Temporal Lobe Necrosis in Head and Neck Cancer Patients after Proton Therapy to the Skull Base

Purpose: To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naive patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods: Medical records and dosimetric data for radiation-naive patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with <3 months of follow-up, receiving <45 GyRBE or nonconventional fractionation, and/or no follow-up magnetic resonance imaging (MRI) were excluded. TLN was determined using MRI and graded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Clinical (gender, age, comorbidities, concurrent chemotherapy, smoking, radiation techniques) and dose-volume parameters were analyzed for TLN correlation. The receiver operating characteristic curve and area under the curve (AUC) were performed to determine the cutoff points of significant dose-volume parameters. Results: Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2-69.3). Overall TLN rates of any grade, >= grade 2, and >= grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm(3) volume receiving the maximum dose (D0.5cm(3), D1cm(3), and D2cm(3), respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm(3) gave the highest AUC (0.935) among dose parameters. The 11-cm(3) cutoff value for aV50 and 62 GyRBE for D2cm(3) showed maximum specificity and sensitivity. Conclusion: The estimated 2-year TLN rate was 4.6% with a low rate of toxicities >= grade 3; aV50 <= 11 cm(3), D2cm(3) <= 62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.