Chemotherapy Induced Peripheral Neuropathy: Risk Factors, Pathophysiology, Assessment, and Potential Physical Therapy Interventions

Chemotherapy induced peripheral neuropathy (CIPN) affects many people treated for various types of cancer. Though advances in cancer treatment have led to improved survival rates, patients are now exposed to greater levels of neurotoxic agents, resulting in increased incidence of CIPN. Symptoms of CIPN include pain, sensory loss, proprioceptive deficits, distal weakness, decreased fine motor control, reduced balance, and gait impairments. Chemotherapy induced peripheral neuropathy interferes with function, social roles, and quality of life. The purpose of this literature review is to present chemotherapeutic agents frequently associated with peripheral neuropathy, describe pathogenesis and symptoms, and describe potential impact of the physical therapist in assessment and treatment of persons affected by CIPN. Key Words: chemotherapy, peripheral neuropathy, physical therapy.






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Publication: Rehabilitation Oncology
Author: Pignataro, Rose M
Date published: April 1, 2010

INTRODUCTION

Approximately 1.5 million new diagnoses of cancer were anticipated in 2009 in the United States.1 Improved medical treatments and advances in technology have allowed many people with cancer to increase their lifespan; however, these life-saving interventions come with many potential risks. Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating and disabling condition that affects approximately 3% to 7% of patients who are treated with a single agent, and more than 38% of patients being treated with a combination of drugs.2 Damage to neurologic structures seems to be related to dose. Therefore, prevalence is expected to increase as newer medications to counteract myelosuppression make it possible to administer higher doses of chemotherapy. Increased prevalence may also be a consequence of longer life expectancy and improved survival rates, and the higher possibility of treatment with multiple agents.2

Prevalence of CIPN has been underestimated. Some experts feel that CIPN may be underdiagnosed because the initial onset of symptoms primarily manifests as subjective reports from patients that are difficult to confirm using objective clinical measures such as electrophysiologic testing and quantitative sensory assessment.3 Additionally, measures which fail to account for the patient's perspective may overlook the impact of CIPN on activities of daily living and overall quality of life.4 Some patients report feeling as though their symptoms are ignored or undervalued by medical personnel due to lack of objective findings.5 Comparison of medical assessment with patient reports shows that symptoms most bothersome to the patient such as burning and paresthesias are frequently under-recognized by clinical signs and testing.6 Survey research has demonstrated that CIPN is frequently cited by patients as one of the most bothersome side-effects of cancer treatment with the greatest overall impact on quality of life.7 The situation is further complicated by attempts to balance maximum therapeutic effect of chemotherapy with unwanted side-effects, including neurotoxicity.5

The purpose of this review is to present chemotherapeutic agents frequently associated with CIPN, describe its pathogenesis and symptom manifestation, and highlight the potential role of physical therapists in the assessment and treatment of persons affected by CIPN.

PATHOPHYSIOLOGY OF CIPN

Though pathogenesis and symptom manifestation may vary, there are common hypotheses regarding ClPN and the specific parts of the peripheral nerve affected by different classes of agents (Figure 1). Damage to microtubules within neurological structures is one such factor.3·8 Paclitaxel and vincristine bind to the protein tubulin and likely interfere with axonal transport mechanisms.8 Taxanes also cause tangles of microtubules within the dorsal root ganglion and Schwann cells.9

The platinum agents, specifically cisplatin, may induce apoptosis in the dorsal root ganglion by binding to the DNA.8,9 Postmortem studies of patients who had received chemotherapy with cisplatin found highest concentrations of the drug in the dorsal root ganglia.10 Damage to the ganglion is thought to be responsible for permanent symptoms." Oxaliplatin may interfere with the ion exchange across the excitable membrane making it difficult for neurons to conduct an action potential.12

Mitochondrial dysfunction is another proposed mechanism in CIPN. Animal studies with paclitaxel show abnormalities of mitochondria within the axons of sensory nerves." Cisplatin may also potentially impair mitochondria! function by contributing to abnormal calcium metabolism.14

Damage to neurons and delayed recovery may be explained by reduced levels of nerve growth factor. This has been shown to occur after treatment with cisplatin, oxaliplatin, and paclitaxel.7 Chemotherapy induced peripheral neuropathy due to agents that primarily affect the nerve fiber without damage to the ganglion show better potential for recovery.14 Some animal studies have shown a change in blood supply to peripheral nerves as a result of taxanes and thalidomide.15

In most cases of CIPN, damage seems to be mostly concentrated in the sensory fibers. This may be partially explained by the anatomical location of the dorsal root ganglion. It is difficult for most chemotherapeutic agents to cross the blood-brain barrier, and cell bodies for motor nerves are protected by their location within the spinal cord at the anterior horn as compared with sensory neurons whose cell bodies are located away from the cord at the dorsal root ganglion. Also, within the peripheral nervous system, motor nerves tend to be more heavily myelinated than the smaller diameter sensory nerves. Myelin may serve some protective function against axonal damage. ' Symptoms tend to effect the distal upper and lower extremities (stocking-glove distribution) because the longest never fibers have the largest surface area, and are therefore more vulnerable to damage from chemotherapeutic agents.3

In addition to sensory symptoms, some patients also experience myalgias, or muscle aches, exacerbated by activity.1' There may also be damage to autonomie nerve fibers leading to symptoms such as dry mouth, constipation, urinary retention, orthostatic hypotension,9 and irregular pulse.12 Autonomie fibers are poorly myelinated and this may contribute to their vulnerability towards developing CIPN.9

Individual patient susceptibility to CIPN can be hard to predict. However, patients with conditions involving pre-existing neurological damage are at greater risk. Such conditions include diabetes, alcoholism, nutritional issues (ie, low thiamine and B12 levels), Lyme disease, lupus, and HIV.10,16,17 Since vincristine is processed by the liver, pre-existing hepatic impairment could also increase risk of CIPN.18

Prognosis for recovery in persons with CIPN is largely dependent on the mechanism responsible for neurological impairments as well as individual variations in susceptibility and resilience including age, comorbidities, and predisposing factors for peripheral nerve damage including smoking and alcohol use. For drugs primarily affecting the axon, regeneration is possible once the drug has been metabolized and removed from the system. However, the likelihood of recovery is significantly diminished for agents that result in damage to the cell bodies themselves at the dorsal root ganglion.7

CHEMOTHERAPYAGENTS IMPLICATED IN CIPN

The most common agents associated with CIPN are the taxanes (paclitaxel, docetaxel), platinum drugs (cisplatin, carboplatin, oxaliplatin), vinca alkaloids (vincristine, vinblastine, vindestine, and vinorelbine), thalidomide, and bortezomib. Pathogenesis for neurological side effects from each of these drug classes differs with some overlap in symptoms and clinical manifestation.3 Microtubule inhibition and impaired axonal transport is a shared mechanism in CIPN due to taxanes, platinum agents, and vinca alkaloids. Damage to the dorsal root ganglion may be seen in bortezomib and cisplatin therapies. Other mechanisms related to onset of CIPN include disruptions in cellular metabolism and interference with the function of the excitable membranes within the neural tissues. When multiple agents are used, there is greater likelihood of neuiOtoxicity."'A summary of chemotherapy agents, mechanisms of nerve damage, and symptoms is shown in the Table 1.

Manifestations of CIPN include sensory, motor, and autonomie neuropathy depending on the location and extent of neurological damage. Sensory involvement can result in pain and paresthesias, usually with a stocking, glove distribution, as well as reduced vibratory and position sense. Motor damage can lead to muscle cramps, weakness, ataxia, and gait disturbances. Involvement of the autonomie nervous system can lead to orthostatic hypotension, as well as bowel and bladder dysfunction.7

Taxanes

Two specific medications in the taxane class have been associated with CIPN: paclitaxel and docetaxel. Paclitaxel is an agent commonly used in the treatment of ovarian cancer not responsive to primary treatment methods, metastatic breast cancer, Kaposi's sarcoma, bladder, testicular, lung, and head and neck cancers.3·10 The effectiveness of taxanes as cancer drugs is dependent on their effectiveness as microtubule inhibitors.12 By inhibiting the microtubules needed for cellular mitosis, taxanes prevent further replication of cancerous cells. However, this same property contributes to neurotoxic side effects. It is thought that taxanes may interfere with axonal transport in peripheral nerves leading to trophic changes in motor and sensory fibers which then results in CIPN.12 Peripheral neuropathy induced by paclitaxel seems to be dose-related, with predominance of peripheral sensory symptoms and sparing of motor function at lower doses, while at higher dosages, motor and autonomie involvement also may be seen.19

Docetaxel, used for treatment of breast cancer,2" is another taxane drug associated with CIPN, with symptoms similar to those experienced by subjects receiving treatment with paclitaxel. Common reported side effects include pain, paresthesias, hypoesthesias, proprioceptive loss, and unsteady gait. There may also be some motor symptoms, primarily distal weakness at the foot and ankle. Prevalence of neurotoxicity due to treatment with docetaxel ranges from 9.5% to 63% depending on total dose and delivery schedule.21

Platinum Agents

Platinum agents include cisplatin, carboplatin, and oxaliplatin. These drugs are generally used to treat lung, ovarian, breast, and colorectal cancers.3 The platinum agents also work by inhibition of microtubules, decreasing the ability of cancer cells to undergo mitosis, but also disrupting axonal transport, particularly in longer peripheral nerve fibers.12 Estimated prevalence of CIPN in patients treated with platinum agents is 30%." With cisplatin, CIPN has been linked to cumulative doses of 300 mg/nror more.14 Patients may also experience "coasting" ie, onset or worsening of symptoms after chemotherapy has been terminated. Recovery is frequently delayed over the course of months or years. Permanent CIPN as a result of cisplatin occurs in 30% to 50% of patients even after therapy has been discontinued.1-1 However, likelihood of partial return of neurological function is high.14 Symptoms of cisplatin-induced CIPN include distal sensory neuropathy with tingling, burning, and/or pinprick-like paresthesias in a stocking-glove distribution. There is reduced proprioception and nerve damage can progress to loss of deep tendon reflexes in the affected extremities. Motor symptoms occur less commonly.14

Patients receiving carboplatin experience similar symptoms, although they are less frequent and severe. Generally, carboplatin is thought to be less toxic than cisplatin.3'14 Coasting is also less frequent." It is likely that higher doses of carboplatin are avoided due to associated hepatoxicity, thus reducing incidence of severe neurologic involvement.14

Like the other platinum agents, damage and symptoms from oxaliplatin are related to total cumulative dose. However, oxalplatin has the ability to induce both acute onset and delayed neurologic symptoms. Acute symptoms tend to occur at higher doses and can be partially suppressed by using a slower infusion rate while administering the agent.14 The occurrence of oxaliplatin neurotoxicity is much higher than that of cisplatin and carboplatin: acute symptoms occur in 85% to 95% of patients.14 Acute symptoms associated with oxaliplatin administration include paresthesias, hypoesthesias, and dysesthesias affecting the hands, feet, perioral area, and throat.'·14 Particularly distressing to patients are reports of jaw spasms and subjective dysphagia.14 Muscle cramps may occur in the distal extremities, and symptoms are known to be aggravated by exposure to cold.14 It has been suggested that the acute symptoms induced by oxaliplatin may be due to disruption in sodium channel function within the excitable membrane and at the synapses of affected neurons.3 Acute motor symptoms may be caused by hypocalcemia and hypomagnesia after infusion of the chemotherapeutic agent.14 Longer term onset of symptoms may be the result of damage to the dorsal root ganglia of sensory neurons where toxins are known to accumulate.3 Coasting can also occur, making it difficult to regulate dose in an attempt to avoid neurotoxicity.9 The delayed onset of symptoms with oxaliplatin is similar to those experienced by patients undergoing therapy with cisplatin. Patients report reduced sensation in the distal extremities that can interfere with fine motor control and activities, such as dressing and fastening buttons.14 The chances of recovery from chronic CIPN due to oxaliplatin are higher than those following treatment with cisplatin.14

Vinca Alkaloids

Vincristine is a chemotherapeutic agent within the class of vinca alkaloids and is used in the treatment of lymphoma, leukemia, and solid tumors.8 It is commonly used in childhood acute lymphoblastic leukemia.22 Like the platinum agents and taxanes, vincristine is also a microtubule inhibitor.12 Most commonly, patients experience sensory neuropathy, although autonomie dysfunction is also possible.8 Chemotherapy induced peripheral neuropathy as a result of vincristine has been tied to individual treatment dose, infusion rate, and cumulative dose.8 Occurrence of Grade 3 to 4 sensory neuropathy in persons receiving treatment with vincristine is estimated at 31%.12 Motor symptoms may include distal weakness, especially dorsiflexion and wrist extension.23 Foot drop may lead to gait impairments.23 Other vinca alkaloids such as vinblastine, vindesine, and vinorelbine have similar manifestations, but with less severity and decreased prevalence as compared with vincristine.3 Rates of recovery of peripheral neuropathy in pediatrie patients receiving vincristine are high with most symptoms resolving within months of discontinuing therapy.22

Thalidomide

Thalidomide is an antiangiogenesis agent used in treatment of multiple myeloma, gliomas, renal cell cancer, colon cancer, and breast cancer, and Kaposi's sarcoma.3·5·11·" Chemotherapy induced peripheral neuropathy is a common side effect, occurring in up to 20% to 40% of patients," and is likely to be more severe as compared with other chemotherapeutic agents, resulting in significant permanent damage. The mechanism behind neurotoxicity is unknown, but damage to the dorsal root ganglia is suspected.8 Research has shown Wallerian degeneration without demyelination.8 Onset of CIPN related to thalidomide increases with age of the patient and cumulative dose or length of treatment."

Bortezomib

Bortezomib is an intravenous medication used in the treatment of multiple myeloma. It acts by inhibiting proteasomes and disrupting the cellular metabolism of neoplastic growth.5 It may also interfere with calcium homeostasis.24 Chemotherapy induced peripheral neuropathy due to bortezomib is thought to target small unmyelinated C-fibers resulting in very painful, burning paresthesias in the distal extremities.'' However, bortezomib may also induce changes in the dorsal root ganglion.24 Effects may be magnified in patients who have received both bortezomib and thalidomide." Occurrence of peripheral neuropathy due to chemotherapy with bortezomib is estimated at 9% to 41%25 and increases with recurrence of cancer and repeated therapy.24 Prognosis for recovery from CIPN after reduction of dose or discontinuation of bortezomib is good.26

ASSESSMENT OF CIPN

Assessment of CIPN can be somewhat difficult since clinical manifestations do not always correlate with severity of patient complaints. Evaluation for CIPN and associated impairments should include electrophysiologic testing, sensory testing and neurological assessment, gait and balance assessment, and evaluation of the impact of symptoms on patients' quality of life and ADLs. Helpful guidelines for physical therapists concerning thorough assessment and treatment planning for persons with CIPN can be found in the Guide to Physical Therapist Practice, practice pattern, 5G, "Impaired Motor Function and Sensory Integrity Associated with Acute or Chronic Polyneuropathies."27

Electrophysiologic Testing

Certain chemotherapeutic agents cause damage to the peripheral nerves that result in characteristic findings on electrophysiologic evaluation. Patients who develop CIPN as a result of cisplatin therapy show a decrease or absence of the compound sensory nerve action potential (CSNAP), delayed conduction velocity in distal sensory nerves, and a prolonged or absent H-reflex.2S In contrast, electromyography (EMG) results are usually normal.28 Nerve biopsies reveal evidence of segmental demyelination and remyelination.28 Following treatment with vincristine, electrodiagnostic studies may show normal or near normal conduction velocity in motor and sensory nerves, with decreased amplitude of the compound motor action potential (CMAP) and CSNAP.2S The EMG may show evidence of denervation, but the H-reflex is generally unimpaired, even when deep tendon reflexes show an absent Achilles tendon response.28 With docetaxel exposure, there is a decreased amplitude of the CMAP and CSNAP, with moderate delay in nerve conduction velocity.1" In bortezomib, nerve conduction studies generally reveal decreased CSNAP and increased latency or absence of the ?-reflex.23 It is also possible to show decreases in CMAP.24 In rat models, thalidomide induced ClPN also presents with electrophysiologic evidence of damage to sensory fibers.13

An important limitation of electrophysiologic testing for CIPN is a lack of sensitivity in detecting small fiber damage.19·17 The fibers that mediate pain are small diameter and particularly vulnerable to CIPN. These fibers (?-delta and C) correspond to symptoms most frequently cited as bothersome and distressing by patient report. For these reasons, electrodiagnostic studies must be augmented by other clinical measures in order to perform an accurate assessment.4

Sensory Testing and Neurologic Assessment

In persons with CIPN, the clinician must take into account both negative and positive symptoms such as sensory loss (negative) and pain (positive). Symptoms must be evaluated in a consistent, organized fashion that is readily reproduced in assessing patients' response to treatment and comparing outcomes.2'

Neurologic pain and sensory deficits can manifest in a variety of ways such as dysesthesia, or reports of abnormal, unpleasant sensations in the affected area, and paresthesias, or abnormal sensations that are not necessarily unpleasant. Pain can be spontaneous or in response to a stimulus. Hyperalgesia is an increased nociceptive response to a stimulus that is normally painful. Allodynia is pain evoked by a stimulus that is normally benign.10 Sensory mapping can assist the physical therapist or other health care provider in determining the distribution of these symptoms. The assessment should begin outside the perimeter of the area of interest and progress inward in a set pattern.29

Assessing light touch provides information regarding the integrity of low-threshold mechanoreceptors and large myelinated ?-beta fibers. This can be done by using a piece of cotton or a small paint brush.29,30

Semmes-Weinstein monofilament testing can be used to assess slowly adapting low-threshold mechanoreceptors and quantify threshold for tactile perception as well as thresholds for punctate allodynia. In patients with diabetic peripheral neuropathy, the 5.07 diameter monofilament is frequently used as the threshold for identifying loss of protective sensation.29

The European Federation of Neurological Societies Task Force recommends use of a wooden cocktail stick to examine loss of pin prick or allodynia in response to shaip stimuli. These symptoms reflect involvement of small diameter C-fibers.29

Vibratory perception may be assessed using a 128 Hz tuning fork applied to the hallux, medial malleolus, patella, distal interphalangeal joint of the second finger, ulnar styloid, and medial epicondyle.29 With the Biothesiometer, clinicians can determine the threshold of vibration perception. 2'UI Pressure pain thresholds can be determined using a sphygnomometer that is gradually inflated according to patient tolerance. Though this is only useful in examining the extremities, it will help assess the integrity of slowly adapting mechanoreceptors29 and is well suited to neuropathic pain due to CIPN, which generally has a stocking-glove distribution.

Thermal stimuli are perceived through activation of A-delta and C fibers. When assessing thermal perception, the clinician needs to be consistent in stimulus size and duration to account for spatial summation.29 Thermal perception may be tested through the use of cold and warm Lindblom rollers.32

Possible limitations of sensory testing include fluctuations in the subject's reaction time, level of alertness, compliance and willingness to participate, as well as psychological status.31 Clinicians should consider these factors when interpreting test results. Strategies for accurate assessment include use of a noninvolved reference site for comparison and use of null stimuli, times when no stimulus is delivered, spaced at random. Tests should be considered invalid if a person repeatedly reports perception of the null stimulus.-9 Neurological assessment should also include deep tendon reflex testing,31 although deficits in DTRs may reflect latestage pathology.19

Gait and Balance Assessment

No studies to date have examined gait or balance issues in people with CIPN, but patients with ClPN report difficulty with ambulation and increased fear of falling,7 and literature concerning other forms of peripheral neuropathy strongly suggest that these areas should be assessed. Persons undergoing treatment with cisplatin have been noted to experience vestibular toxicity that may lead to balance deficits while those receiving therapy with taxane drugs often present with decreased postural stability.34 Decreased distal lower extremity strength and loss of sensation, including proprioception, are risk factors for increased falls and balance deficits.-15 In subjects with age-related peripheral neuropathy, the greatest risk ratios were associated with sensory loss followed by risk due to decreased strength.36 Subjects with diabetic peripheral neuropathy involving loss of sensation at the foot and ankle are more likely than those without neuropathy to use a hip strategy when their balance is challenged,35 and gait assessment revealed reduced ankle range of motion resulting in decreased stride length and cadence.37 Patients with diabetic peripheral neuropathy also tended to use the hip flexors to advance the limb during swing phase rather than relying on forceful plantarflexion at push off due to impaired ability to generate torque at the ankle.17

Physical therapists are uniquely positioned through our education and skill set to perform thorough neuromuscular and functional assessments that will assist in generating a problem list, identifying appropriate goals, and establishing a tailored intervention strategy based on the individual patient presentation. Within the realm of our professional expertise are measures such as manual muscle testing, handheld dynamometry, grip testing, goniometry, sit and reach, timed up and go, qualitative gait assessment, timed sit to stand, as well as the Berg and Tinetti Scales for balance assessment.14

Quality of Life Assessment and Activities of Daily Living

Chemotherapy induced peripheral neuropathy can result in disruption of functional abilities in occupational, social and family roles, as well as hobbies and recreational activities.5 Patients with CIPN sometimes report reduced ability to walk due to burning pain in the feet. They may also experience impaired fine motor control needed for dressing and other daily tasks due to numbness of the hands and fingers.7 Studies in patients with other types of peripheral neuropathies have found a reduced ability to maintain unilateral stance, and an increased fall risk.3R A history of falls or fear of falling may lead to functional decline as patients may tend to self-limit their activities.17

Standardized patient questionnaires and surveys may be helpful in examining the patient's perspective and gathering more information about impaired daily function and reports of pain. Such measures include the Patient Neurotoxicity Questionnaire,3 the Functional Assessment of Cancer Therapy - General (FACTG),-11 the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire,3' and the Total Neuropathy Scale.4 Surveys that are specific to neurological symptoms due to chemotherapy include the CIPN-20,4 an inventory that uses 3 scales to assess sensory, motor and autonomie symptoms,4 and questionnaires pertaining to the chosen chemotherapeutic agents, eg, Oxaliplatin Associated Neurotoxicity Interview,4 and the Oxaliplatin-Specific Neurotoxicity Scale (NTX-1 2). 39 Nonspecific measures familiar to the physical therapist may also be employed in assessing limitations in the ability to perform daily tasks for oncology patients including the Brief Fatigue Inventory and Berg Rating Scale of Perceived Exertion.34

Treatment for CIPN

There are several treatment options for CIPN, some primarily medical, and others where physical therapy could provide potential avenues for conservative management.

Pharmacologie Intervention

Dosing options to mitigate or prevent CIPN include lower quantities of the agent when possible, a prolonged infusion rate per treatment, and delivery of the total dose over a longer period of time.40 Some studies suggest the simultaneous administration of neuroprotective agents, such as amifostine, to prevent toxicity and damage. Amifostine is thought to prevent or decrease damage to peripheral nerves while not interfering with the action of the agents in treating malignant tissues."' However, other neuroprotective drugs show limited efficacy. A Cochrane review indicates little compelling evidence for the use of neuroprotective agents in platinum-induced CIPN" and other authors cite similar concerns for bortezomib.24

Nerve growth factor (NGF) has been effectively used as a neuroprotectant in animal studies involving cisplatin and paclitaxel.41 Investigations have shown that levels of NGF in the circulation decrease and can sometimes disappear completely when subjects are receiving chemotherapy.25 Nerve growth factor is also known to have a trophic effect on the dorsal root ganglia, an area prone to damage from accumulation of cisplatin, leading to severe and lasting neuropathy.41

Insulin-like growth factor (IGF-I) has also been shown to positively influence nerve regeneration in animal models and may serve as a neuroprotectant during chemotherapy using vincristine.41 Positive results were obtained using IGF-I to preserve motor function in mice during vinca alkaloid treatment.24,41 For both IGF-I and NGF, gene therapy may provide an effective vehicle for delivery in future treatment.42

Vasoendothelial growth factor (VEGF) is another substance that may be used to counteract CIPN by reducing and reversing damage to the vascular supply of peripheral nerves. Experimental intervention for animal subjects with diabetic and ischemie neuropathy show positive results using gene-therapy to administer VEGF.15 However, there are legitimate concerns that the administration of VEGF might aide angiogenesis and promote growth of cancerous cells, making this a less attractive treatment option.15

Several nutrients appear to have potential for CIPN treatment or prevention. Vitamin E is an antioxidant that may reduce the incidence and intensity of CIPN induced by cisplatin.2 Glutamine may increase the availability and production of NGF.2

Infusion with calcium and magnesium may prevent neurotoxicity with oxaliplatin.2·' Oxaliplatin breaks down into oxalate that binds to calcium and magnesium, and is thought to affect the conductance and threshold in excitable cells.2

Various medications are often used to mitigate pain associated with CIPN including NSAIDs,26 narcotics, carbamazepine, and gabapentin.14 Antidepressants may also be prescribed, possibly producing analgesia by release of endogenous opiates and inhibition of sodium channel activation in nociceptive fibers.43 Narcotic medications may help reduce conduction in A delta and C fibers but are less effective in mediating activity in A beta fibers,43 rendering only partial relief. There is little evidence to support the effectiveness of narcotics in neuropathic pain.43 Efficacy must be balanced by concern for deleterious consequences including sedation, impaired judgment, and dependence.

Platinum agents and taxanes may make peripheral nerves more vulnerable to damage from compression due to impaired function of the microtubules and delayed axonal transport. This may be more frequent in patients with pre-existing or predisposing conditions such as prior occupations or hobbies that involved repetitive motion or cumulative stress. If clinical assessment shows signs of a nerve entrapment at a specific site such as the carpal or tarsal tunnel in patients with CIPN, selective surgical decompression may provide another treatment alternative.44

Nonpharmacologic Interventions for CIPN

Pharmaceutical management of pain related to CIPN is usually only partly effective.43 Since pain and paresthesias can play such significant roles in reducing function and diminishing patients' quality of life, noninvasive measures without the associated side-effects of many medications provide an important alternative for patients with peripheral neuropathy. Studies involving the direct effect of adjunctive treatment measures in CIPN are difficult to find. However, information may be extrapolated from sources examining effects of interventions in other populations with peripheral neuropathy.

Research investigating the effects of acupuncture in subjects with HIV-related peripheral neuropathy has demonstrated decreased pain and paresthesias.45 A second study found similar results and no adverse reactions were noted.44 Proposed mechanisms of action for acupuncture include the gate theory and release of endogenous opiates. Possible stimulation of NGF has also been suggested.44

Gait, balance, and strength impairments may be effectively addressed by physical therapy interventions and treatment strategies. Two studies found that increased ankle flexibility and strength improved balance and stability during ambulation in subjects with diabetic peripheral neuropathy.15·46 Patients with CIPN at risk for falls may benefit from training with an appropriate assistive device. Studies report reduced loss of balance in persons with peripheral neuropathy when using a single axis cane while ambulating on uneven surfaces or in low lighting conditions.35,46

Research examining the effects of therapeutic exercise for people with peripheral neuropathies have shown mixed results, probably due to variety in possible exercise prescription and the need to tailor interventions to the individual needs of each patient rather than the group as a whole. In a systematic review, the Cochrane group found evidence that therapeutic exercise has the potential to increase strength in subjects with peripheral neuropathy, however, not enough information exists in the form of randomized controlled trials to draw reliable conclusions about the impact of therapeutic exercise on restored function.47 Therapeutic exercise does not appear to be detrimental to recovery47 and could be justified in persons with CIPN accompanied by deficits in strength, balance, or flexibility.48

Therapeutic Exercise

Presence of neuromuscular deficits as a result of CIPN suggests potential benefit of therapeutic exercise for this patient population. Research regarding effects of these interventions vary with severity of disease, treatment rendered, and lifestyle of the patient49 as well as stage of treatment.50 Benefits of physical activity in improving strength, cardiovascular fitness, gait, and endurance must be balanced with patients' ability to tolerate levels of exercise as well as the potential harms of remaining inactive.50 Some authors suggest working within the following stages: "buffering before treatment, coping during treatment, rehabilitation immediately post-treatment, (and) long-term health promotion for those with positive treatment outcomes."50 While previous literature reviews suggest that physical exercise had little if any adverse effects during and after cancer treatment, and could potentially result in less fatigue and greater cardiovascular fitness, the effect sizes were small, indicating a need for further research50 as well as a need to carefully monitor and adapt the intervention to the individual needs and responses of each patient. The ability to assess adverse reactions is limited by study designs that tend to favor a per-protocol analysis where persons with complications or worsening of disease were omitted from the outcome measurements due to an inability to complete the program. Our profession would benefit from future studies that examine difference in responders and nonresponders through intention-to-treat analyses.50

Use of Physical Agents

Low intensity light therapy (LILT), or the use of nonthermal red and infrared light sources, has been used successfully to expedite healing in peripheral nerve injuries in noncancer populations.51 One proposed mechanism of action is increased production of transforming growth factor beta-1, a neuroprotective substance.51 Wound and tissue healing studies have demonstrated an increase in VEGF52 and NGF53 with LILT, suggesting possible utility in CIPN. In studies of patients with diabetic peripheral neuropathy, monochromatic infrared energy (MIRE) helped restore loss of sensation.53 Another study examining the effects of MIRE in patients with diabetic peripheral neuropathy reported subjective perceptions of improved balance and decreased fear of falling.54 Low intensity light therapy may also be a suitable intervention for relief of pain in persons with peripheral neuropathy. It has been suggested that LILT helps promote analgesia through both opiod and non-opiod mediated mechanisms.55 However, the use of LILT in patients with cancer presents difficulty as its safety in this population has not yet been established. The general consensus is that use of LILT directly over known malignancies is contraindicated,56 but treatment of peripheral nerves in cancer patients may be a possibility.

Electrical stimulation may provide a viable option in addressing painful symptoms of CIPN, although, once again, treatment rationale must be inferred from research studies examining the effects in patients with peripheral nerve damage due to diabetes. Such inference is appropriate since there are several similarities between diabetic peripheral neuropathy (DPN) and CIPN in terms of nature and location of symptoms and the nerve fiber types that are affected.

Use of ?-wave electrical stimulation (similar to transcutaneous electrical nerve stimulation - TENS) has been successfully used to reduce pain in patients with diabetic peripheral neuropathy.57·58 Subjects also used analgesic medications during intervention with electrical stimulation, demonstrating its usefulness as an adjunctive treatment measure.57·58 However, symptoms returned after treatment was discontinued.57·58 Another option presented use of frequency modulated electromagnetic stimulation applied to the legs at subsensory threshold. This approach resulted in decreased pain for patients with diabetic peripheral neuropathy. Monofilament testing and vibratory testing with a biothesiometer showed improved sensation. Benefits continued at the 4-month follow-up without any further treatment.59

The analgesic effect of TENS may be related to the gate theory of pain relief, ie, modulation of transmission of nociceptive input at the dorsal horn of the spinal cord. Greater likelihood of beneficial results were seen when electrical stimulation was applied at a site proximal to the nerve lesion, eg, at the low back for symptoms affecting the lower extremities.60 Motor level treatment (NMES - neuromuscular electrical stimulation) of the quadriceps has also been used to address symptoms of diabetic neuropathy. When NMES treatment was compared with TENS, subjects reported a greater reduction in nonpainful symptoms (paresthesias and numbness) when receiving NMES.61

Patient Education and Supportive Measures

Patients undergoing treatment with chemotherapy should receive education regarding possible signs and symptoms of CIPN with instructions to consult their medical provider if issues arise. This allows the provider to monitor doses and adjust the treatment plan as needed.2 Women with breast cancer treated with paclitaxel reported improved ability to manage side-effects, including CIPN, when they were anticipated prior to onset.2 Unexpected symptoms provoked an increase in overall anxiety and distress.6 In a qualitative study, half of participants reported being suiprised by the onset of CIPN and did not recall any prior counseling regarding this possible side effect.5 This can be particularly disturbing because of the unfamiliar nature of CIPN symptoms, often leading patients to interpret them as signs of other medical problems including heart attack or stroke.5

For patients with CIPN, physical therapists can provide training in fall reduction strategies, as well as education in proper foot care and guarding against trauma in areas affected by reduced sensation.2 Often, rehabilitation specialists will be able to recommend modifications to the home environment to enhance patient safety such as the use of handrails and removal offall hazards.12 Patients receiving agents thought to cause autonomie symptoms should also be educated in management of orthostatic hypotension.12

Clinical Implications

Chemotherapy induced peripheral neuropathy is a relatively common side effect in patients receiving chemotherapy for a variety of malignant conditions including breast cancer, myeloma, renal cell cancer, lung cancer, and colorectal cancer. As survival rates and lifespan for these cancers improve, the prevalence of CIPN will likely increase, and so will the impact on patients' functional ability and quality of life. Chemotherapyinduced peripheral neuropathy may be under-recognized due to lack of sensitivity in objective screening measures. As rehabilitation specialists, physical therapists are uniquely qualified to measure not only subjective patient reports but disability related to CIPN. This skill set enables the physical therapist to provide effective patient education and implement strategies that enhance functional outcomes. The literature suggests that functional deficits and pain associated with cancer treatment represent an unmet need.62 Pharmacologie management of CIPN is limited and comes with many undesirable side-effects, making potential physical therapy interventions an attractive alternative. Analgesic treatments as well as gait, balance, and strength training require much further study to determine optimal approach, treatment timing, and patient populations who will receive the most benefit.

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Author affiliation:

Rose M. Pignataro, PT, DPT, CWS1

Ame K. Swisher, PT PhD, CCS2

1 Department of Community Medicine, Program in Public Health, West Virginia University, Morgantown, WV

2 Division of Physical Therapy and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV

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