Chemotherapy Induced Peripheral Neuropathy: Risk

Factors, Pathophysiology, Assessment, and Potential

Physical Therapy Interventions
Rose M. Pignataro, PT, DPT, CWS1
Anne 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

ABSTRACT are frequently under-recognized by clinical signs and testing.6

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, result­
ing in increased incidence of CIPN. Symptoms of CIPN include
pain, sensory loss, proprioceptive deficits, distal weakness,
decreased fine motor control, reduced balance, and gait impair­
ments. 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
INTRODUCTION
Approximately 1.5 million new diagnoses of cancer were
anticipated in 2009 in the United States.1 Improved medical treat­
ments 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, prev­
alence 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
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 CIPN 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
1. Dorsal root ganglion-cisplatin
2. Microtubules-taxanes, vincristine
3. Schwann cells-taxanes
4. Excitable membrane-oxaliplatin

assessment.3 Additionally, measures which fail to account for the
patient’s perspective may overlook the impact of CIPN on activi­
ties 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
Figure 1. Locations of chemotherapy-induced peripheral
sensory nerve damage.
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

10 Rehabilitation Oncology
Vol. 28, No. 2, 2010
dorsal root ganglia.10 Damage to the ganglion is thought to be
responsible for permanent symptoms.11 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.13 Cisplatin may
also potentially impair mitochondrial 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 concen­
trated in the sensory fibers. This may be partially explained by
the anatomical location of the dorsal root ganglion. It is diffi­
cult 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 myelin­
ated than the smaller diameter sensory nerves. Myelin may serve
some protective function against axonal damage.3 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 experi­
ence myalgias, or muscle aches, exacerbated by activity.9 There
may also be damage to autonomic nerve fibers leading to symp­
toms such as dry mouth, constipation, urinary retention, ortho­
static hypotension,9 and irregular pulse.12 Autonomic 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 impair­
ments as well as individual variations in susceptibility and resil­
ience 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
CHEMOTHERAPY AGENTS IMPLICATED IN CIPN
The most common agents associated with CIPN are the taxanes
(paclitaxel, docetaxel), platinum drugs (cisplatin, carboplatin,
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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 neurotoxicity.16 A summary of chemotherapy agents,
mechanisms of nerve damage, and symptoms is shown in the
Table 1.
Manifestations of CIPN include sensory, motor, and auto­
nomic 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 autonomic nervous system can lead to ortho­
static hypotension, as well as bowel and bladder dysfunction.7
Taxanes
Two specific medications in the taxane class have been associ­
ated 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 autonomic involvement also may
be seen.19
Docetaxel, used for treatment of breast cancer,20 is another
taxane drug associated with CIPN, with symptoms similar to
those experienced by subjects receiving treatment with pacli­
taxel. 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 inhibi­
tion 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%.11 With cisplatin,
CIPN has been linked to cumulative doses of 300 mg/m2 or more.14
11
Table 1. Common Chemotherapeutic Agents and Effects of CIPN
Chemotherapeutic Agent Types of Cancer Treated with This Agent Mechanism for CIPN Common Symptoms of CIPN
Taxanes
• Paclitaxel Ovarian Microtubule Distal sensory
Metastatic Breast Inhibition neuropathy
Kaposi’s sarcoma
Bladder Impaired axonal transport In higher doses, motor and auto­
Testicular nomic
Lung May cause microtubule tangles in dorsal Dysfunction
Head and neck root ganglion and Schwann cells

• Docetaxel Breast Ca Same as paclitaxel, usually less

severe
Platinum Drugs Lung Microtubule
Ovarian Inhibition
Breast
Colorectal Impaired axonal transport

• Cisplatin Apoptosis in dorsal root ganglion Distal sensory neuropathy

Motor loss is less common

• Carboplatin
Same as cisplatin, usually less
severe

• Oxaliplatin
Acute neurological symptoms may be due Delayed effects: Same as cisplatin
to disruption in Na+ channel function,
hypocalcemia and hypomagnesia resulting Acute symptoms: paresthesias/
in cell hyperexcitability dysesthesias hands, feet & peri­
oral area, jaw spasms, subjective
dysphagia
Vinca Alkaloids
• vincristine Lymphoma Microtubule Distal sensory neuropathy
Leukemia Inhibition
Solid tumors Autonomic dysfunction possible
Impaired axonal transport
Motor loss especially dorsiflexion
and wrist extension
Thalidomide Multiple myeloma Antiangiogenesis leading to impaired Distal sensory neuropathy
Gliomas axonal circulation
Renal cell
Colon Wallerian degeneration
Breast
Damage to the dorsal root ganglion

Otherwise unknown
Bortezomib Multiple myeloma Interferes with Ca++ homeostasis Affects C fibers – painful distal
sensory neuropathy
Disrupts cellular metabolism through prote­
asome inhibition

May damage dorsal root ganglion

Patients may also experience “coasting” ie, onset or worsen­
ing 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.12
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
12
is thought to be less toxic than cisplatin.3,14 Coasting is also less
frequent.11 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, oxal­
platin 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 oxalipla­
tin neurotoxicity is much higher than that of cisplatin and carbo­
platin: acute symptoms occur in 85% to 95% of patients.14 Acute
symptoms associated with oxaliplatin administration include
paresthesias, hypoesthesias, and dysesthesias affecting the
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hands, feet, perioral area, and throat.3,14 Particularly distressing
to patients are reports of jaw spasms and subjective dysphagia.14
Muscle cramps may occur in the distal extremities, and symp­
toms 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 cispla­
tin. 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, leuke­
mia, 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 autonomic
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 treat­
ment 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 vinorel­
bine have similar manifestations, but with less severity and
decreased prevalence as compared with vincristine.3 Rates of
recovery of peripheral neuropathy in pediatric patients receiv­
ing 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.3,5,11,8 Chemotherapy induced
peripheral neuropathy is a common side effect, occurring in up
to 20% to 40% of patients,11 and is likely to be more severe as
compared with other chemotherapeutic agents, resulting in signif­
icant permanent damage. The mechanism behind neurotoxicity
is unknown, but damage to the dorsal root ganglia is suspected.8
Research has shown Wallerian degeneration without demyelin­
ation.8 Onset of CIPN related to thalidomide increases with age of
the patient and cumulative dose or length of treatment.11
Bortezomib
Bortezomib is an intravenous medication used in the treat­
ment 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
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induced peripheral neuropathy due to bortezomib is thought to
target small unmyelinated C-fibers resulting in very painful, burn­
ing paresthesias in the distal extremities.9 However, bortezomib
may also induce changes in the dorsal root ganglion.24 Effects
may be magnified in patients who have received both bortezo­
mib and thalidomide.11 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 evalu­
ation of the impact of symptoms on patients’ quality of life and
ADLs. Helpful guidelines for physical therapists concerning thor­
ough 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 periph­
eral nerves that result in characteristic findings on electrophysi­
ologic evaluation. Patients who develop CIPN as a result of cispl­
atin 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.28 In
contrast, electromyography (EMG) results are usually normal.28
Nerve biopsies reveal evidence of segmental demyelination and
remyelination.28 Following treatment with vincristine, electro­
diagnostic 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.28
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.10 In bortezomib,
nerve conduction studies generally reveal decreased CSNAP and
increased latency or absence of the H-reflex.23 It is also possible
to show decreases in CMAP.24 In rat models, thalidomide induced
CIPN 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 (A-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 (nega­
tive) and pain (positive). Symptoms must be evaluated in a
13
consistent, organized fashion that is readily reproduced in assess­
ing patients’ response to treatment and comparing outcomes.29
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 spon­
taneous 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.30
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 myelin­
ated A-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 neuropa­
thy, 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 sharp 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 inter­
phalangeal joint of the second finger, ulnar styloid, and medial
epicondyle.29 With the Biothesiometer, clinicians can determine the
threshold of vibration perception.29,31 Pressure pain thresholds can
be determined using a sphygnomometer that is gradually inflated
according to patient tolerance. Though this is only useful in exam­
ining 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.33
Clinicians should consider these factors when interpreting test
results. Strategies for accurate assessment include use of a nonin­
volved 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.29 Neurological assessment should also include deep
tendon reflex testing,31 although deficits in DTRs may reflect late-
stage pathology.19
Gait and Balance Assessment
No studies to date have examined gait or balance issues in
people with CIPN, but patients with CIPN report difficulty with
ambulation and increased fear of falling,7 and literature concern­
ing other forms of peripheral neuropathy strongly suggest that
these areas should be assessed. Persons undergoing treatment with
14
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.35 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.37
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 presenta­
tion. 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.34
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 abil­
ity to maintain unilateral stance, and an increased fall risk.38 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 help­
ful 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 (FACT-
G),33 the European Organisation for Research and Treatment of
Cancer (EORTC) Quality of Life Questionnaire,31 and the Total
Neuropathy Scale.4 Surveys that are specific to neurological
symptoms due to chemotherapy include the CIPN-20,4 an inven­
tory that uses 3 scales to assess sensory, motor and autonomic
symptoms,4 and questionnaires pertaining to the chosen chemo­
therapeutic agents, eg, Oxaliplatin Associated Neurotoxicity
Interview,4 and the Oxaliplatin-Specific Neurotoxicity Scale
(NTX-12).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
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medical, and others where physical therapy could provide poten­
tial avenues for conservative management.
Pharmacologic 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.16 However, other neuropro­
tective drugs show limited efficacy. A Cochrane review indicates
little compelling evidence for the use of neuroprotective agents in
platinum-induced CIPN11 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 pacli­
taxel.41 Investigations have shown that levels of NGF in the circu­
lation 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-1) 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-1 to
preserve motor function in mice during vinca alkaloid treat­
ment.24,41 For both IGF-1 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 ischemic
neuropathy show positive results using gene-therapy to admin­
ister 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 neuro­
toxicity with oxaliplatin.2,9 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 inhibi­
tion 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
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Vol. 28, No. 2, 2010
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 predispos­
ing 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 associ­
ated side-effects of many medications provide an important alter­
native 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 mecha­
nisms 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 strat­
egies. Two studies found that increased ankle flexibility and
strength improved balance and stability during ambulation in
subjects with diabetic peripheral neuropathy.35,46 Patients with
CIPN at risk for falls may benefit from training with an appro­
priate 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 condi­
tions.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 recov­
ery47 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 physi­
cal 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
15
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 cardio­
vascular 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, mono­
chromatic infrared energy (MIRE) helped restore loss of sensa­
tion.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 address­
ing 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 similari­
ties 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 H-wave electrical stimulation (similar to transcutane­
ous electrical nerve stimulation - TENS) has been successfully
used to reduce pain in patients with diabetic peripheral neuropa­
thy.57,58 Subjects also used analgesic medications during interven­
tion 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
16
The analgesic effect of TENS may be related to the gate
theory of pain relief, ie, modulation of transmission of nocicep­
tive input at the dorsal horn of the spinal cord. Greater likeli­
hood 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 surprised 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 sensa­
tion.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 of fall hazards.12 Patients
receiving agents thought to cause autonomic symptoms should also
be educated in management of orthostatic hypotension.12
Clinical Implications
Chemotherapy induced peripheral neuropathy is a rela­
tively 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. Chemotherapy-
induced peripheral neuropathy may be under-recognized due to
lack of sensitivity in objective screening measures. As reha­
bilitation 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 Pharmacologic 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 opti­
mal approach, treatment timing, and patient populations who
will receive the most benefit.
Rehabilitation Oncology
Vol. 28, No. 2, 2010
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The Bone and Cancer Foundation (BCF) provides information
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Rehabilitation Oncology
Vol. 28, No. 2, 2010