Chemotherapy induced peripheral neuropathy (CIPN)

Agents most commonly associated are: Platinum analogs, anti-tubulins (taxanes, vinca alkaloids, eribulin), proteosome inhibitors (Bortezomib), Immunomodulating agents (thalidomide, lenalidomide, pomalidomide,), and Some biologics (alemtuzumab, Ipilimumab, Brentuximab).

In a meta-analysis of 31 studies the aggregate prevalence of CIPN and was 48%.

Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide.

CIPN causes axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved.

Symptom onset can occur possibly within days for taxanes and platinums, to after several months with bortezomib.

Approximate incidence of CIPN: taxanes 60-70%, vinka alkaloids 20%, proteosome inhibitors 40-80%.

Recovery, in general, is partial with residual deficits in most patients.

Pain, numbness and tingling are most common sensory symptoms but motor weakness, autonomic dysfunction and even cranial nerve involvement may occur.

Can be painful and disabling, causing significant loss of functional abilities and decreasing quality of life.

CIPN can lead to chemotherapy dose reductions or discontinuation of treatment.

Risk factors include: dose per cycle, cumulative dose, treatment schedule, duration of chemotherapy infusion, administration of other neuropathic agents, comorbidities and pre-existing peripheral neuropathy.

Non-modifiable risk factors include: age, race, and genetics.

Modifiable risk factors include: diabetes, sedentary lifestyle, and high systemic chemotherapy exposure.

May be reversible or permanent.

Frequently compromises treatment plans.

Approximately 20-40% of patients with cancer who receive chemotherapy with neurotoxic agents will develop chemotherapy induced peripheral neuropathy.

Frequently associated with axonal degeneration.

Axonal degeneration may occur weeks to months after the initial exposure to the medication, and can continue after the withdrawal of the drug.

CIPN Is predominantly sensory axonal neuropathy with occasional motor and autonomic involvement.
Predominately sensory fibers are affected but some agents can cause a sensory-motor pattern.
Symptoms typically occur during the first two months of treatment, progress during active antineoplastic therapy, and usually stabilize soon after treatment is completed.

Some drugs like paclitaxel or oxaliplatinum are associated with worsening neuropathic syndromes after cessation of therapy.

Utilizing multiple neuropathic drugs increases the risk of peripheral neuropathy, as does cumulative doses of such drugs.

CIPN occurs in a dose dependent manner, usually after several cycles of neurotoxic anti-neoplastic therapy and is typically dependent on the administered single and cumulative doses, although duration of exposure, scheduling and combination therapy�s are also potential risk factors.

With some chemotherapeutic agents: platinum, vinca alkaloids, taxanes and thalidomide, cell bodies in the dorsal root ganglion are more vulnerable to neurotoxic damage due to less protecting blood brain barrier leading to sensory neuropathy..

The presence of preexisting peripheral neuropathy, such as diabetic neuropathy increases the of chemotherapy induced neuropathy.

Clinically the picture may be asymmetrical and predominately involve proprioception sense but does not exclude the motor system.
Concurrent exposure to other neurotoxic agents and pre-existing neuropathy as well as disease/deficiencies predisposing to neuropathy such as alcohol abuse, renal insufficiency, hypothyroidism, vitamin deficiency, HIV infection and autoimmune conditions.
Large sensory nerves are most commonly affected in CIPN by toxicity in a symmetrical length dependent manner.

Smoking increases the risk of long-term prevalent paresthesias.

Symptoms include numbness, tingling, pain, and can lead to difficulty with buttoning, tying shoes, or writing.

Symptoms are typically sensory and usually include: acral pain and paresthesias accompanied by dysesthesia, allodynia and hyperalgesia.
Sensory loss appears in a glove and stocking type pattern and leads to numbness in hands and feet including impaired perception to light touch, vibration sense, pin prick, and proprioception on examination.
Small fiber neuropathy affects nerve terminals of fibers involved in temperature and pain perception.
Small fiber neuropathy leads to painful sensation of burning feet and hands, and even lancinating pain, which can be potentiated by pin testing.
About 33% of patients with CIPN report burning, compared with 77% reporting severe numbness and tingling.
Clinically there is decreased pain perception and temperature sensation typical in painful areas.
Motor fiber involvement is associated with decreased or absent deep tendon reflexes or even distal weakness, atrophy of the small feet muscles, tremor, cramps or autonomic or cranial nerve symptoms can appear.
Autonomic involvement scene with small fiber damage with vincristine and bortezomib can lead to abdominal pain, constipation, postural hypotension, bladder disturbances, delay gastric emptying, and reduced variability of heart rate.

Can lead to difficulty in walking and balance.

Because cancer treatment has extended survival times for many patients, the long-term sequelae of CIPN has become increasingly important.

Painful neuropathy can persist for months to years after completion of chemotherapy, causing impaired function, and quality-of-life.

Most randomized controlled trials utilizing a variety of agents, with diverse mechanisms of action, have no efficaciousness.

In a randomized, double-blind, placebo controlled crossover trial among patients with painful chemotherapy induced peripheral neuropathy the use of duloxetine compared with placebo for five weeks resulted in a greater reduction in pain (Lavoie Smith EM et al).

Presentation is classically that of symmetric, predominately sensory, distal neuropathy in a stocking glove pattern.

Common presenting symptoms include: Paresthesias with burning, tingling and sharp pain, numbness with loss of sensation, and impaired balance.

Occasional patients may have more prominent motor symptoms, autonomic involvement, or cranial neuropathies.

There are no studies demonstrating that any agent is effective preventing CIPN.

While duloxetine, tricyclic antidepressants, Gabapentin, pregabalin may be offered to manage symptoms these agents have no effect on the motor symptoms or the negative sensory symptoms.

The only treatment in moderately recommended is duloxetine.

Early diagnosis enables dose adjustment to prevent worsening symptoms, and possibly avert irreversible nerve damage.

Prior to utilization of neurotoxic drugs patient should have screening for diabetes, vitamin deficiencies such as B12, pyridoxine intoxication, and thyroid abnormalities, with correction of underlying comorbidities.

Patient should undergo a baseline neurologic examination to demonstrate any sensory or motor abnormalities and document deep tendon reflexes.

The loss of Achilles tendon reflex is usually the first clinical sign of CIPN.

Nerve conduction studies and electromyograms can serve as a measurement of severity of peripheral nerve damage and can be used to prognosticate neurologic recovery.

Leave a Reply

Your email address will not be published. Required fields are marked *