Background: Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact. Methods: Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes. Results: Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9–12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1–34.6) and sarcomas (PR, 11.5; 95% CI, 9.1–14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8–24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5–2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1–1.2), anxiety (PR, 2.5; 95% CI, 2.2–2.9), depression (PR, 2.1; 95% CI, 1.9–2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90–0.94) and employment (PR, 0.8; 95% CI, 0.8–0.9). Conclusions: Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes. Impact: Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure.
PURPOSE: Patients with pediatric acute lymphoblastic leukemia (ALL) are at risk for impaired physical function from treatment. Early physical therapy (PT) may improve physical function and health in children with ALL, yet little is known about PT utilization in this population. METHODS: Leveraging the Premier Healthcare Database, we conducted a cohort study including participants hospitalized with ALL at age 0-21 years from January 1, 2010, through March 31, 2017. A generalized mixed linear model assessed sociodemographic and clinical variables associated with receiving PT within 1 year of first hospitalization. RESULTS: Among 5,488 pediatric ALL patients from 330 hospitals (median age 7 years, interquartile range = 4-14 years), only 27.2% overall and 58.9% with neuromuscular conditions received PT within a year of first ALL admission. In multivariable analysis, patients more likely to receive PT were age 10-14 years (odds ratio [OR] = 1.46; 95% CI, 1.20 to 1.76) or 15-21 years (OR = 1.66; 95% CI, 1.36 to 2.02) versus 0-4 years and Hispanic (OR = 1.27; 95% CI, 1.04 to 1.56) versus White. Patients less likely to receive PT were treated by a nonhematology/oncology pediatric (OR = 0.56; 95% CI, 0.46 to 0.70) or adult (OR = 0.50; 95% CI, 0.38 to 0.65) specialist versus a pediatric hematologist/oncologist and treated at a nonteaching hospital (OR = 0.53; 95% CI, 0.36 to 0.79) versus a teaching hospital. CONCLUSION: Only 27.2% of pediatric ALL patients overall and 58.9% with neuromuscular conditions receive inpatient PT within a year of first ALL admission. Interventions to increase inpatient PT services to pediatric ALL patients and address disparities in PT utilization may improve the physical function and long-term health of survivors.
Background Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children’s Oncology Group AALL0932 randomized reduction in vincristine/dexamethasone (every 4-week [VCR/DEX4] vs. 12-week [VCR/DEX12]) during maintenance in the average-risk subset of NCI standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall, and by treatment group. Methods AALL0932 SR AR B-ALL patients ≥3 years old were evaluated at T1-T4 (end-consolidation, maintenance month-1, maintenance month-18, 12-months post-therapy). Physical/occupational therapists (PT/OT) measured motor CIPN (hand/ankle strength, dorsiflexion/plantarflexion range of motion [ROM]), sensory CIPN (finger/toe vibration and touch), and function (dexterity [Purdue Pegboard], walking efficiency [Six Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age/sex matched Z-scores and proportion impaired were measured longitudinally and compared between groups. Results Consent and data were obtained from 150 participants (mean age 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (p<.001) and walking efficiency (p=.02) improved from T1-T4 and only dorsiflexion ROM (46.7% vs. 14.7%, p=.008) and handgrip strength (22.2% vs. 37.1%, p=.03) differed in VCR/DEX4 vs. VCR/DEX12 at T4. Proxy-reported outcomes improved from T1 to T4 (P<.001) and most did not differ between groups. Conclusions CIPN is prevalent early in B-ALL therapy and persists at least 12-months post-therapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency.
Dramatic improvements in cancer survival have occurred in the last decade, but the quality of life for many survivors is compromised due to severe, long-lasting, and often irreversible side effects of chemotherapy. The neurological side effects, chemotherapy induced peripheral neuropathy (CIPN) and cancer related/induced cognitive impairment (CRCI/CICI), are under-recognized and can occur after chemotherapy, immunotherapy, or radiation. The cellular mechanisms underlying these neurological side effects are poorly understood and there are no effective treatments or preventions, other than reduction or termination of cancer therapy. In our preliminary prospective, non-interventional study to examine the side effects of chemotherapy in patients with breast cancer (NCT03872141), patients with breast cancer who received standard of care single agent weekly taxane-based chemotherapy were assessed at baseline, midpoint, and end of treatment for neurological and cognitive changes and for blood levels of potential protein biomarkers (n = 13). CIPN and CRCI both showed an increase in severity with accumulating taxane and these changes were compared to protein alternations over the course of treatment. Using peripheral blood collected from patients (n = 10) during chemotherapy and tested with an antibody array curated by the MD Anderson RPPA Core), we found that 19 proteins were increased, and 12 proteins decreased over 12 weeks of treatment. Among those downregulate were proteins known to be critical for neuronal viability and function including GRB2 (growth factor receptor-bound protein 2) and NCS1 (neuronal calcium sensor 1). Concurrently, proteins associated with apoptosis, including BAK1 (Bcl-1 homologous antagonist/killer), were upregulated. These results support the proposal that CIPN and CRCI increase with increasing taxane exposure, and identified several proteins that are altered with taxane exposure that could be implicated in their pathogenesis. In conclusion, our study provides evidence for progressive neurological changes and the rationale to investigate the molecular basis for these changes with the goal of target identification for mitigation of these neurological side effects.
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