Chemotherapy-Induced Peripheral Neuropathy #197

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity for many anticancer agents. The incidence of CIPN can be variable, with reports ranging from 0% to 70%, but more common figures are 30% to 40% of chemotherapy treated patients. ¹ This Fast Fact will review the clinical features and treatment of CIPN.

Etiology and Risk Factors

Several mechanisms have been postulated to cause CIPN. ² Antineoplastic agents known to cause neuropathies are vinca alkaloids, taxanes, platinum-derived compounds, protease inhibitors (bortezomib), antibodies (brentuximab vedotin), aromatase inhibitors (anastrazole and exemestane), thalidomide, lenalidomide, ixabepilone, and interferon alpha. The risk of CIPN is higher in patients previously exposed to chemotherapy, patients over 50 years old, heavy alcohol users, patients with renal or hepatic insufficiency, and those with preexisting neuropathies. ³

Clinical Characteristics

The onset of symptoms can be sudden or slowly progressive. Sensory symptoms generally improve many months after drug discontinuation, but not in all patients. Motor symptoms are less likely to improve over time.

Sensory symptoms frequently include tingling, numbness, and pain. Motor symptoms include foot drop, wrist drop, and difficulty with fine motor skills, such as buttoning a shirt or holding a pen. Autonomic symptoms include diarrhea, constipation, and difficulty breathing. Pain is often reported as burning, freezing, lancinating, or like an electric shock. Normal touch can be perceived as painful (allodynia) and sensations that would normally be painful can be experienced as excruciating (hyperpathia).

Signs include symmetrical glove and stocking sensory deficit, foot or wrist drop, symmetric motor weakness, loss of deep-tendon reflexes, low blood pressure (autonomic), and irregular heartbeat (autonomic).

The most common pattern of CIPN is an asymptomatic loss of deep tendon reflexes progressing to a sensory and finally motor neuropathy. ¹ The severity of neuropathy usually increases with treatment dose and duration and then decreases after cessation of treatment. A notable exception is the platinum agents, for which symptoms may progress for weeks to months after treatment completion. This is called the “coasting effect.” ⁴

Oxaliplatin can cause both an acute and chronic neuropathy. The acute process can begin during the drug infusion and include cold-induced paresthesias of the hands, feet, throat, and perioral area. The chronic form is a dose-dependent sensory neuropathy similar to other chemotherapy-induced neuropathies. ³

Vincristine can cause pharyngeal myalgias (sore throat) and autonomic neuropathy manifested by constipation, in addition to a typical axonal neuropathy.

Diagnosis

The diagnosis is largely based on history and neurological examination. Clinicians should consider entities other than axonal-neuropathies in their differential (e.g., mass lesion causing a radiculopathy), as well as nonchemotherapy causes of a neuropathy (paraneoplastic; nonneoplastic). ⁴ Nerve conduction studies are helpful only when the diagnosis is unclear, but they do not have 100% sensitivity or specificity.

Prevention

Many agents have been proposed for preventing neuropathy caused by antineoplastic drugs. The mechanisms by which most of these drugs may minimize neuropathy are based on limited preclinical data and informed opinion. There are small clinical trials showing positive results with calcium and magnesium infusion, N-acetyl cysteine, glutamine oxcarbamazepine, omega-3-fatty acid, and ganglioside-monosialic acid (GM1). Larger randomized controlled trials are needed to further evaluate whether or not the above agents are truly chemoprotective. ⁵ Recent clinical trials with vitamin E, xaliproden, amifostine, org 2766, nimodipine, recombinant-human leukemia inhibiting factor, and diethyldithiocarbamate lack positive results. ² One recent randomized, double-blind, placebo-controlled trial of venlafaxine showed a significant reduction of oxaliplatin induced acute neurosensory toxicity. ⁶ These findings have yet to be confirmed in additional studies. Other prevention strategies consist of chemotherapy dose reduction or lower dose intensities, particularly in those patients who are at higher risk to develop CIPN. Nondrug protective measures include hand and feet protection from extremes of temperature (wearing socks, using gloves while cooking), routine inspection for cuts or abrasions, and fall prevention education.

Symptomatic Treatment

Overall, the symptomatic treatment of CIPN remains empiric. Multiple pharmacologic agents have been studied to treat CIPN. Small clinical trials with agents like a topical amitriptyline/baclofen/ketamine gel, alpha-lipoic acid, and acetyl-L-carnitin have shown positive results. ² Pregabalin, ⁷ gabapentin, ⁸ lamotrigine, ⁹ and nortriptyline ¹⁰ have not shown efficacy in controlled trials. One randomized, double-blind, placebo-controlled crossover trial comparing duloxetine with placebo for treating painful CIPN showed a relatively small but significant improvement in pain. ¹¹ Nonpharmacological options, including exercise, acupuncture, and neurostimulation currently lack appropriate evidence to recommend them for the treatment of CIPN. ⁴ Opioids are empirically recommended as a short-term treatment while waiting for an adjuvant to work or for moderate to severe pain despite the use of adjuvant analgesics.