Download 17- dr.hend hamdy neurotoxicity

Dr. Hend Hamdey Rashed
Lecturer of Clinical
oncology & Nuclear
medicine
Notes as regard CINC:
 Neurotoxicity
of chemotherapy is a common problem of many
antineoplastic agents and generally constitutes a dose-limiting side
effect.
 With the recent use of more aggressive treatment regimens and
prolonged survival of cancer patients, neurologic complications of
chemotherapy have been observed with increasing frequency.
 Neurotoxicities are usually temporary and resolve when the
treatment is stopped. But some are permanent and have lifelong
implications for a patient’s quality of life.
Neurotoxic adverse reactions may be recognized as both
acute and delayed treatment complications.
When two or more neurotoxic agents are used in
combination therapy, the neurotoxicity is likely to become
more profound.
Factors that put patients at higher risk for neurotoxicity
include:
1) High-dose therapy.
2) Diabetes mellitus.
3) Alcohol abuse.
4) Previous or concurrent use of other neurotoxic drugs.
Pathogenesis of neurotoxicity
Peripheral nervous system toxicity
Sensory axon damage →degeneration & dying back of axons and
myelin sheaths → damage of cell body.
Sodium channel dysfunction.
Central nervous system toxicity
Toxic metabolites.
Metabolic changes, end organ dysfunctions,fever, direct CNS drug
toxicity.
Commonly Used Anti-cancer Drugs
Causing Central Neurotoxicity
Ifosfamide
Methotrexate
Cisplatin
Capecitabine
Commonly Used Anti-cancer Drugs
Causing Peripheral Neurotoxicity
Platinum Agents (cisplatin, carboplatin,oxaliplatin).
Taxanes (paclitaxel, docetaxel, nanoparticle formulation of
paclitaxel).
Vinca alkaloids (vincristine, vinblastine, vinorelbine, vindesine).
Procarbazine, cytarabine, etoposide, alfa interferon.
Thalidomide, Lenalidomide.
Bortezomib.
Paclitaxel
 Stimulates the cellular microtubule assembly, causing neurotoxicity
by demyelination of nerve fibers and disruption of microtubules in the
neural tissue.
 Dose level and duration of infusion affect the incidence and severity
of neurotoxicity.
 Single doses of paclitaxel exceeding 175 mg/m2 are associated with
more profound neurotoxicity.
 Its main toxicity is a dose-limiting predominantly sensory peripheral
neuropathy with numbness, tingling, and pain, which occurs in
approximately 60% of patients receiving 200 mg/m2 of the drug.
 The neuropathy is reversible in most cases over the course of
several months in the absence of drug exposure.
 Some patients develop arthralgias and myalgias beginning 2–3 days
after a course of paclitaxel and lasting 2–4 days.
 Less commonly, paclitaxel can result in motor neuropathies that
predominantly affect proximal muscles.
 Vitamin E and N-acetyl carnitine may reduce the severity of the
neuropathy. Neuropathies are less common with docetaxel, but
some patients develop sensory and motor neuropathies similar to
paclitaxel.
 Because taxanes do not cross the blood–brain barrier to any
significant degree, CNS toxicities are rare.
Cisplatin
 Neurotoxicity associated with cisplatin administration results from
demyelination of nerve cells and damage to large fibers and injury to
the dorsal root ganglion. The peripheral nerve also will be affected.
 Cisplatin may cause ototoxicity, leading to high-frequency
sensorineural hearing loss and tinnitus. The toxicity is due to
peripheral receptor (hair) loss in the organ of Corti and is related to
dose.
 Cisplatin-related neurotoxicities may be dose-limiting, especially
with cumulative dosing. Neurotoxicities, which are most often seen
with a cumulative dose of 300 mg/m2 to 500 mg/m2.
Primarily affect the peripheral nervous system,
manifesting in subacute burning sensations and
numbness in toes and feet.
Symptoms usually begin distally in extremities and
then spread proximally to affect both legs and arms.
Proprioception is impaired and reflexes are frequently
lost. loss of Achilles tendon reflex (early), loss of deep
tendon reflexes (late), loss of ability to sense vibration,
and sensory ataxia.
Patients with mild neuropathies can continue to receive full
doses of cisplatin. After the neuropathy becomes more
severe and begins to interfere with neurologic function, the
clinician must decide whether to continue with therapy,
reduce the dose of drug, or discontinue the drug and replace
it with less neurotoxic agents.
After cessation of chemotherapy, the neuropathy continues
to deteriorate for several months in 30% of patients. Most
patients show improvement, although recovery may remain
incomplete.
There is no treatment for cisplatin neurotoxicity. Ethiofos,
amifostine, vitamin E and the ACTH analogue, partially
protect peripheral nerves from cisplatin neurotoxicity.
Oxaliplatin
 The occurrence of peripheral neuropathy is the dose-limiting toxicity , which may
occur in up to 50–90% of treated patients.
 Oxaliplatin CIPN has been characterized into two distinct clinical forms:
A) an acute form which is transient and predominantly sensory disturbances in 85% to
95% of patients, which may be precipitated or made worse by cold
exposure, can involve rapid onset within hours to days of treatment, and can
regress between treatment cycles but frequently recurs with further
treatment. Transient acute paresthesias and dysesthesias are seen in the
majority of patients during or immediately after the end of the infusion and
may be associated with muscular contractions of the extremities or the jaw.
TTT: it resolves within 24 hrs and calcium and magnesium supplementation have been
shown to be effective in treating and reducing the severity of neuropathic symptoms
B) A persistent sensory form CIPN that is gradually progressive, is
related to the total oxaliplatin dose, and characterized by sensory
paresthesias, dysesthesia, and hypoesthesias that can interfere with
daily activities and associated sensory ataxia and functional
impairment, similar to the neuropathy seen with cisplatin. This
type of neurotoxicity correlates with the cumulative dose of
oxaliplatin .
TTT: Both amifostine and carbamazepine have been shown to have
benefit
in
treatment
of
oxaliplatin-associated
neuropathy.
Oxcarbazepine, a structural analog of carbamazepine, has been
evaluated in a randomized trial, Other agents in studies include
glutathione, and glutamine.
 Neurologic symptoms and abnormalities are reported by up to 97%
of patients receiving oxaliplatin-based treatment.
 Approximately 13% to 28% of patients receiving oxaliplatin doses
ranging from 85 mg per m2 to 130 mg per m2 experienced severe
neurosensory adverse effects with functional impairment.
 Other reports on oxaliplatin-associated neurotoxicity include visual
disturbances, papilledema, facial paresthesias, seizures, and
posterior reversible leukoencephalopathy.
Vinca alkaloids
 Neurotoxicity is dose-limiting in the use of vincristine, which disrupts
the microtubules, causing degeneration and atrophy of axons.
 Risk factors include:
1)
Doses exceeding 2 mg/m2.
2)
Prior neuropathy.
 Vincristine-related neurotoxicity occurs primarily as peripheral nerve
damage and can include numbness or burning sensations in fingers, toes,
hands, and feet; paraparesis (lower extremity weakness); constipation;
orthostatic hypotension; urinary retention; loss of pain and temperature
sensation; myalgia; and arthralgia.
Cytarabine
 Cytarabine, given intravenously or intrathecally, is commonly associated
with neurotoxicities that include cerebellar dysfunction (most common),
generalized encephalopathy, peripheral neuropathy, and seizures.
 Risk factors include:
1) Doses exceeding 1 g/m2.
2) Age greater than 50 years.
3) Prior cytarabine therapy.
4) Renal dysfunction.
 Signs and symptoms of cerebellar toxicity are altered mentation,
headache, memory loss, somnolence and seizures. Peripheral
neuropathies can include paresthesia, but this is rare.
 Recovery from neurologic sequelae is usually complete within a few days
after cessation of treatment.
Methotrexate
 Methotrexate administered IV, orally,or IM in standard doses rarely
causes neurologic toxicities. But when standard doses are given
intrathecally, + or - brain irradiation, central nervous system
toxicities often occur.
 Risk factors include:
1) The presence of neoplastic cells in the spinal fluid .
2) Cranial irradiation.
3) Cumulative drug dose .
4) Concomitant
use
of
cytarabine,
sulfonamides or vinca alkaloids.
daunorubicin,
salicylates,
 Aseptic meningitis is the most common neurotoxicity
associated
with
intrathecal
methotrexate
therapy.The
incidence ranges from 10% to 50% of patients with evidence
of cumulative toxicity following multiple rounds of
intrathecal application. Symptoms and signs of CNS toxicity
usually begin 2–4 hrs after the drug is injected and may last
for several days. The syndrome is characterized by fever,
headaches, nuchal rigidity, back pain, nausea, vomiting, and
lethargy and is indistinguishable from other types of chemical
meningitis.
 The symptoms are usually self-limited and require no
specific treatment. While symptoms are self-limiting in most
patients, there have been reports of delayed necrotizing
leukoencephalopathy
several
months
after
treatment,
especially in patients receiving high cumulative doses of
intrathecal
methotrexate
combined
with
whole-brain
radiotherapy.
 Aseptic meningitis can be prevented to some extent by
injecting methotrexate with hydrocortisone or using oral
corticosteroids.
The axial MRI shows bihemispheric T2/FLAIR hyperintensities
with frontal and occipital accentuation after intrathecal
methotrexate injection in a 19-year-old male with acute myeloid
leukemia. The patient developed mental status changes and
confusion 1–2 hours after methotrexate injection.
 Transverse myelopathy, a much less common complication of
intrathecal methotrexate, is characterized by back or leg pain
followed by paraplegia, sensory loss, and sphincter dysfunction.
The symptoms usually occur between 30 min and 48 hrs after
treatment but may occur up to 2 weeks later. The majority of cases
show clinical improvement, but the extent of recovery is variable.
 The leukoencephalopathy usually occurs following repeated
administration of intrathecal methotrexate or high-dose intravenous
methotrexate, but has also been described after standard-dose
intravenous methotrexate. It is the major delayed complication of
methotrexate therapy. Symptoms include initial memory loss
progressing to severe dementia and seizures.
Leukoencephalopathy. A 75-year old woman with primary central nervous
system lymphoma was treated with CHOP, ten doses of intraventricular
methotrexate, Three years later, she noted moderate short-term memory
deficits and gait unsteadiness.
MRI (axial T2-weighted image) demonstrated extensive periventricular white
matter changes. The patient’s dementia progressed, and she developed rigidity
and mutism prior to her death one year later.
Clinical Diagnostic Features Of Chemotherapy-induced
Peripheral Neuropathy (CIPN)
 The onset of CIPN is gradually progressive, but some patients
have rapid onset or a sporadic pattern following administration of
neurotoxic chemotherapy.
 The diagnosis of CIPN must be distinguished from other
etiologies that may be confounding, such as:
 Paraneoplastic sensory neuropathy.
 Diabetic neuropathy.
 Toxic/metabolic neuropathies.
 This diagnostic differentiation is based on history and comparison
to baseline findings and the time course of new neurosensory
findings, recognizing that asymmetric, focal or proximal
involvement, or complete loss of sensation are indicative of other
etiologies
Diagnostic Approach To Chemotherapy-induced
Peripheral Neuropathy
1. System involvement: nature of symptoms
 Sensory: paresthesias, dysesthesias, hypoesthesia, burning,pain
 Motor: weakness, atrophy, gait, activities (specific)
 Combined sensory and motor
 Autonomic: diaphoresis, postural weakness,
anhydrosis,orthostatic
2. Distribution of symptoms
 Symmetrical
 Asymmetrical, focal, dermatomal
 Distal: stocking glove
 Proximal
 Combined proximal and distal
3. Presence or aabsence of upper motor neuron involvement
 Sensory deficit absent
 Sensory deficit present
4. Temporal onset and duration of symptoms:
 Acute (hours to days).
 Persistent.
 Waxing and waning.
 Temporal relation of preceding events, recent/prior.
 medication/toxin/venom/infection.
5. Medication history:
 Review medications: nononcology related and oncology
treatment related.
 Prior neurotoxic chemotherapy.
 Medication start/stop, duration, establish temporal relation to
symptoms.
6. Evidence of acquired or hereditary neuropathy
 Diabetes, renal disease, hypothyroid
 Prior history of neuropathy, alcohol
 Family history of neuropathy
 Skeletal deformities
7. Degree of symptom interference with activities of daily living
 Ambulation, use of hands, dressing, eating, driving,
sleeping,climbing stairs, others
 Do these symptoms interfere with your ability to perform daily
activities?
8. Neurologic examination (distal symmetric stocking glove)
Abnormalities in CIPN
 Neurosensory: light touch,pin,dull/sharp,vibration/proprioception
 Neuromotor: signs of atrophy, extensor/flexor muscle strength,
grip, gait
Treatment
 Numerous drugs have been used to try and prevent the neurotoxicity
developing, but the results have been mixed and no one agent has been
sufficiently successful to enter routine practice.
 If early signs of neuropathy appear then reducing the dose of the offending
drug or stopping it completely will usually help ease the problem, but
sometimes this is an unacceptable compromise of the treatment.
 The neuropathy resulting from both Vinca alkaloids and taxanes is
generally reversible, although it may take months after treatment to
disappear completely.
 With platinum compounds the picture is more mixed with the changes
sometimes being permanent, although usually with low to moderate doses
of the drugs there will be a recovery.
Finally,
The mechanisms of chemotherapy-related cellular neurotoxicity have
been studied in more detail in recent years, and it has become clear
that the cause of neurotoxicity is far more complex than simply toxic
effects on proliferating cells within the nervous system. Recognition
of neurologic complications is critically important for any oncologist
or neuro-oncologist in order to prevent irreversible injury, and to
distinguish chemotherapy related complications from metastatic
disease, radiation related toxicity, paraneoplastic disorders, or
opportunistic infections.