Investigation of the combined role of dose and dose-averaged LET in the occurrence of brain necrosis after intensity modulated proton therapy for meningioma and solitary fibrous tumours.

BACKGROUND AND PURPOSE: To investigate the combined effect of RBE-weighted dose (DRBE) and dose-averaged linear energy transfer (LETd) on the development of brain radionecrosis (BRN) in patients with intracranial meningioma and solitary fibrous tumors treated with intensity modulated proton therapy (IMPT).

MATERIALS AND

METHODS

The study included 124 patients with a median follow-up of 47.4 months (range 5.8 ÷ 109.6). Dose prescriptions ranged between 54 and 66 Gy(RBE) (RBE = 1.1) in 28 ÷ 33 fractions. Patients reporting a BRN of grade ≥ 1 (CTCAE v5.0) at follow-up constituted the adverse event (AE) group (n = 26). The remaining 98 patients constituted the control group. The BRN volume was contoured on the follow-up MRI images that first revealed the presence of the AE. We extracted both DRBE and LETd distributions to build the cumulative dose LETd volume histogram (DLVH) of the healthy-brain. Univariable and multivariable logistic regressions were fitted to explore the impact of DLVH indexes on BRN (α = 0.01). Voxel-wise analysis was performed on the AE group using greedy random matching (caliper = 0.1) to match healthy-brain with AE voxels with a 5 Gy(RBE) dose-binning. A logistic mixed-effects model (random intercept) was fitted for each bin (α = 0.05).

RESULTS

The best fitting DLVH index was selected as the median partial brain volume receiving a DRBE > 42.9 Gy(RBE) and LETd > 4.6 keV/µm (8.2 cc for the AE group and 1.1 cc for the control group). The effect of LETd reached the highest statistically significant impact in the dose bin 40-45 Gy(RBE) (OR: 2.24 [1.62; 3.20], q(False Discovery Rate-adjusted) = 0.01).

CONCLUSION

We identified a DLVH constraint, predictive of BRN, to be implemented in clinical practice aiming at a reduction of treatment toxicity.