Pneumonitis after normofractionatedi Radoimmunotherapy: A method for Dose-Volume-Effect Correlation Evaluation

Abstract Background Post-Therapy-Pneumonitis (PTP) is a critical side effect of both, thoracic radio(chemo)therapy (R(C)T) and immune checkpoint inhibition (ICI). However, disease characteristics and patient-specific risk factors of PTP after combined R(C)T + ICI are less understood. Given that RT-triggered PTP is strongly dependent on the volume and dose of RT, driven by inflammatory mechanisms, we hypothesize that combination therapy of R(C)T with ICI influences the dose-volume-effect correlation for PTP. This study focuses on the development of a method for evaluation of alterations in the dose-volume-effect correlation of PTP after R(C)T with and without ICI. Methods and materials PTP volumes were delineated on the follow-up diagnostic Computed Tomography (CT) and deformably matched to the planning CT. Dose data was converted to 2-Gy equivalent doses (EQD2) and dosimetrically analyzed. The method was exemplarily tested on an internal patient cohort including 90 patients having received thoracic R(C)T + ICI (39) and R(C)T (51). Additionally, data on previous chemotherapy and RT, smoking status and pulmonary co-morbidity was conducted. An exploratory analysis has been performed and a matched pair analysis with regard to planning target volumes (PTV) was conducted for curative intended (definitive) and palliative patient cohorts individually. Results The presented method was able to demonstrate differences in the dose-volume-effect-correlation of PTP for the different therapies. The dosimetric analysis revealed large volumetric fractions (55%) of the PTP volumes to be located outside of high dose (EQD2 < 40 Gy) regions for R(C)T + ICI. There was a non-significant trend towards increased AUC values for R(C)T + ICI compared to R(C)T only (3743.6 Gy∙% vs. 2848.8 Gy∙%; p-value = 0.171). In contrast to the data for the palliative intended treatment group, for definitive R(C)T + ICI, data tended towards increased volumes with higher doses. Conclusions The proposed method was capable to demonstrate dosimetric differences in the dose-volume-effect relationship of PTP for patients with R(C)T + ICI and patients with R(C)T only. In this exploratory analysis, the patient cohorts were too small and inhomogeneous to reveal statistically significant dosimetric differences within PTP volumes for the different groups. However, our observations suggest, that for safe application of thoracic R(C)T + ICI, further careful investigation of dosimetric prescription and analysis concepts with larger and conformer study groups is recommendable.