Purpose: This study aimed to assess interfraction stability of the delivered dose distribution by exhale-gated volumetric modulated arc therapy (VMAT) or intensity-modulated arc therapy (IMAT) for lung cancer and to determine dominant prognostic dosimetric and geometric factors.

Methods: Clinical target volume (CTV_Plan) from the planning CT was deformed to the exhale-gated daily CBCT scans to determine CTV_i, treated by the respective dose fraction. The equivalent uniform dose of the CTV_i was determined by the power law (gEUD_i) and cell survival model (EUD_iSF) as effectiveness measure for the delivered dose distribution. The following prognostic factors were analyzed: (I) minimum dose within the CTV_i (D_{min_i}), (II) Hausdorff distance (HDD_i) between CTV_i and CTV_Plan, (III) doses and deformations at the point in CTV_Plan at which the global minimum dose over all fractions per patient occurs (PD_{min_global_i}), and (IV) deformations at the point over all CTV_i margins per patient with the largest Hausdorff distance (HDPw_orst). Prognostic value and generalizability of the prognostic factors were examined using cross-validated random forest or multilayer perceptron neural network (MLP) classifiers. Dose accumulation was performed using back deformation of the dose distribution from CTV_i to CTV_Plan.

Results: Altogether, 218 dose fractions (10 patients) were evaluated. There was a significant interpatient heterogeneity between the distributions of the normalized gEUD_i values (p<0.0001, Kruskal–Wallis tests). Accumulated gEUD over all fractions per patient was 1.004–1.023 times of the prescribed dose. Accumulation led to tolerance of ~20% of fractions with gEUD_i<93% of the prescribed dose. Normalized D_min >60% was associated with predicted gEUD values above 95%. D_min had the highest importance for predicting the gEUD over all analyzed prognostic parameters by out-of-bag loss reduction using the random forest procedure. Cross-validated random forest classifier based on D_min as the sole input had the largest Pearson correlation coefficient (R=0.897) in comparison to classifiers using additional input variables. The neural network performed better than the random forest classifier, and the gEUD values predicted by the MLP classifier with D_min as the sole input were correlated with the gEUD values characterized by R=0.933 (95% CI, 0.913–0.948). The performance of the full MLP model with all geometric input parameters was slightly better (R=0.952) than that based on D_min (p=0.0034, Z-test).

Conclusion: Accumulated dose distributions over the treatment series were robust against interfraction CTV deformations using exhale gating and online image guidance. D_min was the most important parameter for gEUD prediction for a single fraction. All other parameters did not lead to a markedly improved generalizable prediction. Dosimetric information, especially location and value of D_min within the CTV_i, are vital information for image-guided radiation treatment.