This document discusses chemotherapy-induced peripheral neuropathy (CIPN), a common adverse effect of cancer treatment that impacts quality of life. Certain chemotherapy agents are more likely to cause CIPN, including platinum drugs like cisplatin and oxaliplatin, taxanes, vinca alkaloids, and bortezomib. Cisplatin causes an axonal neuropathy by damaging dorsal root ganglia. Symptoms of cisplatin-induced neuropathy include numbness and paresthesia in the toes and fingers that spreads proximally. Paclitaxel and docetaxel cause predominantly sensory neuropathies, while vincristine affects both sensory and motor nerves. CIPN can force

1. CIPN

2. • Chemotherapy-induced peripheral neuropathy
(CIPN) is a common adverse effect of cancer
therapy that can have a profound impact on
quality of life and survivorship.
• Long-term neurotoxicity is an important issue for
the growing number of cancer survivors, with the
highest number of affected patients having been
treated for breast and/or colon cancer.
• CIPN may also adversely affect oncologic
outcomes by forcing dose modifications and/or
premature treatment discontinuation.

3. • The incidence of CIPN varies according to the
chemotherapeutic agent, dose, duration of
exposure, and method of assessment.
• The agents with the highest incidence are the
platinum drugs,
especially cisplatin and oxaliplatin, taxanes,
vinca alkaloids, and bortezomib.

4. • Cisplatin (and oxaliplatin (see 'Oxaliplatin' bel
ow)) enters into the dorsal root ganglion and
binds to nuclear and/or mitochondrial DNA,
causing apoptosis.
• There are two main mechanisms proposed to
explain the pathophysiology of platinum-
induced peripheral neuropathy:

6. CISPLATIN Peripheral neuropathy
• Symmetrical, predominantly sensory
peripheral neuropathy is a common
complication of cisplatin therapy that
develops in most patients typically only after a
cumulative dose of 300 mg/m2 is reached.
• Once established, there is no effective
therapy, and treatment is symptomatic only.
• Most patients improve over time, although
recovery is often incomplete.

7. • Cisplatin causes an axonal neuropathy that
predominantly affects large myelinated sensory
fibers.
• The primary site of damage is the dorsal root
ganglion, although the peripheral nerve may also
be affected.
• Neuropathy usually develops only after a
cumulative cisplatin dose beyond 300 mg/m2,
and at a cumulative dose of 500 to 600
mg/m2 almost all patients have objective
evidence of neuropathy, however, there is
marked interindividual variation in susceptibility

8. • Clinically, cisplatin-induced peripheral
neuropathy is characterized by the subacute
development of numbness, paresthesias
(abnormal sensations), and occasionally pain,
which usually begins in the toes and fingers,
spreading proximally to affect the legs and arms.
• The earliest observable sign is a decreased
vibratory sensitivity in the toes and loss of ankle
jerks.
• Although proprioception is impaired and reflexes
are lost, pinprick, temperature sensation, and
motor strength are usually spared, or less
severely affected. Autonomic neuropathies are
rare.

9. • More prolonged treatment may worsen symptoms and
signs with generalized loss of deep tendon reflexes,
and more proximal vibratory sensory impairment.
• Lhermitte's sign, a shock-like sensation of paresthesias
radiating from the back to the feet during neck flexion,
is occasionally observed, typically after weeks or
months of treatment.
• It has also been reported in patients receiving high
cumulative doses of oxaliplatin.
• Lhermitte's sign is believed to result from transient
demyelination of the posterior columns

10. • Even if cisplatin is discontinued, the neuropathy continues to
worsen for several months in 30 % of patients.
• Neuropathy may even begin after therapy is discontinued.
• It eventually improves in most patients, although recovery is often
incomplete.
• In a study of long-term testicular cancer survivors who had
completed treatment at least five years previously, peripheral
neuropathy was still present in 20 %, and 10 % were symptomatic.
• Higher levels of residual serum platinum, which can persist for years
after treatment, appear to correlate with the severity of long-term
peripheral neuropathy in cisplatin-treated survivors of testicular
cancer.
• In another report, factors that were related to a high risk for
persistent neuropathy included age at diagnosis, smoking history,
excess alcohol use, hypertension, and heritable factors

11. NCS
• Nerve conduction studies show sensory
axonal damage with decreased amplitude of
sensory nerve action potentials (SNAP) and
prolonged sensory latencies.
• Motor nerve conduction velocities and
compound muscle action potentials are
typically unchanged during treatment.
• On sural nerve biopsy, both demyelination and
axonal loss are evident.

12. • For some patients with platinum-induced neuropathy,
pain is a prominent symptom.
• Amelioration of symptoms from the chronic
neuropathy, including pain, may be achieved through
use of antidepressants such as duloxetine.
• For symptomatic patients who fail to respond to
duloxetine, other adjuvant analgesics (eg, tricyclic
antidepressants, anticonvulsants), opioids, physical
modalities such as cutaneous electrical stimulation,
and/or interventional procedures may be indicated.

13. CARBOPLATIN
• Peripheral neuropathy and central nervous
system (CNS) toxicity are uncommon
when carboplatin is given at conventional
doses.
• However, a severe neuropathy can develop
after higher than standard-dose carboplatin,
as used in the setting of high-dose therapy
with hematopoietic cell transplantation.

14. OXALIPLATIN
• Oxaliplatin is a third-generation platinum compound
used in the treatment of metastatic colorectal cancer.
• Acute neurosensory complex, which can appear during
or shortly after the first few infusions, and a cumulative
sensory neuropathy, with distal loss of sensation and
dysesthesias.
• Neuromotor toxicity is much less common.
• Rare manifestations of neurotoxicity include urinary
retention and Lhermitte's sign, which have been
reported in patients receiving high cumulative oxaliplatin
doses, Reversible posterior leukoencephalopathy is also
reported.

15. • Acute neurotoxicity — The majority of patients treated
with oxaliplatin (>85 % in two reports) experience
symptoms of acute neurotoxicity.
• Typical symptoms include discomfort swallowing cold
items; throat discomfort; sensitivity to touching cold
items; paresthesias and dysesthesias of the hands, feet,
and perioral region; and muscle cramps.
• Numbness and tingling are more prominent than
shooting or burning pain.
• Symptoms generally evolve over 24 to 96 hours, and
typically abate over the same time frame.

16. • In addition to muscle cramps, other motor
symptoms that may develop include jaw
tightness, voice changes, ptosis, visual field
abnormalities, and, rarely, priapism.
• One case report suggests that acute motor
symptoms may be particularly responsive to
treatment with oral pregabalin.

17. ●Cold-induced perioral paresthesias – 95 %
●Cold-induced pharyngolaryngeal dysesthesia – 92 %
●Dyspnea – 40 %
●Muscle cramps – 34 %
●Jaw stiffness – 34 %
●Dysphagia – 30 %
●Visible fasciculations – 30 %
●Voice changes – 6 %
●Ocular changes – 0.7 %

18. • Acute symptoms are observed more frequently at
doses of ≥130 mg/m2 than at ≤85 mg/m2 and are
infusion-rate dependent.
• Increasing the duration of infusion from two to six
hours during subsequent treatments has been
reported to diminish the incidence, particularly of the
pseudolaryngospasm.
• While it has been classically thought that acute
neuropathy completely resolves after a few days, more
recent data support the view that it does not
completely resolve between oxaliplatin doses, at least
with repeat dosing every two weeks.

19. • Symptoms tend to recur with subsequent
doses.
• On average, symptoms are twice as severe
after the second dose as compared with the
first dose; acute neurotoxicity does not appear
to worsen cumulatively over time.
• Patients with the most severe acute symptoms
are at higher risk to develop more severe
chronic neuropathy.

20. • Patients with diabetes do not necessarily have
a greater severity of peripheral neuropathy,
but that they develop it at a lower cumulative
dose of oxaliplatin.

21. TAXANES Paclitaxel and docetaxel
• Both are associated with a predominantly sensory
neuropathy, although paclitaxel appears to be more
neurotoxic than docetaxel (overall incidence of any
grade neuropathy 60 versus 15 %).
• In addition, severe (grade 3 or 4) sensory neuropathy is
much more common with paclitaxel than with
docetaxel.
• Motor neuropathy is uncommon with both agents, and
if it is significant, should prompt investigation of
another possible cause.
• The peripheral neuropathy associated with these drugs
may sometimes be confused with hand-foot syndrome
(acral erythema).

22. • Neurotoxic threshold for paclitaxel is 1000 mg/m2, while it
is 400 mg/m2 for docetaxeL.
• The mechanism of taxane-induced peripheral neuropathy
appears to be related to disrupted microtubules of the
mitotic spindle, which interferes with axonal transport,
macrophage activation in both the dorsal root ganglia and
peripheral nerve, as well as microglial activation within the
spinal cord.
• In addition, taxanes evoke a "dying back" process starting
from distal nerve endings followed by effects on Schwann
cells and other neuronal cells, which is an essential
microtubule-based process that moves cellular components
over long distances between neuronal cell bodies and
nerve terminals.

23. PACLITAXEL
• The most common neuropathy caused
by paclitaxel involves sensory nerve fibers.
• The major manifestations are burning
paresthesias of the hands and feet and loss of
reflexes.
• Risk factor is cumulative dose over time; the
neurotoxic threshold is approximately 1000
mg/m2 .
• However,the frequency and time to onset are
also proportional to dose.
• Patients treated with higher doses (≥250 mg/m2)
may develop symptoms after the first cycle

24. • Other risk factors for sensory neuropathy are
concurrent use of a platinum agent, older age,
history of diabetes mellitus, and possibly,
obesity and a lower activity level.
• Paclitaxel also causes a motor neuropathy,
which predominantly affects proximal
muscles.
• The incidence of grade 3 or 4 motor
neuropathy is between 0 and 14 %

25. less common manifestations of paclitaxel neurotoxicity include:
●Perioral numbness.
●Autonomic neuropathies (rare).
●Taxane-associated acute pain syndrome, which is characterized by
severe arthralgias and myalgias accompanied by numbness and
tingling, beginning within one to two days after treatment and
lasting a median of four to five days. Newer data support the view
that this is a form of an acute neuropathy, as opposed to a disorder
of joints and/or muscles. The incidence in patients treated with
unbound paclitaxel varies widely.
●Seizures.
●Transient encephalopathies.
●Phantom limb pain.

26. • The neurotoxicity of paclitaxel is synergistic
with that of concomitant platinum
administration.
• Other risk factors include preexisting
peripheral neuropathy and duration of
infusion (1 to 3 versus 24-hour infusions).
• Risk appears unrelated to older age

27. • There is substantial interindividual variability
in prevalence, severity, and onset of
peripheral neuropathy related to paclitaxel,
and there is some suggestion that inherited
polymorphisms or mutations in some genes,
including those associated with Charcot-
Marie-Tooth disease, and beta-tubulin;
CYP3A4 variants may also contribute

28. NCS
• Nerve conduction studies reveal a decrease of
sensory nerve action potentials (SNAP) or
absence of sensory responses, consistent with
axonal loss from sensory nerves;
• The sural nerve is particularly affected.

29. Dose and schedule
• The risk of sensory neuropathy is proportional to
dose.
• Grade 3 or 4 sensory neurotoxicity occurs in 20 to
35 % of patients receiving 250 mg/m2 every three
weeks compared with 5 to 12 % in large series using
doses ≤200 mg/m2 every three weeks.
• The time to onset was illustrated in a phase III trial
of patients with metastatic breast cancer treated
with paclitaxel (135 or 175 mg/m2) every three
weeks; the mean total dose at the onset of grade 2
neurotoxicity was 715 mg/m2

30. • Weekly paclitaxel is less myelosuppressive than
an every three-week schedule, thereby allowing
increased dose intensity.
• The effect of infusion duration on the incidence
of severe neurotoxicity is uncertain.
• The nanoparticle albumin-bound form
of paclitaxel was originally formulated to enable
lower doses and reduce toxicity, but peripheral
neuropathy still remains a significant treatment-
limiting toxicity.

31. DOCETAXEL
• Like paclitaxel, docetaxel causes both sensory and
motor neuropathies, although both of these
occur less frequently than with paclitaxel.
• Grade 3 or 4 neuropathies occur in 10 % or less.
• Treatment with docetaxel has also been
associated with the development of Lhermitte's
sign, a nonpainful but unpleasant electric shock-
like sensation that shoots down the spine during
neck flexion
• Neurotoxic threshold is approximately 400
mg/m2

32. • Docetaxel has also been associated with an
acute pain syndrome similar to that observed
with paclitaxel.
• The overall incidence, clinical pattern, and
time course appear to be the same.

33. VINCRISTINE
• Mechanism of action involves antimicrotubule
activity.
• The dose-limiting toxicity is an axonal
neuropathy resulting from disruption of the
microtubules within axons and interference
with axonal transport.
• The neuropathy involves both sensory and
motor fibers, although small sensory fibers are
especially affected.

34. • Virtually all patients receiving vincristine have
some degree of neuropathy.
• The earliest symptoms are usually paresthesias in
the fingertips and feet, with or without pain,
muscle cramps, and/or mild distal weakness.
• These symptoms often develop after several
weeks of treatment and after cumulative doses
between 30 and 50 mg, but they may occur after
the first dose.
• Furthermore, symptoms may appear even after
the drug has been discontinued and progress for
several months before improving

35. • Initially, objective sensory findings tend to be relatively
minor compared with the subjective complaints, but
loss of deep tendon reflexes, especially ankle jerks, is
common and develops early.
• Vibration perception is rarely more than mildly
affected.
• Occasionally there may be profound weakness, with
bilateral foot drop, wrist drop, and loss of all sensory
modalities.
• Neurophysiologic studies are compatible with a
symmetric primarily axonal neuropathy

36. • Severity is dose-related.
• Severe neuropathies are also particularly likely to
develop in older or cachectic patients, those who
have received prior irradiation to the peripheral
nerves or concomitant hematopoietic colony-
stimulating factors.
• Autonomic neuropathies are common in patients
receiving vincristine, and may precede
paresthesias or loss of deep tendon reflexes.
• Colicky abdominal pain and constipation occur in
almost 50 % of patients

37. • Vincristine may also cause focal
mononeuropathies, sometimes involving the
cranial nerves; the most commonly involved is
the oculomotor nerve.
• Other nerves that may be involved include
recurrent laryngeal nerve, optic nerve, facial
nerve, and auditory nerve.
• Vincristine may also cause retinal damage and
night blindness, and some patients may
experience jaw and parotid pain during
treatment.