OncologyTier 1Topic

Side effects of systemic cancer therapy - peripheral neuropathy

Overview

Chemotherapy-induced peripheral neuropathy (CIPN) - a common, often dose-limiting toxicity of several drug classes
Predominantly sensory, symmetric, distal, "glove and stocking" - numbness, tingling, pain, sometimes with motor/autonomic features depending on the agent
A major driver of dose reduction, delay, or early cessation of otherwise effective chemotherapy - clinically significant beyond the symptom itself

Affects ~30-40% of patients overall on neurotoxic chemotherapy, higher with platinum agents and taxanes specifically
Risk rises with cumulative dose, pre-existing neuropathy (diabetes, alcohol, hereditary), and combination neurotoxic regimens

Platinum agents (oxaliplatin, cisplatin) - oxaliplatin causes a distinctive acute cold-induced dysaesthesia within hours of infusion (pharyngolaryngeal dysaesthesia, cold-triggered hand/perioral tingling), separate from its chronic cumulative sensory neuropathy; cisplatin - dorsal root ganglion neuronal damage, can worsen for months after stopping ("coasting")
Taxanes (paclitaxel, docetaxel) - microtubule disruption impairs axonal transport - sensory > motor, dose- and schedule-dependent
Vinca alkaloids (vincristine) - similarly microtubule-mediated, can include autonomic features (constipation, ileus) and motor involvement
Bortezomib (proteasome inhibitor) - painful sensory neuropathy, less common/severe with subcutaneous vs IV administration and weekly vs twice-weekly dosing
Immune checkpoint inhibitors - rare but distinct immune-mediated neuropathy (Guillain-Barre-like or chronic inflammatory patterns) - mechanistically different, may need immunosuppression rather than dose modification

Symmetric distal sensory symptoms (numbness, tingling, pain), assess for motor involvement (weakness, gait change) and functional impact (buttons, handwriting, falls risk)
Graded by common toxicity criteria (CTCAE) - grade determines whether to continue, reduce, or hold the causative drug
Distinguish oxaliplatin's acute cold-triggered phenomenon (transient, resolves between cycles initially) from its separate chronic cumulative neuropathy (persistent, dose-dependent)

Atypical pattern (asymmetric, rapidly progressive, significant motor/autonomic involvement) - consider nerve conduction studies and alternative causes (paraneoplastic, nutritional - B12, disease infiltration)
Checkpoint inhibitor-associated neuropathy with rapid progression - urgent neurology input, consider it an immune-related adverse event requiring its own work-up

A. Prevention - the evidence is disappointing

No pharmacological agent is proven to prevent CIPN - trials of calcium/magnesium, glutamine, acetyl-L-carnitine, and gabapentinoids for prevention have all failed to show benefit and are not recommended
Cryotherapy or compression therapy (frozen gloves/socks) during taxane infusion - some evidence for reducing incidence/severity, a reasonable non-pharmacological option
Oxaliplatin - avoid cold exposure/cold drinks around infusion to reduce acute dysaesthesia symptoms (does not prevent chronic neuropathy)

B. Dose modification - the primary management lever

Dose reduction, delay, or discontinuation of the causative agent based on CTCAE grade - the most effective intervention once significant neuropathy develops; balancing oncological efficacy against irreversible neurotoxicity is a core chemotherapy delivery decision

C. Treatment of established painful CIPN

Duloxetine - the only agent with adequate evidence supporting benefit for established painful CIPN, recommended first-line
Gabapentin/pregabalin, tricyclic antidepressants - commonly used despite weaker evidence base, reasonable second-line trial given limited alternatives
Topical agents (menthol, lidocaine) - adjunct, limited evidence but low risk

D. Checkpoint inhibitor-associated neuropathy

Managed as an immune-related adverse event - hold the checkpoint inhibitor, corticosteroids +/- IVIG/plasma exchange for severe cases, neurology co-management

Pre-existing neuropathy (diabetes, alcohol use, hereditary neuropathy) - amplifies risk and severity
Cumulative dose and combination neurotoxic regimens (e.g. platinum + taxane)
Falls risk, reduced quality of life, and functional impairment (fine motor tasks) - often underreported by patients relative to objective severity

Many cases improve over months after stopping the causative agent, but a substantial proportion have persistent symptoms beyond a year, particularly with platinum agents
Cisplatin - can worsen for weeks-months after cessation ("coasting phenomenon") before any improvement begins
Severity and persistence are major factors in long-term cancer survivorship quality of life, independent of oncological outcome
Early recognition and proactive dose modification reduce the risk of severe, potentially irreversible neuropathy - waiting for grade 3-4 symptoms before acting risks permanent deficit

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