Chemotherapy-induced Peripheral Neuropathy Guidelines

The following organizations have released guidelines for the management of chemotherapy-induced peripheral neuropathy (CIPN) in oncology patients:

• American Society of Clinical Oncology (ASCO)
• Oncology Nursing Society (ONS)
• European Society for Medical Oncology/European Association of Neuro-Oncology/European Oncology Nursing Society (ESMO–EONS–EANO)

The ASCO guidelines were first published in 2014 and were updated in 2020. ^{[1, 2]} The ONS reaffirmed its 2007 guidelines in 2014. ^[3] The ESMO–EONS–EANO guidelines were published in 2020. ^[4]

Prevention

Due to lack of high-quality, consistent evidence, the ASCO guidelines do not recommend any agents for prevention of CIPN. The guidelines strongly recommend that clinicians should not offer, and should discourage use of, acetyl-l-carnitine for the prevention of CIPN in patients with cancer. The guidelines also include a moderate recommendation against offering the following agents for the prevention of CIPN ^[2] :

• All-trans retinoic acid
• Amifostine
• Amitriptyline
• Calcium magnesium
• Calmangafodipir
• Cannabinoids
• Carbamazepine
• l-carnosine
• Diethyldithiocarbamate (DDTC)
• Gabapentin/pregabalin
• Glutamate
• Glutathione (GSH) for patients receiving paclitaxel/carboplatin chemotherapy
• Goshajinkigan (GJG)
• Metformin
• Minocycline
• N-acetylcysteine
• Nimodipine
• Omega-3 fatty acids
• Org 2766
• Oxcarbazepine
• Recombinant human leukemia inhibitory factor
• Venlafaxine
• Vitamin B
• Vitamin E

ASCO advises that outside the context of a clinical trial, no recommendations can be made on the use of the following for the prevention of CIPN:

• Acupuncture
• Cryotherapy
• Compression therapy
• Exercise therapy
• Ganglioside-monosialic acid (GM-1)

Treatment

The ASCO guidelines recommend duloxetine to treat painful CIPN. The guidelines advise that outside the context of a clinical trial, no recommendations can be made on the use of the following for the treatment of CIPN:

• Exercise therapy
• Acupuncture
• Scrambler therapy
• Gabapentin/pregabalin
• Topical gel treatment containing baclofen, amitriptyline HCL, plus/minus ketamine
• Tricyclic antidepressants
• Oral cannabinoids

ASCO notes that although preliminary evidence suggests that exercise, acupuncture, and scrambler therapy offer potential benefit, larger sample-sized definitive studies are needed to confirm efficacy and clarify risks.

The ONS guidelines include the following recommendations for treatment of chemotherapy-induced peripheral neuropathy ^[3] :

• Duloxetine is likely to be effective
• Lamotrigine is unlikely to be effective
• Carnitine/L-carnitine and human leukemia inhibitory factor are not recommended

In addition, the ONS guidelines note that the effectiveness of the following treatments could not be determined:

• Acupuncture
• Alpha lipoic acid
• Amifostine
• Amitriptyline
• Bee venom
• Calcium and magnesium infusion
• Calcium channel blockers
• Cannabis/cannabinoids
• Carbamazepine
• Cutaneous stimulation
• Gabapentin and opioid combination
• Gabapentin monotherapy
• Glutamine
• Glutathione
• Goshajinkigan
• KRN5500
• Nortriptyline
• Omega-3 fatty acids (eicosapentaenoic acid and others)
• Palmitoylethanolamide
• Pregabalin
• Topical ketamine formulations
• Venlafaxine
• Vitamin E

The ESMO–EONS–EANO guidelines include the recommendations on peripheral neurotoxicity summarized below. ^[4]

Prevention

Pharmacologic agents

Although many pharmacological agents have been studied for their potential to prevent chemotherapy-induced peripheral neurotxicity (CIPN), none has yet been proven effective, so no positive recommendation can be given for any of the following ^[4] :

• Acetyl-L-carnitine
• Acetylcysteine
• Alpha-lipoic acid
• Amifostine     
• Amitriptyline 
• Calcium/magnesium 
• Calmangafodipir
• Diethyldithiocarbamate (DDTC)       
• Glutathione (GSH)     
• Goshajinkigan
• Minocycline
• MR309 (selective sigma-1 receptor antagonist)
• Nimodipine
• Omega-3 fatty acids
• Vitamin B      
• Vitamin E      

Nonpharmacologic approaches:

• Medical exercise to improve muscular strength and sensorimotor functions (distal motor skills, body coordination and balance) can be offered.
• Cryotherapy can be considered, although the study results are somewhat heterogeneous.
• Compression therapy using surgical gloves can be considered; there is less evidence for its efficacy than for cryotherapy, but it seems to pose little harm.
• The available evidence discourages the use of acupuncture.

Treatment

Recommendations for pharmacologic therapy include the following:

• Duloxetine is recommended for the treatment of neuropathic pain; it is so far the only drug shown in a large randomized trial to provide a moderate clinical benefit in patients with painful CIPN.
• Venlafaxine can be considered.ent
• Anticonvulsants and tricyclic antidepressants may be a reasonable option if duloxetine has failed or is contraindicated; these agents need to be given at least for 2 weeks at the appropriate dose in order to assess their efficacy.
• Opioids may be used as a salvage option to relieve neuropathic pain.
• No data support the benefit of nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids in the setting of CIPN.
• Topical low-concentration menthol cream should be considered, as its cost is low and no adverse events have been reported.
• Capsaicin 8%-containing patches can be considered.
• Topical treatment with a baclofen/amitriptyline and ketamine-containing gel is not recommended.

Recommendations for nonpharmacologic therapy include the following:

• Growing evidence indicates that physical exercise and functional training (eg, vibration training) reduces CIPN symptoms. Training to improve coordination, sensorimotor and fine motor function should begin (at the latest) with the onset of manifest CIPN, but can be started earlier, when potentially neurotoxic cancer treatment is initiated.
• Acupuncture might be considered in selected patients.
• Proactive Self-Management Program for Effects of Cancer Treatment (PROSPECT), a self-guided online cognitive and behaviour-based pain management program, can be weakly recommended.
• Neurofeedback is wealy recommended.
• Spinal cord stimulation with percutaneously or surgically implanted electrodes in the epidural space may be discussed for selected patients with truly refractory neuropathic pain in whom conservative approaches failed.
• Scrambler therapy (ie, use of a device that provides noninvasive cutaneous electrostimulation) is not recommended

Peripheral neuropathy is a common adverse effect of chemotherapy, caused by agents such as paclitaxel, docetaxel, vinorelbine, and vinblastine, among others. Multiple studies and meta-analyses have failed to identify any drug that can prevent chemotherapy-related neuropathy. Duloxetine is the only drug that has demonstrated efficacy for the treatment of chemotherapy-related peripheral neuropathy.