Anti-cancer therapy-induced peripheral neuropathy (AIPN) is a common dose-limiting, treatment-related adverse effect that may affect quality of life. It is often dose-related and cumulative. Onset of symptoms commonly develops after several weeks of treatment; it may, however, occur after the first dose of anti-cancer therapy. AIPN has the potential to result in anti-cancer drug dose reduction, delays or discontinuation of treatment.r
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 in a glove and stocking-like distribution.
Pathophysiology
Peripheral neuropathy is a common complication of several classes of anti-cancer drugs. Anti-cancer drugs cause 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 anti-cancer therapies can potentially cause irreversible symptoms, so it is important to identify symptoms early and adjust treatment accordingly. When symptoms are severe or irreversible, AIPN can lead to a serious decrease in quality of life and adverse clinical consequences for patients.
Incidence/prevalence
The incidence of AIPN varies according to the anti-cancer agent, dose, duration of exposure and method of assessment. It has been estimated that approximately 38% of patients treated with multiple agents experience AIPN.r
Commonly used agents causing peripheral neuropathy include 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 emtansine, brentuximab vedotin and immunotherapy agents, such as checkpoint inhibitors, are associated with AIPN. 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:
- Acute - rapid onset and occurs during, or shortly after infusion and can last a few days
- Most patients experience mild to moderate symptoms - 85%
- Chronic – Cumulative and dose related increases with doses > 800 mg/m².
- Can affect up to 66% of patients
|
- Acute - distal or perioral paresthesias and/or dysesthesias, changes can be induced by exposure to cold
- Read more about Laryngopharyngeal dysaesthesia associated with oxaliplatin
- Chronic - non-cold related distal sensory changes that can persist between cycles, and increase in intensity with subsequent treatments
- Symptoms may
- continue to worsen for several months following the discontinuation of therapy
- resolve over 6-12 months after treatment end or not resolve and remain long termr
|
Carboplatin:
- uncommon when given at conventional doses.
|
|
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.
|
- Usually improves more rapidly than paclitaxel (median 22 days).
|
Docetaxel:
- cumulative and dose related, with neurotoxic threshold ~ 400 mg/m²r
- grade 3 or 4 neuropathies occur in 10% or less.
|
|
Cabazitaxel:
- appears to have less cumulative toxicity, any grade is reported in 13-17% of treated patients, but fewer than 1% are severe.r
|
|
Epothilones |
Eribulin:
- reported that 25% of patients developed AIPN, most being grade 1 or 2, and the majority continuing eribulin after AIPN 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
- AIPN reason for dose reduction or cessation of treatment in up to 60 % of patients.
|
- Predominately lower extremities neuropathies, such as foot and leg dysesthesia, sensory loss, tingling, impaired reflexes, and painful muscle cramps
- Neuropathy frequently improves with dose-reductions or pauses in treatment. It may be only partially reversible with treatment discontinuation.r
|
Lenalidomide:
- does not seem to cause substantial neurotoxicity
- long term follow up study, AIPN grade 3 reported to be only 1.4%.r
|
Pomalidomide:
- causes very few incidences of AIPN; 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 AIPN than bortezomib.rr
|
|
Brentuximab vedotin |
- peripheral neuropathy occurs in 36–53% of patients, and is severe in 10–14% of patients
- cumulative toxicity, possible to restart at lower dose once neuropathy is improved to Grade 1.
|
- Symptoms improve and reverse in 50% at 3 months of discontinuation.
|
Enfortumab vedotin |
- peripheral neuropathy occurs in 46.3% of patients, and is severe in 3.7% of patients.r
- higher exposure was associated with higher incidence of grade ≥2 peripheral neuropathy
|
- Presenting predominantly as sensory events.
- Median time to onset: 2.7 months.r
- Symptoms resolved in 76% of patients at the time of last follow-up in EV-201 study.r
|
Ado-trastuzumab emtansine |
- Any grade peripheral neuropathy 13% when used as single agent.r
|
- Symptoms increase with duration, therefore Grade 3-4 peripheral neuropathy should trigger discontinuation until improvement to Grade 1.
|
Risk factors
Risk factors include:
- pre-existing peripheral neuropathy
- prior treatment with other neurotoxic drugs
- combination of neurotoxic anti-cancer 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.