Multifactorial Contributors to Dose Limiting and Post-Treatment Neurologic Toxicity During Chemotherapy Treatment

BACKGROUND AND OBJECTIVES: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a complex and dose-limiting toxicity of cancer treatment leading to increased disability and reduced quality of life. Inconsistent use of outcome measures in previous studies have limited our ability to identify clinical risk factors for CIPN. This study aimed to use a comprehensive multimodal battery of neuropathy assessment to investigate the association between clinical variables and CIPN in individuals treated with neurotoxic cancer treatment. METHODS: We conducted a cross-sectional, multisite study of individuals who had received neurotoxic treatments from oncology centers in Australia (taxanes, platinum, vinca alkaloids, bortezomib, and thalidomide). CIPN was assessed through clinical grading, neurologic evaluation (Total Neuropathy Score [TNS], sural nerve conduction studies), and patient-reported outcome measure (European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy-Induced Peripheral Neuropathy Questionnaire [EORTC-CIPN20]). Clinical variables included demographic (age, sex), metabolic (body mass index [BMI], diabetic status), and medical history (preexisting peripheral neuropathy, prior neurotoxic treatment). Dose information was extracted from clinical notes to identify dose modification of neurotoxic treatments due to CIPN. Least absolute shrinkage and selection operator (LASSO) regression was used to identify candidate variables, followed by multivariable regression to construct final models. The results were presented as odds ratio (OR) or β (95% CI). RESULTS: The study included 901 individuals (median age 61 [interquartile range 19] years, 66% female) assessed 12 (median; interquartile range 18) months postneurotoxic treatment. In total, 37% had moderate-to-severe CIPN (n = 337, clinical grade ≥2), and 31% required dose modification due to CIPN. Multivariable logistic regression identified female sex (OR 1.7, 95% CI 1.2-2.5) to be associated with dose-limiting CIPN. Post-treatment CIPN was evaluated using multiple assessment tools. Patient-reported neuropathy was associated with older age (β = 3.9, 95% CI 2.0-5.7), diabetes (β = 3.3, 95% CI 0.1-6.5), higher BMI (overweight β = 3.1 [95% CI 0.9-5.2], obese β = 3.8 [95% CI 1.4-6.2]), and prior neurotoxic treatment (β = 5.1, 95% CI 1.3-8.9). Similar factors were associated with neurologic evaluation (TNS, sural amplitude). Clinical grading was associated with age (OR 3.0, 95% CI 2.2-4.2), higher BMI (overweight OR 2.1 [95% CI 1.5-3.0], obese OR 1.6 [95% CI 1.1-2.4]), and prior neurotoxic treatment (OR 2.9, 95% CI 1.2-6.8). Variables associated with severe CIPN (defined as highest quartile scores or moderate/severe clinical grading) across all assessment tools included older age (EORTC-CIPN20 OR 1.9 [95% CI 1.3-2.6], TNS OR 3.2 [95% CI 2.2-4.8], clinical grading OR 1.8 [95% CI 1.3-2.4]), and prior neurotoxic treatment (EORTC-CIPN20 OR 1.9 [95% CI 1.0-3.4], TNS OR 2.0 [95% CI 1.1-3.7], clinical grading OR 2.1 [95% CI 1.2-3.7]). DISCUSSION: CIPN is a significant toxicity that affects patients' ability to receive anticancer therapies and continues to affect long-term survivorship. We identified clinical variables that are readily available at beginning of treatment, which suggest increasing susceptibility to developing dose-limiting, post-treatment, and severe CIPN.