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Chemotherapy-Induced Peripheral Neuropathy

Nursing Implications

Kanzawa-Lee, Grace A. PhD, RN

Author Information
doi: 10.1097/NAN.0000000000000368
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Abstract

This article provides the detailed supporting evidence for the following key points:

  • More than half of neurotoxic chemotherapy-receiving patients develop chemotherapy-induced peripheral neuropathy (CIPN).1,2
  • Patients with CIPN are at a significantly higher risk for falls and reduced quality of life.3–6
  • The incidence, characteristics, mechanisms of, and potential treatments for CIPN vary based on the type and dose of inducing neurotoxic chemotherapy.7
  • CIPN manifests with sensory symptoms (numbness, tingling, and neuropathic pain) in the bilateral upper and lower extremities and sometimes motor and autonomic symptoms.8
  • Proactive patient education on and nursing assessment and intervention of CIPN may significantly improve patients' quality of life and cancer treatment outcomes.
  • Physical assessment (eg, using the clinical version of the total neuropathy score [TNS]) and patient-report surveys may be the optimal methods to assess CIPN severity.9,10
  • Duloxetine 60 mg/d is the only treatment recommended by the American Society of Clinical Oncology (although not approved by the US Food and Drug Administration) for chronic CIPN.11,12
  • Lack of careful literature evaluation before clinical implementation can lead to physical and financial harms to the patient.

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY PRESENTATION

CIPN is among the top distressing, chronic, and dose-limiting side effects of neurotoxic chemotherapies. About 60% of neurotoxic chemotherapy-receiving individuals develop CIPN.1,2 Patients describe CIPN as symptoms of numbness, tingling, cold sensitivity, and burning, shooting, freezing, and zapping pain in their bilateral upper and lower extremities.8 Sometimes individuals develop motor symptoms, including bilateral extremity weakness and cramps, difficulty with fine motor tasks, and foot drop.8 The clinician may detect early signs of CIPN, such as loss of deep tendon reflexes, proprioception, strength, and sensation to vibration, pinprick, and temperature stimuli.13 Infrequently, neurotoxic chemotherapy can affect the autonomic system and cause orthostatic hypotension, erectile dysfunction, constipation, urinary retention, dysphagia, and hearing loss.14

Trajectory of CIPN Symptoms

Numbness and tingling symptoms usually manifest first in the tips of the fingers and toes and progress proximally along with an increase in CIPN severity. The signs and symptoms of CIPN can occur as early as the first cycle.2,15 The symptoms often peak within the first several days after the infusion and then wean up until or disappear by the next infusion.15 With each cycle, the symptoms may increase in severity and duration and may no longer resolve between cycles.2,15 Neuropathic pain symptoms may appear later during or after the completion of neurotoxic chemotherapy treatment.16 Some patients exhibit a coasting effect: worsening or development of CIPN during the 3 months to a year after neurotoxic chemotherapy completion.2,15 Ultimately, CIPN may resolve after treatment completion or may become permanent.17

Impact of CIPN on the Patient

The new challenge for cancer survivors is weighing their length versus quality of life. Difficulty writing, typing on a laptop, and buttoning a shirt; loss of independence; depression; and falls are just a few of the potential consequences of CIPN.4–6 Individuals with CIPN are at nearly double the risk of falls compared with cancer survivors without CIPN.3 Providers and patients are becoming aware of the potentially long-term devastating effects of CIPN; hence, CIPN has become a leading cause for neurotoxic chemotherapy discontinuation and dose reduction.2,18,19 However, patients are often unprepared for CIPN. Some patients have difficulty interpreting and reporting their CIPN symptoms to their providers.20 Providers report a perceived lack of knowledge and time to properly assess for CIPN.21 Thus, CIPN often progresses unnoticed and/or unmanaged until it becomes severe and likely chronic.

The nurse can play a key role in informing patients and helping them to manage a significant side effect of neurotoxic chemotherapy. This review is intended to help prepare nurses to address patients' concerns and questions about CIPN, such as the following:

  • “I've heard about neuropathy. What is it?”
  • “Does neuropathy go away after I stop chemotherapy?”
  • “What causes neuropathy?”
  • “What can I do to avoid getting neuropathy?”
  • “What are the treatments for neuropathy?”

This review will equip nurses with applicable knowledge about CIPN by addressing the following objectives: to discuss (1) the causes, underlying mechanisms, and risk factors of CIPN; (2) evidence regarding the prevention and management of CIPN; (3) CIPN assessment techniques; and (4) nursing implications related to CIPN.

CAUSES OF CIPN

Platinum compounds, vinca alkaloids, taxanes, antiangiogenesis agents, and proteasome inhibitors are the most common types of neurotoxic chemotherapy known to cause CIPN. These neurotoxic chemotherapies can damage or alter the sensory, motor, and autonomic nerves and lead to CIPN.

Broad CIPN Mechanisms

The pathophysiologic mechanisms of CIPN are still under investigation; however, the current evidence suggests that CIPN primarily develops from degeneration, apoptosis (neuron cell death), and sensitization (neuronal changes/irritation that cause hyperactivity) of the peripheral and central nerves.8,22 Degeneration occurs in the peripheral nerve axons: potentially the sensory, motor, and autonomic nerves. Apoptosis of the peripheral sensory nerves generally occurs first; however, neurons in the central nervous system (CNS) may secondarily undergo apoptosis. Sensitization may affect both the peripheral nerves and CNS.8,22

Axonal Degeneration and Neuronal Apoptosis

Axonal degeneration and neuronal apoptosis—the dying back process of the peripheral nerves—may result from disturbances of neuronal metabolism (energy-making process) and homeostasis, as well as oxidative stress.8,22,23 The longest and largest axons may be particularly vulnerable because they may have the highest energy requirements.24 Thus, the nerves that degenerate first are those with axons that extend to the toes and fingers, and potentially, the vagus nerve (the longest cranial nerve that links with the autonomic system and controls the vasculature, bowel and bladder, pharynx and larynx, and the tympanic membrane).25 Anti-angiogenesis and ischemia may also contribute to nerve degeneration. The sensory neuron cell bodies are encased in bunches in the dorsal root ganglia. The dorsal root ganglia lie just outside of the spinal cord and blood-nerve barrier and are primary sites for neurotoxic chemotherapy pooling and neuronal apoptosis.22,26

Sensitization

Sensitization leads to neuropathic pain, hyperalgesia (exaggerated pain experience in response to a painful stimuli), allodynia (pain experience to a usually nonpainful stimuli), and cold sensitivity.27,28 The potential mechanisms of sensitization include neuronal receptor upregulation and ion channel dysfunction,27,29 oxidative stress, neurotransmitter imbalances, and inflammation.8 The key receptors associated with sensitization include the transient receptor potential vanilloid (TRPV), transient receptor potential ankyrin 1 (TRPA1),30 N-methyl-D-aspartate (NMDA), and serotonin receptors that react to pain-facilitating chemicals, free radicals, and nitrogen agents.28,31 Alterations in the presence, sensitivity, and activity of the sodium, potassium, and calcium ion channels lead to an imbalance in the neuron membrane status and homeostasis and contribute to neuronal hyperexcitability and spontaneous nerve conduction.27,29 Excessively elevated levels of corrosive nitrogen free radicals, such as nitric oxide, particularly in the CNS, signal a cascade that contributes to sodium and calcium channel hyperactivity that facilitates neuronal hypersensitivity.28,31 Finally, inflammation primarily occurs because of cytokine release and macrophage infiltration into the neurons.32,33

The mechanisms of CIPN may interact in a vicious cycle and feed into one another. For example, oxidative stress signals a cascade that leads to increased calcium channel activity and accumulation of intraneuronal calcium, which secondarily increases TRPV1 activation, disrupts neuronal homeostasis, induces apoptosis, and increases oxidative stress.28,31 Neurotoxic chemotherapy may also directly cause TRPV1 hyperactivity and mitochondrial dysfunction that contribute to the impairment of neuronal metabolism and homeostasis and an excess of intraneuronal calcium.34 Neuronal injury leads to the release of nitric oxide (associated with oxidative stress), glutamate, and proinflammatory cytokines by the supportive and immune cells surrounding the neuron.35–37 Excess glutamate facilitates the upregulation of TRPV1, TRPA1, and NMDA receptors and binds to them to facilitate caustic hyperexcitation, axonal degeneration, and neuropathic pain.38 These pathophysiologic processes are just a few of the proposed mechanisms of CIPN.28,31

Peripheral Nerve Fibers Associated With CIPN Manifestations

Three types of peripheral sensory nerve fibers, 2 motor fiber types, and 1 autonomic nerve fiber type compose the peripheral nervous system; neurotoxic chemotherapy can affect each of these fibers. The alpha beta and alpha delta large myelinated sensory nerves are affected first; they have the longest largest axons.8,22,24 They send sensory signals from the periphery to the spinal cord. Damage to these nerves lead to the CIPN symptoms of numbness, tingling, and loss of vibration sensation, reflexes, and proprioception.22 The small c unmyelinated fibers sense painful stimuli and deliver the pain signals to the spinal cord. Damage to the c sensory fibers causes neuropathic pain, tingling, and loss of sensation to pinprick stimuli and hot/cold temperatures.22

The motor and autonomic nerve fibers are less frequently affected. The motor fibers (Aa types 1a and 1b fibers) are large myelinated fibers that send motor impulses from the spinal cord to the muscles. Damage to the motor fibers leads to symptoms of weakness, foot drop, and muscle cramping and contributes to proprioception loss.22 Finally, the c sympathetic fibers may infrequently be affected, leading to autonomic symptoms (ie, hypotension, erectile dysfunction, constipation, diarrhea, urinary retention, dysphagia, and hearing loss).22 Although the mechanisms of peripheral nerve damage and sensitization may vary, the progression of acute CIPN to chronic painful CIPN generally follows a similar process called central sensitization.

CNS Mechanisms

Sensitization in the CNS can result from direct chemotherapy-induced damage, persistent noxious input from damaged peripheral nerves, and dysfunctional descending pain moduling pathways.28 Some evidence suggests that chemotherapy can cross the blood–nerve barrier.39 However, chemotherapy-induced central sensitization may mainly result secondary to peripheral sensitization. Sensitized or damaged peripheral nerves persistently send pain signals and overstimulate the CNS pain-processing structures, which results in central sensitization. The primary sites of central sensitization include spinal cord sensory neurons, such as the wide dynamic range neurons (WDRNs), surrounding supportive cells, and pain-processing areas of the brain. Further, neurotoxic chemotherapy-induced dysfunction of the descending pain modulating system may facilitate central sensitization.40–42 The WDRNs are first affected in the spinal cord, because they receive the persistent pain signals from the peripheral nerves and input from the descending pain-modulating pathway. The interneurons and supportive Schwann and glial cells that surround the WDRNs can release free radicals, neurotrophic and inflammatory factors, and glutamate that leads to degeneration and imbalanced inhibition/control of the WDRNs. Thus, nonpainful input from the peripheral large myelinated sensory nerve fibers becomes interpreted as pain signals. The limbic system (thalamus and hypothalamus) and prefrontal cortex are key pain-processing regions in the brain that may also undergo sensitization.8

NEUROTOXIC CHEMOTHERAPY-SPECIFIC CIPN PRESENTATION AND MECHANISMS

Evidence suggests that the pathophysiologic mechanisms, and thus incidences and symptom profiles, of CIPN vary based on the type of caustic neurotoxic chemotherapy.7 The hallmark extremity numbness and tingling symptoms are common to all types of CIPN. Table 1 delineates the other symptoms—neuropathic pain, motor, and autonomic symptoms—that are specific to each type of CIPN based on neurotoxic agent. The following sections will review the uses and CIPN presentation associated with each neurotoxic chemotherapy class. The potential pathophysiologic mechanisms of each type of CIPN will also be introduced.

TABLE 1
TABLE 1:
Differing CIPN Symptoms Based on the Neurotoxic Chemotherapya

Platinum Compounds

Platinum compounds are used often to treat gastrointestinal cancers (oxaliplatin), lung and genitourinary cancers (cisplatin and carboplatin), and breast cancer (carboplatin). About 50% to 85% of individuals may develop CIPN from platinum compounds, which may be irreversible.4 The risk of severe CIPN is the lowest for carboplatin- and highest for oxaliplatin-receiving individuals. Additionally, oxaliplatin induces a unique acute CIPN cold-sensitivity syndrome that affects the face, throat, hands, and feet in more than 85% of cases as early as after the first cycle of chemotherapy. All platinum compounds can cause painful and motor CIPN; however, only cisplatin is known to cause ototoxicity (an autonomic CIPN symptom). These symptoms may worsen or appear within the 3 to 6 months immediately after platinum compound-treatment completion. Platinum-induced peripheral neuropathy is likely caused by DNA destruction, mitochondrial and ion channel dysfunction, oxidative stress, and neuronal apoptosis and may lead to irreversible CIPN.43–45

Vinca Alkaloids

Vinca alkaloids, such as vincristine, vinblastine, vinorelbine, and vindesine, are used primarily to treat pediatric hematologic cancers, neuroblastoma (adrenal cancer), and Wilms tumor (renal cancer). These chemotherapies have also been used to treat sarcomas (eg, rhabdomyosarcoma and Kaposi's), melanoma, and recurrent or refractory testicular, breast, and lung cancers. Nearly one third46 of vincristine- and vinblastine-receiving individuals develop CIPN that often manifests with autonomic (eg, hypotension and constipation)47 and motor symptoms.48 Some individuals may develop neuropathic pain and experience a worsening of symptoms for up to a year after vinca alkaloid treatment completion. The risk of CIPN from vinblastine and other synthetic vinca alkaloids is lower. The primary mechanism of action of vinca alkaloids is binding microtubules, which arrests cellular division and causes axonal swelling and apoptosis.49 Vinca alkaloids can also induce inflammatory-, serotonin-, and oxidative stress-mediated sensitization and neuronal degeneration.32,50 Reduced pain-inhibiting endogenous opioids in the descending pain modulating pathway may also lead to central sensitization and chronic neuropathic pain.40–42

Taxanes

Taxanes including paclitaxel and docetaxel are the first-line chemotherapies for breast and lung cancer. They may also be used to treat bladder, gynecologic, prostate, gastric, esophageal, pancreatic, skin, and head and neck cancers. About 45% to 70% of individuals develop taxane-induced peripheral neuropathy.2,51 Neuropathic pain and motor symptoms are common manifestations.2,52 Some scientists suggest that taxane-induced peripheral neuropathy includes a severe myalgia syndrome.15 Although the myalgias mirror the pattern of acute CIPN, these symptoms mechanistically do not align with CIPN. Taxane-induced peripheral neuropathy is thought to primarily result from disruption of the nerve cell cycle and metabolism, leading to potentially irreversible CIPN.8,26,32,53 About half of the individuals with high-grade taxane-induced peripheral neuropathy experience a significant reduction in symptom severity within a month of their last cycle. However, taxane-induced peripheral neuropathy may or may not completely resolve.54

Anti-Angiogenesis Agents

Thalidomide and, less commonly, lenalidomide are used to treat multiple myeloma and induce CIPN in about half of patients.55 Thalidomide is most known for its autonomic CIPN symptoms, such as orthostatic hypotension, constipation or diarrhea, urinary retention, and erectile dysfunction. Patients usually report disappearance of thalidomide-induced peripheral neuropathy after treatment is complete; however, some evidence suggests that irreversible neurophysiologic effects can develop.13 Immunomodulation13,52 and anti-angiogenesis52 are thought to be the primary neurotoxic mechanisms of thalidomide. Its immunomodulating action signals inactivation of the neurotrophins brain-derived neurotrophic factor (BDNF)56 and nuclear factor-κB (NFκB), which may lead to neuronal apoptosis.52

Proteasome Inhibitors

Bortezomib, a proteasome inhibitor, is used to treat hematologic cancers, including mantle cell lymphoma and multiple myeloma.57 The incidence of bortezomib-induced peripheral neuropathy is about 25% to 33%.14 Acute neuropathic pain (burning, freezing, shock-like pain) is characteristic of bortezomib-induced peripheral neuropathy.58 Bortezomib-induced peripheral neuropathy may develop within the first couple cycles of bortezomib; thus, it does not follow the usual trajectory of CIPN of late neuropathic pain development. The severity of bortezomib-induced peripheral neuropathy generally plateaus after the eighth cycle of chemotherapy and resolves after chemotherapy completion. Bortezomib causes cell cycle arrest and apoptosis of the peripheral nerves, disruption of neuronal metabolism and homeostasis,23,59–61 oxidative stress,58 inflammation,58,62 TRPV1 upregulation,63 and increases in glutamate.64

Epothilones (Ixabepilone), Gemcitabine, and Ifosfamide

Ixabepilone (for breast cancer), gemcitabine (for various cancers), and ifosfamide (for osteosarcoma) have been suggested to induce less severe CIPN at an incidence rate of 8% to 15%.65

FACILITATING FACTORS

Neurotoxic chemotherapy dosage, pre-existing conditions, lifestyle, demographics, and genetic factors may predict the development of CIPN.13,65,66 The neurotoxic chemotherapy regimen (type, dose, duration, and coadministration of neurotoxic chemotherapy) is the greatest predictor of CIPN incidence and severity.2,18,19 Higher cumulative doses and worse acute CIPN4,67 within the first few cycles of chemotherapy are linked with a higher incidence and severity of chronic CIPN. Additionally, pre-existing peripheral neuropathy, sensory deficits,67–69 and conditions associated with peripheral neuropathy, such as diabetes mellitus, HIV, chronic kidney disease, and nutritional deficiency, are known predictors of poor CIPN outcomes.70–73

Individuals who are obese,51,66,73,74 smoke, abuse alcohol, physically inactive,66,75 older in age,51,76,77 and are genetically predisposed78 may also develop more severe, debilitating, and chronic CIPN. The factors that are specifically predictive of chronic painful CIPN include high chronic comorbidity burden, pre-existing chronic pain conditions (eg, osteoarthritis and back pain), and lower financial income.79

Co-Occurring Symptoms

Fatigue, insomnia, anxiety, and depression are common symptoms that cluster with CIPN.80–82 Some evidence suggests that these symptoms are neurobiologically linked through the same structures that process pain: the prefrontal cortex, limbic system, and descending pain modulating system.18,83

ASSESSMENT

In-depth assessment should cover the patient's medical history, as well as CIPN presentation and impact on the patient. The medical history may reveal the presence of interacting symptoms and key CIPN risk factors. Given their significance in predicting CIPN, special attention should be given to the patient's history regarding previous cancer treatment (ie, receipt of neurotoxic chemotherapy), pre-existing peripheral neuropathy, and comorbidities associated with peripheral neuropathy. Proactive clinician assessment is also integral to understand the patient's CIPN experience, as well as emotional and financial sequelae and needs.

Clinician Assessment

Simple questions may be used to screen for CIPN, including:

  • “Do your fingers or hands feel numb?
  • “Do you feel like pins and needles are poking your fingers or hands?”
  • “Do you have burning, freezing, or electric shock-like pain in your fingers or hands?”

These questions may be repeated to assess the patient about symptoms in their toes or feet.

If the patient screens positive for CIPN, the clinician could ask whether the patient has difficulty with walking, tripping, picking up small objects, and weakness while standing from a chair or removing jar or bottle lids. The presence of autonomic symptoms could be screened by asking the patient whether they have begun experiencing dizziness, constipation, hearing loss, and difficulty urinating, swallowing, and gaining an erection.

Clinician-Graded Scales

Although burgeoning evidence suggests stronger validity of patient self-report surveys,10 clinician-graded scales have previously been used to aid clinicians in quickly assessing the grade of CIPN according to a standardized scale. The National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE)84 is most often used in clinical trials and practice. This scale evaluates CIPN based on the following grades: (1) asymptomatic: loss of deep tendon reflexes or paresthesias; (2) moderate symptoms: limiting instrumental activities of daily living; (3) severe symptoms: limiting self-care activities of daily living; (4) life-threatening consequences: urgent intervention indicated; and (5) death.84(p54) Other clinician-graded scales include the Eastern Clinical Oncology Group,85 World Health Organization,86 and Ajani scales.87 Clinician-graded scales alone are insufficient to adequately assess CIPN; they often underestimate the incidence of CIPN compared with physical assessment and patient report.88,89

Physical Assessment

Abundant evidence supports the use of the TNS clinical version to assess subclinical CIPN signs among adults and children.9 Various versions of the TNS include assessment of and highlight the importance of testing patients' deep tendon reflexes (the Achilles, patellar, biceps, triceps, and brachioradialis tendons), strength in the extremities, and vibration (using a 125-Hz tuning fork), pinprick, and cold sensation.90–92 Signs of CIPN are reflected by reduced reflexes, strength, and vibration sensitivity, as well as hyper- or hypo-sensitivity to pinprick and/or temperature stimuli. Instead of assessing the severity of the symptoms, the clinician assesses the extent of progression of the symptoms up the extremities.

Additionally, the clinician may test proprioception by having the patient close their eyes while the clinician manually flexes or extends 1 of the patient's phalanges; the patient is asked to say whether their finger/toe was moved up or down. Gross and fine motor strength can be tested by observing the patient's gait, ability to stand from a sitting position without using their arms, and ease of picking up small objects (eg, coins) and placing them in a designated location.

Nerve conduction studies and quantitative sensory testing are integrated in some versions of the TNS. These tests generally require referral to trained professionals with specialized equipment. Nerve conduction studies, conducted by a neurologist, are semi-invasive tests that evaluate the speed and amplitude of nerve conduction in select sensory and motor nerves. Many types of quantitative sensory testing involve the use of specialized instruments to quantify vibration, temperature, light touch, pain, pressure, and/or temperature sensitivity. Thus, nerve conduction studies and quantitative sensory testing may have limited use in the clinical practice setting.

Patient Report Surveys

Evidence-based patient-report surveys may provide key information about the severity and breadth of a patient's CIPN and related impairments. Some of the most commonly used and reliable patient report surveys include the Patient-Reported Outcomes version of the CTCAE (freely available at https://healthcaredelivery.cancer.gov/pro-ctcae/),93 European Organisation of Research and Treatment of Cancer Quality of Life–Chemotherapy-Induced Peripheral Neuropathy,94 and Functional Assessment of Cancer Treatment (FACT) Gynecologic Oncology Group–Neurotoxicity.95,96 These brief surveys can be completed by patients usually in less than 5 minutes. Some surveys focus on specific aspects or types of CIPN (eg, Oxaliplatin-Associated Neurotoxicity Questionnaire,97 FACT-Taxane,98 and Neuropathic Pain Scale for chemotherapy-induced neuropathy).99 Studies are beginning to test integration of these measures into the medical record.100,101 With comprehensive nursing assessment, an optimal care plan can be developed to reduce the patient's risk of poor CIPN outcomes.

PREVENTION AND MANAGEMENT

No known therapies have been effective for preventing or curing CIPN.11 Duloxetine (60 mg/d) is the only palliative treatment proven to significantly reduce chronic CIPN.12 In a randomized, blinded, placebo-controlled, crossover trial conducted among 231 individuals with chronic moderate-to-severe paclitaxel and oxaliplatin-induced peripheral neuropathy, a third of patients experienced a clinically significant (30%) reduction in CIPN severity by 6 weeks.12 Mild side effects of nausea, insomnia, and fatigue occurred in 3% to 7% of patients.12

Current clinical practice to reduce CIPN is to decrease or cease neurotoxic chemotherapy treatment and refer individuals as needed to physical therapy for CIPN motor deficits. Some drugs used to treat other neuropathic pain conditions—gabapentin and pregabalin, nortriptyline, amitriptyline, and lamotrigine—have been used for CIPN but have not shown effectiveness in CIPN clinical trials.11 These conclusions are based on abundant but weak evidence; thus, research on promising therapies is ongoing and rapidly growing.11,102

Promising CIPN Treatments

Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI). It increases the available pain-inhibiting serotonin and norepinephrine neurotransmitters in the CNS descending pain modulating pathways. The descending pain modulating system links with and suppresses noxious input to the WDRN. Thus, other SNRIs such as venlafaxine are also being investigated for their effects on CIPN.103 One phase III randomized, placebo-controlled clinical trial has suggested efficacy of topical baclofen, amitriptyline, and ketamine combination gels for treating acute or chronic moderate-to-severe CIPN sensory and motor symptoms (N = 150).104,105 Topical baclofen, amitriptyline, and ketamine may work synergistically to target the pain pathways involving the sodium channels, as well as NMDA, serotonin, norepinephrine, and other (eg, adenosine A and GABA) receptors.106

Nonpharmacological treatments have also shown preliminary efficacy in helping to alleviate CIPN. Exercise has shown efficacy in treating CIPN sensory and motor symptoms. Sensorimotor (balance) training, as low as 3 weeks, appears particularly beneficial in reducing CIPN, potentially because of its neuroplastic effects.107,108 Endurance training may promote neuroplasticity, regeneration, and repair109,110; endogenous opioid111,112 and pain-inhibiting neurotransmitter release113,114; adaptive coping115,116; and circulation that reduces oxidative stress, inflammation, and the pooling of chemotherapy in the dorsal root ganglia.110,117–119 Acupuncture,120 transcutaneous electrical nerve stimulation,121–123 photobiomodulation (nonionizing, low laser therapy),124,125 and reflexology (massage therapy)126 are thought to reduce CIPN by stimulating neurogenesis and repair, blood flow, and activation of pain-inhibiting receptors.127 Cognitive therapies (eg, cognitive behavioral and mindfulness therapies)128 and neurofeedback (real-time electroencephalogram feedback)129 have been used to treat other neuropathic pain conditions and may reduce CIPN by strengthening the brain's pain modulating pathways. Finally, neutraceuticals such as antioxidants, α-lipoic acid, and vitamin E that help protect and repair nerves have begun to show promise in helping to reduce CIPN.130

Promising CIPN Preventative Therapies

Duloxetine, exercise, neutraceuticals, and herbal medicines have shown preliminary efficacy in reducing the development of CIPN. Duloxetine could help prevent chronic painful CIPN by blocking peripheral nerve sodium channels, spontaneous nerve impulses, and overstimulation of the WDRN. Exercise could target various pathophysiologic mechanisms of the different types of CIPN. It promotes blood circulation, reduced oxidative stress, and mitochondrial adaptation110,117–119; neurogenesis, repair, and neuroplasticity109,110; reduced inflammation131–133; endogenous opioid and pain-inhibiting neurotransmitter release111,114; and adaptive coping.115,134 Neutraceuticals (eg, α-lipoic acid, vitamin E, glutathione, and glutamate) and herbal medicines (eg, goshajinkigan) may also prevent CIPN through their antioxidant and neuroprotectant properties.135,136

Additionally, cryotherapy is an example of an intervention indicated only for a specific type of CIPN. It has shown preliminary efficacy in reducing paclitaxel-induced peripheral neuropathy.137 However, it is strongly contraindicated for individuals receiving oxaliplatin; cold-sensitivity is characteristic of acute oxaliplatin-induced peripheral neuropathy and may be provoked by cold weather and contact with cold objects.138

Limitations of Previous CIPN Intervention Studies

The evidence on CIPN treatments and preventative interventions has been critically limited by the lack of rigorousness of many trials. Some major limitations include mismatch between the treatment's mechanism of action and the suspected pathophysiology of the patients' CIPN type, as well as the lack of a gold-standard CIPN measurement and control for confounding factors (ie, key CIPN risk factors).

Supportive Nursing Interventions for CIPN

Knowledge about the presentation and modifiable risk factors of CIPN can inform proactive nursing assessment and intervention that help patients avoid developing and/or manage CIPN. Patients often report being unaware of and unprepared for the CIPN experience. Key patient education points include the signs, symptoms, trajectory, and potential sequelae of CIPN; safety and management tips; and the importance of communicating with the provider or a mediating trusted health professional. Discussion about CIPN presentation should be tailored to the patient based on the type of neurotoxic chemotherapy that they are receiving. Fall precautions (eg, ensure adequate lighting, removing tripping hazards) and hand and foot care (eg, wear gloves when working with sharp, hot, or cold objects and proper-fitting shoes) are top priorities in safety education.

The nurse can help the patient to reduce their CIPN risk by helping them to manage their co-occurring symptoms and comorbidities: diabetes mellitus, peripheral arterial and renal disease, chronic pain, and vitamin deficiencies. The nurse can also support the patients' healthy CIPN risk-reducing behaviors: limiting alcohol intake, quitting tobacco use, eating a vitamin-rich diet, maintaining physical activity, and controlling inflammation-inducing stress.

If a patient develops CIPN, proactive referral to supportive resources can help to optimize patient outcomes. Physical therapy, cognitive behavioral therapy, palliative care, social work (if financial toxicity is an issue), and support groups could holistically help patients cope and manage their CIPN. Finally, the nursing presence, empathy, and acknowledgement of the patient's experience may be the most therapeutic intervention for a patient.

Ultimately, a Cancer Survivorship Care Plan section regarding CIPN could significantly aide patients before, during, and after neurotoxic chemotherapy receipt. An example of a tailored care plan CIPN synopsis for an adult who has diabetes mellitus, smokes, and will receive oxaliplatin could be, “You are receiving oxaliplatin, a drug that causes most patients to have neuropathy: cold-sensitivity, tingling, numbness, and sometimes weakness in your face, throat, hands, and feet. The symptoms may increase up to a year after stopping treatment and could affect other aspects of your physical, emotional, and financial well-being. Tell your health care provider if you have neuropathy symptoms so they can help lower your risk for long term neuropathy and seek supportive resources for you. You can lower your own risk by managing your blood sugar, staying physically active, nourishing yourself with vitamins, and limiting your alcohol intake and cigarette use.”139 More information can be found at copingmag.com/coping-with-cancer/chemotherapy-induced-peripheral-neuropathy.

CONCLUSION

Effective multidisciplinary care for patients with or at risk for CIPN depends heavily on nurses' evidence-based knowledge and ability to educate patients about CIPN and effectively communicate with the health care team their assessment and recommended course of action. For patients in neurotoxic chemotherapy treatment, CIPN is among the most common side effects that can compromise a patient's quality of life and cancer treatment trajectory. Patients are often unaware of and have difficulty communicating their CIPN symptom experience. Nurses can assess for and honestly inform the patient of their individual risk of developing CIPN. Nurses can proactively support their patients by educating them on CIPN risk-reducing measures, the expected CIPN trajectory, and management strategies for CIPN. Nurses can also advocate for the integration of CIPN assessment tools in the clinical setting to streamline the measurement of this important side effect.

However, the evidence must be cautiously evaluated before clinical practice implementation. Premature or haphazard implementation of suspected CIPN interventions may lead to patient physical and financial harm. For example, using cryotherapy for patients receiving oxaliplatin could exacerbate their CIPN progression. Prescribing ineffective drugs such as gabapentin could further patients' financial toxicity and lead to harmful side effects. Ultimately, the gaps in the knowledge of CIPN mechanisms, assessment, and management limit the ability to recommend treatments to patients. Duloxetine 60 mg/d is the sole treatment known to effectively palliate chronic moderate-to-severe CIPN. Most studies of CIPN interventions have had critical limitations and have not provided conclusive results. Research on various nonpharmacological and pharmacological interventions that have shown preliminary efficacy for CIPN is rapidly accumulating. The literature on CIPN has doubled within the last 5 years. Nurses can be the front-runners in critically evaluating and spreading the new evidence about CIPN to their colleagues and patients. Nurses can significantly influence the trajectory of patients' cancer survivorship outcomes by being well-informed, proactively assessing and referring patients to resources for CIPN, advocating for the patient, empathizing with patients, and helping them to develop strategies to prevent and manage CIPN.

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Keywords:

cancer; chemotherapy-induced peripheral neuropathy; neuropathic pain; neurotoxicity; nursing; survivorship

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