Risk of Cerebrovascular Events among Childhood and Adolescent Patients Receiving Cranial Radiotherapy: A PENTEC Normal Tissue Outcomes Comprehensive Review

Abstract

<h3>Purpose/Objective(s)</h3> Radiation (RT)-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. Although multiple retrospective series and case reports discuss the association between cranial RT in children and subsequent cerebral vasculopathy, useful dose-response data to guide practitioners in the counseling or prevention of these events is lacking. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial RT. This report presents our updated modeling results which will be the basis for our PENTEC publication. <h3>Materials/Methods</h3> A literature search was performed for studies reporting pediatric RT associated cerebral vasculopathy. When available, we utilized individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. <h3>Results</h3> The search identified 766 abstracts, five of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack (TIA), stroke, <i>Moyamoya</i>, or arteriopathy. Logistic model parameters with 95% confidence intervals were: dose for 50% response (D50 = 75.6 Gy; 68.4-89.4 Gy) and normalized dose-response slope at D50 (γ50 = 2.69; 2.05–3.60). For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9-1.3%, 1.8-2.7%, and 2.8-4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared to a baseline risk of 0.2-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1-4.2%, 4.5-8.6%, and 6.7-13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared to a baseline risk of 0.5-1.0%). <h3>Conclusion</h3> The risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. Further, since the stroke hazard was based on prescribed dose rather than CW dose our reported stroke risk is likely underestimated. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.