Does Time to Retreatment Matter? A Normal Tissue Complication Probability Model to Predict Radionecrosis After Repeat Stereotactic Radiosurgery for Recurrent Brain Metastases Incorporating Time-dependent Discounted Dose.

Purpose: To develop and compare normal tissue complication probability (NTCP) models for recurrent brain metastases (BMs) treated with repeat single-fraction stereotactic radiosurgery (SRS), considering time-dependent discounted prior dose.

Methods And Materials: We developed three NTCP models (M0, M1-retreat, and M1-combo models) of BMs treated with GammaKnife-based SRS. The maximum dose is 0.2 cc (D) of the lesion-specific brain, and the 1-year radionecrosis risk is modeled using a logistic response with doses converted into equivalent dose in 2-Gy fractions (EQD2) based on a linear quadratic linear model. The M0 and M1-retreat models, respectively, predicted radionecrosis risk after SRS to 1029 nonrecurrent lesions (patients, 262) and second SRS to 149 recurrent lesions (patients, 87). The M1-combo model accounted for the second SRS and time-dependent discounted first SRS dose for recurrent lesions estimated using a modified Gompertzian function.

Results: All 3 models fitted the data well (χ, 0.039-0.089, and P = 0.999-1.000). The fitted EQD2 was ∼ 103 Gy for the M0 model, ∼ 88 Gy for the M1-retreat model, and ∼ 165 Gy for the M1-combo model. The fitted γ exhibited a progressively flatter dose-response curve across the three models, with values of 1.2 per gray for the M0 model, 0.6 per gray for the M1-retreat model, and 0.4 per gray for the M1-combo model. For the brain D of 29 and 19 Gy, the steepest to shallowest dose-response or largest change in NTCP values, ie, NTCP - NTCP, was observed in the M1-retreat (0.16), M0 (0.14), and M1-combo (0.06) models.

Conclusions: The model-fitted parameters predicted that recurrent BMs would have a lower threshold dose tolerance and a more gradual dose response to the second SRS than nonrecurrent BMs. This gradual dose-response becomes even more apparent when considering the time-dependent discounted first SRS as a cumulative second SRS. Tailoring SRS retreatment protocols based on NTCP modeling can potentially enhance therapeutic efficacy.