Chemotherapy-Induced Peripheral Neuropathy in Long-term Survivors of Childhood Cancer: Clinical, Neurophysiological, Functional, and Patient-Reported Outcomes

Abstract

Importance: In light of the excellent long-term survival of childhood cancer patients, it is imperative to screen for factors affecting health, function, and quality of life in long-term survivors.

Objective: To comprehensively assess chemotherapy-induced peripheral neuropathy in childhood cancer survivors to define disease burden and functional effect and to inform screening recommendations.

Design, setting, and participants: In this cross-sectional observational study, cancer survivors who were treated with chemotherapy for extracranial malignancy before age 17 years were recruited consecutively between April 2015 and December 2016 from a single tertiary hospital-based comprehensive cancer survivorship clinic and compared with healthy age-matched controls. Investigators were blinded to the type of chemotherapy. A total of 169 patients met inclusion criteria, of whom 48 (28.4%) were unable to be contacted or declined participation.

Exposures: Chemotherapy agents known to be toxic to peripheral nerves.

Main outcomes and measures: The clinical peripheral neurological assessment using the Total Neuropathy Score was compared between recipients of different neurotoxic chemotherapy agents and control participants and was correlated with neurophysiological, functional, and patient-reported outcome measures.

Results: Of the 121 childhood cancer survivors included in this study, 65 (53.7%) were male, and the cohort underwent neurotoxicity assessments at a median (range) age of 16 (7-47) years, a median (range) 8.5 (1.5-29) years after treatment completion. Vinca alkaloids and platinum compounds were the main neurotoxic agents. Clinical abnormalities consistent with peripheral neuropathy were common, seen in 53 of 100 participants (53.0%) treated with neurotoxic chemotherapy (mean Total Neuropathy Score increase, 2.1; 95% CI, 1.4-2.9; P < .001), and were associated with lower limb predominant sensory axonal neuropathy (mean amplitude reduction, 5.8 μV; 95% CI, 2.8-8.8; P < .001). Functional deficits were seen in manual dexterity, distal sensation, and balance. Patient-reported outcomes demonstrating reduction in global quality of life and physical functioning were associated with the Total Neuropathy Score. Cisplatin produced long-term neurotoxicity more frequently than vinca alkaloids.

Conclusions and relevance: Clinical abnormalities attributable to peripheral neuropathy were common in childhood cancer survivors and persisted long term, with concurrent deficits in patient-reported outcomes. Both the type of neurotoxic agent and a targeted clinical neurological assessment are important considerations when screening survivors for long-term neuropathy. Further development of peripheral neuropathy-specific pediatric assessment tools will aid research into neuroprotective and rehabilitative strategies.

Figure 1.. Shift in Distribution of Population Sensory Amplitudes

Shift in the population distribution of sural sensory amplitudes in childhood cancer survivors (n = 85) compared with controls (n = 40). The mean (SD) frequency was 23.3 (1.2) μV for controls and 17.6 (0.9) μV for survivors. A total of 65 of 85 childhood cancer survivors (76%) exposed to neurotoxic chemotherapy have sensory amplitudes below the control mean. The dotted line indicates the control mean.

Figure 2.. Functional Deficits in Childhood Cancer Survivors (CCS)

A, Functional assessments using the Movement Assessment Battery for Children (MABC) in child and adolescent CCS exposed to neurotoxic chemotherapy compared with population reference ranges. Functional deficit is seen in 2 of 3 manual dexterity tasks and 1 of 3 balance tasks and is represented as the number of standard deviations below the population mean. The dotted line indicates the population mean and the error bars, SEM. B-D, Functional assessments in adult CCS exposed to neurotoxic chemotherapy compared with laboratory controls. B, Fingertip sensory threshold for light touch using Von Frey monofilaments (increased threshold in CCS, 0.1 mN; 95% CI, 0.03-0.2; P = .01). C, Fingertip cutaneous resolution threshold using the grating orientation task (increased threshold in CCS, 0.7 mm; 95% CI, 0.1-1.2; P = .003). D, Manual dexterity using the grooved peg board task (increased time to completion in CCS, 5.9 s; 95% CI, 1.6-10.1; P = .008). The black bar indicates the median and the error bars, interquartile ranges.