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

Abstract

Purpose To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve 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-naïve 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 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, 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 D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 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 cm3, D2cm3 ≤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.

Study of relationship between dose, LET and the risk of brain necrosis after proton therapy for skull base tumors

“…Performing systematic study on brain tissue necrosis is challenging. Apart from uncertainties discussed above, other clinical covariates might also contribute to the bias as for instance patient comorbidities and lifestyle [39]. In this context, the setup of inter-institutional studies and standardization of methods of analysis, including the consistency in LET calculation, might be essential to identify a relationship between brain injury and D RBE /LET d effects [40].…”

A Systematic Review of Proton Therapy for the Management of Nasopharyngeal Cancer

“…Of note, IMRT overall TLN rates of up to 15% have been reported with longer follow-up (beyond 5 years) [ 31 , 32 ]; however, these were not graded, thus highlighting the lack of consistency in the reporting of rates. Literature suggests earlier onset of TLN following treatment with proton therapy compared to IMRT [ 33 ], which may be due to lack of conformality at the high-dose region, particularly with older proton techniques as used in the study by Beddok and colleagues [ 19 ]. Furthermore, the dose delivered may be higher at the distal edge, as the RBE can be higher than 1.1.…”

Clinical Outcomes Following Dose-Escalated Proton Therapy for Skull-Base Chordoma

“…McDonald et al [ 26 ] reviewed the outcomes of 66 patients treated for skull-base malignancies and reported a 15% 3-year risk of any-grade temporal lobe radiation necrosis when the absolute volume of a temporal lobe receiving 60 GyRBE exceeded 5.5 cm 3 or 70 GyRBE exceeded 1.7 cm 3 . Other groups have shown similar thresholds, such as using a dose of 62 GyRBE to 2 cm 3 as the relative OAR tolerance dose for planning constraints [ 27 , 28 ]. Although the present rate of temporal lobe injury is less than that found in IMRT series on other advanced skull-base tumors [ 29 – 31 ], further analysis is forthcoming from our group analyzing the relationship of temporal lobe dose to other potential contributing factors.…”