Management of paclitaxel-

induced neurotoxicity

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Abstract
Microtubules are important for the The risk of neurotoxicity
Paclitaxel exerts its antitumor activity by
development and maintenance of neurons 
promoting microtubule assembly and depends on dose, duration and schedule
neurotoxicity is one of the drug’s major side
stabilizing microtubules of paclitaxel
effects

Risk increases : Patients with paclitaxel-induced neurotoxicity (PINT), the clinical

pre-existing conditions that may cause neuropathy,
prior exposure to other neurotoxic chemotherapy
such as platinum-based drugs, vinca alkaloids,
immunomodulators, proteasome inhibitors, and
epothilones
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.
Introduction
A 69-year-old white man with prior history
of coronary artery bypass grafts and stroke
was diagnosed with adenocarcinoma of the
60 mg/m2 and paclitaxel 180 mg/m2 every
esophagus, metastatic to liver, with
Neurological
exam was normal
The patient was started on cisplatin
2 weeks as palliative chemotherapy.
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. Chemotherapy was
changed to weekly cisplatin and irinotecan
contemplating paclitaxel as the cause of
neuropathy[[

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.
The most common neurotoxicity is
sensory peripheral neuropathy.
The assessment of neurologic toxicity
Motor neuropathy and autonomic
has
neuropathy are also reported.
been conducted differently among the
Other, less common manifestations of
studies in terms of diagnostic
approaches, grading and severity PINT include perioral numbness,
assessment seizures, transient encephalopathy,
vocal cord paralysis, facial nerve palsy,
and phantom limb pain
Pathogenesis

The survival and function of peripheral nerves require microtubules to mediate active transport of proteins and other components along long
axons from a neuron’s cell body to its distal synapses

Paclitaxel treatment likely interrupts this active axonal transport and disturbs cytoplasmic flow in the affected neurons

As a result a ‘‘dying back’’ process starts from distal nerve endings followed by effects on Schwann cells and the neuronal Body

Important targets of paclitaxel are dorsal root ganglia and large afferent and efferent axons, located outside of the central nervous
system (CNS)

Unlike the CNS, dorsal root ganglia and peripheral axons lack an efficient neurovascular barrier.
Paclitaxel is a hydrophobic drug that requires a vehicle for solubilization; the most commonly used
preparation (Taxol) is composed of cremophor and dehydrated ethanol. Cremophor is
responsible for the hypersensitivity reactions associated with Taxol and has also been
implicated in neurotoxicity

Experimental data indicates that cremophor concentrations associated with therapeutic

doses of paclitaxel produce axonal swelling, vesicular degeneration, and demyelination in
rat dorsal root ganglia

Neurotoxicty has also been seen with intravenous cyclosporine dissolved in cremophor,
further supporting a causal relationship. Approximately 25% of patients receiving
intravenous cyclosporine (with cremophor) develop neurotoxicity, but rarely does this
occur with
Clinical progressive distal symmetric numbness, tingling, ‘‘pins and needles’’, burning, decreased or altered sensation,
or increased sensitivity that may be painful in hands or feet.
manifestations

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

Sensory findings includediminished or absent proprioception, vibration, touch twopoint

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

Other serious neurologic events following paclitaxel administration are rare (\1%) and include grand mal
seizures, syncope, ataxia, headache, neuroencephalopathy
Risk-modifying factors

Paclitaxel scheduling changes have been evaluated in

The incidence of PINT depends on cumulative dose,
several clinical studies in an effort to optimize
dose per treatment cycle, the schedule of treatment,
therapeutic efficacy while minimizing toxicity. A higher
duration of infusion, and comorbidity such as
incidence of PINT has been reported when paclitaxel
diabetes.
is infused over 3 h as compared to 24 h.

Prior or simultaneous exposure to agents capable of

producing neuropathy such as platinum compounds,
vinca alkaloids, immunomodulators, proteasome
inhibitors, and epothilones may increase the risk of
PINT. Platinum compounds (cisplatin and carboplatin)
are commonly used with taxanes (paclitaxel and
docetaxel) in the treatment of ovarian and upper
aerodigestive tract cancer.
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
neuropathy by polyoxyethylated
castor oil-based paclitaxel experienced
improvement within 9 months after
cessation of paclitaxel treatment
Grade 3 or 4 peripheral neuropathy
induced by ABI-007
improved in a median 22 days after
interruption of 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

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