sprouting and regeneration. CIPN may involve motor fibers as well, resulting in distal muscle weakness (i.e., foot drop), myalgias, difficulty with ambulation, ataxia, athetosis, or cramping. If autonomic nerves are affected, patients can have orthostatic hypotension, constipation, urinary retention, irregular heart rate, and sexual dysfunction.
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