Towards individualized dose constraints: Adjusting the QUANTEC radiation pneumonitis model for clinical risk factors

Abstract

Background. Understanding the dose-response of the lung in order to minimize the risk of radiation pneumonitis (RP) is critical for optimization of lung cancer radiotherapy. We propose a method to combine the dose-response relationship for RP in the landmark QUANTEC paper with known clinical risk factors, in order to enable individual risk prediction. The approach is validated in an independent dataset. Material and methods. The prevalence of risk factors in the patient populations underlying the QUANTEC analysis was estimated, and a previously published method to adjust dose-response relationships for clinical risk factors was employed. Effect size estimates (odds ratios) for risk factors were drawn from a recently published meta-analysis. Baseline values for D₅₀ and γ₅₀ were found. The method was tested in an independent dataset (103 patients), comparing the predictive power of the dose-only QUANTEC model and the model including risk factors. Subdistribution cumulative incidence functions were compared for patients with high/low-risk predictions from the two models, and concordance indices (c-indices) for the prediction of RP were calculated. Results. The reference dose- response relationship for a patient without pulmonary co-morbidities, caudally located tumor, no history of smoking, < 63 years old, and receiving no sequential chemotherapy was estimated as D₅₀⁰ = 34.4 Gy (95% CI 30.7, 38.9), γ₅₀⁰ = 1.19 (95% CI 1.00, 1.43). Individual patient risk estimates were calculated. The cumulative incidences of RP in the validation dataset were not significantly different in high/low-risk patients when doing risk allocation with the QUANTEC model (p = 0.11), but were significantly different using the individualized model (p = 0.006). C-indices were significantly different between the dose-only and the individualized model. Conclusion. This study presents a method to combine a published dose-response function with known clinical risk factors and demonstrates the increased predictive power of the combined model. The method allows for individualization of dose constraints and individual patient risk estimates.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

ALA and IRV are supported by CIRRO – The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research. ALA acknowledges support from the Region of Southern Denmark. IRV is supported by the Global Excellence in Health program of the Capital Region of Denmark. SMB acknowledges support from the National Cancer Institute grant no. 2P30 CA 014520-34.