Chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is peripheral neuropathy, often of the polyneuropathic type, that arises as an adverse effect of chemotherapy. It is progressive, enduring, and often irreversible, involving paresthesia (such as tingling), hypoesthesia (numbness), pain, and sensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs. CIPN affects between 30% and 40% of patients undergoing chemotherapy.^[1] Chemotherapy drugs associated with CIPN include thalidomide, the epothilones such as ixabepilone, the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin.^[1][2][3] Whether CIPN arises, and to what degree, is determined by the choice of drug, duration of use, the total amount consumed and whether the patient already has peripheral neuropathy. Though the symptoms are mainly sensory – pain, tingling, numbness and temperature sensitivity – in some cases motor nerves are affected, and occasionally, also, the autonomic nervous system.^[4]

CIPN often follows the first chemotherapy dose and increases in severity as treatment continues, but this progression usually levels off at completion of treatment. The platinum-based drugs are the exception; with these drugs, sensation may continue to deteriorate for several months after the end of treatment.^[5] Some CIPN appears to be irreversible.^[5] Pain can often be helped with drug or other treatment but the numbness is usually resistant to treatment.^[6]

CIPN disrupts leisure, work and family relations, and the pain of CIPN is often accompanied by sleep and mood disturbance, fatigue and functional difficulties. A 2007 American study found that most patients did not recall being told to expect CIPN, and doctors monitoring the condition rarely asked how it affects daily living but focused on practical effects such as dexterity and gait.^[7] It is not known what causes the condition, but microtubule and mitochondrial damage, and leaky blood vessels near nerve cells are some of the possibilities being explored.^[5]

Possible preventative interventions

As possible preventative interventions, the American National Cancer Institute Symptom Management and Health-related Quality of Life Steering Committee recommends continued investigation of glutathione, and intravenous calcium and magnesium, which have shown early promise in limited human trials; acetyl-L-carnitine, which was effective in animal models and on diabetes and HIV patients; and the anti-oxidant alpha-lipoic acid.^[1]

Glutathione

Glutathione was studied in two large double-blind placebo-controlled trials and seemed to reduce neurotoxicity without interfering with the therapeutic effect, but shortcomings in the trial designs make confident interpretation of the results impossible. As of September 2013, patients are being recruited for a more definitive study.^[8]

Intravenous calcium and magnesium

In a study of patients receiving oxaliplatin treatment, only 4 percent of those also receiving intravenous calcium and magnesium (ca/mg) before and after each oxaliplaten dose had to discontinue treatment due to neurotoxicity, compared to 33 percent who were receiving intravenous placebo; onset of neuropathy was also significantly delayed in the ca/mg patients, and only 22 percent of the ca/mg patients had long-term CIPN of grade 2 or worse compared with 41 percent of those on placebo. Overall, trials of ca/mg infusion suggest there are no serious harmful side effects and it may be an effective preventative therapy — the number of patients so far studied is small, however, and confident conclusions cannot be drawn.^[9][8]

Nutraceuticals

Acetyl-L-carnitine

Though preclinical trials and a phase II trial of acetyl-L-carnitine indicated it may be effective for CIPN, a 2013 review concluded there is no solid evidence to support its use; and the 2013 report of a randomized double-blind placebo-controlled trial (409 patients) of acetyl-L-carnitine for the prevention of taxane-induced neuropathy found "no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks."^[10][11]

Glutamine

Two small randomized controlled trials (RCTs) and one larger RCT (86 subjects) tested glutamine in the prevention of platinum treatment-induced neuropathy and showed promise. As of September 2013 a larger, placebo-controlled trial is running.^[8]

Other nutraceuticals

A 2013 systematic review of the use of the oral nutraceuticals acetyl-L-carnitine, glutamine, vitamin E, glutathione, vitamin B6, omega-3 fatty acids, magnesium, calcium, alpha lipoic acid and n-acetyl cysteineas as anti-CIPN adjuvants concluded that "currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN."^[10]

Antidepressants

Venlafaxine

Forty eight patients experiencing acute neurotoxicity during oxaliplatin treatment were given either the antidepressant venlafaxine or placebo. Of those given venlafaxine, 31.3 percent experienced complete relief of symptoms as opposed to 5.3 percent of those on placebo. After three months, 38.5 percent of the venlafaxine-treated patients had no neuropathy, vs. 5.6 percent of those on placebo, and while 33.3 percent of the placebo-treated patients had grade 3 neuropathy after 3 months, none of the venlafaxine-treated patients did.^[8][12]

Duloxetine

A trial of the antidepressant duloxetine suggested it may be useful in controlling the pain of neurotoxicity due to taxane or platinum treatment.^[12]

Valproate

The anticonvulsant valproate, an effective treatment for diabetic neuropathy, appeared to offer some protection against cisplatin-induced neuropathy in rats.^[8]

Interleukin-6

Interleukin-6 prevented peripheral nerve damage in animals without inhibiting the anti-cancer effect.^[8]

References