Nationwide epidemiologic and economic burden analysis of neurologic disorders associated with cancer treatment

Background: Neurologic disorders associated with cancer treatment (CIND) are common dose-limiting toxicities of many chemotherapies. They can persist long after treatment, impair function, and quality of life. Despite their import, large scale data on incidence, dose-response, and health care utilization and economic burden is limited. Objective: Quantify the epidemiology of CIND, stratified by cancer status, agent, and route of administration, evaluate clinical and treatment-related risk factors, measure health care utilization and economic cost burden, all in a nationwide cohort. Methods: Using longitudinal IBM Marketscan claims data, we applied multi-tier drug matching to identify adults with incident chemotherapy and classify cancer and neurologic status using ICD 9 neoplasm and neurologic codes. Patients were categorized as having same day or incident neuropathy relative to the cancer diagnosis or first chemotherapy dispensing date. CIND cumulative incidence and time to first event were assessed at 3-month intervals. We modeled adjusted odds and hazards of CIND by cancer status and chemotherapy route and evaluated dose-response in multivariable Cox model adjusted for age, sex, and comorbidities. Results: Across three cohorts (totaling ~ 3.1M patients), CIND incidence was highest in cancer patients receiving chemotherapy (40.4%) compared to cancer patients alone (34.1%) which was higher still relative to the general population (12%). Higher mean incremental daily dose was significantly associated with increased CIND hazard, with oral agents showing HRs per 1-SD from 1.09-2.23 (bexarotene, capecitabine, hydroxyurea, mercaptopurine, tretinoin; all p≤0.046) and IV methotrexate showing HR 1.34 (95% CI 1.00-1.79; p=0.048). Most CIND events occurred within one year of the last dose, indicating substantial on treatment and delayed CIND risk. Compared with IV administration, oral chemotherapy was associated with a modestly lower hazard of CIND (HR 0.862). Older age and comorbidities (hypertension, peptic ulcer, depression, chronic pulmonary disease, diabetes, and coagulopathy) provide additional independent risk. Healthcare burden analyses revealed opioid dispensing, CIND-directed pharmacotherapy, and rehabilitative services were more frequently used in chemotherapy recipients, accompanied by 51-fold higher per-patient costs (~$53k) relative to general population. Conclusion: In this nationwide cohort, CIND is common, often delayed, and shaped by route of administration, indication, dose intensity, and patient comorbidity. CIND care concentrates substantial utilization and financial burden in chemotherapy exposed populations, underscoring the need for dose optimized regimens, proactive surveillance, and better supportive care strategies.