Which chemotherapy agents are most associated with peripheral neuropathy?

Chemotherapy Agents Most Associated with Peripheral Neuropathy

The chemotherapy agents most strongly associated with peripheral neuropathy are platinum compounds (particularly oxaliplatin), taxanes (paclitaxel and docetaxel), vinca alkaloids (especially vincristine), and the newer agents bortezomib and thalidomide. 1

Primary Neurotoxic Chemotherapy Classes

Platinum Compounds

• Oxaliplatin causes the highest prevalence of CIPN among all platinum agents and presents with two distinct neuropathy patterns 2:
  • Acute neuropathy characterized by cold sensitivity, throat discomfort, difficulty swallowing cold liquids, and muscle cramps that begin during infusion and peak 2-3 days after each dose 1, 3, 4
  • Chronic/cumulative neuropathy that is more severe in upper limbs than lower limbs and exhibits a "coasting phenomenon" where symptoms worsen for 2-3 months after therapy completion before beginning to improve 3, 4
• Platinum-based agents cause more pronounced damage to ulnar and tibial nerves compared to other chemotherapy classes 5
• Cisplatin and carboplatin also cause peripheral neuropathy but with lower incidence than oxaliplatin 1, 5

Taxanes

• Paclitaxel causes peripheral neuropathy in 60% of all patients (3% severe) and in 52% (2% severe) of patients without pre-existing neuropathy 6
• The frequency of peripheral neuropathy increases with cumulative dose, with symptoms observed in 27% of patients after the first course and 34-51% from courses 2-10 6
• Paclitaxel causes an acute pain syndrome occurring 2-3 days after each dose, primarily in truncal/hip distribution, which represents acute neuropathy rather than simple myalgia 1, 3, 4
• When paclitaxel 175 mg/m² is given by 3-hour infusion with cisplatin 75 mg/m², severe neurotoxicity occurs in 21% of patients, compared to only 3% when paclitaxel 135 mg/m² is given by 24-hour infusion with the same cisplatin dose 6
• Docetaxel also causes peripheral neuropathy with similar patterns to paclitaxel 5

Vinca Alkaloids

• Vincristine is the chemotherapeutic agent most commonly associated with peripheral neuropathy, presenting with "glove and stocking" distribution, mechanical allodynia, sensory/tactile disorders, and numbness in hands and feet 4
• Autonomic manifestations are particularly common with vincristine, including pain, constipation, postural hypotension, bladder disturbances, and reduced heart rate variability 4
• Pre-existing neuropathy significantly increases both incidence and severity of vincristine-induced neuropathy 4
• Advanced age (>65-75 years) is associated with more severe vincristine neuropathy 4

Newer Agents

• Bortezomib and thalidomide cause peripheral neuropathy that has become a leading cause of iatrogenic neurotoxicity in multiple myeloma patients 4, 2
• These agents frequently exert neurotoxic effects on peripheral nerves similar to traditional chemotherapy agents 7

Clinical Characteristics of CIPN

Typical Presentation Pattern

• CIPN characteristically presents with symmetric, distal, length-dependent "glove and stocking" distribution 1, 3, 4
• The neuropathy predominantly consists of sensory rather than motor symptoms and is dose-dependent 1
• Sensory axonal damage with reduced amplitude of sensory nerve action potentials (SNAPs) is the common finding on nerve conduction studies 1
• Motor nerve function consistently remains unchanged during treatment with most neurotoxic agents 1

Incidence and Risk Factors

• The overall incidence of CIPN is approximately 38% in patients treated with multiple agents, though this varies by regimen, duration, and assessment method 1
• Approximately 90% of patients self-report neuropathic symptoms, with polyneuropathy confirmed on nerve conduction studies in 60% 5
• Pre-existing neuropathy from any cause (diabetes mellitus, renal insufficiency, hypothyroidism, vitamin deficiencies, HIV infection, autoimmune conditions, alcohol abuse) significantly increases CIPN risk and severity 4
• Co-administration with other neurotoxic agents significantly increases neuropathy risk 4

Management Implications

Dose Modification Strategy

• Clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment 1
• Peripheral neuropathy was the cause of paclitaxel discontinuation in 1% of all patients 6
• Sensory symptoms usually improve or resolve within several months of paclitaxel discontinuation 6

Treatment of Established CIPN

• Duloxetine is the only agent with appropriate evidence to support its use for patients with established painful CIPN, though the amount of benefit is limited 1, 4
• Gabapentin or pregabalin serve as alternatives for neuropathic pain, though CIPN trials are inconclusive regarding their efficacy 4
• Tricyclic antidepressants (such as nortriptyline) and compounded topical gel containing baclofen, amitriptyline HCL, and ketamine may be offered based on data supporting their utility in other neuropathic pain conditions, given limited CIPN treatment options 1

Prevention Strategies

• No agents are recommended for the prevention of CIPN based on paucity of high-quality, consistent evidence 1
• The use of acetyl-L-carnitine for prevention of CIPN should be discouraged 1
• Baseline neurological evaluation is recommended before initiating neurotoxic medications, with monitoring of neurological symptoms before each treatment cycle 4

Common Pitfalls to Avoid

• Do not assume that pre-existing neuropathy is a contraindication to paclitaxel therapy; it is not, though it increases risk of worsening symptoms 6
• Do not overlook the combination effect: when paclitaxel is given with cisplatin in NSCLC patients, severe neurotoxicity rates (13%) are higher than in ovarian or breast cancer patients receiving single-agent paclitaxel 6
• Do not ignore the schedule-dependent effects: paclitaxel 175 mg/m² by 3-hour infusion causes more severe neurotoxicity than 135 mg/m² by 24-hour infusion when combined with cisplatin 6
• Recognize that CIPN can exhibit "coasting" where symptoms worsen for 2-3 months after treatment completion before improving, particularly with oxaliplatin 3, 4