FAST FACT AND CONCEPT #197: Chemotherapy Associated Peripheral Neuropathy

Authors: Jagdeep K. Mehr MD and Neil M. Ellison MD

Background - Chemotherapy associated peripheral neuropathy (CAPN) is a common dose-limiting toxicity of many anti-cancer agents. This Fast Fact will review the clinical features and treatment of CAPN.

Etiology & Risk Factors - CAPN is a common and expected part of treatment with the platins (cisplatin, oxaliplatin), vincristine, taxols (paclitaxel and docetaxel) and more recently with bortezomib. CAPN is less commonly seen with cytosine arabinoside, inteferons, procarbazine, and thalidomide. The risk of CAPN is higher in patients over 50 years old, heavy alcohol users, patients with renal or hepatic insufficiency, and those with preexisting neuropathies. The severity of CAPN is correlated with both cumulative and high single doses of the causative chemotherapeutic agent. The physiology of CAPN varies among different drugs and can involve damage to the neuron, vasa vasorum, or myelin sheath.

Clinical Features -

• CAPN usually presents as a symmetric, axonal neuropathy, although focal and autonomic neuropathies can also occur. Symptoms usually begin within the first 3 cycles of chemotherapy, and may peak in severity up to 3 months after the drug is discontinued. Sensory symptoms generally improve over many months following discontinuation, but not in all patients; motor symptoms are less likely to improve.
• Symptoms include sensory (tingling, numbness, burning, peri-oral numbness), motor (foot, wrist drop, difficulty buttoning a shirt or holding a pen), autonomic (constipation), or myalgias or muscle cramps.
• Signs include loss of deep-tendon reflexes, sensory deficits (stocking glove distribution is most common), foot or wrist drop, or symmetric motor weakness.
• The most common pattern is an asymptomatic loss of deep tendon reflexes, progressing to a sensory, and finally motor neuropathy. 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. Vincristine can cause pharyngeal myalgias (sore throat) and autonomic neuropathy manifested by constipation, in addition to a typical axonal neuropathy.
• Diagnosis is based on a history and neurological exam. Nerve conduction studies and electromyelography, while confirmatory, are usually not needed.
• Differential diagnosis includes direct tumor effects, non-chemotherapy induced neuropathies (e.g. postoperative, post-radiation, diabetic), or paraneoplastic syndromes.

Prevention - Early detection is key, allowing for dose reduction or drug discontinuation. Even after discontinuation, symptoms may progress for several months and then stabilize or slowly improve over a period of weeks to months. Neuroprotective agents including amifostine, vitamin E, glutamine, L-carnitine, and magnesium, have been proposed to prevent CAPN. There is currently no consensus on their use due to limited evidence and likely variable efficacy for different chemotherapies. Other protective measures advised to patients are to protect hands and feet from extremes of temperature (wearing socks, using gloves while cooking), routinely inspect for cuts or abrasions, and fall prevention education.

Treatment - No specific treatment exists to reverse CAPN, however pain should be treated symptomatically. There is little research to guide analgesic therapy, but clinical experience suggests treating this as any other painful peripheral neuropathy with adjuvant analgesics including gabapentin and pregabalin (see Fast Fact #49), tricyclic antidepressants such as amitriptyline, and serotonin-norepinephrine reuptake inhibitors such as duloxetine and venlafaxine (see Fast Fact #187). Opioids are recommended as a short-term treatment while waiting for an adjuvant to work, and for ongoing moderate to severe pain despite the use of adjuvant analgesics.

References:

1. Walker M and Ni O. Neuroprotection during chemotherapy: A systematic review. Am J.Clin.Onc. 2007;30:82-90.
2. Albers J, Chaudhry V, Cavaletti G, Donehower R. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database of Systematic Reviews. 3, 2007, Issue 1. Art. No.: CD005228. DOI: 10.1002/14651858.CD005228.pub2.
3. McDonald AA, Portenoy RK. How to use antidepressants and anticonvulsants as adjuvant analgesic in the treatment of neuropathic cancer pain. J Supportive Oncology. 2006; 4:43-52.
4. Cata JP, et al. Clinical and experimental findings in humans and animals with chemotherapy induced peripheral neuropathy. Minerva Anesthesiologica. 2006; 72; 151-69.
5. Wen PY, Plotkin SR. Neurologic complications of cancer chemotherapy. In: UpToDate, Rose, BD (Ed). Waltham, MA, 2007.
6. Kirchmair W, et al. Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: Attenuation or reversal by local Vascular Endothelial Growth factor Gene therapy without augmenting tumor growth. Circulation. 2005;111(20):2662-2670.
7. Wang, L et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal patients. Oncologist. 2007; 12(3):312-319.
8. Faltters S, et al. Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy. Neuroscience Letter. 2006; 397:219-223.
9. Kane RC et al. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist.2003;8(6):508-13.

Fast Facts and Concepts are edited by Drew A. Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For comments/questions write to: drosiell@mcw.edu. More information, as well as the complete set of Fast Facts, is available at EPERC: www.eperc.mcw.edu.

Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Mehr JK, Ellison NM. Fast Fact and Concept #197. Chemotherapy Associated Peripheral Neuropathy. February 2008. End-of-Life/Palliative Education Resource Center ( www.eperc.mcw.edu).

Disclaimer: Fast Facts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Fact information cites the use of a product in dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

Purpose: Self-Study Guide, Teaching

Audience(s)

ACGME Competencies: Medical Knowledge

Categories: Non pain symptoms/syndromes, cancer (D, O)