A Novel TCP and NTCP Modeling Framework Incorporating Interfractional Deviations and Biological Effectiveness for Hyperfractionated Radiation Therapy

High-dose hyperfractionated radiation therapy has been recently included in NCCN guidelines for limited-stage small cell lung cancer (LS-SCLC), whose clinical outcomes depend on the actually delivered biologically effective dose (BED). However, most tumor control probability (TCP) and normal tissue complication probability (NTCP) models rely on planned physical dose without considering interfractional deviations and BED of fractionization. This study aimed to develop TCP and NTCP models for LS-SCLC incorporating CBCT-based interfractional anatomies and hyperfractional radiobiological dose.

Interfractional dose was accumulated based on deformable image registration between CBCT and planning CT (pCT). Both TCP and NTCP were formulated within a BED-based framework, using dose-volume parameters calculated from planned dose and CBCT-based accumulated dose for comparison. The LQ model with "4R" effects and Gompertzian tumor growth and Lyman-Kutcher-Burman models were used for TCP and NTCP modeling. Based on the receiver operating characteristic curve (AUC), negative log-likelihood (NLL), and Akaike information criterion, model performances were assessed for local progression-free survival, radiation pneumonitis, and radiation esophagitis.

Compared with pCT dose, CBCT dose showed superior discrimination of normal tissue toxicity. For grade ≥2 radiation pneumonitis, the CBCT-based NTCP model achieved a significantly higher AUC (0.67 vs 0.59) and a lower NLL (62.39 vs 66.13) than the pCT-based model. Superiority of the CBCT-based NTCP model was also observed for grade ≥3 radiation esophagitis, that is, AUC (0.62 vs 0.58) and NLL (55.55 vs 56.64). Using the observed local progression-free survival as the reference, marginally improved TCP modeling was observed using CBCT dose compared with pCT, where the AUC values were 0.80 versus 0.79 (GTV 45 Gy) and 0.77 versus 0.75 (GTV 54 Gy).

By incorporating interfractional deviation and biological effectiveness, the improved accuracy of TCP and NTCP models provides preliminary evidence supporting the treatment planning and toxicity management for LS-SCLC patients treated with hyperfractionated radiation therapy, which needs further clinical validation.