Management of Neuropathy in Cancer

Transcription

S U P P L E M E N T
Volume 7 Supplement 5
JNCCN
Journal of the National Comprehensive Cancer Network
NCCN Task Force Report:
Michael D. Stubblefield, MD; Harold J. Burstein, MD, PhD;
Allen W. Burton, MD; Christian M. Custodio, MD; Gary E. Deng, MD, PhD;
Maria Ho, PhD; Larry Junck, MD; G. Stephen Morris, PT, PhD;
Judith A. Paice, PhD, RN, FAAN; Sudhakar Tummala, MD; and
Jamie H. Von Roenn, MD
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Volume 7 Supplement 5
JNCCN
Journal of the National Comprehensive Cancer Network
NCCN Task Force: Management of Neuropathy in Cancer
*C,PMichael D. Stubblefield, MDÞτ
Cancer Center
*PHarold J. Burstein, MD, PhD†
Dana-Farber Cancer Institute
*PAllen W. Burton, MD£ϕ
*PChristian M. Custodio, MDτ
Cancer Center
*PGary E. Deng, MD, PhDδ
Cancer Center
*Maria Ho, PhD
National Comprehensive
Cancer Network
*PLarry Junck, MDΨ
University of Michigan
Medical School
*PG. Stephen Morris, PT, PhDτ
*PJudith A. Paice, PhD, RN, FAAN#£
Cancer Center of
*PSudhakar Tummala, MDÞΨ
*PJamie H. Von Roenn, MD‡
Cancer Center of
KEY:
*Writing Committee Member; CChair;
P
Presenter
Specialties: ÞInternal Medicine;
τPhysical Medicine, Including Physical
Therapy and Rehabilitation Medicine;
†Medical Oncology; £Pain Management;
ϕAnesthesiology; δIntegrative Medicine;
ΨNeurology/Neuro-Oncology; #Nursing;
‡Hematology/Hematology Oncology
Disclosure of Affiliations and Significant Relationships
Dr. Stubblefield has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and
devices discussed in this report or who may financially support the educational activity. He is on the speakers’ bureau for Pfizer Inc.
(that total $10,000 or more) and Allergan, Inc.
Dr. Burstein has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and
devices discussed in this report or who may financially support the educational activity.
Dr. Burton has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices
discussed in this report or who may financially support the educational activity. He is on the speakers’ bureau for Pfizer Inc.
Dr. Custodio has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and
Dr. Deng has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and
Dr. Ho has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices
discussed in this report or who may financially support the educational activity. She is an employee of the National Comprehensive
Cancer Network.
Dr. Junck has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and
Dr. Morris has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and
Dr. Paice has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and
Dr. Tummala has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and
Dr. Von Roenn has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and
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This educational program is designed to meet the needs of oncologists, advanced
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Educational Objectives
After completion of this CME activity, participants should be able to:
• Explain the etiology of neuropathy in cancer patients.
• Describe the manifestations of chemotherapy-induced peripheral neuropathy.
• List agents associated with neuropathy.
• Describe tools to assess neuropathy in cancer patients.
• Outline strategies to manage peripheral neuropathy associated with chemotherapy.
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permission from the NCCN.
S-1
Supplement
NCCN Task Force Report: Management of
Neuropathy in Cancer
Michael D. Stubblefield, MD; Harold J. Burstein, MD, PhD; Allen W. Burton, MD; Christian M. Custodio, MD; Gary E. Deng, MD, PhD;
Maria Ho, PhD; Larry Junck, MD; G. Stephen Morris, PT, PhD; Judith A. Paice, PhD, RN, FAAN; Sudhakar Tummala, MD;
and Jamie H. Von Roenn, MD
Key Words
NCCN Task Force, neuropathy, cancer treatment
Abstract
Neuropathy is a common, often debilitating complication of cancer
and its treatment. Effective management of this disorder depends
on early diagnosis and an understanding of its underlying causes
in the individual patient. In January 2009, NCCN gathered a multidisciplinary group to review the literature and discuss intervention strategies currently available to patients as well as areas that
require research efforts. The task force, which comprised experts
in anesthesiology, medical oncology, neurology, neuro-oncology,
neurophysiology, nursing, pain management, and rehabilitation,
was charged with the goal of outlining recommendations for the
possible prevention, diagnosis, and management of neuropathy.
This report documents the proceedings of this meeting with a general background on neuropathy and neuropathy in oncology, followed by discussions on challenges and research issues, evaluation
criteria, and management of different symptoms associated with
this disorder. (JNCCN 2009;7[Suppl 5]:S1-S26)
Overview
What Is Neuropathy?
Neuropathy, or peripheral neuropathy, is defined as the
condition arising from the damage and dysfunction of the
peripheral nerves—the motor, sensory and autonomic
nerves that connect the brain and spinal cord to the rest of
the body. The major anatomic demarcations of the peripheral nervous system include the nerve root, plexus, and
peripheral nerves. Although the terms neuropathy and peripheral neuropathy generally refer to the part of the nervous
system distal to the plexus, it should be noted that any
or all levels of the peripheral nervous system may be affected depending on the etiology of insult. There are more
than 100 known types of neuropathy, each with its specific
prognosis, set of symptoms, and progressive pattern.
Neuropathy is most common in people over age
55, with a prevalence of 3% to 4%. Among the general
population, about a third of cases are caused by diabetes, while another third is termed idiopathic (cause unknown). Neuropathy can also result from a variety of
factors, including medications (such as chemotherapeutic agents), genetics, autoimmune disorders, infections,
nutritional deficiencies, and metabolic imbalances.
Neuropathy is a common complication of cancer and its
treatment that can lead to serious clinical consequences
for the patient. This report presents the views of the
NCCN Task Force on the assessment and management
of neuropathy in cancer patients as discussed at the
meeting in January 2009.
Signs and Symptoms
The severity of neuropathy ranges from discomfort to
being severely debilitating, and the onset of symptoms
can be sudden or slowly progress over time. Initially, patients often feel abnormal sensations like tingling, pain,
or numbness. Many complain of difficulty in walking,
dropping things, or feeling like they are wearing gloves
and stockings when they are not. If internal organs are
affected, patients may experience diarrhea or constipation, low blood pressure, irregular heartbeat, or even
difficulty breathing.
Neuropathy in Cancer
Consequences of neuropathy can be severe for patients
with cancer and may result in reduced quality of life, interference with activities of daily living, disability, and
potentially shorter survival. Neuropathic symptoms resulting from therapeutic interventions such as the chemotherapy can cause treatment delays, dose reductions,
or even discontinuation of therapy, which can affect
outcomes and compromise survival.
© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 5 | September 2009
S-2
Supplement
NCCN Task Force Report
Patients with cancer have a heightened risk
of developing neuropathy. Cancer-related causes
include:
• Neurotoxicity of cancer treatment, such as surgery, radiotherapy, and chemotherapy (addressed
further in detail)
• Tumor pathology: direct compression or infiltration of nerves by primary or metastatic lesions
• Nutritional deficiencies
• Metabolic disturbances
• Opportunistic infections
• Paraneoplastic neurologic disorders (PND), or
nervous dysfunction caused by the remote effects
of cancer
Chemotherapy-Induced Peripheral Neuropathy
Neuropathy is a major dose-limiting toxicity of many
chemotherapeutic regimens.1 Among the various
types of neuropathies seen in cancer patients, chemotherapy-induced peripheral neuropathy (CIPN)
is the most widely reported and has been the focus of
research efforts. For these reasons, much of the panel
discussion and conclusions is focused on CIPN.
CIPN usually manifests as sensory symptoms
such as paresthesia and dysesthesia (numbness, tingling, abnormal touch sensations), or cold sensitivity. Pain is often reported and may be described as
burning, freezing, lancination, shock-like, or electric. Normal touch can be perceived as painful (allodynia), with sensations that would normally be
painful experienced as excruciating (hyperpathia).
Motor symptoms are uncommon and usually milder.
These may manifest as mild weakness in the lower
limbs. Reflexes at the ankles may be diminished or
absent. Some patients experience altered proprioception, which can lead to accidents or falls. Autonomic impairment is thought to be rare, although
this has not been systematically studied. Evidence of
this impairment might include constipation after use
of vinca alkaloids,2,3 orthostasis, urinary dysfunction,
and sexual dysfunction.
CIPN has a number of diagnostic features that
can help physicians distinguish it from other neuropathies (e.g., PND, carpal tunnel syndrome, diabetic
neuropathy, metabolic neuropathy). These are:
• Symmetrical, distal, length-dependent “glove
and stocking” distribution
• Predominantly sensory symptoms (especially
pain), both in frequency and severity, rather
than motor symptoms
• Onset after administration of chemotherapy,
which may be progressive, rapid, or “coasting”
• Dose-dependent
Table 1 is a general but not exhaustive list of
chemotherapeutic drugs and anticancer biologics
frequently reported as associated with symptomatic
neuropathy.1,4 These include platinum-containing
agents, vinca alkaloids, taxanes, bortezomib, thalidomide, lenalidomide, and ixabepilone. Many of these
drugs (e.g., paclitaxel and cisplatin) are widely used
in a variety of cancers. The onset dose is an approximation of the cumulative dose when neuropathy
typically starts to occur. For most regimens, severity of neuropathy increases with dose and duration
until cessation of treatment. A notable exception is
the platinum agents, for which symptoms may progress for weeks to months after treatment completion.
This is called the coasting effect.5
Another exception to the typical pattern of CIPN
is oxaliplatin, which is unique in that 2 patterns have
been observed: acute transient (cold-induced) and
cumulative persistent (dose-limiting) neuropathy.6,7
Symptoms of CIPN usually subside with time for
most drugs, although long-term sequelae can occur.
Challenges in Oncology and Research Issues
Despite the high overall reported occurrence across
different cancers, data on neuropathic toxicity appears scattered and at times confusing, especially for
older drugs such as cisplatin or vincristine. Historically, CIPN has not been a research focus in chemotherapeutic medicine. Neurotoxicity is typically
reported as one of many adverse events in clinical trials the goal of which is to test other health outcomes
(e.g., response or survival), and this broadly defined
term renders comparison across studies difficult.
As shown in Table 1, the frequency of documented neuropathic events ranges widely for many
agents. One main reason is that the severity and
frequency of the adverse effects heavily depends on
the dose, duration, and schedule. This can be illustrated using paclitaxel given to breast cancer patients: a dose of 175 mg/m2 is associated with 2% to
12%25,28,30,31 grade 3 to 4 sensory neuropathy (based
on the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]),
compared with 22% to 33%29,30 for a dose of 250 mg/
m2 (infusion over 3 hours every 3 weeks for either
dose). Within the same trial, increasing the infusion
period from 3 to 24 hours at the 250 mg/m2 dose re-
75–100 mg/m2
11%–64% (overall)
3%–14% (severe)
Docetaxel1,25,34,36–38
* Dose-limiting or grade 3 or 4 neuropathy according to the grading scale used by the study authors.
Lenalidomide
(thalidomide analog)54,55
unclear
20 g
10%–23% (overall), 1%–3%
(severe)
Symmetrical tingling or numbness, pain.
Occasionally weakness, sensory ataxia, and
gait dysfunction
Similar to thalidomide
40–120 mg/m2
63% (overall), 14% (severe)
+ capecitabine:
67% (overall), 21% (severe)
25%–83% (overall), 15%–
28% (severe)
Ixabepilone45,46
Thalidomide47–53
Painful paresthesia, burning sensation
1.3 mg/m2
31%–55% (overall)
9%–22% (severe)
Painful paresthesia, burning sensation,
occasionally weakness, sensory ataxia,
and gait dysfunction. Rare autonomic
dysfunction including orthostatic
hypotension
Similar to paclitaxel
Similar to paclitaxel
Symmetrical painful paresthesia or
numbness in stocking-glove distribution,
decreased vibration or proprioception,
occasionally weakness, sensory ataxia, and
gait dysfunction
Symmetrical tingling paresthesia, loss
of ankle stretch reflexes, constipation,
occasionally weakness, and gait dysfunction
Similar to cisplatin
Bortezomib39–44
Others
unclear
100–300 mg/m2
4–10 mg
73% (overall)
10%–15% (severe)
+ Carboplatin: 4%–16%
(severe)
57%–83% (overall),
2%–33% (severe)
+ Cisplatin: 7%–8% (severe)
30%–47% (overall)
750–850 mg/m
Abraxane (albuminbound paclitaxel)31,35
Paclitaxel10–12,25–34
Taxanes
Vincristine, vinblastine,
vinorelbine, vindesine21–24
Vinca alkaloids
Oxaliplatin (persistent/
chronic)17–20
FOLFOX: 10%–18% (severe)
Cold-induced painful dysesthesia
2
any
Oxaliplatin (acute)1,15,16
Similar to cisplatin but milder
800–1600 mg/m2
6%–42% (overall)
+ paclitaxel: 4%–9% (severe)
85%–95% (overall)
Carboplatin1,9–14
Symmetrical painful paresthesia or
numbness in a stocking-glove distribution,
sensory ataxia with gait dysfunction
Clinical Manifestation
300 mg/m2
Onset Dose
28%–100% (overall)
+ paclitaxel: 7%–8%
(severe*)
Incidence
Cisplatin1,8–11
Platinum compounds
Drug
Table 1 Common Antineoplastic Agents Known to Induce Neuropathy
Unclear
May persist for over 1 year
Resolution in 4–6 weeks
Resolution usually within 3
months, may persist
months, may persist
weeks
months, may persist
Resolution usually within
3 months, may persist for
vincristine
Resolution in 3 months, may
persist long-term
Resolution within a week
Similar to cisplatin
Partial, symptoms may
progress for months after
discontinuation
Recovery
Supplement
S-3
S-4
Supplement
duced the incidence of severe neuropathy from 22%
to 13%,29 while the increasingly adopted weekly
schedule of 1-hour infusion (80 mg/m2) increased
neuropathic events compared with the conventional
3-hour infusion (175 mg/m2) every 3 weeks (24% vs.
12%).28 Also, chemotherapy regimens often include
more than one potentially neurotoxic drug, and the
potential additive or synergistic effects of different
drug combinations remain largely elusive.
In addition, cancer patients may have preexisting peripheral nervous system dysfunction such
as radiculopathy from degenerative disease or neuropathy from diabetes or other causes. This can predispose them to manifesting earlier and more severe
neuropathic symptoms when challenged with a neurotoxic chemotherapeutic or other cancer-related
insult.56 By the nature of the modern medical system,
most cancer patients enrolling in a clinical trial have
advanced disease and have already been exposed to
a number of chemotherapeutic drugs, many of which
may be neurotoxins. This poses significant difficulty
in properly attributing subsequent neuropathy to
the agent or regimen tested. For example, in a trial
of 113 advanced breast cancer patients who have
been heavily pretreated, mild peripheral neuropathy
(grade 1–2) was already evident in 27% of the women before administration of the neurotoxic ixabepilone.45 Similarly, Richardson et al.44 documented an
81% and 83% baseline incidence of symptomatic
neuropathy before bortezomib treatment based on
patient questionnaires and neurologist examination
reports, respectively, in a group of 256 patients with
recurrent/relapsed myeloma. In the group, 11% also
had a history of diabetes, which may have contributed to the development of CIPN.
Unfortunately, these 2 studies are among the few
that include such complete information. The Task
Force panelists expressed concern about the lack of
standardization in quality reporting of CIPN. Across
clinical trials, neuropathic cases have been recorded
in a number of formats: specific symptoms (e.g., pain),
development of functional impairment resulting from
symptoms, neurophysiologic testing, and prevalence
by grade or incidence of only severe cases according
to different scoring systems. Even when the same scale
is used, grading can vary due to differences in training
and experience in patient assessment.
Compounding the problem is the issue of underreporting. Most clinical trials rely on patient self-
report of symptoms rather than active query by the
evaluator. Such voluntary symptom reporting can be
influenced by patient personality, physician-patient
relationship, and the medical system in which the
study is conducted. The subjective nature of CIPN
symptoms adds to the variability of reported incidence and severity. Underestimation and underreporting of CIPN are also suggested by studies that
show that physician evaluation results in lower pain
assessments than invited patient questionnaire.57–59
Admittedly, most existing evaluation tools are designed to measure neuropathy in other settings (e.g.,
diabetes) and have not been validated for CIPN.
More sensitive and comprehensive assessment systems are needed for the chemotherapy setting.
Terminology clarification is also important for
differential diagnosis. Panelists noted that health
professionals and patients are often confused about
the various medical terms describing pain (pain,
neuropathy, paresthesia, dysesthesia), and with the
different clinical conditions associated with pain. A
patient experiencing paclitaxel-induced arthralgia is
a classic example. Arthralgia is a transient, inflammatory joint pain that typically develops 24 to 48
hours after infusion and persisting for 3 to 5 days,
as opposed to the symmetrical glove-stocking distribution of numbness, tingling, or burning related to
CIPN that progresses with accumulating dose. However, the patient may only complain of a generic
“pain” during a doctor visit. Becoming familiar with
the clinical diagnostic features of CIPN and asking
specific questions will help the evaluator identify the
condition and implement proper intervention, such
as dose reduction.
Quality assessment and reporting leading to accurate diagnosis is a crucial step that must precede
clinical decisions regarding treatment. Unfortunately, CIPN presents a diagnostic dilemma because, to
date, approved, effective treatment options are lacking. Although many therapeutic agents to treat or
prevent CIPN have been proposed over the years,
few are supported by adequate data. As opposed to
studies investigating drug efficacy, conducting clinical trials to test strategies for lowering toxicity may
be difficult because of financial support, physician
perception, and public concern. Because some treatments for neuropathy are over-the-counter supplements (e.g., glutamine), obtaining financial support
for a large, robust clinical trial may be difficult.
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Also, the balance between lowering or preventing neurologic toxicity and maintaining drug efficacy
may be fine, because the 2 may be closely related.
Randomized studies on preventative agents have
been closed prematurely because of preliminary concerns on their negative impact on the efficacy of chemotherapy, although retrospective review did not
support these concerns (see Prevention, page S-11).
Other clinical trials are still ongoing, but these
studies will need to show reduced neurotoxicity without compromise of antineoplastic toxicity. This poses
a major challenge, because large patient numbers are
needed to provide sufficient power for proving noninferiority. However, the persistent pattern of CIPN
may present the opportunity to use a crossover design on intervention strategies, in which patients are
randomized to 2 treatment sequences: placebo-agent
or agent-placebo.60 Provided that carry-over effects
are carefully considered, within-patient comparisons
of crossovers can significantly enhance the statistical power by eliminating between-patient variation.
This study approach has been effectively applied to
polyneuropathic pain management,61 as well as cancer supportive care strategies.62–64
Mechanisms of Neuropathy
Neurotoxicity Mechanisms of Chemotherapeutic
and Biologic Agents
Neuropathy arises from damage to the peripheral
nerves. Within the peripheral nervous system, the
motor axons (nerve fibers) are large and myelinated,
and the sensory and autonomic axons are mostly
small and unmyelinated or thinly myelinated. The
type of neuropathic symptom experienced depends
on the type of nerve affected:
• Sensory nerves affect sensation, such as with
painful paresthesia, dysesthesia, cold-sensitivity,
tingling, numbness, alteration in vibration and
proprioception, or a change in reflexes.
• Motor nerves affect muscles and motion, such as
with muscle weakness.
• Autonomic nerves affect internal organs, such
as with orthostatic hypotension, constipation,
urinary retention, irregular heart rate, and
sexual dysfunction.
Most neurotoxic drugs (taxanes and vinca alkaloids) used in chemotherapy cause axonal damage, a
condition termed axonopathy. Primary nerve toxic-
ity of the platinum drugs seems to occur at the dorsal root ganglion (DRG), resulting in neuronopathy.
Small sensory fibers are affected early and most frequently by chemotherapeutic agents. Because these
nerves have little capacity for regeneration, damage
to them is responsible for the predominance of sensory symptoms found in CIPN. Also, the cell bodies
of the peripheral sensory neurons are located in the
DRG, where they are outside the protective bloodbrain barrier and thus more vulnerable.
The DRG also has a rich supply of capillaries that
are highly permeable to toxic compounds circulating
in the blood. Motor nerves are generally less frequently or seriously affected by neurotoxic chemotherapy.
Motor nerves that have survived a chemotherapeutic
insult have the capacity for distal sprouting and reinnervation of muscle fibers that have lost their innervation. Clinically, this capacity for regeneration
results in the recovery of the patient’s strength and
function. Autonomic nerves are also usually less sensitive to the effects of neurotoxic chemotherapy.
The exact mechanism of damage remains to be
fully elucidated for each class of chemotherapy drugs,
but various mechanisms based on in vitro and in
animal models have been proposed. The platinum
compounds have been reported to accumulate in the
DRG and exert direct damage to the DRG neurons,
inducing DNA derangement, morphologic changes,
and subsequent apoptosis.65,66 Cisplatin can also
disrupt axonal microtubule growth that is essential
for axonal transport.67 Studies suggest that the acute
form of oxaliplatin toxicity may be associated with
calcium chelation by oxalate released from the drug,
adversely affecting
��
ion��
��
channels and synaptic
��
trans68,69
mission. Like cisplatin, taxanes and vinca alkaloids
have also been found to disrupt axonal transport via
microtubule damage.70–73 Of note, vinca alkaloids
are known to induce severe acute neurotoxicity
in patients with Charcot-Marie-Tooth disease, a
Correspondhereditary sensorimotor neuropathy.74 ��
ingly, the genetic mutations involved in this disorder
are also linked to malfunction in microtubules and
axonal transport.75,76
Among newer agents, a role in neuronal
degeneration has been attributed to thalidomide.77
Bortezomib, a novel proteasome inhibitor, may
induce neuronal injury via multiple mechanisms such
as cytoskeletal change, mitochondrial disturbance,
and disruption in tubulin polymerization.78–80
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The extent of nerve damage affects the distribution of symptoms. One useful classification of neuropathy is as follows:
• Mononeuropathy: damage to a single peripheral
nerve
• Mononeuropathy multiplex: involvement of several isolated nerves
• Polyneuropathy: simultaneous malfunction of
many peripheral nerves
• Autonomic neuropathy: damage to nerves affecting internal organs
CIPN is primarily polyneuropathic, with symmetric stocking-glove “dying back” distribution,
with the earliest symptoms developing at the finger
tips and toes��
(Figure 1)��
. The length-dependent, distal pattern seems to indicate distal involvement of
the longest peripheral axons, followed by progression
of the symptoms proximally along the limbs as the
neuropathy worsens. One explanation is that these
longest fibers have the greatest surface area exposed
to a CIPN drug and hence are subject to greater
toxicity. Existing mononeuropathy such as median
nerve damage found in carpal tunnel syndrome can
worsen as CIPN polyneuropathy develops.
Neuropathic Mechanisms From Other Conditions
As previously discussed, PND is a rare condition
that typically precedes tumor diagnosis and can
lead to neuropathic symptoms in cancer patients.
PND is thought to arise from autoimmune response
directed against tumor antigens, which also crossreact with proteins normally found in the nervous
system. A number of paraneoplastic antibodies
have been characterized, many of which are commonly found in lung cancer patients (reviewed
by Darnell and Posner81). Examples are the antiCV2/CRMP5 and the anti-Hu antibodies associated with peripheral neuropathy and autonomic
dysfunction. Detecting a paraneoplastic antibody
can aid in the diagnosis of a previously unknown
tumor, tumor recurrence, or rarely, a new second
malignancy. In cancer patients with known PND,
the most common etiology of CIPN, however, is
still neurotoxic treatment.
A slightly greater incidence of other autoimmune
neuropathies is found in cancer patients compared
with the general population. These neuropathies include Guillain-Barré syndrome, an acute onset neuropathy that includes acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy,
acute motor sensory axonal neuropathy, and Miller
Fisher syndrome. Chronic idiopathic demyelinating
polyneuropathy and multifocal motor neuropathy can
also be seen with greater frequency in cancer patients.
In these cases, the body’s immune system mistargets
the nerve tissues, causing inflammation or injury. Autoimmune mechanisms should be considered in HIV
patients with cancer and transplant patients with
neuromuscular symptoms, including neuropathy.
Diabetes is a common pre-existing comorbidity
in cancer patients and is associated with a high incidence of peripheral neuropathy. The neuropathyinducing mechanism of diabetes is still not fully
understood, but it is widely attributed to hyperglycemia. Impaired glucose tolerance is seen in many
non-diabetic cancer patients and can cause symptoms that are clinically similar to those of early
diabetic neuropathy.
Systemic factors like weight loss predispose patients to focal compression neuropathies. The most
common is peroneal nerve compression at the fibular head resulting in foot drop and sensory disturbance along the lateral aspect of the leg and over
the foot. Patients with head and neck or gastrointestinal cancers are examples of patients who may
experience significant weight loss within a short
time period.
Patients with paraproteinemia such as monoclonal gammopathy of unknown significance; multiple myeloma; Waldenström’s macroglobulinemia;
and polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy, and skin changes syndrome can develop neuropathy from various mechanisms. Patients may have antibodies against the
nerve, develop secondary amyloid nerve deposition,
or have circulating cryoglobulins causing vasculitis.
However, even in these patients, neuropathy mostly
is secondary to chemotoxicity.
Evaluation
CIPN is typically evaluated under 2 settings. First,
it is commonly assessed during a clinical trial, either
as part of the toxicity profile of a new antineoplastic
drug or as the end point to determine the efficacy of
a neuroprotective agent. Evaluation is also required
during routine oncology practice, when patients
complain of symptoms during the course of treatment. The following questions must be addressed:
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• Are the symptoms due to
neuropathy?
• If so, is the neuropathy a result of cancer treatment, cancer pathology, or other causes
unrelated to cancer?
• Are the symptoms severe
enough to require intervention?
• If so, what are the options
for intervention or symptom
management?
• Is modification or discontinuation of the present cancer
treatment necessary?
To date, a gold standard for
evaluating CIPN has not been
defined. The assessment methods
currently available include clinical evaluation (grading systems),
objective testing, and patient
questionnaires. However, standardization is lacking across these
modalities. The largely subjective
nature of pain and other neuropathic symptoms render objective
measurement inherently difficult.
Poor correlation between objective findings or physician evaluation and patient-reported symptom severity is frequently noted.
Neurophysiologic and Other
Objective Testing
Pinprick, temperature,
vibration, motor strength
Normal
Diminished
Lost
AQ-X
Hyperesthesia,
contact sensitivity
Normal or decreased
knee reflexes
Decreased or normal
strength
Decreased ankle
reflexes
Neurophysiologic tests such as electromyography (EMG), nerve conduction studies (NCS), and quantitative sensory tests (QST) are
Decreased pin, temperature,
objective quantitative assessments
vibration
of the function of the peripheral
nervous system. Limitations to obFigure 1 Symptoms of chemotherapy-induced peripheral neuropathy.
jective testing include cost and the
Adapted from: Simpson DA, Tagliati M, Gonzales-Duarte A, Mongello S. Neurologic
need for subspecialty expertise that
manifestations. In: Mildvan D, ed. International Atlas of AIDS, 4th edition. Hoboken,
NJ: Current Medicine Group LLC; 2007; with permission.
may not be readily accessible at all
medical sites. Some of these tests
in a study of 38 cancer patients receiving second-line
are also invasive, leading to low patient adherence.
paclitaxel, 71% of patients reported symptoms of
Also, reports��
��
of the added value to physician examiparesthesias and numbness in a questionnaire, but only
nation or patient questionnaires for CIPN have been
82–85
48% showed an increase in the vibration perception
In general, objective
��
neurophysiolog��
inconsistent.
ic findings correlate poorly with subjective reports by
threshold (QST).83 Changes on EMG and NCS may
patients, with a tendency to underassess. For example,
also lag behind the onset of symptoms.
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A series of laboratory and imaging tests is
available to help evaluate for other possible causes
of neuropathy, such as the paraneoplastic panel
(anti-Hu, anti-Yo, anti-Mag) for PND diagnosis,
blood tests for metabolic or nutritional deficiencymediated neuropathy, or MRI for identifying
compressive radiculopathy. However, these are
usually only conducted on outlier cases in the cancer
setting. In-office skin biopsy at proximal and distal
anatomic sites is performed for density measurement
of intra-epidermal nerve fibers to evaluate small fiber
neuropathies. Although highly specific, it has low
sensitivity��
and the same limitations as neurophysiological testing (cost, pain, inadequate correlation
with patient reports).
Clinical Assessment
As opposed to specialized neurophysiologic testing,
clinical assessment (history and physical examination)
is performed by the treating oncologist and typically
the first-line evaluation of CIPN. Patient history
should include associated comorbidity, personal and
family history of neuropathy, alcohol use and other
toxic exposures, and any CIPN experienced during
previous treatment. The temporal profile should be
described in detail (regimen dosage, duration, schedule,
coasting), as well as the characteristics and distribution
of signs and symptoms. Physical examination should
describe clinical features of the neuropathy, such as
sensory abnormalities, deep tendon reflex dysfunction, motor weakness, pain characteristics, autonomic
symptoms, and most importantly, functional impairment. For individuals with pre-existing or hereditary
neuropathy, related musculoskeletal findings should
be documented. Such abnormalities can include foot
deformities such as high arches, flat fee, or hammertoes (deformity of the proximal interphalangeal joint
of the second, third, or fourth toe causing them to be
permanently bent).
A number of physician-based grading systems have
been developed for CIPN assessment. The most widely
used are the NCI-CTCAE, Ajani Sensory, WHO, and
ECOG systems (Table 2).86–89 These systems grade
CIPN from grade 0 (normal) to 4 (severe) or 5 (death).
However, variability is apparent among examiners and
different scoring systems. In a key study conducted
by Postma et al.,90 2 neurologists independently rated
the severity of CIPN in 37 patients using the NCICCTCAE (adapted from the NCI-CTC), WHO,
ECOG, and Ajani scales. In 80% of the cases, the
neurologists disagreed on at least one scale; complete
agreement on all 4 scales was noted in only 20%
of patients. Interobserver agreement ranged from
46% (NCIC-CTC) to 84% (WHO), and interscale
agreement for the dichotomy grade 2 and under; grade
3 varied from 68% (WHO and NCIC-CTCAE) to
100% (WHO and ECOG). This study highlights the
disparity in interpretation among physicians, as well
as the substantial variation in grading when using
different grading systems.
The significant problem of variability is in part
caused by the lack of clearly defined evaluation parameters. For instance, the phrase “interfering with
function but not interfering
��
��
with ��
activities of daily living” in grade 2 of the NCI-CTCAE specifies neither
the function nor activity and thus is open to interpretation. Other criticisms include mixing of objective
parameters (e.g., loss of reflex) with subjective symptoms (e.g., paresthesias), lack of pain assessment, and
failure to account for chronic toxicity and changes in
symptoms.91 More recently, a newer tool, Total Neuropathy Score (TNS),92 was developed that was reported to
be more sensitive than the NCI-CTCAE in detecting
changes in CIPN.93
Patient-Based Evaluation
As previously discussed, underestimation and
underreport��
ing��
of CIPN using
��
physician-based methods is substantial.57–59 Neuropathic symptoms such as
pain and paresthesias are predominantly subjective,
and individuals may have different thresholds of tolerance for these symptoms. Direct input from the patient is therefore critical in the evaluation, because
the requirement for intervention is largely based
on patient preference. Patient-based instruments
that have been developed to address this need include the Functional Assessment of Cancer Therapy
(FACT)/Gynecology Oncology Group-Neurotoxicity,94 FACT-Taxane,95 and Patient Neurotoxicity
Questionnaire (PNQ).1 These are self-administered
questionnaires designed to determine the level and
incidence of clinically significant functional impairment resulting from CIPN.
Recommendations
For routine oncology practice, the Task Force panel
strongly encourages physicians to actively query can��
cer patients on signs and symptoms of neuropathy.
Before neurotoxic therapy is administered, a baseline
assessment should be performed and recorded. Iden-
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Table 2 Commonly Used Physician-Based Grading Scales for Evaluation of CIPN
Scale
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
87
WHO
Paresthesias and/
or decreased
tendon reflexes
Severe
paresthesias
and/or mild
weakness
Intolerable
paresthesias and/or
marked motor loss
Paralysis
NA
ECOG88
Decreased deep
tendon reflexes,
mild paresthesias
or constipation
Absent deep
tendon
reflexes, severe
paresthesias or
constipation,
mild weakness
Disabling sensory
loss, severe
peripheral
neuropathic pain,
obstipation, severe
weakness, bladder
dysfunction
Respiratory
dysfunction
secondary to
weakness,
obstipation
requiring
surgery,
paralysis
confining
patient to bed/
wheelchair
NA
Neuropathy-sensory
Asymptomatic:
loss of deep
tendon reflexes
or pasresthesia
(including
tingling) but not
interfering with
function
Sensory
alteration or
paresthesia
(including
tingling),
interfering with
function but
not with ADL
Sensory alteration
or paresthesia
interfering with
ADL
Disabling
Death
Neuropathy-motor
Asymptomatic,
weakness by
exam/testing
only
Symptomatic
weakness
interfering with
function but
not interfering
with ADL
Weakness
interfering with
ADL: bracing or
assistance to walk
indicated
Lifethreatening:
disabling
(e.g.,paralysis)
Death
Sensory
Paresthesia,
decreased deep
tendon reflexes
Mild objective
abnormality,
absence of
deep tendon
reflexes, mild
to moderate
functional
abnormality
Severe paresthesia,
moderate objective
abnormality,
severe functional
abnormality
Complete
sensory loss, loss
of function
NA
Motor
Mild or transient
muscle weakness
Persistent
moderate
weakness but
ambulatory
Unable to ambulate
Complete
paralysis
NA
NCI-CTCAE (v3.0)89
Ajani86
Abbreviations: ADL, activities of daily living; CIPN, chemotherapy-induced peripheral neuropathy; NA, not applicable; NCICTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
tifying pre-existing conditions that may predispose
patients to and potentially exacerbate CIPN is imperative. Of special concern are patients with hereditary motor and sensory neuropathies, such as Charcot-Marie-Tooth disease, who may develop severe
neuropathic paralysis when receiving vincristine.
Routine assessment should continue during
therapy. Because most cases of CIPN progress with
dose accumulation, early report of mild cases is important for detecting the onset of neuropathy during continuous monitoring. For a list of diagnostic
features of CIPN that distinguishes it from other
types of neuropathy��
, see Chemotherapy��
-I��
nduced ��
P��
eripheral Neuropathy (page S-2).
The main goal of routine clinical assessment is
to determine whether the patient is experiencing
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significant neuropathic symptoms that require intervention. For this purpose, the use of grading systems
is helpful but not sufficient alone. In particular, pain
is a major symptom that is not well addressed by existing scales. The panel suggests the following pain
assessment tools commonly used under other clinical settings: Brief Pain Inventory,96,97 Neuropathic
Pain Scale,98,99 and Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale (LANSS).100,101
Whether to intervene with the neuropathic symptoms that arise depends on patient preference and
the medical judgment of the physician.
Table 3 lists recommendations by the NCCN
Task Force panel on the key points to include during assessment of neuropathy on a cancer patient.
In addition to a history and physical examination,
functional assessment is critical. Simple skill tests
and questions about activities of daily living provide
important information. Physicians can also refer to
existing patient questionnaires.1,94,95
Panelists agree that referral to a specialist can
also be helpful. This may be a neurologist or physiatrist (specialist in physical medicine and rehabilitation) experienced in managing neuromuscular
disorders in the cancer setting. When pain is a predominant issue, referral to a supportive care or pain
management specialist may improve overall patient
management. The exact point of referral will depend on physician discretion and the infrastructure
of individual medical centers, but it is important
that such a system be in place. In general, oncologists should consider referral when the patient case
is out of their usual clinical experience, such as
when a patient has atypical signs, severe symptoms,
or underlying neuropathic disorders.
Specialists can help delineate the neuropathic
etiology, which may affect decisions about cancer
treatment, suggest treatment, or point to resources
for patient support and rehabilitation (see Management of Functional Deficits, page S-17). However,
the panel emphasized that specialist scheduling
should be in parallel with ongoing oncologist visits
so that logistics do delay appropriate antineoplastic
treatment. Communication between the treating
physician and specialist is essential.
Objective neurophysiologic testing ��
is��
not sufficiently reliable to be used alone for decision making.
But such testing may be used as an adjunct to clinical assessment for confirming or ruling out a diag-
nosis. Similarly, the need for additional laboratory
testing, imaging, or biopsying depends on the initial
clinical assessment. The decision to order these tests
is usually made by the specialist.
For clinical trials, multimodality assessment is
preferable. Simple QST like the Von Frey or Neuropen may be easier for standardization than tests that
require extensive setup or equipment. Given the
high variability of commonly used physician-based
scoring systems, multicenter studies must reach a
consensus on the grading scale as well as interpretation of the chosen scale. As pointed out by panelists, pain assessment and functional impairment are
critical endpoints, and the integration of pain scales
(Brief Pain Inventory, LANSS, Neuropathic Pain
Scale), patient-based questionnaires (FACT, PNQ)
and skill tests (timed pellet retrieval, pegboard test)
is strongly encouraged.
Prevention
Many agents have been proposed for preventing neuropathy caused by antineoplastic drugs. The mechanisms by which most of these drugs might minimize
neuropathy are based on limited preclinical data and
informed opinion. Most of these agents have been
studied in clinical trials with designs inadequate for
definitive assessment of the impact on neuropathy.
A few have been evaluated in randomized controlled
trials. Most have been assessed during platinumbased chemotherapy. Table 4 lists these agents, the
proposed mechanism for preventing CIPN, and findings from clinical trials.121
Vitamin E may mitigate neuropathy associated
with platinum-based chemotherapy. Three small,
open-labeled studies randomized 30 to 47 cancer
patients receiving chemotherapy mostly consisting
of cisplatin to vitamin E or control.102–104 The active arms were consistently associated with a lower
incidence of CIPN (21%–31%) compared with the
control arm (69%–86%), with statistical significance
(P < .03). The severity of neuropathy as measured by
toxicity scores was also reduced.
A double-blinded, randomized, placebo-controlled study of 81 patients undergoing cisplatin
therapy is ongoing. Interim analysis of the first 50
patients showed a significantly lower median toxicity score in the supplement group.105 Because vitamin E is an antioxidant, concerns have been raised
Supplement
about the possibility that it may suppress chemotherapeutic efficacy by interfering with the oxidative breakdown of DNA and membranes of cancer
cells. Preclinical models have shown no difference in
cisplatin-induced tumor inhibition with or without
vitamin E.104,122 In a randomized study of 136 lung
cancer patients receiving paclitaxel and carboplatin,
multiple high-dose antioxidant supplementation
including vitamin E affected neither the response
rate nor survival.123 These results are reassuring, but
a well-designed, adequately-powered trial to confirm the safety of vitamin E is important before its
general adoption.
Intravenous administration of calcium and magnesium (CaMg) has been proposed as prophylaxis
against neurologic damage induced by oxaliplatin,
on the basis that heightened extracellular calcium
could facilitate closing of sodium channels, thereby
decreasing the hyperexcitability of neurons exposed
to oxaliplatin.124 Two concurrent randomized controlled trials, N04C7 and CONcePT, were initiated
to test the effect of CaMg on oxaliplatin-related neuropathy. Both trials were terminated after CONcePT
investigators reported diminished response to chemotherapy in the CaMg arm.125 After study termination, however, a subsequent independent radiology
review suggested the opposite finding with respect to
tumor response.121,126
Despite early termination, the N04C7 study revealed a reduction in CIPN incidence in the active
arm.106 Gamelin et al.127 released an interim report
on their multicenter, double-blind trial (Neuroxa)
randomizing patients on the FOLFOX4 regimen.
There was no difference in the response or survival
rates between the arms, but significantly lower frequency and severity of neuropathy were seen in one
group (blind not yet broken). Future updates should
clarify the effectiveness and safety of CaMg.
Despite various rationales for their evaluation,
other drugs such as amifostine, nimodipine, Org
2766, and rhuLIF have all failed to show clinical
benefit in randomized trials. Recently, new agents,
including acetyl-L-carnitine, alpha lipoic acid, and
vitamin B12/B6, have entered phase III randomized
clinical testing.
Conclusions
Although several agents have shown potentially
encouraging results as mitigators of neuropathy,
current data are inadequate to recommend any for
Table 3 Key Points to Report During Clinical Assessment of CIPN
History
•Personal history of neuropathy and CIPN from previous
cancer treatment
•Personal and family history of hereditary neuropathy
(patients with Charcot-Marie Tooth disease should
avoid vincristine-based chemotherapy)
•Related comorbid conditions (e.g., diabetes, HIV,
Guillain-Barré syndrome, CIDP, radiculopathy)
•Alcohol use
•Temporal profile: regimen dosage, duration, schedule,
“coasting” effects
•Symptoms
•Type: sensory, motor, or autonomic
•Distribution: distal symmetric or asymmetric
•Severity
•Pain assessment: BPI, LANSS, NPS
•Time course of CIPN, including onset and resolution of
symptoms
•Treatment delays or discontinuation related to CIPN
Physical Examination
•Sensory assessment: light touch, vibration,
proprioception, pin-prick, temperature
•Deep tendon reflex: presence, absence, diminishment
•Motor weakness
•Autonomic symptoms (e.g., constipation, orthostatic
hypotension, urinary dysfunction, sexual dysfunction)
•Related musculoskeletal abnormalities (e.g.,
hammertoes, high or flattened arches)
Sample Questions for Patient
•Do you feel numbness or tingling in your hands or
feet?
•Do you feel pain in your hands and feet? (Rate it on a
scale of 0 to 10.)
•Do you feel like having gloves and stockings on?
•Do these sensations bother you? Are they getting
worse?
•Do you feel weakness in your arms and legs?
•Do you drop things often?
•Have you fallen recently?
•Do you have difficulty walking or climbing stairs?
•Do these sensations interfere with your work or daily
activities?
Examples of Functional Assessment Skill Tests
•Getting up and straight-line walking (observe gait and
balance)
•Name writing
•Buttoning
•Timed pellet retrieval (for clinical trials)
•Pegboard test (for clinical trials)
Abbreviations: BPI, Brief Pain Inventory; CIDP, chronic
idiopathic demyelinating polyneuropathy; CIPN,
chemotherapy-induced peripheral neuropathy; LANSS, Leeds
Assessment of Neuropathic Symptoms and Signs Pain Scale;
NPS, Neuropathic Pain Scale.
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Table 4 Proposed Agents for Preventing CIPN
Drug
Mechanism of Action
Findings From Randomized Controlled Trials (N)
Agents with Positive Findings in Randomized Controlled Trials
Vitamin E
Antioxidant/minimizes neuronal damage
CIPN incidence and severity reduced (30-47)102–104
CIPN severity reduced (81)105
Ongoing trial: NCT00363129*
Ca++/Mg++
Facilitates Na channel function; binds
oxalate (metabolite of oxaliplatin)
CIPN incidence reduced (104)106
Glutamine
Upregulation of nerve growth factor
CIPN incidence reduced (86)107
Glutathione
Hampers accumulation of platinum adducts
in DRG
CIPN incidence reduced/trend towards reduction
(50-151)108–110
N-acetylcysteine
Antioxidant; increases blood concentrations
of glutathione
Incidence of grade 2-4 neuropathy reduced (14)111
Oxcarbazepine
Inhibits high-frequency firing of nerves;
modulates ion channels
Neuropathy incidence reduced (32)112
Xaliproden
Non-peptide neurotrophic agent
Shift of CIPN from grade 3 to grade 2 (649)113
Agents With Negative Findings in Randomized Controlled Trials
Amifostine
Detoxifies chemotherapy; facilitates DNA
repair
Not effective (66)114
Improvement on NCI-CTC scale but not on patient
questionnaire (72)115
Nimodipine
Calcium channel antagonist
Not effective; randomized trial closed early (51)116
Org 2766
Nerve growth factor family,
adrenocorticotrophic hormone analog
Vibration perception maintained (55)117
Not effective (150-196)118,119
rhuLIF
Neuroprotective cytokine
Not effective (117)120
Additional Agents Being Tested in Ongoing Phase III Randomized Controlled Trials
Vitamin B12/B6
Essential for nerve function
Acetyl-L-carnitine
Oxidation of free fatty acids/nerve
regeneration
New trial: NCT00775645*
Alpha lipoic acid
Antioxidant
Abbreviations: CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglion; NCI- CTC, National Cancer
Institute Common Toxicity Criteria.
*ClinicalTrials.gov identification number
ordinary use in patients, and the panel did not endorse any of the existing agents. This lack of endorsement reflects the small sample size and variable treatment regimens, modest observed effects,
and lingering concerns over impairment of efficacy
for anti-cancer therapy. In 2007, Albers et al.128
performed a systematic review of 16 randomized
controlled studies of neuroprotective agents (amifostine, metal chelator diethyldithiocarbamate,
glutathione, Org 2766, and vitamin E) and found
the data inconclusive. Separate literature on the
use of neuron-protective agents has developed from
the evaluation and treatment of non-cancer–related neuropathy, predominantly diabetic neuropathy.
Whether experience from non-chemotherapy–related neuropathies is relevant for clinical recom-
mendations for cancer patients is unclear. Larger
randomized controlled studies specifically in cancer
are needed to delineate the safety and efficacy of
neuropathy prophylaxis, although these may be met
with several challenges, as discussed previously.
The panel was concerned by the inconsistency of
end points used among the various trials examining
neuropathy and potential interventions. Frequently,
discordance is apparent between symptom reports
and objective measures, and satisfactory neuropathy
evaluation tools are currently lacking, as discussed
previously. Panelists agreed that multimodal measurement of functionality is of primary importance
and the incorporation of simple skill tests (e.g., the
pegboard test) will add valuable information at a relatively low cost.
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Treatment
Non-Cancer–Related Neuropathy
Treatment of neuropathy in cancer patients remains
a challenge and depends on etiology. As discussed,
a main complication is that an individual patient
may experience neuropathic symptoms caused by a
combination of factors. Distinguishing CIPN from
other types of neuropathy is important in deciding
whether the antineoplastic treatment needs to be
modified. Damage to the peripheral nervous system
at other levels, including the nerve root and plexus,
may mimic peripheral neuropathy. Care should be
taken in evaluation and exclusion of such disorders,
particularly in patients with a history of degenerative spine disease or radiation therapy that affects
the nerve root or plexus. Identifying underlying neuropathy is essential, because specific treatment or
management strategies are available for certain noncancer–related neuropathies:
• Hereditary: cancer patients with Charcot-MarieTooth disease should avoid vincristine-based
chemotherapy74
• Diabetes: control of glucose level and weight,
exercise, and pain relief can be helpful
• Alcohol: avoiding alcohol, improving nutrition
(vitamin supplement), and pain relief can be
helpful
• HIV: controlling HIV and selecting medication
that has a low risk of contributing to neuropathy
• Guillain-Barré syndrome: intravenous immunoglobulin (IVIg) and apheresis129
• Chronic idiopathic demyelinating polyneuropathy (CIDP): steroids, intravenous immunoglobulin, and apheresis
• Mononeuropathy (i.e., median mononeuropathy
causing carpel tunnel syndrome, ulnar mononeuropathy): resting hand splints, physical or
occupational therapy, corticosteroid injection,
surgical decompression (it should be noted that
surgical decompression in patients on active antineoplastic treatment was thought to be relatively contraindicated by the panel)
Cancer-Related Neuropathy
In most instances, control of the tumor remains a
priority for stabilizing or improving cancer-related
neuropathic conditions. Surgery remains the most
efficient way to relieve symptoms, particularly when
the neuropathy is the result of direct tumor compres-
sion. Radiation therapy and chemotherapy may also
be of benefit when treating tumors responsive to
these therapeutic modalities. Steroids or intravenous
immunoglobulin may be effective against specific
subtypes of PND such as Lambert-Eaton myasthenic
syndrome and paraneoplastic dermatomyositis.130
Randomized trials have shown brief efficacy of
intravenous immunoglobulin in treating anti-MAG
neuropathy.131,132 Current treatment schema also includes rituximab133 and apheresis. For the rare polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome, surgery
and radiation against the plasmaproliferative disorder
is the mainstay of treatment; steroids are also effective.
CIPN
To date, no approved effective treatment is available for CIPN, although a number of medications
are useful for pain control (see subsequent sections).
Because CIPN symptoms may progress with cumulating exposure, close monitoring is necessary during chemotherapy. In severe cases, dose reduction or
treatment discontinuation may be indicated at the
discretion of the treating oncologist, but this must be
weighed against the oncologic risks.
Symptom Management: Pain Medications
Various pharmacologic agents have been tested in
symptom control trials to alleviate established neuropathy. Drugs that have been approved by the FDA
have been so based on their efficacy in reducing pain
intensity for other types of neuropathic pain disorders, mainly diabetic neuropathy and post-herpetic
neuralgia. Most clinical trials on the use of other
drugs to moderate CIPN have failed to yield positive findings,134–137 although results from 2 recent
studies are more encouraging.138,139 To date, no agent
has been approved specifically for treating CIPN.
Table 5 lists the medications that are currently being used off-label to relieve the positive symptoms
of CIPN (pain, paresthesias, dysesthesias, allodynia).
It should be noted that none of these agents are effective in the treatment of negative neuropathic
symptoms such as weakness or the loss of sensory
modalities, including light touch or proprioception.
Many of these agents should be administered at a
low starting dose and slowly titrated to the dose that
confers the best efficacy with limited side effects.
Specifications for administration and side effects are
listed. Readers can also refer to the NCCN Clinical
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Table 5 Common Agents for Pain Management in Neuropathy
Drug
Starting Dose
Titration
Maximum Dose
Duration of
Adequate Trial
Duloxetine
20–30 mg/d
No evidence that
higher dose is
more effective
120 mg/d
2 wk
Nausea, xerostomia,
constipation, diarrhea
Gabapentin*
100–300 mg
nightly or
100–300 mg 3
times/d
increase by
100–300 mg 3
times/day, every
1–7 days
3600 mg
(depending on
absorption)
1–2 wk at max
tolerated dose
Somnolence, dizziness, GI
symptoms, mild edema,
cognitive impairment
(elderly), exacerbation of
gait problems
5% Lidocaine
patch
Maximum of 3
patches daily
Non-applicable
3 patches
2 wk
Rash/erythema
Opioids
(oxycodone,
morphine,
methadone)
5–15 mg every
4h
Convert to longacting after 1 wk,
titrate based on
breakthrough use
No ceiling effect
4–6 wk
Constipation, nausea,
vomiting (self-limited),
sedation, confusion,
respiratory depression
Pregabalin
25–50 mg 3
times/d
Increase by 50 mg/
dose after 1 wk
200 mg 3 times/d
Unclear (likely
2–4 wk)
Dizziness, somnolence,
xerostomia, edema,
blurred vision, decreased
concentration
Tramadol
50 mg 1–2/d
Increase by 50-100
mg/d, individual
doses every 3-7
days
400 mg/d (100
mg 4 times/d);
elderly 300 mg/d
4 wk
Dizziness, constipation,
nausea, somnolence,
orthostatic hypotension,
increased risk of seizure,
serotonin syndrome
Tricyclic
antidepressants
(amitriptyline,*
nortriptyline,*
desipramine)
Starting dose:
10-25 mg
nightly
Increase by 10-25
mg every 3-7 days
75–150 mg; may
increase if blood
level of drug
plus metabolite
<100 ng/mL
6-8 wk; 1-2 wk
at max dose
Cardiovascular disease
(needs screening),
anticholinergic
effects, interact with
drugs metabolized
by cytochrome P450
2D6 (e.g., cimetidine,
phenothiazine)
Potential Side Effects
*Negative results in randomized controlled clinical trials on chemotherapy-induced peripheral neuropathy
Practice Guidelines in Oncology: Adult Cancer Pain
(to view the most recent version of these guidelines,
visit the NCCN Web site at www.nccn.org) for pain
management strategies in cancer patients.
Antiepileptic Drugs: Gabapentin is an anti-epileptic
drug widely used for neuropathic pain. In randomized
controlled trials involving mixed populations, gabapentin was found to relieve pain and improve sleep,
mood, and quality of life.140–144 However, in a doubleblinded, controlled, crossover trial (n = 115) gabapentin was no better than placebo in reducing CIPN.137
Pregabalin has the same mechanism of action
as gabapentin and is approved for the treatment of
diabetic neuropathy and post-herpetic neuralgia.
Its efficacy in reducing neuropathic pain has been
shown in 6 randomized trials.145–150 A phase IV trial
of pregabalin (NCT00380874) in advanced colorectal cancer patients was terminated due to insufficient
conditional power to detect differences. Nonetheless, panelists reported from their clinical experience
that both pregabalin and gabapentin may be helpful
in treating pain associated with CIPN. Compared
with gabapentin, pregabalin has similar and perhaps
milder side effects, faster onset of action, better absorption, and less need for dosage titration.
Local Anesthetics: The 5% lidocaine patch has the
advantage of minimal side effects (local rash) and
ease of administration. It has been shown to alleviate
allodynia (a form of dysesthesia) mainly in patients
with post-herpetic neuropathy,151 but has not been
shown to have a significant impact on pain intensity
in cancer patients with postsurgical pain.152
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Antidepressants: Duloxetine is a serotonin and
norepinephrine reuptake inhibitor (SNRI) that
is effective in reducing pain in patients with diabetic neuropathy.153–155 It has the advantage of being fast-acting, with rapid onset of action within
the first few doses. However, duloxetine should be
avoided in patients on tamoxifen because it will
decrease the concentration of endoxifen, an active
metabolite of tamoxifen. As a serotonin reuptake
inhibitor, duloxetine is relatively contraindicated
when used with other drugs that affect serotonin
reuptake, including the selective serotonin reuptake inhibitors, tricyclic antidepressants, tramadol,
and triptans commonly used to treat migraines for
fear of causing the potentially fatal serotonin syndrome. A randomized, placebo-controlled trial of
duloxetine in cancer patients with CIPN is ongoing (NCT00489411). Another SNRI, venlafaxine,
has recently been reported to reduce the incidence
of acute oxaliplatin-induced neuropathic pain compared with placebo (35% vs. 76%) in a small trial
of 54 patients.139
Tricyclic antidepressants (TCAs; amitriptyline, nortriptyline, and desipramine) are FDA-approved for relieving symptoms of depression, not
neuropathic pain. Despite this, they were the first
class of nonopioid medications to gain widespread
use in the treatment of neuropathic pain, based
on benefits seen primarily in diabetic patients.156
Unfortunately, studies of these agents are limited
by substantial side effects (high drop-out rates)
and their pharmacologic interactions with drugs
metabolized by cytochrome P450 2D6. Their potential negative impact on cardiovascular function necessitates screening, especially in elderly
patients. Despite TCA’s efficacy on diabetic neuropathy, 2 randomized, placebo-controlled trials
(n = 44 and 51, respectively) of amitriptyline and
nortriptyline yielded negative results in patients
with CIPN.134,135 Given these limitations, TCAs
are not typically used as a first-line pain medication for CIPN. More recently, a topical gel formulation BAK-PLO (baclofen, amitriptyline, and ketamine in pluronic lecithin organogel) moderately
improved CIPN symptoms in a randomized trial of
208 cancer patients.138
Opioids: Tramadol is a centrally acting analgesic. It
is often considered a mild opioid but has other analgesic properties and may be considered a novel
agent. It has shown efficacy in relieving painful diabetic neuropathy and improving patients’ quality of
life.157,158 The maximum dose is 400 mg per day for
most adults and 300 mg per day for elderly patients.
The opioids morphine and oxycodone provide
analgesia and lessened sleep interference for diabetic neuropathy when used alone or in combination with gabapentin.141,159–161 Task Force members
pointed out that although the opioid methadone is
used frequently, its use is complicated by a very long
half-life, effect on QT intervals, and many drug–
drug interactions that can result in serious adverse
events. Current recommendations suggest that only
clinicians with experience administering methadone
should prescribe this medication. Other opioids (tramadol, morphine, oxycodone) that have been tested
for neuropathy may be considered safer alternatives
in treating CIPN.
Other medications that have been studied include lamotrigine,136 selective serotonin reuptake
inhibitors, mexiletine, 0.75% capsaicin, and intravenous lidocaine. However, these are not recommended for routine use because of mixed results or
safety issues.
Recommendations: Currently, the general approach
to pain medication for CIPN is to choose an agent
based on the clinician’s experience and expectation
of efficacy and safety, and titrate that agent to the
maximal tolerated dose. If a single agent is effective,
then it should be continued. If a single agent confers partial but incomplete benefit, then a second
agent with a different mechanism of action should
be chosen and added. If the first agent is ineffective
or poorly tolerated, then it should be discontinued
and another agent chosen and titrated. Often many
agents will be needed for adequate analgesia. Panelists agreed that the clinical context of the treatment
will determine the choice of medication. For example, a fast-acting agent with low risk of nausea will
be most suitable for a patient going through active
adjuvant chemotherapy before surgery. Unfortunately, there is inadequate evidence on the best order of
administration and combination. Two randomized,
double-blinded trials in 41 to 338 patients, primarily with diabetic neuropathy, showed more effective
pain reduction with the combination of an opioid
(morphine or oxycodone) and gabapentin compared
with gabapentin alone, with little exacerbation of
side effects.141,160
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Symptom Management: Neurostimulation
Therapies
Medication is often insufficient to mitigate neuropathic pain, and alternative nonpharmacological
therapies have been investigated. In particular, electrical stimulation therapies, typically administered
by a specialist, have elicited some benefits. They are
generally considered reversible, although they vary
widely in their degree of invasiveness. These neurostimulation techniques are generally based on the
gate control theory proposed by Melzack and Wall;162
they are designed to relieve pain by somatotopically
“masking” the affected area with non-painful stimulation of A-beta afferent fibers, thereby blocking
out the painful stimuli. Hence these modalities are
seldom effective towards patients with deafferented
nerves leading to numbness or tingling. The European Federation of Neurological Forces (EFNS)163
recently produced a detailed review and recommendations on these techniques for neuropathic
pain. As with pain medications, most evidence supporting neurostimulation came from studies on diabetic or other types of neuropathy. Data on CIPN
are anecdotal.
Spinal cord stimulation (SCS) involves the surgical placement of electrodes into the epidural space
that can send non-noxious electrical stimulation
across the spine to displace the painful sensation.
SCS has been shown to provide good pain relief in
small case series of patients with refractory CIPN
(n = 2–4)164,165 and other types of neuropathy (n =
6–19).166–169 Long-term effects up to 8 years are reported. Of note, SCS is an invasive technique that
includes the risks and costs of surgery, although a
temporary lead is typically tested for a trial period
before permanent implantation. There were initial
concerns that cancer patients with SCS may suffer
neurologic injury during an MRI, but published case
reports as well as panelists’ experience indicate that
it is safe to perform MRI with the SCS temporarily
turned off.170–172
Similar techniques include motor cortex stimulation and deep brain stimulation, which require
surgical implantation into the brain. These procedures are highly invasive and have little evidence
to support their use for treating neuropathic pain.
High frequency (5–20 Hz) repetitive transcranial
magnetic stimulation is a noninvasive technique
that applies the coil of a magnetic stimulator above
the scalp. There is evidence that it alleviates pain for
post-stroke central pain syndromes, but its effects are
short-lived and moderate.163
Electrical nerve stimulation, either transcutaneous (TENS) or percutaneous, originally developed
in the 1960s for treating nociceptive and musculoskeletal syndromes, uses portable skin patches to
pass electrical current through the cutaneous tissues.
Nine small trials involving an aggregate of approximately 200 patients with neuropathic pain generally
associate TENS with a positive effect on pain control (reviewed by Cruccu et al.163).
One randomized study involving 41 diabetic
patients showed a higher response rate with highfrequency muscle stimulation (69%) than with
TENS (25%). However, the study had no placebo.173
Other studies have shown that acupuncture-like low
frequency TENS is better than sham stimulations.
An emerging technique called anodyne therapy
uses monochromatic near-infrared photo energy
to increase circulation to nerves and reduce pain.
Small studies (n = 21–27) have shown a benefit for
diabetic patients,174,175 but a strong placebo effect
was present in 2 randomized, sham-controlled trials.174,176 Several panelists noted that burns are a
potential risk in patients with sensory deficits and
that no efficacy studies have been performed in oncology patients.
Recommendations: Current literature is inconclusive on the benefits of neurostimulation in treating
CIPN, and more rigorous studies are needed. Despite
a lack of evidence, panelists generally agreed that
TENS can be a helpful adjuvant therapy for CIPN
patients with contraindications to or for whom pain
medication is ineffective, considering its ease of application, reversibility, and relatively low cost.
Complementary and Alternative Medicine
Therapies
According to the National Center for Complementary and Alternative medicine, complementary and
alternative medicine (CAM) is a group of diverse
medical and health care systems, practices, and products that are not generally considered part of conventional medicine. CAM therapies have achieved
widespread use among patients with neurologic disorders. A questionnaire-based study found that 77 of
180 (43%) patients with peripheral neuropathy used
CAM, such as megavitamins (35%) and acupuncture (30%).177 In another report of 450 patients, pa-
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tients indicated massage (35%), meditation (18%),
and acupuncture (10%) as common self-care strategies for HIV-related peripheral neuropathy.178
Clinical studies investigating natural products
as prophylactics for neuropathy and neurostimulation techniques for pain management have been
discussed in previous sections. Among other CAM
approaches, most research focused on acupuncture.
Originally from Chinese traditional medicine, modern acupuncture is based on the theory that insertion
and manipulation of a needle at specific acupuncture
points in the body induces signals in afferent nerves
that subsequently regulate spinal signal transmission
and neural pain perception. This theory is supported
by preclinical studies and animal models (reviewed
by Wang et al.179).
Alimi et al.180 randomized 90 cancer patients
with mainly neuropathic pain to auricular acupuncture and 2 placebo groups (acupuncture or auricular
seeds at placebo points). At 2 months, pain intensity decreased by 36% from baseline with acupuncture versus 2% with placebo (P < .0001). Another
randomized controlled trial enrolling 250 patients
with HIV-related neuropathy found that both acupuncture and amitriptyline reduced symptoms, with
a favorable trend over placebo that did not reach
statistical significance.181 A non-randomized trial
of 47 patients with idiopathic neuropathy reported
improvement both in symptoms and objective NCS
measurements for 76% of patients receiving acupuncture compared with only 15% receiving best
medical care.182 For CIPN, only one pilot, singlearm, prospective case series of 5 patients was performed. The pain scores were lowered in all patients
(average 8 points reduced to average 3 points) after
two 6-week courses of acupuncture.183
Evidence is scarce on the efficacy of other CAM
therapies on neuropathic symptoms. Case series of
successful treatment of neuropathic pain by biofeedback have been reported,184 but no data from prospective trials are available. Dietary supplements
have also been studied for prevention and treatment of neuropathy. They include alpha-lipoic acid,
acetyl-L-carnitine, benfotiamine, methylcobalamin, topical capsaicin, vitamin E, glutathione, folate, pyridoxine, biotin, myo-inositol, omega-3 and
-6 fatty acids, L-arginine, L-glutamine, taurine, Nacetylcysteine, zinc, magnesium, chromium, and St.
John’s wort.185
Conclusions: The increasingly widespread use of
CAM therapies among patients and the current
paucity of evidence on their safety and efficacy in
treating CIPN raise the need for more controlled,
sufficiently powered studies. Acupuncture is a more
promising approach supported by scientific plausibility, although the technique lacks standardization. As
with TENS, it is noninvasive and relatively inexpensive, and it may be considered as an adjunct option
in treating patients with medication-resistant CIPN.
Several natural products available to the public as
dietary supplements also showed promise, although
their definitive efficacy has not been established.
Management of Functional Deficits
Cancer patients with CIPN often present with significant functional deficits especially as their condition worsens. These deficits may include decreased
balance, gait abnormalities, muscle weakness, and
sensory loss, which can lead to an increased fall
risk, difficulties in performing activities of daily living, safety concerns, and diminished participation.
Rehabilitation specialists, particularly physical and
occupational therapists, are uniquely qualified to assess patients with CIPN and provide interventional
strategies (both remedial and compensatory) to help
patients either reverse or safely deal with these interrelated deficits.
The brain requires sensory and proprioceptive
information from the periphery to maintain balance;
therefore, the sensory losses associated with CIPN
can result in balance deficits. For example, Visovsky
and Daly186 recorded a slight decline of 12% in balance over the course of 12-week carboplatin treatment in cancer patients. Similarly, Wampler et al.187
significantly correlated increasing balance deficits
with increasing CIPN severity in 20 breast cancer
patients who had received taxane chemotherapy.
Clinical assessments of balance can be made using
simple tests such as the Single Limb Stance Test (time
patient can stand on one leg), Tandem Standing Test
(time patient can stand heel to toe), or the Timed Up
and Go test (the patient stands up, walks 10 feet, returns
and sits down), or more complex tests such as the Berg
balance test or the Rhomberg balance test. Computerbased biomechanical analysis of balance, which provides quantitative assessment, is increasingly available
for use in a clinical setting.188 Questionnaires like the
Activities-Specific Balance Confidence Scale are also
used clinically to evaluate balance.
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Therapeutic interventions aimed at improving
balance typically involve progressive task training
starting with static standing activities (firm and hard
surfaces) and then advancing first to static standing
coupled with simple manipulation activities (e.g.,
holding a glass of water, passing a basketball), then
to walking (different surfaces) and finally to walking coupled with simple manipulation activities.189
Modification or elimination of visual input can also
be included to make these tasks more demanding.
In a case report discussing a patient with stage III
breast cancer with docetaxel-associated neuropathy,
such a program (45–60 minutes per session, 2 times
per week, 4 weeks total) improved the patient’s sense
of balance.190
Gait training and lower extremity strengthening
exercises are important therapeutic activities that
improve balance, as shown by a study (n = 20) of
diabetic patients undergoing intense daily strengthening exercises (e.g., toe raises, heel raises, wall
slides). Compared with a control exercise regimen,
these strengthening exercise significantly enhanced
balance.191 Assistive devices including canes, walkers, wheelchairs, and ankle-foot orthoses may also be
recommended, less to reverse this deficit and more to
compensate for it.
Although the incidence of falls in patients with
CIPN has not been reported, the risk for falls is 5
times greater in older patients with peripheral neuropathy than in healthy age-matched controls.192
Therefore, rehabilitation staff must be particularly
alert to an increased fall risk in patients with CIPN.
Asking cancer patients whether they have fallen recently is a simple screening question for determining
heightened fall risk. Impaired gait and balance are
the most reliable predictors of this serious medical
problem.193 Results from clinical tests such as the
timed up and go, single limb stance, gait analysis,
and sensory assessment also provide further assessment of fall risk in CIPN patients.
Therapeutic interventions aimed at reducing
fall risk typically include lower extremity strengthening exercises and gait training combined with
balance training and issuance of assistive devices.
Patient and caregiver education regarding issues
such as recognizing potential environmental hazards, performing necessary home and environmental modifications (removing throw rugs, installing
adequate lighting, and maximizing visual con-
trasts), and increasing diligence when the patient
is in a novel environment should be provided. For
patients with CIPN who also have cognitive, visual, or auditory deficits, caregiver education is of
particular importance.
The presence of peripheral neuropathy can also
contribute to detrimental changes in gait patterns.
In a study of 24 older women, those with peripheral
neuropathy showed a gait pattern that was slower
and less efficient as measured by various gait parameters (e.g., increased step time) than the control
group, with differences magnified under challenging
walking environments.194 Clinical gait assessment
involves visual and auditory observation of gait pattern, shoe wear (e.g., marred shoe top may indicate
foot drag), foot slap, and toe dragging. Biomechanical analysis systems are available that provide sophisticated quantitative analysis of specific gait parameters. Gait training typically incorporates balance
training, lower extremity strengthening, endurance
activities, and walking under simple (smooth, level
surface) and complex conditions (time constraints,
physical load, and terrain obstacles). Labor-intensive
programs, such as training with body weight support
systems, are more widely used for stroke patients
but may be useful for patients with CIPN. Appropriate assistive devices (canes, walkers, and anklefoot orthoses) can also be helpful for improving
gait characteristics.195
Identifying muscle weakness caused specifically
by CIPN is difficult because this condition can be the
result of a variety of factors already present in many
cancer patients, including deconditioning, fatigue,
nutritional deficiency, sleep disorders, depression,
medication regimens, and pre-existing neurologic
disorders. Chemotherapeutic agents that cause CIPN
damage sensory neurons much more frequently than
motor neurons, reducing the likelihood that muscle
weakness is associated with CIPN. Of note, many
cancer patients receive corticosteroids, a drug wellknown for its muscle-wasting effects, particularly on
respiratory and proximal lower extremity muscles.
Regardless of the cause of muscle weakness,
muscle function must be assessed in these patients.
Manual muscle testing of specific muscles or muscle
groups is the most frequently used method of assessing muscle strength. Hand-held dynamometers can
be used to directly measure specific muscle strength
or infer muscle strength such as grip strength. Ul-
Supplement
trasound is used to image skeletal muscle for architectural changes consistent with decreases in muscle
strength. Therapeutic management schemes for increasing muscle strength are similar whether muscle
loss is attributable directly to CIPN or indirectly to
other cancer-related causes. Resistance training is
consistently shown to be effective in improving muscle strength. For example, a 9-hour weekly training
program over 6 weeks increased muscular strength
by an average of 41% in 70 cancer patients undergoing chemotherapy.196 One key to a successful exercise
program is to distinguish patients who require supervision in an inpatient or outpatient training program
from self-motivated patients who often derive comparable or greater benefit from participating in a selfdirected exercise program.
Special attention must be paid to safety for cancer patients engaging in exercise and physical training (Table 6). Physicians and rehabilitation therapists should observe contraindications for training
to avoid injury and symptom exacerbation.196 Attention must also be paid to the use of proper footwear,
daily foot inspections, and reporting foot injury.
As with muscle weakness, cancer patients with
CIPN may have difficulties performing activities of
daily living because of sensory and motor loss. Successful rehabilitation of these deficits requires that
they first be identified. Then strategies must be developed to either correct or compensate for the deficit and maximize patient independence. Therapeutic
interventions may include musculoskeletal therapies
(strengthening, range of motion), environmental
modification, teaching energy conservation techniques, and providing adaptive equipment. Practical
adaptive approaches adopted by occupational therapists are very helpful:
• Modifying tasks, such as switching to loafer-style
shoes or using Velcro shoe laces
• Providing adaptive equipment, such as enlarged
handles on eating utensils, buttonhooks, Velcro
on computer keys to stimulate sensation
• Teaching increased use of vision and attention
when performing household tasks
• Increasing proprioceptive input, such as
putting weights on the patient’s arm for better
proprioception
• Educating patients on protective household
adaptation
• Strengthening
Table 6 Safety Notes and Tips in the Management of Functional Deficits
Avoid or Discontinue Physical Training If: 197
•Resting diastolic blood pressure > 115 mm Hg or
resting systolic blood pressure > 200 mm Hg
•Diastolic pressure rises > 10 mm Hg above resting value
and systolic pressure > 250 mm Hg
•Heart rate to increase with increasing exertional
demand
•Signs of poor perfusion (light-headedness, confusion,
pallor, cyanosis, or cold and clammy skin) are present
or become present
•Angina or angina like symptoms are present or begin
•Body temperature > 38°C
•Hemoglobin < 8.0 g/dL
•Ongoing bleeding or fresh petechiae or bruises are
presnt; sample question: “Do you bleed often while
brushing your teeth?”
Footwear
•Avoid heels
•Insoles should not be too soft
•Grip surface on shoes
•Loafer-style, Velcro straps if having difficulty with
shoelaces
•Examine feet for signs of injury including abrasions,
blisters, etc.
Orthosis
•Watch out for skin abrasion
•Wear protective clothing underneath the orthosis
•Select good shoes with proper support, have a closed
back and toe, come up over the top of the feet and
have a slightly wider width to accommodate the
orthoses
•Remove if pain occurs, see the orthotist if pain persists
Household Environment
•Avoid or protect against thermal stress (reduce hot
water temperature, wear gloves, use potholders)
•Keep rooms well-lit, use night lights
•Remove or tack down loose rugs
•Tidy loose wires across hallways
•Use non-skid bath mats
•Employ energy conservation
Recommendations: The Task Force panel emphasized the importance of physicians integrating the
identification and assessment of functional deficits
into the evaluation of patients with CIPN. Sample
questions and simple skill tests that oncologists can
use to accomplish this are listed in Table 3. Overall,
panelists strongly recommend referring patients with
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CIPN that interferes with functioning to a physical
or occupational therapist. Therapeutic interventions, education, and practical advice provided by
these rehabilitation specialists can prove invaluable in helping patients to both correct CIPN-induced functional deficits and to cope with the difficulties and challenges these deficits cause in their
everyday life.
Management of Autonomic Symptoms
Although CIPN primarily affects sensory nerves, autonomic impairment is sometimes seen after the use
of antineoplastic agents such as vincristine, cisplatin,
carboplatin, paclitaxel, and bortezomib. For example, in a phase II study of bortezomib in patients with
metastatic neuroendocrine tumors, 6 of 10 patients
with moderate sensory neuropathy also experienced
grade 2 to 3 dizziness, orthostasis, syncope, ileus, or
abdominal cramping.198 As discussed, it is difficult
to specifically attribute neuropathic symptoms to a
single drug because other cancer-related factors may
also be involved. Autonomic neuropathy induced
by chemotherapy has not been well documented
or studied.
Recommendations: Autonomic dysfunction can
manifest with a wide variety of symptoms. The more
common symptoms seen in patients undergoing chemotherapy are dizziness or lightheadedness related to
orthostatic hypotension, bloating, urinary retention,
constipation or diarrhea, and impotence. The EFNS
developed guidelines on the management of orthostatic hypotension.199 Advice for mild cases include
getting up slowly (supine position to sitting, sitting
to standing) as well as maintaining adequate salt intake and hydration. Abdominal binders or graded
compression stockings decrease venous pooling and
may be helpful for some patients. For more severe
cases, midodrine, fludrocortisone, or their combination may be prescribed.
Urinary retention can often be related to underlying medical disorders such as benign prostatic
hyperplasia or an obstructive tumor and worsened by
treatment with medications that have anticholinergic properties such as TCAs and opioids. In such cases, discontinuation of the offending agent may result
in resolution of symptoms. The addition of alphablocking medications may be indicated in patients
with benign prostatic hyperplasia. Chronic urinary
retention from neurogenic bladder can be effectively
managed using hygienic, intermittent self-cathe-
terization (reviewed by Selius and Subedi200). Lowfriction, hydrophilic-coated catheters are preferable
over regular catheters for the prevention of urinary
tract infection. Use of urethral indwelling catheters
is not recommended due to possible complications
such as sepsis, stones, prostatitis, urethral erosions,
and development of squamous cell carcinoma.
Constipation can also be related to underlying
medical disorders, including obstruction by tumor,
electrolyte abnormalities, and endocrine dysfunction such as hypothyroidism, and worsened by treatment with medications, particularly opioids. A well
thought-out bowel program may include adequate
water and fiber intake, stool softeners, and, when
needed, cathartic agents. The timing of cathartic
agents should be deliberate, with the goal of producing bowel movement at a specific time of day. For
instance, the use of agents before sleep coupled with
the ingestion of breakfast and warm liquid may help
reliably produce a morning bowel movement in some
patients. Methylnaltrexone is an effective medication for opioid-induced constipation,201,202 but its efficacy is unclear when constipation is related to autonomic neuropathy from chemotherapy.
Conclusions
With the continued use of neurotoxic drugs, emergence of newer neuropathy-inducing antineoplastic
agents, and the adoption of dose-dense regimens, the
problem of CIPN is more relevant than ever in oncology. In reviewing the current literature, panelists
noted a paucity of rigorous studies on the assessment,
prevention, and management of cancer treatment–
related neuropathy. More well-designed, sufficiently
powered trials specifically on patients with CIPN are
necessary to validate evaluation tools, explore different combinations and sequence of pain medications,
and test the efficacy and safety of therapeutic methods and preventative supplements.
In the interim, improving education and awareness within both the medical and general community will be an essential primer in efforts to overcome neuropathy. Physician and patient education
are required to address the issues of underdiagnosis,
underassessment, and failure of intervention. Patient
participation in clinical trials is strongly encouraged.
While the community awaits more study data,
existing measures can aid patients with CIPN. A
Supplement
number of medications are available to mitigate neuropathic pain, as are various interventional measures
and devices to improve or compensate for functional
deficits. For patients for whom pain medications are
ineffective, noninvasive techniques such as TENS or
acupuncture may be considered.
15. Park SB, Goldstein D, Lin CS, et al. Acute abnormalities of
sensory nerve function associated with oxaliplatin-induced
neurotoxicity. J Clin Oncol 2009;27:1243–1249.
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139. Durand JP, Deplanque G, Gorent J, et al. Efficacy of venlafaxine
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the symptomatic treatment of painful neuropathy in patients
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142. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial
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157. Freeman R, Raskin P, Hewitt DJ, et al. Randomized study of
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159. Gimbel JS, Richards P, Portenoy RK. Controlled-release
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enhances the effects of existing gabapentin therapy in painful
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161. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release
oxycodone relieves neuropathic pain: a randomized controlled
trial in painful diabetic neuropathy. Pain 2003;105:71–78.
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164. Cata JP, Cordella JV, Burton AW, et al. Spinal cord stimulation
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165. Bruel BM, Burton A, Are M, et al. Dorsal column stimulation for
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169. de Vos CC, Rajan V, Steenbergen W, et al. Effect and safety of
spinal cord stimulation for treatment of chronic pain caused by
diabetic neuropathy. J Diabetes Complications 2009;23:40–45.
186. Visovsky C, Daly BJ. Clinical evaluation and patterns of
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170. Roebling R, Huch K, Kassubek J, et al. Cervical spinal MRI in
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187. Wampler MA, Miaskowski C, Hamel K, et al. The modified
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171. Shah RV, Smith HK, Chung J, et al. Cervical spinal cord neoplasm
in a patient with an implanted cervical spinal cord stimulator: the
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172. De Andres J, Valia JC, Cerda-Olmedo G, et al. Magnetic
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173. Reichstein L, Labrenz S, Ziegler D, Martin S. Effective treatment
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174. Leonard DR, Farooqi MH, Myers S. Restoration of sensation,
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175.Prendergast JJ, Miranda G, Sanchez M. Improvement of sensory
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190. Wampler MA, Hamolsky D, Hamel K, et al. Case report: painful
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breast cancer. Clin J Oncol Nurs 2005;9:189–193.
191. Richardson JK, Sandman D, Vela S. A focused exercise regimen
improves clinical measures of balance in patients with peripheral
neuropathy. Arch Phys Med Rehabil 2001;82:205–209.
192. Richardson JK, Hurvitz EA. Peripheral neuropathy: a true risk
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194. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA. A
comparison of gait characteristics between older women with
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195. Richardson JK, Thies SB, DeMott TK, Ashton-Miller JA.
Interventions improve gait regularity in patients with peripheral
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196. Quist M, Rorth M, Zacho M, et al. High-intensity resistance
and cardiovascular training improve physical capacity in cancer
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the proteasome inhibitor bortezomib (PS-341) in patients
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201. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for
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2008;358:2332–2343.
S-27
Post-test
Please circle the correct answer on the enclosed answer sheet.
1. Cancer-related causes of neuropathy include:
a. Myelosuppressive chemotherapy
b. Tumor pathology
c. Nutritional deficiency
d. Radiotherapy
e. All of the above
2. Which of the following is NOT a diagnostic feature
of CIPN?
a. Dose-dependent symptoms
b. Progressive onset following drug administration
c. Concomitant sensory, motor, and autonomic
impairment of comparable severity
d. “Glove and stocking”, “dying back” distribution
of abnormal sensations
3. Which of the following is/are TRUE regarding
chemotherapeutic agents known to induce
neuropathy?
a. In most cases, CIPN aggravates with the
accumulation of dose and duration.
b. Neuropathy is only associated with older,
traditional chemotherapy such as cisplatin
and is not a reported side effect of newer
antineoplastic agents.
c. Neuropathic symptoms disappear almost
immediately upon completion of the
chemotherapy cycle.
d. All of the above
4. Which of the following represents significant
challenges in the management of neuropathy in
cancer patients?
a. Patients often have underlying neuropathy
or pre-existing conditions that increase their
risk of developing CIPN when exposed to a
neurotoxic drug.
b. CIPN is underestimated and underreported.
c. No effective treatment has been approved for
CIPN.
d. All of the above
5. Which of the following is/are a patient-based tool
for evaluation of neuropathic symptoms?
a. NCI-CTCAE
b. FACT-Taxane
c. TNS
d. ECOG
e. All of the above
6. Which of the following is a pain assessment tool
that can complement existing neuropathy grading
systems?
a. PND
b. PNQ
c. NPS
d. NCI-CTCAE
7. Which statement(s) accurately describes the current
status of prevention therapy for CIPN?
a. Larger randomized controlled studies are still
needed to confirm the safety and efficacy of
preventative agents.
b. Vitamin E is the only approved neuropathyprophylactic agent.
c. CaMg injection is showing promise in reducing
the incidence of paclitaxel-related neuropathy.
d. All of the above
8. Which of the following is FALSE regarding pain
medications for CIPN?
a. No pain-killing drug has been specifically
approved for CIPN.
b. Gabapentin, pregabalin, duloxetine, and
oxycodone are medications commonly used for
CIPN.
c. There is no consensus on the best order of
administration and combination of drugs to
relieve neuropathic pain in cancer patients.
d. All are true
9. Use of electrical neurostimulation and acupuncture
to relieve neuropathic pain in cancer patients should
be avoided due to their invasiveness and excessive
side effects.
a. True
b. False
10. Which of the following is NOT useful in managing
functional deficits related to CIPN?
a. Consult a physical therapist or occupational
therapist.
b. Wear tight-fitting orthosis and ensure direct
skin contact.
c. Enroll in exercise programs to improve gait and
balance.
d. Modify the household environment for safety,
such as removing loose rugs and enhancing
lighting.
S-28
Please circle the correct answer below.
Post-Test Answer Sheet
Please circle one answer per question. A score of at least 70% on the post-test is required.
1.
a
b
c
d
2.
a
b
c
3.
a
b
4.
a
5.
a
e
6.
a
b
c
d
d
7.
a
b
c
d
c
d
8.
a
b
c
d
b
c
d
9.
a
b
b
c
d
10.
a
b
c
d
e
The activity content helped me to achieve the following objectives:
(1 = Strongly disagree; 3 = Not sure; 5 = Strongly agree)
Explain the etiology of neuropathy in cancer patients
1
2
3
4
5
Describe the manifestations of chemotherapy-induced peripheral neuropathy
1
2
3
4
5
3
4
5
4
5
List agents associated with neuropathy
1
2
Describe tools to assess neuropathy in cancer patients
1
2
3
Outline strategies to manage peripheral neuropathy associated with chemotherapy
1
2
3
4
5
Please indicate the extent to which you agree or disagree with the following statements:
You were satisfied with the overall quality of this activity.
Strongly agree
Agree
Undecided
Disagree
Strongly disagree
This activity addressed issues that will help me improve my professional competence and/or performance.
Strongly agree
Agree
Undecided
Disagree
Strongly disagree
You will make a change in your practice as a result of participation in this activity.
Strongly agree
Agree
Undecided
Disagree
Strongly disagree
The activity presented scientifically rigorous, unbiased, and balanced information.
Strongly agree
Agree
Undecided
Disagree
Strongly disagree
Disagree
Strongly disagree
Individual presentations were free of commercial bias.
Strongly agree
Agree
Undecided
S-993
Registration for Credit
NCCN Task Force Report:
Management of Neuropathy in the
Treatment of Cancer
Release Date: September 14, 2009
Expiration Date: September 14, 2010
To receive credit, please complete this page, the post-test,
and the evaluation, and mail to the following address:
Continuing Education Department
NCCN
275 Commerce Drive, Suite 300
Fort Washington, PA 19034
There is no fee for participating in this activity.
Comments and suggestions: Please print clearly.
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Affiliation (University or Hospital)
Business Address
City
State
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Business Fax Zip
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I am claiming credits
(maximum 1.0)
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Signature
Date
TO RECEIVE CREDIT, YOU MUST SUBMIT THIS FORM BY SEPTEMBER 14, 2010.

Management of Neuropathy in Cancer

Transcription

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