Pencil beam scanning (PBS) proton therapy enables better dose conformality for complex anatomical geometries than passive proton scattering techniques, but is more susceptible to organ motion. This becomes an issue when treating moving tumours in the thorax or abdomen. Novel four-dimensional treatment planning approaches have been developed to increase the robustness of PBS plans against motion. However, their efficacy still needs to be examined by means of 4D dynamically accumulated dose (4DDD) analyses.This study investigates the potential use of 4D robust optimisation to maintain sufficient target coverage in the presence of organ motion, while sparing surrounding healthy tissue, for hepatocellular carcinoma (HCC). The liver is particularly suited to study motion interplay effects since the treatment region exhibits smaller density gradients and more homogeneous tissue than targets in the thorax, making it less prone to range errors. A facility-specific beam time model, developed and experimentally validated previously, was used for the clinical evaluation.4DDD analyses of eleven target volumes did not show a significant improvement of the target coverage using 4D robust optimisation, but a reduction of the dose to close-by organs at risk. Interplay effects were averaged out for the applied fractionation scheme of 15 fractions. Contrary to PBS, passive double scattering (DS) plans yielded homogeneous 4DDD dose distributions in a single fraction. But, in some cases, they exceeded organ at risk dose limits, which were only satisfied in PBS. The average normal liver dose could be decreased by almost 6% compared to non-robustly optimised PBS plans and by 16% compared to DS plans when implementing 4D robust optimisation.Except for some very small tumours with large motion amplitudes, 4D robustly optimised PBS plans were found to be clinically acceptable even without supplementary motion mitigation techniques.

Proton therapy makes use of the favorable depth-dose distribution with its characteristic Bragg peak to spare normal tissue distal of the target volume. A steep dose gradient would be desired in lateral dimensions, too. The widespread spot scanning delivery technique is based, however, on pencil-beams with in-air spot full-widths-at-half-maximum of typically 1 cm or more. This hampers the sparing of organs-at-risk if small-scale structures adjacent to the target volume are concerned. The trimming of spot scanning fields with collimating apertures constitutes a simple measure to increase the transversal dose gradient. The current study describes the clinical implementation of brass apertures in conjunction with the pencil-beam scanning delivery mode at a horizontal, clinical treatment head based on commercial hardware and software components. Furthermore, clinical cases, which comprised craniopharyngiomas, re-irradiations and ocular tumors, were evaluated. The dosimetric benefits of 31 treatment plans using apertures were compared to the corresponding plans without aperture. Furthermore, an overview of the radiation protection aspects is given. Regarding the results, robust optimization considering range and setup uncertainties was combined with apertures. The treatment plan optimizations followed a single-field uniform dose or a restricted multi-field optimization approach. Robustness evaluation was expanded to account for possible deviations of the center of the pencil-beam delivery and the mechanical center of the aperture holder. Supplementary apertures improved the conformity index on average by 15.3%. The volume of the dose gradient surrounding the PTV (evaluated between 80 and 20% dose levels) was decreased on average by 17.6%. The mean dose of the hippocampi could be reduced on average by 2.9 GyRBE. In particular cases the apertures facilitated a sparing of an organ-at-risk, e.g. the eye lens or the brainstem. For six craniopharyngioma cases the inclusion of apertures led to a reduction of the mean dose of 1.5 GyRBE (13%) for the brain and 3.1 GyRBE (16%) for the hippocampi.

ObjectiveRadiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden.MethodRetrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE – Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT.ResultsIn total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4–9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date.ConclusionPBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.

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