ResearchGate

Management of paclitaxel-
induced neurotoxicity

Oleh:
dr. Puspita Sari
Peserta PPDS Obstetri dan Ginekologi
 ABSTRACT

Paclitaxel exerts its antitumor activity by promoting microtubule assembly and stabilizing microtubules.
Microtubules are important for the development and maintenance of neurons. As a consequence, neurotoxicity is
one of the drug’s major side effects. The risk of neurotoxicity depends on dose, duration and schedule of
paclitaxel. Risk increases for patients with pre-existing conditions that may cause neuropathy (such as alcohol
consumption, diabetes, or renal disease) or with simultaneous or prior exposure to other neurotoxic
chemotherapy such as platinum-based drugs, vinca alkaloids, immunomodulators, proteasome inhibitors, and
epothilones.

Patients with paclitaxel-induced neurotoxicity (PINT) experience a constellation of symptoms over the
course of treatment and beyond, ranging from mild to severe. Typically, the clinical presentation reflects an
axonal peripheral neuropathy with glove-and-stocking distribution sensory loss, combined with features
suggestive of nerve hyperexcitability including paresthesia, dysesthesia, and pain.

Proprioceptive and motor effects become apparent as neuropathy becomes more advanced. These
symptoms may be prolonged, severe, disabling, relatively resistant to intervention and adversely affect activities
of daily living and thereby quality of life. Management is mainly symptomatic and supportive. Despite attempts to
minimize PINT with changes in dose, vehicle, delivery systems, infusion schedule and premedication or co-
treatment with neuroprotective agents, PINT remains dose-limiting in many instances and is a barrier to achieving
the desired clinical response.
 Introduction

Case scenario: A 69-year-old white man with prior history of coronary artery
bypass grafts and stroke was diagnosed with adenocarcinoma of the esophagus,
metastatic to liver. Examination was unremarkable, except for liver edge
palpable 3 cm below the right costal margin. Neurological exam was normal. The
patient was started on cisplatin 60 mg/m2 and paclitaxel 180 mg/m2 every 2
weeks as palliative chemotherapy. He noted muscle pain and cramping and some
joint pain after the first course. These symptoms continued with further courses,
but would resolve after 3–4 days of last dose of chemotherapy in each cycle.
 Introduction

By the fourth course, some persistence of the muscle pain was noted, as
was severe fatigue. Because of a good radiological (diameter of liver mass
decreased from 8 to 6.3 cm) and clinical response, chemotherapy was continued.
After the fifth course (900 mg/m2 paclitaxel), the patient developed a foot drop
on the left side. He was referred to neurology. Examination revealed unsteady
gait, absent Achilles reflex on left and distal weakness in both lower extremities.
Upper extremity examination was normal except for bilateral decreased arm
swing. EMG and nerve conduction studies showed severe sensorimotor
peripheral and axonal neuropathy, worse on the left.
 Introduction

Workup for paraneoplastic syndrome was negative. Serum protein

electrophoresis, serum B12, serum calcium, and bone scan were normal. The
patient was started on gabapentin and low-dose prednisone. Chemotherapy was
changed to weekly cisplatin and irinotecan contemplating paclitaxel as the cause
of neuropathy.

However, after two weekly doses of chemotherapy the joint pains and
weakness worsened and chemotherapy was changed to docetaxel
and capecitabine. Further neurological deterioration was noted. The patient
arrived in a wheelchair, the foot drop was worse, and he had developed burning
pain, numbness and tingling in the feet bilaterally along with pedal edema.
Romberg was abnormal, and the gait was wide based, and ataxic.
 Introduction
MRI of the brain was negative for metastatic disease. Gabapentin and prednisone
were stopped, and he was prescribed a four wheel walker. Chemotherapy was
discontinued. He developed deep vein thrombosis in the lower extremities
bilaterally and was treated with enoxaparin.

Physical and occupational therapy were started, and pain control improved.
Imaging showed stable disease. After 2 months of stable disease, the imaging
results revealed progression of cancer.

Patient was started on capecitabine and irinotecan, but developed severe nausea,
vomiting and diarrhea necessitating a dose reduction of the irinotecan.
 Introduction

Approximately 4 This case

Capecitabine and
months after the illustrates a
irinotecan were
PET/CT showed stable last chemotherapy severe course of
reinitiated. However,
disease after four dose, imaging PINT, likely
the patient’s disease
courses, so chemotherapy showed exacerbated
continued to progress
was discontinued. progressive by concurrent
despite palliative
Neuropathy continued to disease with platinum
radiation to the
improve. multiple chemotherapy
esophageal mass and and/or previous
metastases in the
the patient expired.
liver. stroke.
 Introduction
Paclitaxel, a taxane originally derived from the bark of
the western yew tree Taxus brevifolia, has a wide range of activity against several
tumors including carcinoma of the ovary, breast, lung and head and neck.

Neurotoxicity is its major non-hematologic toxicity. With the widespread use of growth
factors for hematologic toxicity and anti-allergic cocktails for hypersensitivity
reactions, neurotoxicity has ssumed great importance as the dose-limiting side effect
with paclitaxel-based regimens.

The paclitaxel-induced neurotoxicity (PINT) is widely reported in various controlled

and uncontrolled trials, but the exact incidence and prevalence as well as the
proportion of patients with persistence or resolution of PINT following treatment are
not known.
 Introduction

The assessment of neurologic toxicity has been conducted differently among the studies in terms of
diagnostic approaches, grading and severity assessment.

The number of patients included in the studies and reporting methodologies have varied. The
frequency and severity of neurologic manifestations have been influenced by dose and schedule
of paclitaxel and prior and/or concomitant therapy with neurotoxic agents, especially cisplatin
and carboplatin.

The most common neurotoxicity is sensory peripheral neuropathy. Motor neuropathy and
autonomic neuropathy are also reported. Other, less common manifestations of PINT include
perioral numbness, seizures, transient encephalopathy, vocal cord paralysis, facial nerve palsy,
and phantom limb pain
 Pathogenesis
The survival and function of
Paclitaxel binds to and
peripheral nerves require
stabilizes tubulin, thereby
The underlying microtubules to mediate
inhibiting microtubule
pathophysiologic mechanism active transport of proteins
disassembly, which
of PINT has and other components along
results in cell-cycle arrest at
not been fully elucidated. long axons from a neuron’s
the G2/M phase and cell
cell body to its distal
death.
synapses

As a result a
Paclitaxel treatment likely
‘‘dying back’’ process starts
interrupts this active axonal
from distal nerve endings
transport and disturbs
cytoplasmic followed by effects on
Schwann cells and the
flow in the affected neurons
neuronal body
 Pathogenesis
Important targets of Unlike the CNS, dorsal
paclitaxel are dorsal root This allows the diffusion of
root ganglia and peripheral large molecular
ganglia and large afferent and
axons lack an efficient
efferent axons, located weight compounds from the
neurovascular
outside of the central nervous surrounding interstitium.
system (CNS) barrier.

Both protein bound and

unbound paclitaxel can gain
direct access to the epineurium
and readily diffuse along the
nerve fascicles, a process that is
facilitated by the hydrostatic
pressure gradient
The endoneural fascicles lack
lymphatics, which further limits
removal of drug from the
fluid.
 Pathogenesis
Paclitaxel is a hydrophobic Experimental data
drug that requires a vehicle indicates that cremophor
Cremophor is responsible
for solubilization; the most concentrations associated
for the hypersensitivity
commonly used with therapeutic doses of
reactions associated with paclitaxel produce axonal
preparation
Taxol and has also been swelling, vesicular
(Taxol) is composed of degeneration, and
implicated in neurotoxicity
cremophor and dehydrated demyelination in rat dorsal
ethanol. root ganglia

Approximately 25% of
Neurotoxicty has also been patients receiving intravenous
seen with intravenous cyclosporine (with
cyclosporine dissolved in cremophor)
cremophor, further
develop neurotoxicity, but
supporting a causal rarely does this occur with
relationship. oral formulations (which do
not contain cremophor)
 Clinical manifestations

• The most common neuropathy seen with paclitaxel treatment is sensory peripheral
neuropathy.

• The clinical manifestations are subjective: progressive distal symmetric numbness,

tingling, ‘‘pins and needles’’, burning, decreased or altered sensation, or increased
sensitivity that may be painful in hands or feet. The clinical findings of paresthesia,
hypoesthesia, hyperesthesia and dysesthesia appear earlier with more pronounced
symptoms in the toes and feet, and later involvement of fingers and hands in a
stocking-glove distribution
 Clinical manifestations

• Sensory findings include diminished or absent proprioception, vibration,

touch twopoint discrimination, sharp/dull discrimination, temperature
and touch/pain in symptomatic patients.

• Neurosensory symptoms may progress with additional treatment, and in

some cases may manifest with concurrent loss of deep tendon reflexes
(loss of distal usually earlier than proximal) in the affected extremities
and gait unsteadiness with eyes closed or in the dark.
 Clinical manifestations

• Symptoms of motor weakness due to PINT are less commonly reported,

and, when present, are observed in patients with more persistent and
severe sensory findings

• Isolated motor weakness with the complete absence of sensory

symptoms has not been reported, and should prompt evaluation for
other conditions, such as steroid myopathy, recall with prior use of
vincristine, Eaton–Lambert syndrome, diabetic motor neuropathy,
cachexia with decreased activity level, paraneoplastic motor neuropathy,
and unmasked Charcot–Marie–Tooth disease.
 Clinical manifestations

• In some patients it is challenging to differentiate PINT from distal

symmetrical neurosensory changes that are associated with paraneoplastic
syndromes, diabetes, or toxic/metabolic neuropathies.

• Careful evaluation of the time course with comparison to baseline and new
findings remains the cornerstone of diagnosis. Asymmetric, focal or proximal
involvement or complete loss of sensation indicates other etiologies. Diabetic
neuropathy poses the greatest diagnostic dilemma, since it has many
different clinical manifestations. Its most common form, distal symmetric
polyneuropathy, may be very similar to PINT. Appropriate neuroimaging tests
may also be indicated to rule out metastatic compressive myelopathy.
 Clinical manifestations

• The onset of PINT occurs commonly after several cycles of chemotherapy and is
usually gradually progressive. Some patients experience rapid onset of symptoms
as early as 24–72 h after administration of high single doses of paclitaxel.

• Mild symptoms may improve or resolve completely within several months after
discontinuation of therapy. Often patients with severe neuropathy have pain that
can be prolonged, severe, and relatively resistant to intervention. These symptoms
have a negative impact on quality of life, reducing activities of daily living and
exercise, hampering cancer treatment and recovery. Furthermore, neuropathy can
be so severe as to limit the dose of chemotherapy given, reducing the potential for
curative treatment in adjuvant settings.
 Clinical manifestations
Other serious neurologic events following
paclitaxel administration are rare (\1%) and
include grand mal seizures, syncope, ataxia,
headache, neuroencephalopathy
[18], and autonomic neuropathy resulting in
paralytic ileus
Optic nerve and/or visual disturbances (scintillating
scotomata) and ototoxicity (hearing loss and
tinnitus) have also been reported, particularly in
patients who have received higher doses than
those recommended
Risk-modifying factors

• The incidence of PINT depends on cumulative dose, dose per

treatment cycle, the schedule of treatment, duration of
infusion, and comorbidity such as diabetes.

• The onset of PINT generally depends on the cumulative dose

of paclitaxel. It usually occurs at cumulative doses in excess
of 1,400 mg/m2

• Despite the frequent improvement before the next

cycle, symptoms tend to increase after additional
cycles.
Risk-modifying factors

• The dose of paclitaxel per treatment cycle also affects the

incidence. In a randomized study of paclitaxel in breast cancer,
severe peripheral neuropathy was observed in 7% of patients
receiving paclitaxel at 175 mg/m2 but in only 3% of patients
receiving paclitaxel at 135 mg/m2

• In the Cancer and Leukemia Group B (CALGB) 9342 trial,

grade 3 or 4 sensory peripheral neuropathy 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 = 0.0001)
Risk-modifying factors

• There is a significant difference in the incidence of PINT depending on treatment

schedules. In the phase III CALGB 9840 trial of breast cancer comparing paclitaxel 80
mg/m2 weekly with paclitaxel 175 mg/m2 every 3 weeks, grade 3 sensory peripheral
neuropathy occurred in 21% of patients in the weekly infusion group and in 12% of
patients in the every 3 weeks group (P = 0.004)

• Paclitaxel scheduling changes have been evaluated in several clinical studies

in an effort to optimize therapeutic efficacy while minimizing toxicity.
• A higher incidence of PINT has been reported when paclitaxel is infused over
3 h as compared to 24 h. In the National Surgical Adjuvant Breast and Bowel
Project B-26 adjuvant trial in breast cancer, grade 3 or 4 peripheral
neuropathy was observed in 22% of patients receiving a 3-h infusion of
paclitaxel (250 mg/m2 per cycle; n = 279) and in 13% of patients eceiving a 24-h
infusion (n = 284)
Risk-modifying factors

• In order to minimize the toxicity of paclitaxel associated with the use of

cremophor, alternate delivery strategies free of cremophor have been utilized,
including biological approaches (oral administration), chemical approaches
(prodrugs, analogs) and pharmaceutical approaches (use of co-solvents,
emulsions, liposomes, cyclodextrins, microspheres, nanoparticles)

• These approaches decrease the incidence, severity and duration of

neurotoxicity. ABI-007 (Abraxane; American BioScience Inc, Santa
Monica, CA) is the most commonly used alternative option. It is a
novel, nanometer-sized albumin-bound paclitaxel particle initially
developed to avoid the toxicities associated with polyethylated
castor oil.
Risk-modifying factors

• Compared with paclitaxel, at equivalent doses, ABI-007 produced more

complete regressions, longer time to recurrence, longer doubling times, and
prolonged survival. In a randomized phase III trial Grade 3 sensory
neuropathy was more common in the ABI-007 260 mg/m2 intravenously
without premedication (n = 229) arm than in the standard arm of paclitaxel
175 mg/m2 intravenously with premedication (n = 225) (10 vs. 2%, respectively;
P\0.001) but was easily managed and improved rapidly (median 22 days)

• However, this incidence was substantially lower than that reported with
standard paclitaxel 250 mg/m2 in the CALGB trial (32% grade 3 sensory
neuropathy) . Therefore, at equivalent doses the neuropathy with ABI- 007 may
be less than with standard paclitaxel.
Assessment of severity and grading

• Diagnosing and grading PINT is challenging. First, patients often do not report painful
neuropathy during general pain screening, out of concern that the symptoms may necessitate
dose reductions of potentially life-saving chemotherapeutic medications. Second, oncology
practitioners may consider chemotherapy-related neuropathic pain as a minor, self-limited
problem.

• It is extremely important to include neuropathy and neuropathic pain assessment in routine

clinical practice as patients may not report symptoms without prompting. Certain toxicities
(e.g., pain or discomfort) cannot be measured objectively but have a huge impact on quality of
life (QOL) and decisions regarding modification, interruption, or discontinuation of treatment
with paclitaxel. Accordingly, a coordinated clinical approach involving patients, nursing and
medical staff must be taken that enables reliable, reproducible, and convenient assessment and
management of PINT (Fig. 1).
Assessment of severity and grading

• PINT is graded by subjective complaints of patients and objective assessments by clinicians.

Limitations result from intra- and inter-observer variation and from inconsistent interpretation
of components of these systems; see Table 1.

• The most widely used grading systems are the National Cancer Institute-Common Terminology
Criteria for Adverse Events (NCI-CTC AE) [34], Eastern Cooperative Oncology Group (ECOG)
criteria , and World Health Organization (WHO) criteria , listed in Table 2. More comprehensive
neuropathy-focused composite instruments have been developed such as Neuropathy
Symptom Score, Neuropathy Impairment Score and Total Neuropathy Score (TNS)
Assessment of severity and grading

• Scoring depends on patient cooperation, introducing subjectivity and the potential for large
variations between assessments. Some of these scales combine neuropathy signs and
symptoms into one grading category (e.g., reflexes and paresthesias in the NCICTCAE scale).

• This may under represent the severity, as the neuropathy is generally more severe if both
findings are present. Despite the problems, grading scales continue to be accepted in clinical
and research settings, because of their ease of use.
Assessment of severity and grading

• Questionnaires assess impact of symptoms from chemotherapy- induced toxicities on patients’

lives and functional status and hence QOL. The Functional Assessment of Cancer Therapy–
Taxane system and European Organisation for Research and Treatment of Cancer Quality of Life
Questionnaire C30 (EORTC QLQ C30) are self reporting instruments that measure health-related
QOL in patients receiving chemotherapy

• These questionnaires assess physical, social, emotional, and functional well-being including
neurologic symptoms. Some of these systems have been validated in randomized trials. Thus, a
questionnaire-based assessment of symptoms may be useful for measuring subjective PINT.
Objective tests are used to overcome inter-observer discordance. Quantitative sensory testing
(QST) measures the sensory threshold for a particular stimulus, such as vibration, by delivering
a stimulus many times at various intensities via a specific algorithm
Steps in the diagnosis and management
of paclitaxel-induced neurotoxicity
Steps in the diagnosis and management
of paclitaxel-induced neurotoxicity
Steps in the diagnosis and management
of paclitaxel-induced neurotoxicity
Steps in the diagnosis and management
of paclitaxel-induced neurotoxicity
Table 1 Tools to assess and grade paclitaxel-induced neurotoxicity
Table 2 Chemotherapy induced peripheral neuropathy grading systems
 Neuroprotective agents

Various attempts have been made to prevent toxic neuropathies by administration

of rescue drugs to allow for increased dose-intensity for paclitaxel. Such agents
must not reduce the antitumor activity of the antineoplastic therapy and/or alter the
agent’s pharmacokinetic profile.

Many agents have been proposed as neuroprotectants, including acetyl-L-carnitine ,

amifostine , glutamate , vitamin E, alpha lipoic acid , nerve growth factor , and
insulin like growth factor .

Although preliminary reports have been promising, general use of these agents
cannot be recommended because of inadequate clinical evidence to support their
use.
 Management and supportive care
No specific treatment for PINT
is available. Neuropathy
generally improves when
paclitaxel dose is reduced or
therapy is delayed or
completed
Approximately half of
the patients with peripheral Grade 3 or 4 peripheral
neuropathy by neuropathy induced by ABI-
polyoxyethylated 007
castor oil-based paclitaxel improved in a median 22 days
experienced improvement after interruption of
within 9 months after treatment
cessation of paclitaxel
treatment
 Management and supportive care
Relief of paclitaxel-induced
neuropathic pain by amitriptyline
has been reported

Gabapentin has been used

for amelioration of taxane-induced
myalgia/arthralgia

Topical therapy with capsaicin or lidocaine patches is

useful in some patients, especially those with more localized
pain or those in whom interactions with existing oral
medications is a concern.
 Management and supportive care

Other agents like duloxetine, pregabalin, carbamazepine, oxcarbazepine,

and opioids are used for symptomatic relief, but are not validated in clinical
trials.

Besides analgesia, benefits from these agents include improved sleep,

an altered perception of pain, and an increase in the pain threshold.

Some of these drugs have central and peripheral anticholinergic effects, and
require
careful evaluation of effectiveness and toxicity every 4–6 weeks to tailor the
treatment.
 Management and supportive care

A preliminary screen for

depression can be accomplished by asking two
In addition to pain, we must evaluate sleep and mood
simple questions: (1) During the past month,
by appropriate questionnaires. The triad of pain, sleep
have you often been bothered by feeling down,
disturbances, and depression/anxiety is inter-related.
depressed, or hopeless? and (2) During the
We should address each component of the triad in
past month, have you often been bothered by
order to restore patient to optimal functionality.
having little interest or pleasure in doing
things?
 Management and supportive care

Cancer rehabilitation is the most important aspect of the overall management of PINT and involves a
multidisciplinary team approach to assist the cancer patient to obtain maximal physical, social,
psychological, and vocational functioning within the limits created by the disease and its resulting
treatment.

Goals must be objective, realistic, and attainable in a reasonable time. Patients, family members, and
significant others must be active participants in goal setting.

This motivates the patients to comply with the management protocol. Periodic follow-up visits are
required to monitor neuropathic progression, as well as to assess functional deficits and the effectiveness
of other interventions (e.g. alcohol cessation, diabetic management, gait/balance training).
 Management and supportive care

Physical therapy is a useful adjunct, especially when muscular pain and weakness are a
manifestation of the patient’s neuropathy.

The aim is to enroll patient in an exercise program to maintain mobility and

strength. For patients with autonomic neuropathy, balance training and fall
prevention education is paramount.

Transcutaneous electrical nerve stimulation (TENS) is useful for neuropathic

pain, and physical therapists can be helpful in teaching and monitoring the
patient in its use.

Occupational therapy is necessary in cases where there is severe loss of functional

status. Functional restoration of limbs requires home modifications and adaptive
equipments.
 Conclusion
• As new cancer treatments using neurotoxic agents like paclitaxel ultimately prolong
life, the effect of chronic, disabling neuropathy will become even more apparent. There
is a need to develop a simple, clinically useful, and psychometrically sound
measurement tool that can be used by oncology nurses and physicians to assess
neuropathy and facilitate discovery of ameliorating interventions. Effective treatment
that addresses pain and comorbidities can enhance outcomes for patients with chronic
painful neuropathy. Even the most effective therapies may not provide complete pain
relief; in these cases a supportive program is a key to improvement in functionality and
quality of life. The effect of PINT on QOL should be studied extensively using well
validated, reliable instruments to enable treating physicians to formulate a treatment
plan that includes palliative, restorative, and supportive interventions.