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JOURNAL OF CLINICAL ONCOLOGY
R E V I E W
A R T I C L E
Peripheral Neuropathy Induced by
Microtubule-Stabilizing Agents
James J. Lee and Sandra M. Swain
From the Breast Cancer Section,
Medical Oncology Branch, Center for
Cancer Research, National Cancer
Institute, National Institutes of Health,
Bethesda, MD.
Submitted August 29, 2005; accepted
January 20, 2006.
Supported by the Intramural Research
Program of the National Institutes of
Health, National Cancer Institute, Center
for Cancer Research, Bethesda, MD.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Address reprint requests to Sandra M.
Swain, MD, Breast Cancer Section,
Medical Oncology Branch, Center for
Cancer Research, National Cancer Institute, Bldg 8, Rm 5101, 8901 Wisconsin
Ave, Bethesda, MD 20889-5015;
e-mail: [email protected].
0732-183X/06/2410-1633/$20.00
DOI: 10.1200/JCO.2005.04.0543
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Microtubule-stabilizing agents (MTSAs), including the taxanes and epothilones, are effective chemotherapeutic
agents for the treatment of many cancers. Neuropathy is a major adverse effect of MTSA-based chemotherapy, with severe peripheral neuropathy (grade 3 or 4) occurring in as many as 30% of patients treated with a
MTSA. MTSA-induced neuropathy usually resolves gradually after cessation of the treatment. The most
reliable method to accurately assess MTSA-induced neuropathy is by clinical evaluation, although additional
techniques are being developed and evaluated. Among MTSA-induced neuropathy, the most extensively
studied is that induced by taxanes; such a neuropathy usually presents as sensory neuropathy and is more
common with paclitaxel than docetaxel. The incidence of MTSA-induced neuropathy seems to depend on the
MTSA dose per treatment cycle, the schedule of treatment, and the duration of the infusion. Although there
have been several small clinical trials with neuroprotective agents, early recognition and supportive care are the
best approaches for prevention and management of MTSA-induced neuropathy. In the future, research should
focus on elucidating the mechanism of MTSA-induced neuropathy, developing reliable in vivo and in vitro
preclinical models to study MTSA-induced neuropathy, developing a more reliable grading system for
MTSA-induced neuropathy, developing more reliable methods for evaluating MTSA-induced neuropathy, and
evaluating the efficacy of potential neuroprotective agents in clinical trials.
J Clin Oncol 24:1633-1642.
INTRODUCTION
Microtubule-stabilizing agents (MTSAs), including
the taxanes and epothilones, stabilize microtubules,
block mitosis, and induce cell death.1,2 Taxanes include polyoxyethylated castor oil– based paclitaxel,
docetaxel, and ABI-007 and are effective chemotherapeutic agents for various cancers. ABI-007 is a
new polyoxyethylated castor oil–free formulation of
paclitaxel with good antitumor activity in phase III
clinical trials of breast cancer.3-6 Epothilones are
newly emerged MTSAs in active clinical trials and
include ixabepilone (BMS-247550), BMS-310705,
patupilone (EPO906), epothilone D (KOS-862),
and ZK-EPO.7
A major toxicity associated with MTSAbased chemotherapy is peripheral neuropathy
(PN).8,9 Severe PN (National Cancer Institute
[NCI] Common Toxicity Criteria grade 3 or 4)
occurs more frequently in paclitaxel-based chemotherapy than in docetaxel-based chemotherapy
(Tables 1 and 2). A clinical assessment, including a
physical examination, is currently the most reliable
method to assess MTSA-induced PN because we
lack more reliable objective methods. Although neuroprotective agents such as amifostine have been
evaluated in clinical trials, no neuroprotective agent
has performed better than early recognition and
supportive care.32-36
In this review, we summarize the characteristics, assessment, and management of MTSA-induced
PN, mainly based on breast cancer trials. We also
point out areas of future research.
PRECLINICAL INVESTIGATIONS ON
THE MECHANISM OF
MTSA-INDUCED NEUROPATHY
PN is caused by morphologic or functional abnormalities in peripheral nerves and is separated into axonopathy (axonal abnormalities) or myelinopathy
(myelin sheath abnormalities).37 MTSA-induced PN
presents as axonopathy or axonopathy plus myelinopathy. The mechanism of MTSA-induced PN is
unclear. However, because the survival and function
of neurons require that proteins and other components be actively transported along long axons from
a neuron’s cell body to its distal synapses, MTSA
treatment likely interrupts this active transport.
Addition of paclitaxel (10 ␮g/mL) to dorsal root
ganglia cell cultures inhibited anterograde axonal
transport,38 which was reversible and did not damage cells. Also, incubation of rat sciatic nerve with
paclitaxel 200 ␮mol/L induced vesicle accumulation
on both proximal and distal sides of the nerve, indicating that paclitaxel treatment blocked fast axonal
transport.39 In another study involving rats, injection of paclitaxel into neurons induced microtubule
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Lee and Swain
Table 1. Incidence of Peripheral Neuropathy in Breast Cancer Patients Treated With Taxanes
Grade 3 or 4 Severe
Neuropathy
Drug
Polyoxyethylated castor oil–based
paclitaxel
Treatment Schedule
Infusion
every
Infusion
every
over 1 hour
week
over 3 hours
3 weeks
No. of
Assessable
Patients
No.
%
No.
%
Seidman et al11
228
NA
19
NA
7
Winer et al10
150
11
7
8
5
250
Gradishar et al
Ravdin et al13
Seidman et al11
Paridaens et al14
Winer et al10
Winer et al10
Smith et al12
Smith et al12
225
222
224
164
152
149
278
279
5
NA
NA
14
29
49
NA
NA
2
5
12
9
19
33
13
7
0
NA
NA
NA
16
20
NA
NA
0
5
4
NA
11
14
9
7
60
Mouridsen et al15
150
NA
1
NA
NA
75
100
100
Mouridsen et al15
Chan et al16
Mouridsen et al15
Nabholtz et al17
Ravdin et al13
Kruijtzer et al18
Blum et al19
188
159
186
200
222
253
106
NA
NA
NA
NA
NA
6
NA
2
5
4
5
9
2
4
NA
NA
NA
NA
NA
2
NA
NA
5
NA
NA
9
1
NA
125
175
O’Shaughnessy et al4
Ibrahim et al5
75
43
NA
0
17
0
NA
0
NA
NA
260
300
Gradishar et al6
Ibrahim et al5
229
63
24
7
11
11
0
NA
0
NA
Dose
(mg/m2)
80
175
Study
6
200
210
250
Infusion
every
Infusion
every
Docetaxel
ABI-007 (polyoxyethylated castor
oil–free paclitaxel)
over 24 hours
3 weeks
over 1 hour
3 weeks
Infusion over 30 minutes
every week
Infusion over 30 minutes
every 3 weeks
Sensory
Motor
Abbreviation: NA, data not available.
aggregation without degenerative changes in peripheral nerves40; microtubules aggregated first in Schwann cells and then in axons. Finally,
systemic paclitaxel injection of rats induced microtubules accumulation in Schwann cells and axons but caused minimal damage to their
sciatic nerve.41 Microtubule aggregation was not observed in sural
nerve biopsies from patients with MTSA-induced neuropathy.42,43
Thus, the mechanism of MTSA-induced neuropathy remains unclear.
INCIDENCE AND RISK FACTORS OF
MTSA-INDUCED NEUROPATHY
The incidence of MTSA-induced PN depends on risk factors including dose per cycle, treatment schedule, duration of infusion, cumulative dose, and comorbidity such as diabetes. Associations between
these risk factors and the incidence of MTSA-induced PN have been
confirmed in clinical trials, as discussed below.10-12,44 Although the
clinical response of tumors to a specific MTSA is the most important
reason to select a chemotherapy regimen, it is also prudent to evaluate
the risk of developing PN associated with each chemotherapy regimen, especially for patients already at high risk of neuropathy.
Dose per Cycle
The incidence of PN depends on the dose of MTSA per treatment cycle. In a randomized study of paclitaxel in breast cancer, severe
1634
PN (WHO grade 3 or 4) was observed in 7% of patients receiving
paclitaxel at 175 mg/m2 but in only 3% of patients receiving paclitaxel at 135 mg/m2.44 In the Cancer and Leukemia Group B
(CALGB) 9342 trial, grade 3 or 4 sensory PN was observed in 33%
of patients receiving paclitaxel at 250 mg/m2 (n ⫽ 149), in 19% of
patients receiving paclitaxel at 210 mg/m2 (n ⫽ 152), and in 7% of
patients receiving paclitaxel at 175 mg/m2 (n ⫽ 150; P ⫽ .0001).10
In a phase II trial of breast cancer, grade 3 or 4 sensory PN was
observed in 4% of patients receiving ABI-007 at 100 mg/m2 weekly
(n ⫽ 106) and in 17% of patients receiving ABI-007 at 125 mg/m2
weekly (n ⫽ 75).4
Treatment Schedule
There is a significant difference in the incidence of PN depending
on treatment schedules. In the phase III CALGB 9840 trial of breast
cancer comparing paclitaxel 80 mg/m2 weekly (n ⫽ 234) with paclitaxel 175 mg/m2 every 3 weeks (n ⫽ 230), grade 3 or 4 sensory PN
occurred in 19% of patients in the weekly infusion group and in 12%
of patients in the every 3 weeks group (P ⫽ .001).11
Duration of Infusion
Polyoxyethylated castor oil– based paclitaxel can be infused over
1 hour, 3 hours, or 24 hours. Mielke et al45 reported the pharmacodynamic effect of paclitaxel on the development of PN. There was no
difference in the development of PN between the 1-hour and 3-hour
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Microtubule-Stabilizing Agents and Neuropathy
Table 2. Incidence of Peripheral Neuropathy in Patients Treated With Epothilones
Grade 3 or 4 Severe
Neuropathy
Drug
Ixabepilone (BMS-247550)
Patupilone (EPO906)
Epothilone D (KOS-862)
No.
%
No.
%
Low et al20
37
1
3
0
0
Zhuang et al21
54
2
4
0
0
2.5
Galsky et al
Thomas et al23
Roche et al24
Hussain et al25
Eng et al26
Hussain et al27
47
42
38
42
25
45
6
NA
NA
7
5
0
13
7
16
17
20
0
NA
NA
NA
1
NA
0
NA
NA
NA
2
NA
0
120 (40 mg/m2/d ⫻ 3)
Piro et al28
10
1
10ⴱ
NA
NA
100
Yee et al29
Overmoyer et al30
Piro et al28
Piro et al28
Mekhail et al31
35
10
10
10
17
0
1
0
3
2
0
10
0
30ⴱ
12
NA
NA
NA
NA
1
NA
NA
NA
NA
6
Treatment Schedule
Infusion over 1 hour
daily ⫻ 5 every 3
weeks
Infusion over 3 hours
every 3 weeks
Infusion over 5 minutes
every week
Infusion over 1 hour
daily ⫻ 3 every 3
weeks
Infusion over 90 minutes
every week
Infusion every 3 weeks
BMS-310705
No. of
Assessable
Patients
2
Infusion over 15 minutes
every 3 weeks
Dose (mg/m )
Study
30 (6 mg/m2/d ⫻ 5)
22
35
40
120
150
40
Sensory
Motor
Abbreviation: NA, data not available.
ⴱ
Cognitive abnormality.
infusion of polyoxyethylated castor oil– based paclitaxel 100 mg/m2.
There was no significant difference in the peak concentration of total
paclitaxel, unbound paclitaxel, and polyoxyethylated castor oil between patients with and without PN. However, the duration of the
time of total paclitaxel above the concentration of 0.05 ␮mol/L
(ⱖ 10.6 hours) was the most important pharmacokinetic risk factor
for the development of PN (relative risk ⫽ 18.43; P ⫽ .036).
In the National Surgical Adjuvant Breast and Bowel Project B-26
trial of breast cancer, grade 3 or 4 PN was observed in 22% of patients
receiving a 3-hour infusion of paclitaxel (250 mg/m2/cycle; n ⫽ 279)
and in 13% of patients receiving a 24-hour infusion (n ⫽ 284).12 In a
randomized phase III trial of paclitaxel (135 or 175 mg/m2) in patients
with ovarian cancer, there was no significant difference in the incidence of grade 3 or 4 PN between the 3-hour (n ⫽ 187) and 24-hour
(n ⫽ 204) infusion (0.7% v 0.6%, respectively).46
Cumulative Dose
The onset of PN generally depends on the cumulative dose of
MTSAs. In a randomized phase III study comparing docetaxel 100
mg/m2 every 3 weeks (n ⫽ 225) with paclitaxel 175 mg/m2 every 3
weeks (n ⫽ 224) in metastatic breast cancer, the mean cumulative
dose to onset of grade ⱖ 2 PN was 371 mg/m2 for docetaxel and 715
mg/m2 for paclitaxel.47 In patients treated with ixabepilone (every 3
weeks or daily ⫻ 5 every 3 weeks), the median onset of grade ⱖ 2 PN
occurred after five to six cycles.22,48
Other Risk Factors
Other risk factors may include diabetes mellitus, concurrent administration of cisplatin, or age with limited data. PN is a major
complication of diabetes mellitus, and grade 3 or 4 sensory neuropathy has been reported in diabetic patients with cancer who were
treated with high-dose paclitaxel.49,50 In a retrospective analysis of
paclitaxel-induced PN in 18 diabetic patients, neuropathic symptoms
were exacerbated in 50% of patients; these symptoms then worsened
in 11% of these patients to grade 3 neuropathy.51
Because platinum compounds induce PN, the possibility that
coadministration of platinum compounds increased the incidence of
MTSA-induced PN was examined in a phase III trial, in which 327
patients were randomly assigned either to paclitaxel (175 mg/m2) and
carboplatin every 3 weeks or to paclitaxel (175 mg/m2) and epirubicin
every 3 weeks. Results showed that grade 3 or 4 PN occurred in 2.5% of
patients in both groups.52 However, a smaller prospective analysis of
neurotoxicity of combined paclitaxel and cisplatin treatment in 21
patients with solid tumors found that patients with pre-existing neuropathy experienced more grade 3 or 4 PN earlier in the treatment and
at a lower cumulative paclitaxel dose (⬍600 mg/m2) than patients
without pre-existing neuropathy.53
Older patients are more prone to MTSA-induced PN. In a phase
II trial of paclitaxel (150 mg/m2 weekly), age was significantly associated with neurotoxicity during cycle 2 (P ⫽ .008).54 There has been
interest in various genetic predispositions for neuropathy, such as
Wlds (slow Wallerian degeneration gene) or CYP3A genotypes.55-59
ASSESSMENT OF MTSA-INDUCED NEUROPATHY
Clinical Assessment
Symptoms. Accurate information must be ascertained on the
onset, distribution, and severity of neuropathic symptoms and on
their interference of daily activities. Sensory neuropathy presents as
paresthesia, numbness, and pain in the feet and hands,60 with symptoms generally appearing in the toes and then in the fingers.61 Paresthesia occurs in distal lower extremities with a glove-and-stocking
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distribution and is most severe on plantar surfaces.62 The severity of
most symptoms is mild to moderate, and symptoms generally disappear on cessation of therapy.44,60,63 Acute tingling in fingertips and
toes may occur within 24 hours after paclitaxel infusion.62 Paroxystic
pain reaction seems mainly to involve muscles and bones of lower
extremities and usually occurs 2 to 4 days after paclitaxel infusion.64,65
Motor neuropathy is usually mild and presents as muscle weakness
such as foot drop or difficulty in climbing stairs.50,66 Fine motor skills
(eg, buttoning a shirt or putting on earrings) may be diminished.62
Physical examination. The first sign of sensory neuropathy is an
elevated vibratory perception threshold in distal extremities60 and is
often associated with loss of pain and temperature sensation.67 The
vibratory perception threshold increases more in feet than in hands.68
The sense of position is usually lost in grade 3 or 4 neuropathy.
MTSA-induced neuropathy is frequently manifested by decreased
deep-tendon and ankle reflexes.69 Motor neuropathy presents as muscle wasting, weakness, and fasciculation.
Neuropathy grading. Neuropathy is graded by subjective complaints of patients and physical examinations by clinicians. The most
widely used grading systems are the NCI Common Toxicity Criteria,70,71 Eastern Cooperative Oncology Group criteria,72 and WHO
criteria73 (Table 3). The use of subjective patient complaints to assess
neuropathy introduces large variations between assessments, and because clinical examinations depend on patient cooperation, this
method is not entirely objective.74,75 Although these grading systems
have been widely used, limitations result from intra- and interobserver
variation and from the inconsistent interpretation of components of
these grading systems (Table 4).76,77
Questionnaire
Certain chemotherapy-induced toxicities (eg, pain or discomfort) cannot be measured objectively but have a high impact on quality
of life (QOL) and treatment decisions. Questionnaires assess symptoms via patient-based measurements of chemotherapy-induced toxicities, and their analyses can help to determine the impact of such
toxicities on QOL.78 The Functional Assessment of Cancer Therapy–
Taxane system and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 are self-reporting
instruments that measure health-related QOL in patients receiving
chemotherapy.78,79 These questionnaires query physical, social, emotional, and functional well-being including neurologic symptoms.
These systems have been validated in randomized trials.80-84 Thus, a
questionnaire-based assessment of symptoms may be useful for measuring subjective MTSA-induced symptoms.
Quantitative Sensory Testing
Quantitative sensory testing (QST) is used to overcome interobserver discordance when assessing neurologic dysfunction. It measures the sensory threshold for a particular stimulus, such as vibration,
by delivering a stimulus many times at various intensities via a specific
algorithm.85 A prospective analysis of paclitaxel-induced neuropathy investigated the utility of QST to assess chemotherapy-induced
neuropathy.86 The most sensitive test of QST was the vibration threshold of great toes, but QST was less sensitive for diagnosis of PN than
clinical assessment.76,86 Although QST is relatively simple, noninvasive, and easily repeated, it may not have significant advantage to assess
MTSA-induced neuropathy.
Table 3. Peripheral Neuropathy Grading Systems
Type
Grade 1
Grade 2
Grade 3
Grade 4
Subjective weakness but no
objective findings
Mild objective weakness
interfering with
function but not
interfering with
activities of daily living
Objective sensory loss
or paresthesia
interfering with
function but not
interfering with
activities of daily living
Objective weakness interfering
with activities of daily living
Paralysis
Sensory loss or paresthesia
interfering with activities of
daily living
Permanent sensory loss
interfering with function
Symptomatic weakness
interfering with
function but not
interfering with
activities of daily living
Sensory alteration or
paresthesia interfering
with function but not
interfering with
activities of daily living
Severe paresthesias
and/or mild weakness
Absent DTRs; severe
paresthesias; severe
constipation; mild
weakness
Weakness interfering with
activities of daily living;
bracing or assistance to
walk (eg, cane or walker)
indicated
Sensory alteration or
paresthesia interfering with
activities of daily living
Life threatening; disabling
(eg, paralysis)
Intolerable paresthesias and/or
marked motor loss
Disabling sensory loss; severe
peripheral nerve pain;
obstipation; severe
weakness; bladder
dysfunction
Paralysis
70
NCI-CTC version 2
Motor
Sensory
Loss of DTRs or paresthesia
(including tingling) but not
interfering with function
NCI-CTC version 371
Motor
Sensory
WHO73
ECOG72
Asymptomatic, weakness on
examination/testing only
Asymptomatic; loss of DTRs
or paresthesia but not
interfering with function
Paresthesias and/or
decreased DTRs
Decreased DTRs; mild
paresthesias; mild
constipation
Disabling
Respiratory dysfunction
secondary to weakness;
obstipation requiring
surgery; paralysis
confining patient to
bed/wheelchair
Abbreviations: NCI-CTC, National Cancer Institute Common Toxicity Criteria; DTR, deep tendon reflex; ECOG, Eastern Cooperative Oncology Group.
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Microtubule-Stabilizing Agents and Neuropathy
Table 4. Assessment of MTSA-Induced Neuropathy
Category
Test
Comments
Clinical assessment
Questionnaire
Assessment of symptoms and clinical examination
FACT-G
Inter- and intraobserver variation
Objective assessment of
subjective well-being
Quantitative sensory testing
EORTC QLQ C30
Vibration threshold
Psychometric analysis
Monofilament test
The Jebsen Test of Hand Function
Electrophysiologic testing
The Grooved Pegboard Test
Nerve conduction study
Needle electromyography
Histologic examination
Sural nerve or peroneal nerve biopsy
Simple, noninvasive, and easily
repeated but less sensitive
than a clinical assessment
Overall evaluation of neurologic
function
Needs validation in
chemotherapy-induced
neuropathy
Objective evidence of
neuropathy
Needs more study for
sensitivity and specificity
Confirmative but invasive and
permanent nerve damage
Abbreviations: MTSA, microtubule-stabilizing agent; FACT-G, Functional Assessment of Cancer Therapy–General; EORTC QLQ C30, European Organisation for
Research and Treatment of Cancer Quality of Life Questionnaire C30.
Psychometric Analysis
Psychometric analyses measure overall neurologic dysfunction
and have been used to assess neurologic dysfunctions, including diabetic PN. The Semmes-Weinstein monofilament test measures the
touch sensation on extremities with monofilaments.87-89 The Jebsen
Test of Hand Function assesses daily activities requiring use of hands,
such as writing.90,91 The Grooved Pegboard Test measures hand-eye
coordination by assessing how efficiently patients handle grooved
pegs.92-94 We evaluated the ability of these psychometric tests to predict MTSA-induced PN in the NCI ixabepilone phase II clinical trial of
47 patients with breast cancer.48,95 Our preliminary analyses indicated
that results from psychometric tests, especially the Jebsen Test of Hand
Function and Grooved Pegboard Test, have significant utility for
prediction of development of ixabepilone-induced PN.48 Because
these tests have not been evaluated in chemotherapy-induced PN,
they need to be validated in a large prospective trial.
Electrophysiologic Testing
Nerve conduction study (NCS) and needle electromyography
(EMG) are also used to objectively assess PN. Axonal neuropathy is
identified by NCS as a low compound muscle action potential and by
needle EMG as fibrillation; pure demyelinating neuropathy is identified by NCS as slow conduction velocity and prolonged distal latencies
and by needle EMG as no fibrillation or positive sharp wave activity.37
In paclitaxel-induced neuropathy, both axonal degeneration and demyelination patterns are possible on NCS,96 and frequently, sensory
nerve potentials of the sural nerve are reduced or absent.42,96
Docetaxel-induced PN showed low amplitude motor and sensory
potentials on NCS.61 Thus, although both tests seem to provide objective evidence of MTSA-induced neuropathy, additional studies are
required to determine their sensitivity and specificity.
Histologic Examination
Although histologic confirmation of MTSA-induced neuropathy
is desirable, a nerve biopsy may permanently damage the nerve fiber
sampled. Histologic examination of sural nerve or peroneal nerve
from patients with taxane-induced neuropathy have identified axonal
degeneration, reduced myelinated fiber density, and the loss of large
fibers.42,61,97 Paclitaxel and docetaxel induced similar histologic
changes. Although nerve biopsy is helpful for diagnosis of MTSAinduced neuropathy, the utility of this invasive procedure needs to be
further validated.
MANAGEMENT
No specific treatments for MTSA-induced PN are available. MTSAinduced PN generally improves when MTSA dose is reduced or MTSA
therapy is delayed or completed.61,98,99 Approximately half of the
patients with PN by polyoxyethylated castor oil– based paclitaxel experienced the improvement of PN within 9 months after cessation of
paclitaxel treatment.68 Grade 3 or 4 PN induced by ABI-007 improved
in a median 22 days after interruption of treatment.6 The median
interval to improvement of grade ⱖ 2 PN induced by ixabepilone was
46 days for the every-3-week schedule22 and 15 days for the daily ⫻ 5
every-3-week schedule.48
Management of MTSA-Induced Neuropathic Pain
Relief of paclitaxel-induced neuropathic pain by 10 to 50 mg of
amitriptyline has been reported.99 In addition, amelioration of
taxane-induced myalgia/arthralgia by gabapentin (300 mg tid for 2
days before and for 5 days after taxane infusion) was retrospectively
reported in six of 10 patients.100 Gabapentin 400 mg tid was also used
to relieve paclitaxel-induced severe myalgia.101 Thus, amitriptyline
and gabapentin may be helpful for the management of MTSAinduced neuropathic pain.
Neuroprotective Agents
Several types of neuroprotective agents have been tested for
MTSA-induced neuropathy in animal models and clinical trials.
Agents evaluated for potential neuroprotective effect in taxane-based
chemotherapy are listed in Table 5.
1637
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Table 5. Agents That Have Been Evaluated for Potential Neuroprotective Activity in Taxane-Based Chemotherapy
Agent
Amifostine (WR-2721)
BNP7787
Clinical Trial
No. of
Patients
Reference
Chemotherapy Used in the
Trial
Double-blind, placebo-controlled,
randomized phase II
Hilpert et al
102
72
Paclitaxel/carboplatin
Randomized phase II
De Vos et al36
90
Paclitaxel/carboplatin
Randomized phase III
Lorusso et al103
187
Paclitaxel/carboplatin
Phase II
Randomized phase III
Double-blind, placebo-controlled
phase III
Randomized phase II
Phase II
Phase II
Phase II
Moore et al104
Sevelda et al105
Leong et al106
27
89
60
Paclitaxel/cisplatin
Paclitaxel/carboplatin
Paclitaxel/carboplatin/radiation
Gelmon et al107
Socinski et al108
Robinson et al109
National Institutes
of Health110
Takeda et al111
40
21
16
Paclitaxel
Paclitaxel/carboplatin
Paclitaxel
Treatment of paclitaxelinduced neuropathy
Paclitaxel/cisplatin
Phase I
Significant improvement
of sensory
neuropathy in
objective neurologic
assessment but no
difference in selfassessed symptoms
Significantly decreased
incidence of grade 2
sensory neurotoxicity
Significant reduction of
grade 3 or 4
neuropathy
No significant difference
No significant difference
No significant difference
No significant difference
No significant difference
No significant difference
Ongoing
Paclitaxel
Decreased incidence of
grade 2 or higher
neuropathy
Ongoing
Docetaxel/cisplatin
Ongoing
117
Paclitaxel/carboplatin
No significant difference
Bianchi et al115
25
Paclitaxel or cisplatin
Pilot study
Maestri et al116
27
Paclitaxel and/or cisplatin
Phase II
Stubblefield et
al117
46
Paclitaxel
Placebo-controlled, double-blind,
randomized crossover trial
Phase II
Jacobson et al33
36
Paclitaxel
Improved sensory and
motor neuropathy
grade
Improvement of
peripheral neuropathy
in 73% of patients
Significantly less
weakness, less loss
of vibratory
sensation, and less
toe numbness than
controls
No significant difference
Vahdat et al34
45
Paclitaxel
Vitamin E
Randomized
Argyriou et al118
31
Paclitaxel and/or cisplatin
Lamotrigine
Randomized, placebo-controlled,
double-blind phase III
National Institutes
of Health119
Phase III
Dimesna
Randomized phase II
AM424 (rhuLIF)
Randomized, double-blind,
placebo-controlled phase II
Phase II
Acetyl-L -carnitine
Glutamine
National Institutes
of Health112
National Institutes
of Health113
Davis et al32,114
AM424. Recombinant human leukemia inhibitory factor (ie,
AM424) is a cytokine with neuroprotective effects that induces gene
expression, proliferation, and regeneration of neurons.32 In a randomized, double-blind, placebo-controlled phase II trial of 117
patients with solid tumors who were treated with combination
chemotherapy of carboplatin and paclitaxel (175 mg/m2),32
AM424 did not prevent significant PN as measured by standardized composite peripheral-nerve electrophysiology and by the vibration perception threshold.
Amifostine. Amifostine is an inorganic thiophosphate, a prodrug of free thiol (WR-1065), that may act as a scavenger of free
1638
22
Overview of Results
Paclitaxel or other neurotoxic
chemotherapy
Significant reduction in
the severity of
peripheral neuropathy
Reduced incidence of
neurotoxicity
Ongoing
radicals.107,120 In a randomized, nonblinded, phase II study of paclitaxel (250 mg/m2 every 3 weeks) in breast cancer, there was no significant difference in neurotoxicity between patients receiving (n ⫽ 20)
or not receiving (n ⫽ 20) amifostine (910 mg/m2).107 Although there
are several randomized trials studying the neuroprotective effect
of amifostine in patients receiving paclitaxel and carboplatin, the
neuroprotective effect of amifostine has not been proven because
of conflicting study results.36,105,121 The 2002 American Society of
Clinical Oncology practice guideline122,123 stated that “there are no
data to support the use of amifostine for prevention of paclitaxelassociated neurotoxicity.”
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Microtubule-Stabilizing Agents and Neuropathy
Disodium 2,20-dithio-bisethanesulfonate (BNP7787). BNP7787
is reduced to mesna (sodium 2-mercaptoethanesulfonate) in the kidney and liver.124-126 Although the mechanism of neuroprotective effect of BNP7787 in MTSA-induced neuropathy is unclear, a phase I
trial found that BNP7787 substantially reduced the overall incidence
of grade ⱖ 2 paclitaxel-induced neuropathy.111 BNP7787 is currently
being evaluated as a neuroprotective agent for paclitaxel-induced neuropathy in a phase III trial of patients with metastatic breast cancer.112
Glutamine. Glutamine has ameliorated paclitaxel-induced neuropathy in an animal model.127 In a double-blind, randomized, crossover trial of 36 patients receiving glutamine 10 g tid orally for 5 days
with paclitaxel (ⱕ 175 mg/m2), glutamine intake did not affect the
development or severity of paclitaxel-induced myalgias and arthralgias.33 When tested in a high-dose paclitaxel protocol (825 mg/m2),34
in which 33 control patients did not receive glutamine but 12 patients
received glutamine 10 g tid orally for 4 days after completion of
paclitaxel infusion, patients treated with oral glutamine, compared
with patients not treated with glutamine, developed less moderate to
severe dysesthesias (8% v 40%, respectively; P ⫽ .047) and numbness
in the fingers (33% v 73%, respectively; P ⫽ .016), comparing pre- and
postpaclitaxel treatment measurements. However, this finding needs
to be validated in randomized placebo-controlled clinical trials.
Vitamin E. Treatment with vitamin E may reduce neurotoxicity, especially cisplatin-induced neurotoxicity.128,129 A randomized
controlled trial for prophylaxis against chemotherapy-induced neuropathy118 randomly assigned 16 patients to vitamin E 300 mg (⬵ 450
U) bid during chemotherapy (cisplatin, paclitaxel, or combination of
cisplatin and paclitaxel) and up to 3 months after its completion and
assigned 15 patients to no supplementation. Vitamin E supplementation was associated with significantly lower incidence of neuropathy
(all grades) compared with no supplementation (25% v 73.3%, respectively; P ⫽ .019). Although there is a report regarding the harmful
effects of high-dose vitamin E (ⱖ 400 U/d), data regarding both risks
and benefits of vitamin E supplementation for MTSA-induced PN are
still preliminary.130
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Gabapentin has been shown to provide relief of symptoms such as
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FUTURE DIRECTIONS
Because understanding the exact mechanism of MTSA-induced neuropathy is essential for its management and prevention, reliable in
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developed. Current neuropathy grading systems should be consolidated into a reliable system so that neurotoxicity data from different
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effective neuroprotective agents should be developed to prevent
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■ ■ ■
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: James J. Lee, Sandra M. Swain
Provision of study materials or patients: James J. Lee, Sandra M. Swain
Collection and assembly of data: James J. Lee, Sandra M. Swain
Data analysis and interpretation: James J. Lee, Sandra M. Swain
Manuscript writing: James J. Lee, Sandra M. Swain
Final approval of manuscript: James J. Lee, Sandra M. Swain
1642
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Copyright © 2006 by the American Society of Clinical Oncology. All rights reserved.