Anti-neoplastic Drug Induced Peripheral Neuropathy: Chemotherapy Induced Peripheral Neuropathy (William Helms)

Background of CIPN:

The antineoplastic agents may cause drug induced peripheral neuropathy. Some chemotherapy agents particularly seem to cause peripheral neuropathy, which is known as chemotherapy induced peripheral neuropathy (CIPN). Peripheral neuropathy can affect the patients’ quality of life (i.e., performing daily tasks with one’s hands, etc.). There are both short term and long term adverse effects of CIPN. The estimated incidence is approximately 38% in those on multi-drug regimens. This would certainly seem to be an important factor to consider before deciding whether or not to administer palliative care to a cancer patient. In a general sense, cancer is a disease in which cells divide at a rate faster than the body is able to discard.

Clinical Presentation of CIPN:

Short-Term Symptoms: Tingling, Numbness, Neuropathic pain, Muscle cramps, Loss of sensation, Bilateral; Not motor Long-Term Symptoms: Disorders of smell, Disorders of taste, Raynaud’s Syndrome; may see resolution with reappearance of symptoms later which is referred to as coasting

Medications Associated with CIPN:

More Frequent: Platins (i.e., carboplatin), taxanes (i.e., paclitaxel), vinca alkaloids (i.e., vincristine), epothilones (i.e., ixabepilone), bortezomib, aromatase inhibitors (i.e., anastrazole), erubulin, and thalidomide Less Frequent: brentuximab, podophyllins, methotrexate, cytosine arabinoside, gemcitabine, fluorouracil, and topoisomerase inhibitors

Mechanisms of CIPN:

The drugs vincristine, paclitaxel, oxaliplatin, cisplatin, and bortezomib may cause pain by altering the nerve conduction velocity by changing the action potential. Anticancer drugs alter cell levels of ions. The alteration of these levels of ions, especially calcium, may lead to neuropathy. The platins may be causing dorsal root ganglion neuron apoptosis. The vinca alkaloids bind tubulins which is responsible for their neurotoxicity. Taxanes and epothilones may be causing neurotoxicity by causing excessive polymerization which may be impairing axonal transport leading to neurotoxicity. It is not known why thalidomide causes neurotoxicity, but it could be due to its metabolites causing damage to DRG neurons. Bortezomib may be causing neurotoxicity by damaging axons, because it acts at the Dorsal Root Ganglion and peripheral nerves. Aromatase inhibitors and erubulin may have unknown mechanisms of action for causing peripheral neuropathy.

Dose Association and Temporal Relationship of CIPN:

This type of neuropathy (CIPN) is usually dependent on dose and duration; this is evidenced by most of these neuropathies occurring in the third and fourth cycle of chemotherapy. However, toxicities associated with oxalaplatin and the taxanes are not necessarily dose dependent and may cause immediate toxic effects (i.e., neuropathy). Other antineoplastic agents may also have immediate toxic effects, but oxalaplatin and taxanes seem to most commonly cause these effects. The progression of neuropathies may slow after the fourth or fifth cycle of chemotherapy.

Patient Case: LC is a 46 year old male who has been brought to the hospital by his wife. LC is currently on his third cycle of cisplatin for transitional cell carcinoma of the bladder. He is complaining of loss of sensation in his toes and says he has never experienced this before. There are no labs available. Possible offending agents: cisplatin.

Prevention/Risk Factors/Monitoring of CIPN:

Prevention: The preventive drugs typically interact with or decrease the efficacy of therapy. Prevention Strategies: Switch to another antineoplastic agent; Slower infusion; Lower dose of the chemotherapy Preventive Drugs Include: Not Recommended; Vitamin B and E, glutathione, alpha lipoic acid, acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, dithiocarbamate, Org 2766, oxcarbazepine, erythropoietin Risk factors: Neuropathy, Age, Comorbidities, Multiple myeloma (37-44%), Alcohol consumption, Diabetes, and High serum creatinine levels Associated Factors: Neuropathic pain seen in patients who have survived breast, ovarian, and germ cell cancers. African American patients who have one CYP3A5*1 allele may have a lower risk of chemotherapy induced peripheral neuropathy. Patients who have risk factors should be monitored for CIPN. Multiple drug regimens are also associated with CIPN. Monitoring: All patients using antineoplastic agents should be monitored for signs and symptoms of neuropathy.

Treatment: Treatment: Depending on what type of care and the goals of care, the patient could discontinue the chemotherapy agent; would likely do this if possible. There are symptomatic treatments available for cancer patients who are experiencing neuropathic pain due to treatment. Gabapentin and pregabalin, opioids, topical anesthetics, and antidepressants may be used to treat the neuropathic pain. The symptomatic treatments are not preventing the neuropathic pain, and may also have side effects. May use preventative strategies listed above. Duloxetine may be used for treatment of CIPN.

Quiz Questions:

1. Which of the following is NOT a risk factor for chemotherapy induced peripheral neuropathy? A. Neuropathy, B. Patient who survived Breast Cancer, C. Age, D. Patient diagnosed with Diabetes 2. Which of the following agents are likely to have immediate toxicities? A. oxalaplatin, B. Taxanes, C. bortezomib, D. A and B.

References:

1. Albers JW, Chaudhry V, Cavaletti G, and Donehower R. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Review. 2011 Feb 16; DOI: 10.1002/14651858.CD005228.pub3. Accessed 11/02/15. Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005228.pub3/abstract;jsessionid=A3D94DAF1A91424E38C8E53DE32D2880.f01t04?userIsAuthenticated=false&deniedAccessCustomisedMessage,%20http://www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/chemotherapyeffects/peripheralneuropathy/peripheral-neuropathy-caused-by-chemotherapy-how-does-cipn-start

2. Amteshwar Singh Jaggi, Nirmal Singh, Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy. Toxicology. 2012 January 27. 291 (1–3); 1-9. http://dx.doi.org/10.1016/j.tox.2011.10.019. Accessed 11/02/15. Available at: http://www.sciencedirect.com/science/article/pii/S0300483X11004586

3. Grisold W, Cavaletti G, and Windebank, AJ. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro-Oncology (Oxford Journals). 2012. 14(4); iv45-iv54. Accessed 11/02/15. Available at: http://neurooncology.oxfordjournals.org/content/14/suppl_4/iv45.full

4. Hershman DL, Lacchetti C, Dworkin RH, et al: Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014 April 17, 2014. Accessed: 11/06/15. Available at: http://jco.ascopubs.org/content/32/18/1941.full?sid=8ddf5919-3456-4608-b5c4-866d66a6006d

5. “Chemotherapy-Induced Peripheral Neuropathy-Guidelines.” Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Accessed: 11/06/15. Available at: http://www.micromedexsolutions.com/

6. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA. 2013;309:1359-1367. Accessed 11/6/15. Available at: http://jama.jamanetwork.com/article.aspx?articleid=1674238