Chemotherapy induced peripheral neuropathy (CIPN) is a common treatment related adverse effect that may affect long-term quality of life. It has the potential to result in chemotherapy dose reduction and/or delays or discontinuation.r It is often dose related and cumulative with symptoms commonly developing after several weeks of treatment, but may occur after the first dose.
Definition
Peripheral neuropathy is typically a symmetrical sensory neuropathy affecting the fingers and toes, and sometimes as treatment progresses may affect the hands and feet.
Pathophysiology
Peripheral neuropathy is a common complication of several classes of chemotherapy agents. Chemotherapy agents cause an inflammation, injury or degeneration of the peripheral nerve fibre(s) resulting in sensory, motor or cranial nerve dysfunction. The onset of symptoms can be sudden or progressive, and can range from mild to severe.
All chemotherapy agents can potentially cause irreversible symptoms, so it is important to identify symptoms early and adjust treatment accordingly. When symptoms are severe or irreversible, CIPN can lead to a serious decrease in quality of life and adverse clinical consequences for patients.
Incidence/prevalence
The incidence of CIPN varies according to the chemotherapy agent, dose, duration of exposure and method of assessment. It has been estimated that approximately 38% of patients treated with multiple agents experience CIPN.r
Commonly used agents causing peripheral neuropathy include the platinum-based compounds, taxanes, vinca alkaloids, thalidomide-derivatives and proteasome inhibitors. In addition, newer classes of anti-cancer drugs such as conjugated monoclonal antibodies e.g. ado-trastuzumab emtasine, brentuximab vedotin and immunotherapy agents e.g. check point inhibitors, are associated with CIPN. For more details on grading and management of immunotherapy related peripheral neuropathy see Management of immune-related adverse events (irAEs).
Onset/duration
| Drug class |
Onset and incidence |
Clinical pattern and recovery |
| Vinca alkaloids |
- Vinca alkaloids trigger neuropathy in about 20% of cancer patients. Note vincristine has a higher incidence of ~30–40% and usually appears at dose > 4 mg/m².r
- Cumulative and dose related; however may occur after first dose.
- Decreasing incidence and severity in this order: vinCRIStine > vinBLAStine > vinORELbine.
|
- Typical symptoms include lower limb weakness, sensory impairment, altered gait and diminished reflexes.
- Reversible and recovery may occur weeks to months after discontinuing therapy.
|
| Platinum compounds |
Cisplatin:
- cumulative and dose related, increases with doses > 300 mg/m²; however may occur after first dose.r
|
- Paraesthesia, numbness in a stocking-and-glove distribution mild sensory symptoms are commonr
- Usually reversible with dose reduction or treatment delay
- Symptoms may worsen for several months following the discontinuation of therapy, known as “coasting”.r
|
Oxaliplatin:
- cumulative and dose related, increases with doses > 800 mg/m².
- most patients report acute symptoms of sensory change and temperature sensitivity to cold exposure in the extremities and in the throat, peaking at day 3 following the infusion.
|
|
Carboplatin:
- uncommon when given at conventional doses.
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|
| Taxanes |
Paclitaxel:
- frequency and severity increase with cumulative doses; neurotoxic threshold ~1000 mg/m²r.
- dose related, e.g. for doses ≥ 250 mg/m², symptoms may develop after one cycle.r
|
- Paraesthesia, numbness and/or neuropathic pain in a stocking and glove distribution; myalgia, myopathy
- Usually improves within several months of discontinuing treatment, severe symptoms may persist for a longer period.
|
Nab paclitaxel:
- frequency is dose dependent.
- influenced by prior administration of neurotoxic drugs.
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- Usually improves more rapidly than paclitaxel (median 22 days).
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Docetaxel:
- cumulative and dose related, with neurotoxic threshold ~ 400 mg/m²r
- grade 3 or 4 neuropathies occur in 10% or less.
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Cabazitaxel:
- appears to have less cumulative toxicity, any grade is reported in 13-17% of treated patients, but fewer than 1% are severe.r
|
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| Epothilones |
Eribulin:
- reported that 25% of patients developed CIPN, most being grade 1 or 2, and the majority continuing eribulin after CIPN onset.r
|
- Symptoms are generally reversible, however can last beyond a year in approximately 5% of metastatic breast cancer patients.r
|
| Immunomodulatory drugs (IMiDs) |
Thalidomide:
- dose-dependent and cumulative over time
- CIPN reason for dose reduction or cessation of treatment in up to 60 % of patients.
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- Predominately lower extremities neuropathies, such as foot and leg dysesthesia, sensory loss, tingling, impaired reflexes, and painful muscle cramps
- Neuropathy frequently improves, although it may be only partially reversible with treatment discontinuation.r
|
Lenalidomide:
- does not seem to cause substantial neurotoxicity
- long term follow up study, CIPN grade 3 reported to be only 1.4%.r
|
Pomalidomide:
- causes very few incidences of CIPN; no cases of severe neuropathy were seen in large randomized trials of this agent.
|
| Proteasome inhibitors |
Bortezomib:
- weekly rather than the twice weekly treatment schedule and subcutaneous administration significantly reduces the incidence and severity of peripheral neuropathy without affecting efficacy.r
|
- Neuropathic pain and paraesthesia in distal extremities of limbs.
- Reversible; usually improves after three to four months following discontinuation of treatment but it may persist for up to two years or indefinitely in some cases.r
|
Carfilzomib and ixazomib:
- reported to have a lower incidence of CIPN than bortezomib.rr
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| Brentuximab vedotin |
- Peripheral neuropathy occurs in 36–53% of patients, and is severe in 10–14% of patientsr
- cumulative toxicity, possible to restart at lower dose once neuropathy is improved to Grade 1.
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- Symptoms improve and reverse in 50% at 3 months of discontinuation.
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| Ado-trastuzumab emtansine |
- Any grade peripheral neuropathy 13% when used as single agent.r
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- Symptoms increase with duration, therefore Grade 3-4 peripheral neuropathy should trigger discontinuation until improvement to Grade 1.
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Risk factors
Risk factors include:
- pre-existing peripheral neuropathy
- prior treatment with other neurotoxic drugs
- combination of neurotoxic chemotherapeutic agents in regimen
- alcoholism
- smoking
- diabetes mellitus
- vitamin B and/or nutritional deficiencies
- advancing age
- multiple myeloma and Waldenstrom's disease
- family history of hereditary neuropathies.
NOTE: Not all neuropathies are reversible and it is important to refer to individual protocols for recommendations on dose reduction or delay of treatment.