Questions from the Clinic:
What is chemotherapy-induced peripheral neuropathy (CIPN)? What sorts of treatments lead to CIPN most frequently? Is there anything I can do to prevent CIPN? Are any natural remedies available to treat it?
Although chemotherapy has long served as a foundational treatment for various cancers, its continued use often gives rise to troublesome side effects. Among the most common treatment-related adverse events leading to chemotherapy dose reduction and discontinuation is peripheral neuropathy.(1) According to one estimate, between 30% and 40% of patients receiving chemotherapy experience CIPN at some point during treatment.(2) Troublingly, salient symptoms such as pain, muscle weakness, and numbness can persist long after stopping chemotherapy, and their presence substantially diminishes patients’ quality of life (Figure 1).(3) Despite its high prevalence among patients treated for cancer, CIPN notably lacks treatment options with regulatory approval from the U.S. Food and Drug Administration (FDA).(4) The burden of this therapeutic gap is also poised to increase over time as cancer survival rates continue improving. As patients live longer, it will become increasingly important to identify novel treatments that can address the underlying pathophysiology of CIPN.(5)
II. Mechanism of Action
Data from decades of preclinical research indicate that there are a minimum of 4 ways that anticancer drugs induce neurotoxic effects on sensory neurons (Figure 2):(1, 3)
Mitochondrial toxicity, oxidative stress
Ion channel impairment
Because chemotherapeutic agents differ in their mechanisms of action, the deficits observed with each syndrome are specific and distinct. Platinum-based compounds such as cisplatin, oxaliplatin, and carboplatin primarily cause damage to the dorsal root ganglia – a population of sensory neurons – by forming adducts with nuclear and mitochondrial DNA.(3) This interaction eventually leads to inappropriate entry into the cell cycle and culminates in neuronal apoptosis.(6,7) In platinum-based CIPN, the sensory deficits linked to chemotherapy can also mysteriously worsen for several months after therapy discontinuation. Researchers theorize that this phenomenon, known as “coasting,” results from the impairment of mitochondrial DNA transcription.(8) Taxanes, which include paclitaxel, docetaxel, and cabazitaxel, disrupt calcium flow in mitochondria and bind the β-tubulin components of microtubules. This interaction alters the properties of these assemblies and disrupts axonal transport.(1,9) Both CIPN pathways affect mitochondrial function and accentuate the critical importance of this organelle in the function of our nervous system.
Increases in immune signaling among cells forming the spinal cord and peripheral nerves additionally reflect escalating neuroinflammation and contribute to CIPN development.(10) In addition to disrupting microtubule assemblies, taxanes promote the uptake of macrophages in the dorsal root ganglia and the expression of inflammatory cytokines – molecular signals that promote the recruitment of more immune cells.(11) Other members of different drug classes, such as bortezomib and oxaliplatin, disturb sphingolipid metabolism and promote further neuroinflammation.(12) Activation of immune cells, in turn, leads to the secretion of chemical mediators that enhance neuronal excitability and pain hypersensitivity.(1) Use of chemotherapy agents also increases the expression of sodium ion channels and spontaneous neuronal activity. Concurrently, potassium channel expression in primary sensory neurons falls. The combination of the increased sodium channel and decreased potassium channel activity predisposes neural cells to hyperexcitability, which underlies the pain and symptoms seen in CIPN.(13) This imbalance of excitability and suppression leads to the paradox of hypersensitivity and numbness at times in the same extremity.
III. Potential Treatments - Clinical Trail Data
Despite intensive research efforts, scientists have not yet devised therapies or protocols that can prevent the development of CIPN. While understanding of CIPN is continually advancing, it remains unclear why drugs designed to eliminate cancerous cells sometimes exert toxic effects on non-dividing sensory neurons. Efforts to develop agents with prophylactic benefits are also complicated by the reality that their use could possibly interfere with the efficacy of chemotherapeutics.3 That said, some options have emerged to treat CIPN once it has developed.
Perhaps one of the most promising solutions to CIPN is an activity with well-known, universal benefits – exercise. In a secondary analysis of phase III clinical trial, investigators quantified the effects of physical activity on the severity of CIPN symptoms and sought to identify the factors responsible for improvements. For this investigation, participants were randomized into a control group and an experimental arm where patients enrolled in Exercise for Cancer Patients (EXCAP) – a “standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance program.” After completion of the intervention, patients who exercised had significantly reduced CIPN symptoms of hotness and coldness in the hands and feet, as well as improvements in numbness and tingling. These benefits appeared particularly pronounced among older patients, men, and those with breast cancer.(14) Researchers conducting a meta-analysis of randomized controlled trials have also concluded that exercise confers benefits in CIPN, although the best activities to pursue in different patients remain unclear.(15) Such questions, among others, may be addressed in future trials.
For patients incapable of exercise, the development of device-based alternatives to treat CIPN appears underway and poised for imminent approval. NeuroMetrix, a medical device company based in Woburn, Massachusetts, is commercializing Quell: a wearable neurostimulation device for chronic, lower extremity pain. With a form factor the size of a credit card, the Quell device delivers “precise, high-power nerve stimulation” and “automatically adjusts stimulation for an optimal patient experience both day and night.”(4,16) In a company-supporting study, researchers noted statistically significant improvements in numeric ratings of pain, tingling, numbness, and cramping among participants treated with transcutaneous electrical nerve stimulation.(17) These data prompted further evaluation of this technique in an ongoing phase II trial estimated to conclude on January 31, 2023.(18) On the basis of these results, the Quell technology received a breakthrough designation from the FDA for reducing moderate-to-severe symptoms of CIPN in January 2022; the device has not yet received formal approval in this indication.(16)
Beyond duloxetine and gabapentin, significant controversy surrounds the use of drugs and supplements, such as vitamin E, lithium, and analgesics in the management of CIPN.(19,20) In a systematic review of randomized clinical trials assessing the value of natural, complementary therapies for CIPN, researchers concluded that vitamin E could have preventative value.(21) This conclusion contradicts that of a more recent meta-analysis, whose authors found that vitamin E did not reduce the incidence of all-grade CIPN when synthesizing data solely from double-blind, randomized controlled clinical trials.(22) Lithium, a mainstay in the management of the bipolar disorder, appears promising in limiting the effects of CIPN. That said, supporting evidence to date comes from a retrospective study and one conducted in mice models; well-designed clinical studies are needed to further validate these findings in different patient populations with cancer.(23,24)
Some data support the use of neurotropic agents with opioids, such as oxycodone/naloxone and gabapentin or pregabalin. In one study, researchers noted that the combination of these two treatment classes was more effective at controlling CIPN than when used alone. One must gauge the sedating impact of these combinations versus the benefit on the CIPN and titrate appropriately. From these results, further studies appear warranted to confirm the conclusions drawn, especially as the study was conducted over a period spanning 4 weeks.(25) As such, there are no data yet supporting this strategy’s long-term safety and efficacy.(20)
Dreams that CIPN would subside as a substantial clinical problem have largely gone unfulfilled, even as the cancer treatment landscape continues to expand. Until chemotherapies are completely supplanted by next-generation alternatives, clinicians and patients will continue to need medications and protocols that minimize the neurotoxicity of cisplatin, taxanes, and other classes of anticancer agents. Because multiple mechanisms underlie CIPN, it is very likely that a combinatorial approach consisting of pharmacotherapy, lifestyle interventions, and medical devices will prove most fruitful. Although clinical data remain limited, findings from clinical trials indicate that exercise and the antidepressant duloxetine offer patients with CIPN considerable value. Further investigations are required to examine the efficacy of other naturalistic, complementary approaches, namely vitamin E, glutamine, and acetyl-L-carnitine. Given the impact on mitochondria by agents causing CIPN, strategies to foster mitochondrial biogenesis such as redlight therapies, zone 2 exercise, and possibly pretreating fasting may offer an impact. As researchers continue to clarify the mechanisms driving CIPN, patients should work closely with their primary care physicians and members of a multidisciplinary oncology team to select interventions most appropriate for their circumstances. Such collaboration is particularly essential among patients where the risk of discontinuing chemotherapy outweighs the distress and damage posed by CIPN.
Stay strong and curious and be your own best doctor,
Charles J. Meakin MD, MHA, MS
Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
1 Eldridge S, Guo L, Hamre J. A comparative review of chemotherapy-induced peripheral neuropathy (CIPN) in vivo and in vitro models. Toxicol Pathol. 2020;48(1):190-201.
2 Pike CT, Birnbaum HG, Muehlenbein CE, et al. Healthcare costs and workloss burden of patients with chemotherapy-associated peripheral neuropathy in breast, ovarian, head and neck, and nonsmall cell lung cancer. Chemother Res Pract. 2012;2012:913848.
3 Staff NP, Grisold A, Grisold W, et al. Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol. 2017;81(6):772-781.
4 Brusco S. NeuroMetrix’s Quell earns breakthrough status for CIPN. Orthopedic Design & Technology. https://www.odtmag.com/contents/view_breaking-news/2022-01-18/neurometrixs-quell-earns-breakthrough-status-for-cipn/. Published January 18, 2022. Accessed August 10, 2022.
5 Burgess J, Ferdousi M, Gosal D, et al. Chemotherapy-induced peripheral neuropathy: epidemiology, pathomechanisms and treatment. Oncol Ther. 2021;9:385-450.
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10 Li T, Mizrahi D, Goldstein D, et al. Chemotherapy and peripheral neuropathy. Neurol Sci. 2021;42(10):4109-4121.
11 Zhang H, Li Y, de Carvalho-Barbosa M, et al. Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy. J Pain. 2016;17(7):775-786.
12 Singh SK, Spiegel S. Sphingosine-1-phosphate signaling: a novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain. Adv Biol Regul. 2020;75:100670.
13 Colvin LA. Chemotherapy-induced peripheral neuropathy (CIPN): where are we now? Pain. 2019;160(Suppl 1):S1-S10. term=ketogenic+diet&cond=Cancer&Search=Apply&recrs=a&age_v=&gndr=&type=&rslt=/. Accessed July 19, 2022.
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16 NeuroMetrix receives FDA breakthrough device designation for treatment of chronic chemotherapy induced peripheral neuropathy (CIPN) with its wearable neurostimulation technology. Neurometrix. https://www.globenewswire.com/en/news-release/2022/01/18/2368526/0/en/NeuroMetrix-Receives-FDA-Breakthrough-Device-Designation-for-Treatment-of-Chronic-Chemotherapy-Induced-Peripheral-Neuropathy-CIPN-with-its-Wearable-Neurostimulation-Technology.html/. Published January 18, 2022. Accessed August 10, 2022.
17 Gewandter JS, Chaudari J, Ibegbu C, et al. Wireless transcutaneous electrical nerve stimulation device for chemotherapy-induced peripheral neuropathy: an open-label feasibility study. Support Care Cancer. 2019;27(5):1765-1774..
18 Testing the effects of transcutaneous electrical nerve stimulation (TENS) on chemotherapy-induced peripheral neuropathy (CIPN). https://clinicaltrials.gov/ct2/show/NCT04367480/. Updated December 9, 2021. Accessed August 11, 2022.
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22 Chen J, Shan H, Yang W, et al. Vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: a meta-analysis. Front Pharmacol. 2021;12:684550.
23 Mo M, Erdelyi I, Szigeti-Buck K, et al. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2012;26(11):4696-4709.
24 Wadia RJ, Stolar M, Grens C, et al. The prevention of chemotherapy induced peripheral neuropathy by concurrent treatment with drugs used for bipolar disease: a retrospective chart analysis in human cancer patients. Oncotarget. 2018;9(7):7322-7331.
25 Kim BS, Jin JY, Kwon JH, et al. Efficacy and safety of oxycodone/naloxone as add-on therapy to gabapentin or pregabalin for the management of chemotherapy-induced peripheral neuropathy in Korea. Asia Pac J Clin Oncol. 2018;14(5):e448-e454