How to manage oxaliplatin-induced neuropathy?

Management of Oxaliplatin-Induced Neuropathy

Duloxetine is the first-line treatment for established oxaliplatin-induced peripheral neuropathy, particularly for painful symptoms. 1

Understanding Oxaliplatin Neuropathy

Oxaliplatin causes two distinct forms of neuropathy:

1. Acute neuropathy:

   • Occurs within hours or 2 days following a dose
   • Usually resolves within 14 days
   • Characterized by cold-induced paresthesia, dysesthesia, throat discomfort
   • Affects approximately 90% of patients 2

2. Chronic/cumulative neuropathy:

   • Persistent (>14 days) sensory neuropathy
   • Characterized by paresthesias, dysesthesias, hypoesthesias
   • May affect proprioception and interfere with daily activities
   • Typically occurs after cumulative doses >540 mg/m² 2

Treatment Algorithm for Established Oxaliplatin Neuropathy

First-line therapy:

• Duloxetine
  • Starting dose: 30 mg daily for 1 week
  • Target dose: 60 mg daily 1
  • Mechanism: Inhibits ERK1/2 phosphorylation in spinal cord 3 and regulates p53-mediated apoptosis 4
  • Evidence: Significantly decreases pain, numbness, and tingling compared to placebo
  • Note: More effective for oxaliplatin-induced neuropathy than paclitaxel-induced neuropathy 1

Second-line options (limited evidence):

• Tricyclic antidepressants (e.g., nortriptyline)
  • Consider when duloxetine is ineffective or contraindicated 1
  • Less evidence than duloxetine

Not recommended based on current evidence:

• Gabapentinoids (gabapentin, pregabalin)

  • Multiple trials show lack of benefit for established CIPN 1
  • Insurance may require trial before duloxetine, despite contradicting guidelines 1

• Calcium/magnesium infusions

  • No longer recommended as they have not shown benefit in reducing oxaliplatin-induced neurotoxicity 5

• Acetyl-L-carnitine

  • May worsen neuropathy symptoms 1

Prevention Strategies

Dose modification:

• For Grade 2 persistent (>7 days) neuropathy: Reduce oxaliplatin dose to 65 mg/m² 5, 6
• For Grade 3 neuropathy: Permanently discontinue oxaliplatin 5

Treatment scheduling:

• Consider "stop-and-go" approach (OPTIMOX strategy)
  • Discontinue oxaliplatin after 3-4 months or when ≥grade 2 neurotoxicity develops
  • May reintroduce if discontinued for neurotoxicity rather than disease progression 5

Treatment duration:

• For low-risk patients (T1-3, N1): Consider shorter duration (3 months) of oxaliplatin-containing therapy
• For high-risk patients (T4 and/or N2): Standard 6-month duration despite higher neurotoxicity risk 5

Adjunctive Management

• Physical/occupational therapy for patients with balance issues or functional impairment 1
• Avoid cold exposure during and after infusion to reduce acute symptoms 6
• Avoid topical application of ice for mucositis prophylaxis as cold temperature can exacerbate acute neurological symptoms 6

Emerging Therapies

Recent studies suggest duloxetine may also have preventive effects when administered before and during oxaliplatin treatment, showing reduced paresthesia and throat discomfort compared to placebo 7, 8. However, these findings need further confirmation before becoming standard practice.

Monitoring

• Regularly assess neuropathy using validated tools
• Monitor for functional impairment that affects daily activities
• Evaluate the need for dose modification or discontinuation based on severity and persistence of symptoms

Remember that neuropathy symptoms may improve in some patients upon discontinuation of oxaliplatin, but can persist long-term in others, significantly affecting quality of life.