Dose-effect relationships for adverse events after cranial radiotherapy in childhood cancer survivors

*Irma W.E.M. van Dijk, Academic Medical Center (AMC) 

Keywords: cranial radiotherapy, EQD2, late adverse events, childhood cancer survivors

Background: Adverse events (AEs) occur in the majority of long-term childhood cancer survivors, especially in those treated with cranial radiotherapy (CRT). Purpose: To evaluate the prevalence and severity of clinical AEs and treatment-related risk factors in childhood cancer survivors treated with CRT, and to assess dose-effect relationships using the equivalent dose in 2-Gy fractions (EQD2). Methods and materials: In a cohort of 1362 Dutch childhood cancer survivors diagnosed between 1966 and 1996 with a median survival of 17.0 years (range 5.0-38.1) after diagnosis, 285 survivors had CRT. To correct for fractionation dose, individual CRT-doses were converted to the EQD2 using the linear-quadratic model. A complete inventory of standardized graded AEs was available from our hospital-based late effects follow-up program. Dose-effect relationships for the prevalence and severity of AEs were assessed by multivariable logistic regression stratified for brain tumor survivors and survivors of other cancers. Results: The prevalence of AEs was significantly higher in the CRT group compared with the non-CRT group; respectively 81.2% vs. 53.4% of survivors had more than 1 AE (p<.001), and 46.3% vs. 19.2% had at least 5 AEs (p<.001). Significantly more survivors treated with CRT had at least 1 severe, life-threatening or disabling event compared with survivors not treated with CRT (respectively 45.1% vs. 34.8%; p=.002). Alopecia, cognitive, endocrine, metabolic, and neurologic events were among the most frequently scored AEs. Our analyses showed significant dose-effect relationships for these and other AEs. Stratified analyses suggested slightly stronger dose-effect relationships in survivors treated for other cancers than brain tumors. Conclusion: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, taking fractionation dose into account by EQD2 measurements adds strength and precision to the assessment of dose-effect relationships.