Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT. For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LET_d) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve. An overall statistically significant RAIC association with dose and LET_d was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LET_d, respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LET_d effect demonstrated increased risk of RAIC with increasing LET_d for the majority of patients. Estimated probability of RAIC with LET_d = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD₁₅ were estimated to be 63.6 and 50.1 Gy with LET_d equal to 2 and 5 keV/µm, respectively. Our results suggest that the LET_d effect could be of clinical significance for some patients; LET_d assessment in clinical treatment plans should therefore be taken into consideration.

Enhancing treatment of locally advanced non-small cell lung cancer (LA-NSCLC) by using pencil beam scanning proton therapy (PBS-PT) is attractive, but little knowledge exists on the effects of uncertainties occurring between the planning (Plan) and the start of treatment (Start). In this prospective simulation study, we investigated the clinical potential for PBS-PT under the influence of such uncertainties. Imaging with 4DCT at Plan and Start was carried out for 15 patients that received state-of-the-art intensity-modulated radiotherapy (IMRT). Three PBS-PT plans were created per patient: 3D robust single-field uniform dose (SFUD), 3D robust intensity-modulated proton therapy (IMPT), and 4D robust IMPT (4DIMPT). These were exposed to setup and range uncertainties and breathing motion at Plan, and changes in breathing motion and anatomy at Start. Target coverage and dose-volume parameters relevant for toxicity were compared. The organ at risk sparing at Plan was greatest with IMPT, followed by 4DIMPT, SFUD and IMRT, and persisted at Start. All plans met the preset criteria for target robustness at Plan. At Start, three patients had a lack of CTV coverage with PBS-PT. In conclusion, the clinical potential for heart and lung toxicity reduction with PBS-PT was substantial and persistent. Altered breathing patterns between Plan and Start jeopardized target coverage for all PBS-PT techniques.

Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probabil...

Background and purpose: To characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC). Material and methods: 127 patients treated with PT for HNC who had received at least 40 Gy(RBE) to the brain and had ≥ 1 follow-up MRI > 6 months after PT were analyzed. MRIs were reviewed for radiation- associated image changes (RAIC). MRIs were rigidly registered to planning CTs, and RAIC were contoured on T1 (post-contrast) and T2 weighted sequences, and dose-volume parameters extracted. Probability of RAIC over time was calculated using multistate analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose-volume correlates of RAIC development. Results: 17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the RAIC on post-contrast T1 was 0.5 cc at their maximum size. The RAIC spontaneously resolved in 27.3%, progressed in 27.3% and improved or were stable in 29.6% of patients. The 3-year actuarial rate of developing RAIC was 14.3%. Brain and RAIC lesion doses were generally higher for temporal lobe RAIC compared to frontal lobe RAIC. RAIC was observed in 63% of patients when V _{67 Gy(RBE)} of the brain ≥ 0.17 cc. Conclusion: RAIC lesions after PT were asymptomatic and either resolved or regressed in the majority of the patients. The estimated dose–volume correlations confirm the importance of minimizing focal high doses to brain when achievable.