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Purpose: The use of motion mitigation techniques such as breath-hold can reduce the dosimetric uncertainty of lung cancer proton therapy. We studied the feasibility of pencil beam scanning (PBS) proton therapy field delivery within a single breath-hold at PSI's Gantry 2. Methods: In PBS proton therapy, the delivery time for a field is determined by the beam-on time and the dead time between proton spots (the time required to change the energy and/or lateral position). We studied ways to reduce beam-on and lateral scanning time, without sacrificing dosimetric plan quality, aiming at a single field delivery time of 15 seconds at maximum. We tested this approach on 10 lung cases with varying target volumes. To reduce the beam-on time, we increased the beam current at the isocenter by developing new beam optics for PSI's PROSCAN beamline and Gantry 2. To reduce the dead time between the spots, we used spot-reduced plan optimization. Results: We found that it is possible to achieve conventional fractionated (2 Gy(RBE)/fraction) and hypofractionated (6 Gy(RBE)/fraction) field delivery times within a single breath-hold (, Radiotherapy & Oncology, 174, ISSN:0167-8140, ISSN:1879-0887

PURPOSE/OBJECTIVES To develop a normal tissue complication probability (NTCP) model including clinical and dosimetric parameters for high-grade temporal lobe radionecroses (TRN) after pencil beam scanning (PBS) proton therapy (PT). MATERIALS/METHODS Data of 299 patients with skull base and Head and Neck tumors treated with PBS PT with a total dose of ���60 GyRBE from 05/2004-11/2018 were included. Patients with a ��� grade (G) 2 TRN (CTCAE v5.0 criteria) were considered as having a high-grade TRN. Nine clinical and 27 dosimetric parameters were considered for structure-wise modelling. After elimination of strongly cross-correlated variables, logistic regression models were generated using penalized LASSO regression. Bootstrapping was performed to assess parameter selection robustness. Model performance was evaluated via cross-correlation by assessing the area under the curve of receiver operating characteristic curves (AUC-ROC) and calibration with a Hosmer-Lemeshow test statistic. RESULTS After a median radiological follow-up of 51.5 months (range, 4-190), 27 (9%) patients developed a ��� G2 TRN. Eleven patients had bitemporal necrosis, resulting in 38 events in 598 temporal lobes for structure-wise analysis. During Bootstrapping analysis, the highest selection frequency was found for prescription dose (PD), followed by Age, V40Gy[%], Hypertension (HBP) and D1cc[Gy]. During cross validation Age*PD* D1cc[Gy]*HBP was superior in all described test statistics. Full cohort structure wise and patient wise models were built with a maximum AUC-ROC of 0.79 (structure-wise) and 0.76 (patient-wise). CONCLUSION While developing a logistic regression NTCP model to predict ��� G2 TRN, the best fit was found for the model containing Age, PD, D1cc[Gy] and HBP as risk factors. External validation will be the next step to improve generalizability and potential introduction into clinical routine.

Background and purpose: Model-based selection of proton therapy patients relies on a predefined reduction in normal tissue complication probability (NTCP) with respect to photon therapy. The decision is necessarily made based on the treatment plan, but NTCP can be affected when the delivered treatment deviates from the plan due to delivery inaccuracies. Especially for proton therapy of lung cancer, this can be important because of tissue density changes and, with pencil beam scanning, the interplay effect between the proton beam and breathing motion. Materials and methods: In this work, we verified whether the expected benefit of proton therapy is retained despite delivery inaccuracies by reconstructing the delivered treatment using log-file based dose reconstruction and inter- and intrafractional accumulation. Additionally, the importance of two uncertain parameters for treatment reconstruction, namely deformable image registration (DIR) algorithm and α/β ratio, was assessed. Results: The expected benefit or proton therapy was confirmed in 97% of all studied cases, despite regular differences up to 2 percent point (p.p.) NTCP between the delivered and planned treatments. The choice of DIR algorithm affected NTCP up to 1.6 p.p., an order of magnitude higher than the effect of α/β ratio. Conclusion: For the patient population and treatment technique employed, the predicted clinical benefit for patients selected for proton therapy was confirmed for 97.0% percent of all cases, although the NTCP based proton selection was subject to 2 p.p. variations due to delivery inaccuracies., Radiotherapy & Oncology, 182, ISSN:0167-8140, ISSN:1879-0887

AIMS Sacral chordomas are locally aggressive, radio-resistant tumours. Proton therapy has the potential to deliver high radiation doses, which may improve the therapeutic ratio when compared with conventional radiotherapy. We assessed tumour control and radiation-induced toxicity in a cohort of sacral chordoma patients treated with definitive or postoperative pencil beam scanning proton therapy. METHODS AND MATERIALS Sixty patients with histologically proven sacral chordoma treated between November 1997 and October 2018 at the Paul Scherrer Institute with postoperative (n = 50) or definitive proton therapy (n = 10) were retrospectively analysed. Only 10 (17%) patients received combined photon radiotherapy and proton therapy. Survival rates were calculated using the Kaplan-Meier actuarial method. The Log-rank test was used to compare different functions for local control, freedom from distant recurrence and overall survival. Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. RESULTS The median follow-up was 48 months (range 4-186). Local recurrence occurred in 20 (33%) patients. The 4-year local control, freedom from distant recurrence and overall survival rates were 77%, 89% and 85%, respectively. On univariate analysis, subtotal resection/biopsy (P = 0.02), tumour extension restricted to bone (P = 0.01) and gross tumour volume >130 ml (P = 0.04) were significant predictors for local recurrence. On multivariate analysis, tumour extension restricted to bone (P = 0.004) and gross total resection (P = 0.02) remained independent favourable prognostic factors for local recurrence. Twenty-four (40%), 28 (47%) and eight (11%) patients experienced acute grade 1, 2 and 3 toxicities, respectively. The 4-year late toxicity-free survival was 91%. Two patients developed secondary malignancies to the bladder 3-7 years after proton therapy. CONCLUSIONS Our data indicate that pencil beam scanning proton therapy for sacral chordomas is both safe and effective. Gross total resection, tumour volume

Purpose In proton therapy, the potential of using high-dose rates in the cancer treatment is being explored. High-dose rates could improve efficiency and throughput in standard clinical practice, allow efficient utilization of motion mitigation techniques for moving targets, and potentially enhance normal tissue sparing due to the so-called FLASH effect. However, high-dose rates are difficult to reach when lower energy beams are applied in cyclotron-based proton therapy facilities, because they result in large beam sizes and divergences downstream of the degrader, incurring large losses from the cyclotron to the patient position (isocenter). In current facilities, the emittance after the degrader is reduced using circular collimators; however, this does not provide an optimal matching to the acceptance of the following beamline, causing a low transmission for these energies. We, therefore, propose to use a collimation system, asymmetric in both beam size and divergence, resulting in symmetric emittance in both beam transverse planes as required for a gantry system. This new emittance selection, together with a new optics design for the following beamline and gantry, allows a better matching to the beamline acceptance and an improvement of the transmission. Methods We implemented a custom method to design the collimator sizes and shape required to select high emittance, to be transported by the following beamline using new beam optics (designed with TRANSPORT) to maximize acceptance matching. For predicting the transmission in the new configuration (new collimators + optics), we used Monte Carlo simulations implemented in BDSIM, implementing a model of PSI Gantry 2 which we benchmarked against measurements taken in the current clinical scenario (circular collimators + clinical optics). Results From the BDSIM simulations, we found that the new collimator system and matching beam optics results in an overall transmission from the cyclotron to the isocenter for a 70 MeV beam of 0.72%. This is an improvement of almost a factor of 6 over the current clinical performance (0.13% transmission). The new optics satisfies clinical beam requirements at the isocenter. Conclusions We developed a new emittance collimation system for PSI's PROSCAN beamline which, by carefully selecting beam size and divergence asymmetrically, increases the beam transmission for low-energy beams in current state-of-the-art cyclotron-based proton therapy gantries. With these improvements, we could predict almost 1% transmission for low-energy beams at PSI's Gantry 2. Such a system could easily be implemented in facilities interested in increasing dose rates for efficient motion mitigation and FLASH experiments alike., Medical Physics, 48 (12), ISSN:0094-2405, ISSN:2473-4209, ISSN:1522-8541

Central nervous system (CNS) tumors are the most common solid malignancies in children and adolescents and young adults (C-AYAs). Craniospinal irradiation (CSI) is an essential treatment component for some malignancies, but it can also lead to important toxicity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and, thus, potentially reduced acute and late toxicity. This study aims to report the clinical outcomes and toxicity rates after CSI for C-AYAs treated with PBSPT. Seventy-one C-AYAs (median age: 7.4 years) with CNS tumors were treated with CSI between 2004 and 2021. Medulloblastoma (n = 42: 59%) and ependymoma (n = 8; 11%) were the most common histologies. Median prescribed total PBSPT dose was 54 GyRBE (range: 18-60.4), and median prescribed craniospinal dose was 24 GyRBE (range: 18-36.8). Acute and late toxicities were coded according to Common Terminology Criteria for Adverse Events. After a median follow-up of 24.5 months, the estimated 2-year local control, distant control, and overall survival were 86.3%, 80.5%, and 84.7%, respectively. Late grade ≥3 toxicity-free rate was 92.6% at 2 years. Recurrent and metastatic tumors were associated with worse outcome. In conclusion, excellent tumor control with low toxicity rates was observed in C-AYAs with brain tumors treated with CSI using PBSPT.

Purpose In Germany, Austria, and Switzerland, pretreatment radiotherapy quality control (RT-QC) for tumor bed boost (TB) in non-metastatic medulloblastoma (MB) was not mandatory but was recommended for patients enrolled in the SIOP PNET5 MB trial between 2014 and 2018. This individual case review (ICR) analysis aimed to evaluate types of deviations in the initial plan proposals and develop uniform review criteria for TB boost. Patients and methods A total of 78 patients were registered in this trial, of whom a subgroup of 65 patients were available for evaluation of the TB treatment plans. Dose uniformity was evaluated according to the definitions of the protocol. Additional RT-QC criteria for standardized review of target contours were elaborated and data evaluated accordingly. Results Of 65 initial TB plan proposals, 27 (41.5%) revealed deviations of target volume delineation. Deviations according to the dose uniformity criteria were present in 14 (21.5%) TB plans. In 25 (38.5%) cases a modification of the RT plan was recommended. Rejection of the TB plans was rather related to unacceptable target volume delineation than to insufficient dose uniformity. Conclusion In this analysis of pretreatment RT-QC, protocol deviations were present in a high proportion of initial TB plan proposals. These findings emphasize the importance of pretreatment RT-QC in clinical trials for MB. Based on these data, a proposal for RT-QC criteria for tumor bed boost in non-metastatic MB was developed.

BACKGROUND AND PURPOSE: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. MATERIALS AND METHODS: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. RESULTS: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online. CONCLUSION: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org. ispartof: RADIOTHERAPY AND ONCOLOGY vol:160 pages:259-265 ispartof: location:Ireland status: published

Motion of the tumour during a radiotherapy treatment can compromise the clinical outcome for the cancer patient. To address this challenge the suitability and performance of the Intel RealSense™ D415 depth camera has been investigated as a tool for measuring the respiratory motion of the body surface. The precision of the camera depth data has been characterised as a function of the measurement distance up to 1.2 meters from a stationary and moving surface. The latency of the camera system was also measured. The average standard deviation of depth data in stationary measurements ranged from less than 0.2 mm for the shortest camera-surface distance of 400 mm to 3 mm for a distance of 1200 mm. Similar accuracy is reported for the acquisition of breathing motion with a discrepancy from nominal amplitudes of around 0.5 mm and 5 mm for the two extreme measurement distances. No dependence on the measurement precision has been observed as a function of the motion pattern. Finally, the camera was shown to be able to measure the more patient-like motion of a deformable respiratory motion phantom with an amplitude of surface motion varying from 1.5 – 2.5 mm. Although noisier, the camera data showed good agreement when compared with a NDI Polaris Spectra system. The latency of the Realsense™ system was measured to be 68.6 ms ± 9.6 ms. The results of this work indicate that the D415 RealSense™ depth camera is capable of measurement of external respiratory type motion of an irregular surface.

Purpose Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy. Methods and Materials In this retrospective study, we have investigated proton-specific risk factors by comparing common phenomenological normal tissue complication probability models with a multivariate analysis that includes clinical features on a cohort of patients with skull-base and head and neck cancer treated with pencil beam scanning. Results Although predictive power of the Lyman-Kutcher-Burman and Poisson models was limited for this data set, the addition of clinical variables such as age, tumor involvement, hypertension, or sex remarkably increased model performance. Conclusions Based on our assessment, the maximum dose in the optical apparatus is confirmed the most intuitive risk factor. However, above a certain dose threshold, clinical patient characteristics are the deciding factors for the onset of RION. We observed a tendency toward a volume effect that, if confirmed, would imply a benefit for high precision radiation therapy techniques such as proton therapy for the treatment of patients with high clinical risk for RION.

To assess the incidence and severity of changes in hearing threshold in patients undergoing high-dose pencil-beam-scanning proton therapy (PBS-PT). This retrospective cohort study included fifty-one patients (median 50 years (range, 13-68)) treated with PBS-PT for skull base tumors. No chemotherapy was delivered. Pure tone averages (PTAs)were determined before (baseline) and after PBS-PT as the average hearing thresholds at frequencies of 0.5, 1, 2, and 4 kHz. Hearing changes were calculated as PTA differences between pre-and post-PBS-PT. A linear mixed-effects model was used to assess the relationship between the PTA at the follow-up and the baseline, the cochlea radiation dose intensity, the increased age, and the years after PBS-PT. Included patients were treated for chordoma (n = 24), chondrosarcoma (n = 9), head and neck tumors (n = 9), or meningioma (n = 3), with a mean tumor dose of 71.1 Gy (RBE) (range, 52.0-77.8), and a mean dose of 37 Gy (RBE) (range, 0.0-72.7) was delivered to the cochleas. The median time to the first follow-up was 11 months (IQR, 5.5-33.7). The PTA increased from a median of 15 dB (IQR 10.0-25) at the baseline to 23.8 (IQR 11.3-46.3) at the first follow-up. In the linear mixed-effect model, the baseline PTA (estimate 0.80, 95%CI 0.64 to 0.96

Purpose: The purpose of this work was to provide a flexible platform for FLASH research with protons by adapting a former clinical pencil beam scanning gantry to irradiations with ultrahigh dose rates. Methods: PSI Gantry 1 treated patients until December 2018. We optimized the beamline parameters to transport the 250 MeV beam extracted from the PSI COMET accelerator to the treatment room, maximizing the transmission of beam intensity to the sample. We characterized a dose monitor on the gantry to ensure good control of the dose, delivered in spot-scanning mode. We characterized the beam for different dose rates and field sizes for transmission irradiations. We explored scanning possibilities in order to enable conformal irradiations or transmission irradiations of large targets (with transverse scanning). Results: We achieved a transmission of 86 % from the cyclotron to the treatment room. We reached a peak dose rate of 9000 Gy/s at 3 mm water equivalent depth, along the central axis of a single pencil beam. Field sizes of up to 5x5 mm$^{2}$ were achieved for single spot FLASH irradiations. Fast transverse scanning allowed to cover a field of 16x1.2 cm$^{2}$. With the use of a nozzle-mounted range shifter we are able to span depths in water ranging from 19.6 to 37.9 cm. Various dose levels were delivered with a precision within less than 1 %. Conclusions: We have realized a proton FLASH irradiation setup able to investigate continuously a wide dose rate spectrum, from 1 to 9000 Gy/s in a single spot irradiation as well as in the pencil beam scanning mode. As such, we have developed a versatile test bench for FLASH research., Comment: Submitted to Medical Physics

Background and purpose Deformable image registration (DIR) is an important component for dose accumulation and associated clinical outcome evaluation in radiotherapy. However, as an ill-posed problem, the resulting deformation vector field (DVF) is subject to unavoidable discrepancies when different algorithms are applied, leading to dosimetric uncertainties of the accumulated dose. We propose here an approach for proton therapy to estimate dosimetric uncertainties as a consequence of modeled or estimated DVF uncertainties. Materials and methods A patient-specific DVF uncertainty model was built on the first treatment fraction, by correlating the magnitude differences of five DIR results at each voxel to the magnitude of any single reference DIR. In the following fractions, only the reference DIR needs to be applied, and DVF geometric uncertainties were estimated by this model. The associated dosimetric uncertainties were then derived by considering the estimated geometric DVF uncertainty, the dose gradient of fractional recalculated dose distribution and the direction factor from the applied reference DIR of this fraction. This estimated dose uncertainty was respectively compared to the reference dose uncertainty when different DIRs were applied individually for each dose warping. This approach was validated on seven NSCLC patients, each with nine repeated CTs. Results The proposed model-based method is able to achieve dose uncertainty distribution on a conservative voxel-to-voxel comparison within ±5% of the prescribed dose to the 'reference' dosimetric uncertainty, for 77% of the voxels in the body and 66-98% of voxels in investigated structures. Conclusion We propose a method to estimate DIR induced uncertainties in dose accumulation for proton therapy of lung tumor treatments.

The physico-chemical and biological response to conventional and UHDR electron and proton beams was investigated, along with conventional photons. The temporal structure and nature of the beam affected both, with electron beam at ≥1400 Gy/s and proton beam at 0.1 and 1260 Gy/s found to be isoefficient at sparing zebrafish embryos.

Zusammenfassung Klinisches/methodisches Problem Mundhöhlenmalignome stellen weltweit die häufigsten Tumoren im Bereich der Hals-Nasen-Ohrenheilkunde bzw. Otorhinolaryngologie dar. Es handelt sich um eine heterogene Gruppe an Tumoren, deren Kenntnis erforderlich ist, um den unterschiedlichen Anforderungen an Diagnostik und Therapie gerecht zu werden. Radiologische Standardverfahren Computertomographie (CT), Magnetresonanztomographie (MRT), Sonographie, nuklearmedizinische Verfahren (NUK). Leistungsfähigkeit Die o. g. Diagnostika werden komplementär eingesetzt. Bewertung Eine frühzeitigere Diagnose des Tumors verbessert das Staging und somit die Therapie und Prognose des Patienten. Schlussfolgerung Dem Radiologen kommt bei der interdisziplinären Behandlung von Malignomen der Mundhöhle eine bedeutende Rolle zu. Trotz großer Fortschritte in der Radiotherapie, Onkologie und Immuntherapie spielt die Chirurgie weiterhin eine wichtige Rolle in der Behandlung maligner Erkrankungen der Mundhöhle.

Proton therapy is delivered to selected cancer patients presenting with rare tumours, for which a dose escalation paradigm and/or a reduced dose-bath to the organs at risk is pursued. It is a costly treatment with an additional cost factor of 2–3 when compared to photon radiotherapy. Notwithstanding the 180′000 patients treated with protons, scars robust clinical evidence is available to justify the administration of this treatment modality. The European Particle Therapy Network (EPTN) was created in 2015 to answer the critical European needs for cooperation among protons and carbon ions centres in the framework of clinical research networks. EPTN with other European groups will launch a number of prospective clinical trials that could be practice changing if positive. Alternative way to generate clinical data could be provided by alternative methodologies, such as the Dutch model-based approach, or could be provided by European infrastructure projects.

Purpose To evaluate why small- and certain medium-sized parapapillary choroidal melanoma (pcM) patients treated with hypo-fractionated proton therapy (PT) retain excellent long-term visual acuity (VA) and assess the negative predictive factors for retaining good vision (≤ 0.2 logMAR (≥ 0.6 decimal) after 5 years. Methods This single-center, retrospective, comparative study recruited consecutive pcM patients that were treated with PT. Between 1984 and 2005, 609 patients received a total of 60 CGE, of whom 310 met the following inclusion criteria: posterior tumor border ≤ 2.5 mm from the optic disc, largest tumor diameter ≤ 17.9 mm, tumor thickness ≤ 5.2 mm and available follow-up data for at least 5 years. Results Mean follow-up was 120.8 ± 48.8 months (54.0–295.0). Out of 310 patients, 64 (21%) maintained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years following PT and were allocated to the “good visual outcome” (GVO) group, while the remaining 246 (79%) constituted the “poor visual outcome” (PVO) group, subdivided into 70 (22%) with a VA of 0.3–1.0 logMAR (0.1–0.5 decimal) and 157 (57%) patients with a VA > 1.0 logMAR (P = 0.04), tumor localization ≤ 0.5 mm to the fovea (P P = 0.02 and P Conclusions Of 310 small- to medium-sized pcM patients successfully treated with PT, 21% retained a VA ≤ 0.2 logMAR (≥ 0.6 decimal) for at least 5 years. Strongest negative predictive factor for retaining good long-term vision was the volume of the macula irradiated with at least 30 Gy.

More efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma.Nineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2-8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation.The mean result of maximum organ motion was 2.7 mm (cranial-caudal), 1.2 mm (left-right), 1.0 mm (anterior-posterior). Four anaesthetised children (21%) showing5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, -0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7-49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2-4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed.The early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of5 mm.

Particle therapy using protons or heavier ions is currently the most advanced form of radiotherapy and offers new opportunities for improving cancer care and research. Ions deposit the dose with a sharp maximum – the Bragg peak – and normal tissue receives a much lower dose than what is delivered by X‐ray therapy. Particle therapy has also biological advantages due to the high linear energy transfer of the charged particles around the Bragg peak. The introduction of particle therapy has been slow in Europe, but within the last decade, more than 20 clinical facilities have opened and facilitated access to this frontline therapy. In this review article, the basic concepts of particle therapy are reviewed along with a presentation of the current clinical indications, the European clinical research, and the established networks., Particle therapy using protons, or heavier ions, is the most advanced form of radiotherapy today and offers new opportunities for improving cancer care and research. Within the last decade, more than 20 new clinical facilities have opened in Europe, facilitating access to this frontline therapy. This review presents the physics, biology, and clinical aspects of particle therapy.

Background and purpose Non-small cell lung cancer (NSCLC) patients show typically large anatomical changes during treatment, making recalculation or adaption necessary. For report and review, the applied treatment dose can be accumulated on the reference planning CT using deformable image registration (DIR). We investigated the dosimetric impact of using six different clinically available DIR algorithms for dose accumulation in presence of inter-fractional anatomy variations. Materials and methods For seven NSCLC patients, proton treatment plans with 66 Gy-RBE to the planning target volume (PTV) were optimised. Nine repeated CTs were registered to the planning CT using six DIR algorithms each. All CTs were acquired in visually guided deep-inspiration breath-hold. The plans were recalculated on the repeated CTs and warped back to the planning CT using the corresponding DIRs. Fraction doses warped with the same DIR were summed up to six different accumulated dose distributions per patient, and compared to the initial dose. Results The PTV-V95 of accumulated doses decreased by 16% on average over all patients, with variations due to DIR selection of 8.7%. A separation of the dose effects caused by anatomical changes and DIR uncertainty showed a good agreement between the dose degradation caused by anatomical changes and the dose predicted from the average of all DIRs (differences of only 1.6%). Conclusion The dose degradation caused by anatomical changes was more pronounced than the uncertainty of employing different DIRs for dose accumulation, with averaged results from several DIRs providing a good representation of dose degradation caused by anatomy. However, accumulated dose variations between DIRs can be substantial, leading to an additional dose uncertainty., Radiotherapy & Oncology, 147, ISSN:0167-8140, ISSN:1879-0887

Purpose Ocular proton therapy is an effective therapeutic option for patients affected with uveal melanomas. An optical eye-tracking system (ETS) aiming at noninvasive motion monitoring was developed and tested in a clinical scenario. Materials and methods The ETS estimates eye position and orientation at 25 frames per second using the three-dimensional position of pupil and cornea curvature centers identified, in the treatment room, through stereoscopic optical imaging and infrared eye illumination. Its capabilities for automatic detection of eye motion were retrospectively evaluated on 60 treatment fractions. Then, the ETS performance was benchmarked against the clinical standard based on visual control and manual beam interruption. Results Eye-tracking system detected eye position successfully in 97% of all available frames. Eye-tracking system-based eye monitoring during therapy guarantees quicker response to involuntary eye motions than manual beam interruptions and avoids unnecessary beam interruptions. Conclusions Eye-tracking system shows promise for on-line monitoring of eye motion. Its introduction in the clinical workflow will guarantee a swifter treatment course for the patient and the clinical personnel.

The physico-chemical and biological response to conventional and UHDR electron and proton beams was investigated, along with conventional photons. The temporal structure and nature of the beam affected both, with electron beam at ≥1400 Gy/s and proton beam at 0.1 and 1260 Gy/s found to be isoefficient at sparing zebrafish embryos.

Objective.This paper reports on the implementation and shows examples of the use of theProTheRaMonframework for simulating the delivery of proton therapy treatment plans and range monitoring using positron emission tomography (PET).ProTheRaMonoffers complete processing of proton therapy treatment plans, patient CT geometries, and intra-treatment PET imaging, taking into account therapy and imaging coordinate systems and activity decay during the PET imaging protocol specific to a given proton therapy facility. We present theProTheRaMonframework and illustrate its potential use case and data processing steps for a patient treated at the Cyclotron Centre Bronowice (CCB) proton therapy center in Krakow, Poland.Approach.TheProTheRaMonframework is based on GATE Monte Carlo software, theCASToRreconstruction package and in-house developed Python and bash scripts. The framework consists of five separated simulation and data processing steps, that can be further optimized according to the user’s needs and specific settings of a given proton therapy facility and PET scanner design.Main results.ProTheRaMonis presented using example data from a patient treated at CCB and the J-PET scanner to demonstrate the application of the framework for proton therapy range monitoring. The output of each simulation and data processing stage is described and visualized.Significance.We demonstrate that theProTheRaMonsimulation platform is a high-performance tool, capable of running on a computational cluster and suitable for multi-parameter studies, with databases consisting of large number of patients, as well as different PET scanner geometries and settings for range monitoring in a clinical environment. Due to its modular structure, theProTheRaMonframework can be adjusted for different proton therapy centers and/or different PET detector geometries. It is available to the community via github (Boryset al2022).

Purpose: To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer.Materials and methods: All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%(iCTVtotal)) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes.Results: All PT and XT plans complied with V95% (iCTVtotal) >99% for the nominal plan and V95% (iCTVtotal) >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95% (iCTVtotal) in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95% (iCTVtotal) was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%(iCTVtotal) was >85%.Conclusion: Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans. (C) 2022 The Author(s). Published by Elsevier B.V.

BACKGROUND AND PURPOSE: Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. MATERIALS AND METHODS: We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. RESULTS: Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). CONCLUSION: Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT. ispartof: RADIOTHERAPY AND ONCOLOGY vol:167 pages:7-13 ispartof: location:Ireland status: published

Objective. In pencil beam scanning proton therapy, individually calculated and positioned proton pencil beams, also referred to as 'spots', are used to achieve a highly conformal dose distributions to the target. Recent work has shown that this number of spots can be substantially reduced, resulting in shorter delivery times without compromising dosimetric plan quality. However, the sensitivity of spot-reduced plans to tumour motion is unclear. Although previous work has shown that spot-reduced plans are slightly more sensitive to small positioning inaccuracies of the individual pencil beams, the resulting shorter delivery times may allow for more rescanning. The aim of this study was to assess the impact of tumour motion and the effectiveness of 3D volumetric rescanning for spot-reduced treatment plans. Approach. Three liver and two lung cancer patients with non-negligible motion amplitudes were analysed. Conventional and probabilistic internal target volume definitions were used for planning considering single or multiple breathing cycles respectively. For each patient, one clinical and two spot-reduced treatment plans were created using identical field geometries. 4D dynamic dose calculations were then performed and resulting target coverage (V95%), dose homogeneity (D5%-D95%) and hot spots (D2%) evaluated for 1-25 rescans. Main results. Over all patients investigated, spot reduction reduced the number of spots by 91% in comparison to the clinical plan, reducing field delivery times by approximately 50%. This reduction, together with the substantially increased dose per spot resulting from the spot reduction process, allowed for more rescans in the same amount of time as for clinical plans and typically improved dosimetric parameters, in some cases to values better than the reference static (3D calculated) plans. However, spot-reduced plans had an increased possibility of interference with the breathing cycle, especially for simulations of perfectly repeatable breathing. Significance. For the patients analysed in this study, spot-reduced plans were found to be a valuable option to increase the efficiency of 3D volumetric rescanning for motion mitigation, if attention is paid to possible interference patterns., Physics in Medicine and Biology, 67 (21), ISSN:1361-6560, ISSN:0031-9155

BACKGROUND With improved survival rates for children with cancer, quality-of-life (QoL) issues have increasingly become the focus of attention. We report the QoL of children with Ewing sarcoma (EWS) treated with pencil-beam-scanning proton therapy (PT). METHODS A PEDQOL (QoL questionnaire for children 4-18 years) self/proxy questionnaire was used to prospectively assess the QoL of 23 children

Purpose/objective(s) Calculation of tumor control probability (TCP) and normal tissue complication probability (NTCP) is becoming increasingly relevant for optimizing treatment strategies, for example the selection of patients for proton therapy. While radiobiological models are typically built and evaluated on the planned treatment dose, no consensus exists for their evaluation in the context of varying patient anatomy during treatment. For example, different adaptive strategies can lead to different expected treatment outcomes for the same planned dose. This shows that TCP/NTCP needs to be calculated from the cumulative treatment dose resulting from multiple fraction doses and patient geometries. In this study, different methods of applying TCP and NTCP models to treatments with anatomical changes are developed and compared. These methods were evaluated on an example of locally advanced non-small cell lung cancer (NSCLC) patients using two extreme scenarios: no adaption vs online daily adaptive proton therapy (DAPT). Materials/methods Three methods to calculate TCP/NTCP in the context of anatomical changes were compared: (I) based on the accumulated treatment doses. Six different deformable image registration (DIR) algorithms were used to accumulate the dose, then the TCP/NTCP was calculated on all accumulated doses showing the variation due to the DIR. (II) based on the cumulative effective uniform dose (EUD) of each fraction. (III) based on each fraction dose directly, permitting an evaluation of the mean and variation of TCP/NTCP during treatment. To test and compare these methods, proton therapy treatment plans were generated on deep inspiration breath-hold (DIBH) planning CTs for 5 NSCLC patients (66 Gy-RBE, 33 fractions). Non-adapted and DAPT treatment doses were created by recalculating and reoptimizing these plans on nine repeated CTs. TCP/NTCP calculations were performed with all three methods. Results All methods showed consistent results between no adaption and DAPT. Two patients showed substantial TCP reductions up to 33% without adaption. Three patients, despite anatomical changes and dose differences, did not show a reduced calculated TCP with all methods. For most patients, NTCP differences between DAPT and no adaption were moderate, but one showed improvement in predicted 2-year survival based on heart toxicity with DAPT. Furthermore, the absolute NTCP calculated with method (I) showed variations of up to 7% depending on the DIR algorithm used for dose accumulation. Conclusion The three proposed methods of calculating clinical outcome based on treatment doses showed consistent result between DAPT and non-adapted treatments. Three patients showed benefits with DAPT, so the calculated NTCP could be reduced or calculated TCP maintained. For two patients the dose differences with adaption did not translate in clinically relevant effects. The proposed outcome calculation methods enable a more realistic quantification of TCP/NTCP of different adaptive strategies.