Thromboembolism and event-free survival in children with extracranial solid tumors: A report from CYP-c.

Abstract Background: Thromboembolism (TE) is a known complication in pediatric oncology patients. While its adverse prognostic impact on survival has been shown in hematologic malignancies, limited data exist for children with solid tumors. Objectives: Among children diagnosed with extracranial solid tumors, a) To describe risk factors for TE and b) to evaluate the association between TE and overall survival (OS) and event-free survival (EFS). Methods: We conducted a retrospective cohort study using data from the Cancer in Young People – Canada (CYP-C) population-based registry. The cohort included patients aged 0–<18 years diagnosed with extracranial solid tumors (International Classification of Childhood Cancers-3 diagnostic groups II, IV–XI) between January 1, 2001, and December 31, 2021, at 12 pediatric oncology centers across Canada outside of Ontario. Patients were followed for up to 5 years following cancer diagnosis. The main exposure was the occurrence of grade ≥3 TE as per Common Terminology Criteria for Adverse Event (i.e. requiring medical treatment, life-threatening, or fatal), as abstracted by trained data managers from medical records. Outcomes were 5-year OS and EFS, with EFS defined as time between diagnosis and death from any cause, relapse, or second malignancy (whichever came first). Demographic, clinical, and treatment-related variables for children with and without TE were presented descriptively and were compared using univariate and multivariable logistic regression. We used Kaplan-Meier estimators with log-rank test and multivariable Cox proportional hazards models to evaluate the association between TE and survival. Only TEs that occurred before relapse or second malignancy were considered. Patients without the outcome of interest were censored at last medical follow-up in CYP-C. Multivariable models were adjusted for age, sex, cancer type, treatment intensity (using the Intensity-Treatment Rating version 3.0 scale), and metastatic status. Results are presented using hazard ratios (HR) and 95% confidence intervals (CI). P-values <0.05 were considered statistically significant. Results: We included 5,153 patients, 200 of whom had a thromboembolic event. The median age was 6.7 years (IQR: 2.0-12.8), 52.7% were male, 62.7% self-reported as White. The most common cancer diagnoses were “Lymphomas and reticuloendothelial neoplasms” (25.5%), “Neuroblastoma and peripheral nervous cell tumors” (18.0%), and “Soft tissue and extraosseous sarcomas” (12.2%). Metastatic involvement was present in 38.2% of cases. The 5-year cumulative incidence of TE reached 4.9% (95% CI: 3.5-4.7%). Of note, 35 patients (0.7%) experienced TE within 7 days of cancer diagnosis. The following characteristics were independently associated with TE: primary cancer diagnoses of lymphoma or hepatic tumors, metastatic disease at diagnosis, and exposure to chemotherapy. Sex, race, income quintile, and surgery were not associated with TE. Five-year OS was 73.0% and 85.5% in pediatric cancer patients with and without TE, respectively (absolute difference: 12.5%, log rank test, p<0.0001). TE was independently associated with decreased OS (unadjusted HR=1.90, 95% CI: 1.44-2.50, p<0.001; adjusted HR = 1.55, 95% adjusted CI: 1.17–2.04, p=0.0021). Additionally, in this model, male sex and metastatic status were associated with worse OS. Five-year EFS was 76.8% and 86.1% in pediatric cancer patients with and without TE (absolute difference: 9.3%, log-rank test: p=0.0018). TE was also independently associated with worse EFS (Unadjusted HR= 1,67, 95% CI: 1.21-2.30; p=0.002; Adjusted HR = 1.46; 95% adjusted CI: 1.05-2.02, p=0.023). Conclusion: In this large, population-based cohort of children with extracranial solid tumors, TE was associated with metastatic disease. After adjustment for other known adverse prognostic factors, such as age and metastatic status, TE was independently associated with worse OS and EFS, suggesting that TE may serve as a marker of poor prognosis. Further work is needed to determine whether thromboprophylaxis may reduce TE and its impact on survival in children.