Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports no financial relationships relevant to this field of study.

SYNOPSIS: Long-term symptoms and disability from chemotherapy-induced peripheral neuropathy occur in more than half of childhood survivors of cancer, with vinca alkaloids and platinum agents implicated most often.

SOURCE: Kandula T, Farrar MA, Cohn RJ, et al. Chemotherapy-induced peripheral neuropathy in long-term survivors of childhood cancer: Clinical, neurophysiological, functional, and patient-reported outcomes. JAMA Neurol 2018; May 14. doi:10.1001/jamaneurol.2018.0963. [Epub ahead of print].

Survival for five years or more after a diagnosis of childhood cancer is associated with a normal life span and, given an 80% survival rate for many childhood and adolescent cancers, long-term effects of cancer therapy can result in significant long-term morbidity. What is the disease burden and functional effect of surviving childhood cancer but suffering chemotherapy-induced peripheral neuropathy in the long term?

Kandula et al recruited cancer survivors who had received chemotherapy for extracranial malignancy prior to the age of 17 years between April 2015 and December 2016 from the Long-Term Follow-Up Clinic at the Kids Cancer Centre at Sydney Children’s Hospital in Australia for this cross-sectional observational study. Exclusionary criteria encompassed other diseases associated with neuropathy, including diabetes, critical illness, and hereditary neuropathic or developmental disorders. Neuropathy assessment comprised nerve conduction studies, the pediatric-modified Total Neuropathy Score, the Movement Assessment Battery, the Pediatric Quality of Life Inventory Generic Core Scales, and the Pediatric Outcomes Data Collection Instrument, which, for participants 17 years or older, included Von Frey monofilaments, grating orientation task, grooved peg board task for functional measures, the European Organization for Research and Treatment of Cancer quality-of-life questionnaire, and the chemotherapy-induced peripheral neuropathy
questionnaire. Statistical analysis involved two-tailed t tests and Mann-Whitney U tests for nonparametric subgroup analyses, χ2 tests for nominal data, one-way analysis of variance for multiple groups, and Pearson or Spearman correlations, with a P value < 0.05 considered significant.

Among 169 patients who met inclusion criteria, 48 declined participation or were unreachable, leaving a cohort of 121 long-term childhood cancer survivors to be studied, of whom 53.7% were male, 46.3% were female, with a median age at diagnosis and chemotherapy of four years, and a median age at evaluation of 16 years, which was a median of 8.5 years after completing chemotherapy. Leukemia comprised the largest group (52.9%), followed by solid tumors (29.8%) and lymphoma (14%). Vinca alkaloids were the most common form of chemotherapy (71.1%), among whom 4.1% received multiple vinca alkaloids. Platinum agents were used in 16.5%, including cisplatin or carboplatin (5.8% each), with 5% who received both. Both platinum agents and vinca alkaloids were given in 10.7%, and radiotherapy was given to 43.8% overall.

Peripheral neuropathy was seen in 50.5% of patients treated with neurotoxic chemotherapy, predominantly associated with sensory axonal neuropathy in the legs, accompanied by impaired manual dexterity, distal sensation, and balance, and by patient-reported reduced global quality of life and physical functioning, with cisplatin more frequently causing long-term neurotoxicity than vinca alkaloids. Peripheral neuropathy is common in long-term childhood cancer survivors.

COMMENTARY

No effective pharmacologic intervention is available to prevent chemotherapy-induced peripheral neuropathy, and no consensus exists to evaluate its incidence or severity. Whereas very few conventional, neuroprotection, drug-based trials are available that address this problem, there are an increasing number of non-conventional trials that do, using physical treatments including magnetic field therapy, diathermy, photobiomodulation, or electroacupuncture, alone or in combination with physical therapy. None have shown evidence of clinical effectiveness, although subjective relief is reported occasionally. New methodological approaches are necessary. Nitro-oxidative stress resulting from neuronal mitochondrial dysfunction, representing final common pathways in the development of chemotherapy-induced polyneuropathy, may be such an avenue, using drugs such as metformin or interleukin 10. Hopefully, future research will bridge the gap.^1,2

REFERENCE

1. Ma J, Kavelaars A, Dougherty PM, Heijnen CJ. Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer 2018;124:2289-2298.
2. Cavaletti G, Marmiroli P. Pharmacotherapy options for managing chemotherapy-induced peripheral neurotoxicity. Expert Opin Pharmacother 2018;19:113-121.