First clinical implementation of a highly efficient daily online adapted proton therapy (DAPT) workflow.

OBJECTIVE: This study presents the first clinical implementation of an efficient online daily adaptive proton therapy workflow (DAPT). Approach: The DAPT workflow includes a pre-treatment phase, where a template and a fallback plan are optimized on the planning CT. In the online phase, the adapted plan is re-optimized on daily images from an in-room CT. Daily structures are rigidly propagated from the planning CT. Automated quality assurance (QA) involves geometric, sanity checks and an independent dose calculation from the machine files. Differences from the template plan are analyzed field-by-field, and clinical plan is assessed by reviewing the achieved clinical goals using a traffic light protocol. If the daily adapted plan fails any QA or clinical goals, the fallback plan is used. In the offline phase the delivered dose is recalculated from log-files onto the daily CT, and a gamma analysis is performed (3%/3mm). The DAPT workflow has been applied to selected adult patients treated in rigid anatomy for the last serie of the treatment between October 2023 and April 2024. Main Results: DAPT treatment sessions averaged around 23 minutes [range: 15-30 min] and did not exceed the typical 30-minute time slot. Treatment adaptation, including QA and clinical plan assessment, averaged just under 7 minutes [range: 3:30-16 min] per fraction. All plans passed the online QAs steps. In the offline phase a good agreement with the log-files reconstructed dose was achieved (minimum gamma pass rate of 97.5 %). The online adapted plan was delivered for > 85% of the fractions. In 92% of total fractions, adapted plans exhibited improved individual dose metrics to the targets and/or organs at risk. Significance: This study demonstrates the successful implementation of an online daily DAPT workflow. Notably, the duration of a DAPT session did not exceed the time slot typically allocated for non-DAPT treatment. As far as we are aware, this is a first clinical implementation of daily online adaptive proton therapy. .

Deformable vector fields warping for modelling of irregular breathing.

Purpose 4D computed tomography (4DCT) is the clinical standard to image organ motion in radiotherapy, although it is limited in imaging breathing variability. We propose a method to transfer breathing motion across longitudinal imaging datasets to include intra-patient variability and verify its performance in lung cancer patients. Methods Five repeated control 4DCTs for 6 non-small cell lung cancer patients were combined into multi-breath datasets (m4DCT) by merging stages of deformable image registration to isolate respiratory motion. The displacement of the centre of mass of the primary tumour and its volume changes were evaluated to quantify intra-patient differences. Internal target volumes defined on the m4DCT were compared with those conventionally drawn on the 4DCT. Results Motion analysis suggests no discontinuity at the junction between successive breaths, confirming the method's ability to merge repeated imaging into a continuum. Motion (variability) is primarily in superior-inferior direction and goes from 14.4 mm (8.7 mm) down to 0.1 mm (0.6 mm), respectively for tumours located in the lower lobes or most apical ones. On average, up to 65% and 74% of the tumour volume was subject to expansion or contraction in the inhalation and exhalation phases. These variations lead to an enlargement of the ITV up to 8% of its volume in our dataset. Conclusion 4DCT can be extended to model variable breathing motion by adding synthetic phases from multiple time-resolved images. The inclusion of this improved knowledge of patients' breathing allows better definition of treatment volumes and their margins for radiation therapy. .

Retrospective reconstruction of four-dimensional magnetic resonance from interleaved cine imaging - A comparative study with four-dimensional computed tomography in the lung.

Background and purpose: Imaging of respiration-induced anatomical changes is essential to ensure high accuracy in radiotherapy of lung cancer. We expanded here on methods for retrospective reconstruction of time-resolved volumetric magnetic resonance (4DMR) of the thoracic region and benchmarked the results against 4D computed tomography (4DCT). Materials and method: MR data of six lung cancer patients were collected by interleaving cine-navigator images with 2D data frame images, acquired across the thorax. The data frame images have been stacked in volumes based on a similarity metric that considers the anatomical deformation of lungs, while addressing ambiguities in respiratory phase detection and interpolation of missing data. The resulting images were validated against cine-navigator images and compared to paired 4DCTs in terms of amplitude and period of motion, assessing differences in internal target volume (ITV) margin definition. Results: 4DMR-based motion amplitude was on average within 1.8 mm of that measured in the corresponding 2D cine-navigator images. In our dataset, the 4DCT motion and the 4DMR median amplitude were always within 3.8 mm. The median period was generally close to CT references, although deviations up to 24 % have been observed. These changes were reflected in the ITV, which was generally larger for MRI than for 4DCT (up to 39.7 %). Conclusions: The proposed algorithm for retrospective reconstruction of time-resolved volumetric MR provided quality anatomical images with high temporal resolution for motion modelling and treatment planning. The potential for imaging organ motion variability makes 4DMR a valuable complement to standard 4DCT imaging.

Exploring beamline momentum acceptance for tracking respiratory variability in lung cancer proton therapy: a simulation study.

Objective. Investigating the aspects of proton beam delivery to track organ motion with pencil beam scanning therapy. Considering current systems as a reference, specify requirements for next-generation units aiming at real-time image-guided treatments.Approach. Proton treatments for six non-small cell lung cancer (NSCLC) patients were simulated using repeated 4DCTs to model respiratory motion variability. Energy corrections required for this treatment site were evaluated for different approaches to tumour tracking, focusing on the potential for energy adjustment within beamline momentum acceptance (dp/p). A respiration-synchronised tracking, taking into account realistic machine delivery limits, was compared to ideal tracking scenarios, in which unconstrained energy corrections are possible. Rescanning and the use of multiple fields to mitigate residual interplay effects and dose degradation have also been investigated.Main results. Energy correction requirements increased with motion amplitudes, for all patients and tracking scenarios. Higher dose degradation was found for larger motion amplitudes, rescanning has beneficial effects and helped to improve dosimetry metrics for the investigated limited dp/pof 1.2% (realistic) and 2.4%. The median differences between ideal and respiratory-synchronised tracking show minimal discrepancies, 1% and 5% respectively for dose coverage (CTV V95) and homogeneity (D5-D95). Multiple-field planning improves D5-D95 up to 50% in the most extreme cases while it does not show a significant effect on V95.Significance. This work shows the potential of implementing tumour tracking in current proton therapy units and outlines design requirements for future developments. Energy regulation within momentum acceptance was investigated to tracking tumour motion with respiratory-synchronisation, achieving results in line with the performance of ideal tracking scenarios. ±5% Δp/p would allow to compensate for all range offsets in our NSCLC patient cohort, including breathing variability. However, the realistic momentum of 1.2% dp/prepresentative of existing medical units limitations, has been shown to preserve plan quality.

A bi-directional beam-line energy ramping for efficient patient treatment with scanned proton therapy.

Objective.The treatment of mobile tumours using Pencil Beam Scanning (PBS) has become more prevalent in the last decade. However, to achieve the same beam delivery quality as for static tumours, treatments have to be combined with motion mitigation techniques, not limited but including, breath hold, gating and re-scanning, which typically prolong treatment time. In this article we present a novel method of bi-directional energy modulation and demonstrate our initial experience in improvement of treatment efficiency. Approach.At Paul Scherrer Institute Gantry 2 mobile tumours are treated by combining PBS with gating and volumetric re-scanning (VR), where the target volume is irradiated multiple times. Initial implementation of VR used only descending beam energies, creating a substantial dead time due to the beam-line initialization (ramping) before each re-scan. In 2019 we commissioned an energy meandering strategy that allows us to avoid beam line ramping in-between energy series while maintaining beam delivery quality.Main results.The measured beam parameters difference for both energy sequence are in the order of the typical daily variations: 0.2 mm in beam position and 0.2 mm in range. Using machine log files, we performed point-to-point dose difference calculations between original and new applications where we observed dose differences of less than 2%. After three years of operation employing bi-directional energy modulation, we have analysed the individual beam delivery time for 181 patients and have compared this to simulations of the timing behaviour assuming uni-directional energy sequence application. Depending on treatment complexity, we obtained plan delivery time reductions of up to 55%, with a median time gain of 17% for all types of treatments.Significance. Bi-directional energy modulation can help improving patient treatment efficiency by reducing delivery times especially for complex and specialised irradiations. It could be implemented in many existing facilities without significant additional hardware upgrades.

Detection of range shifts in proton beam therapy using the J-PET scanner: a patient simulation study.

OBJECTIVE: The Jagiellonian PET (J-PET) technology, based on plastic scintillators, has been proposed as a cost effective tool for detecting range deviations during proton therapy. This study investigates the feasibility of using J-PET for range monitoring by means of a detailed Monte Carlo simulation study of 95 patients who underwent proton therapy at the Cyclotron Centre Bronowice (CCB) in Krakow, Poland. Approach: Discrepancies between prescribed and delivered treatments were artificially introduced in the simulations by means of shifts in patient positioning and in the Hounsfield unit to the relative proton stopping power calibration curve. A dual-layer, cylindrical J-PET geometry was simulated in an in-room monitoring scenario and a triple-layer, dual-head geometry in an in-beam protocol. The distribution of range shifts in reconstructed PET activity was visualised in the beam's eye view. Linear prediction models were constructed from all patients in the cohort, using the mean shift in reconstructed PET activity as a predictor of the mean proton range deviation. Main results: Maps of deviations in the range of reconstructed PET distributions showed agreement with those of deviations in dose range in most patients. The linear prediction model showed a good fit, with coefficient of determination r^2 = 0.84 (in-room) and 0.75 (in-beam). Residual standard error was below 1 mm: 0.33 mm (in-room) and 0.23 mm (in-beam). Significance: The precision of the proposed prediction models shows the sensitivity of the proposed J-PET scanners to shifts in proton range for a wide range of clinical treatment plans. Furthermore, it motivates the use of such models as a tool for predicting proton range deviations and opens up new prospects for investigations into the use of intra-treatment PET images for predicting clinical metrics that aid in the assessment of the quality of delivered treatment. .

Clinical outcome after pencil beam scanning proton therapy and dysphagia/xerostomia NTCP calculations of proton and photon radiotherapy delivered to patients with cancer of the major salivary glands.

OBJECTIVES: The purpose of this study is to report the oncological outcome, observed toxicities and normal tissue complication probability (NTCP) calculation for pencil beam scanning (PBS) PT delivered to salivary gland tumour (SGT) patients. METHODS: We retrospectively reviewed 26 SGT patients treated with PBSPT (median dose, 67.5 Gy(RBE)) between 2005 and 2020 at our institute. Toxicities were recorded according to CTCAEv.4.1. Overall survival (OS), local control (LC), locoregional control (LRC) and distant control (DC) were estimated. For all patients, a photon plan was re-calculated in order to assess the photon/proton NTCP. RESULTS: With a median follow-up time of 46 months (range, 3-118), 5 (19%), 2 (8%), 3 (12%) and 2 (8%) patients presented after PT with distant, local, locoregional failures and death, respectively. The estimated 4 year OS, LC, LCR and DC were 90%, 90%, 87 and 77%, respectively. Grade 3 late toxicity was observed in 2 (8%) patients. The estimated 4 year late high-grade (≥3) toxicity-free survival was 78.4%. The calculated mean difference of NTCP-values after PBSPT and VMAT plans for developing Grade 2 or 3 xerostomia were 3.8 and 2.9%, respectively. For Grade 2-3 dysphagia, the grade corresponding percentages were 8.6 and 1.9%. Not using an up-front model-based approach to select patients for PT, only 40% of our patients met the Dutch eligibility criteria. CONCLUSION: Our data suggest excellent oncological outcome and low late toxicity rates for patients with SGT treated with PBSPT. NTCP calculation showed a substantial risk reduction for Grade 2 or 3 xerostomia and dysphagia in some SGT patients, while for others, no clear benefit was seen with protons, suggesting that comparative planning should be performed routinely for these patients. ADVANCES IN KNOWLEDGE: We have reported that the clinical outcome of SGT patients treated with PT and compared IMPT to VMAT for the treatment of salivary gland tumour and have observed that protons delivered significantly less dose to organs at risks and were associated with less NTCP for xerostomia and dysphagia. Noteworthy, not using an up-front model-based approach, only 40% of our patients met the Dutch eligibility criteria.

Detailed Monte-Carlo characterization of a Faraday cup for proton therapy.

BACKGROUND: Experiments with ultra-high dose rates in proton therapy are of increasing interest for potential treatment benefits. The Faraday Cup (FC) is an important detector for the dosimetry of such ultra-high dose rate beams. So far, there is no consensus on the optimal design of a FC, or on the influence of beam properties and magnetic fields on shielding of the FC from secondary charged particles. PURPOSE: To perform detailed Monte Carlo simulations of a Faraday cup to identify and quantify all the charge contributions from primary protons and secondary particles that modify the efficiency of the FC response as a function of a magnetic field employed to improve the detector's reading. METHODS: In this paper, a Monte Carlo (MC) approach was used to investigate the Paul Scherrer Institute (PSI) FC and quantify contributions of charged particles to its signal for beam energies of 70, 150, and 228 MeV and magnetic fields between 0 and 25 mT. Finally, we compared our MC simulations to measurements of the response of the PSI FC. RESULTS: For maximum magnetic fields, the efficiency (signal of the FC normalized to charged delivered by protons) of the PSI FC varied between 99.97% and 100.22% for the lowest and highest beam energy. We have shown that this beam energy-dependence is mainly caused by contributions of secondary charged particles, which cannot be fully suppressed by the magnetic field. Additionally, it has been demonstrated that these contributions persist, making the FC efficiency beam energy dependent for fields up to 250 mT, posing inevitable limits on the accuracy of FC measurements if not corrected. In particular, we have identified a so far unreported loss of electrons via the outer surfaces of the absorber block and show the energy distributions of secondary electrons ejected from the vacuum window (VW) (up to several hundred keV), together with electrons ejected from the absorber block (up to several MeV). Even though, in general, simulations and measurements were well in agreement, the limitation of the current MC calculations to produce secondary electrons below 990 eV posed a limit in the efficiency simulations in the absence of a magnetic field as compared to the experimental data. CONCLUSION: TOPAS-based MC simulations allowed to identify various and previously unreported contributions to the FC signal, which are likely to be present in other FC designs. Estimating the beam energy dependence of the PSI FC for additional beam energies could allow for the implementation of an energy-dependent correction factor to the signal. Dose estimates, based on accurate measurements of the number of delivered protons, provided a valid instrument to challenge the dose determined by reference ionization chambers, not only at ultra-high dose rates but also at conventional dose rates.

The impact of organ motion and the appliance of mitigation strategies on the effectiveness of hypoxia-guided proton therapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: To investigate the impact of organ motion on hypoxia-guided proton therapy treatments for non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Hypoxia PET and 4D imaging data of six NSCLC patients were used to simulate hypoxia-guided proton therapy with different motion mitigation strategies including rescanning, breath-hold, respiratory gating and tumour tracking. Motion-induced dose degradation was estimated for treatment plans with dose painting of hypoxic tumour sub-volumes at escalated dose levels. Tumour control probability (TCP) and dosimetry indices were assessed to weigh the clinical benefit of dose escalation and motion mitigation. In addition, the difference in normal tissue complication probability (NTCP) between escalated proton and photon VMAT treatments has been assessed. RESULTS: Motion-induced dose degradation was found for target coverage (CTV V95% up to -4%) and quality of the dose-escalation-by-contour (QRMS up to 6%) as a function of motion amplitude and amount of dose escalation. The TCP benefit coming from dose escalation (+4-13%) outweighs the motion-induced losses (<2%). Significant average NTCP reductions of dose-escalated proton plans were found for lungs (-14%), oesophagus (-10%) and heart (-16%) compared to conventional VMAT plans. The best plan dosimetry was obtained with breath hold and respiratory gating with rescanning. CONCLUSION: NSCLC affected by hypoxia appears to be a prime target for proton therapy which, by dose-escalation, allows to mitigate hypoxia-induced radio-resistance despite the sensitivity to organ motion. Furthermore, substantial reduction in normal tissue toxicity can be expected compared to conventional VMAT. Accessibility and standardization of hypoxia imaging and clinical trials are necessary to confirm these findings in a clinical setting.

Universal and dynamic ridge filter for pencil beam scanning particle therapy: a novel concept for ultra-fast treatment delivery.

Objective.In pencil beam scanning particle therapy, a short treatment delivery time is paramount for the efficient treatment of moving targets with motion mitigation techniques (such as breath-hold, rescanning, and gating). Energy and spot position change time are limiting factors in reducing treatment time. In this study, we designed a universal and dynamic energy modulator (ridge filter, RF) to broaden the Bragg peak, to reduce the number of energies and spots required to cover the target volume, thus lowering the treatment time.Approach. Our RF unit comprises two identical RFs placed just before the isocenter. Both RFs move relative to each other, changing the Bragg peak's characteristics dynamically. We simulated different Bragg peak shapes with the RF in Monte Carlo simulation code (TOPAS) and validated them experimentally. We then delivered single-field plans with 1 Gy/fraction to different geometrical targets in water, to measure the dose delivery time using the RF and compare it with the clinical settings.Main results.Aligning the RFs in different positions produces different broadening in the Bragg peak; we achieved a maximum broadening of 2.5 cm. With RF we reduced the number of energies in a field by more than 60%, and the dose delivery time by 50%, for all geometrical targets investigated, without compromising the dose distribution transverse and distal fall-off.Significance. Our novel universal and dynamic RF allows for the adaptation of the Bragg peak broadening for a spot and/or energy layer based on the requirement of dose shaping in the target volume. It significantly reduces the number of energy layers and spots to cover the target volume, and thus the treatment time. This RF design is ideal for ultra-fast treatment delivery within a single breath-hold (5-10 s), efficient delivery of motion mitigation techniques, and small animal irradiation with ultra-high dose rates (FLASH).

ProTheRaMon - a GATE simulation framework for proton therapy range monitoring using PET imaging.

OBJECTIVE: This paper reports on the implementation and shows examples of the use of the ProTheRaMon framework for simulating the delivery of proton therapy treatment plans and range monitoring using positron emission tomography (PET). ProTheRaMon offers 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 the ProTheRaMon framework 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: The ProTheRaMon framework is based on GATE Monte Carlo software, the CASToR reconstruction 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: ProTheRaMon is 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 the ProTheRaMon simulation 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, the ProTheRaMon framework can be adjusted for different proton therapy centers and/or different PET detector geometries. It is available to the community via github.

Combined proton-photon therapy for non-small cell lung cancer.

PURPOSE: Advanced non-small cell lung cancer (NSCLC) is still a challenging indication for conventional photon radiotherapy. Proton therapy has the potential to improve outcomes, but proton treatment slots remain a limited resource despite an increasing number of proton therapy facilities. This work investigates the potential benefits of optimally combined proton-photon therapy delivered using a fixed horizontal proton beam line in combination with a photon Linac, which could increase accessibility to proton therapy for such a patient cohort. MATERIALS AND METHODS: A treatment planning study has been conducted on a patient cohort of seven advanced NSCLC patients. Each patient had a planning computed tomography scan (CT) and multiple repeated CTs from three different days and for different breath-holds on each day. Treatment plans for combined proton-photon therapy (CPPT) were calculated for individual patients by optimizing the combined cumulative dose on the initial planning CT only (non-adapted) as well as on each daily CT respectively (adapted). The impact of inter-fractional changes and/or breath-hold variability was then assessed on the repeat breath-hold CTs. Results were compared to plans for IMRT or IMPT alone, as well as against combined treatments assuming a proton gantry. Plan quality was assessed in terms of dosimetric, robustness and NTCP metrics. RESULTS: Combined treatment plans improved plan quality compared to IMRT treatments, especially in regard to reductions of low and medium doses to organs at risk (OARs), which translated into lower NTCP estimates for three side effects. For most patients, combined treatments achieved results close to IMPT-only plans. Inter-fractional changes impact mainly the target coverage of combined and IMPT treatments, while OARs doses were less affected by these changes. With plan adaptation however, target coverage of combined treatments remained high even when taking variability between breath-holds into account. CONCLUSIONS: Optimally combined proton-photon plans improve treatment plan quality compared to IMRT only, potentially reducing the risk of toxicity while also allowing to potentially increase accessibility to proton therapy for NSCLC patients.

Influence of Radiation Dose, Photon Energy, and Reconstruction Kernel on rho/z Analysis in Spectral Computer Tomography: A Phantom Study.

BACKGROUND/AIM: The effective atomic number (Zeff) and electron density relative to water (ρe or Rho) of elements can be derived in dual-energy computed tomography (DECT). The aim of this phantom study was to investigate the effect of different photon energies, radiation doses, and reconstruction kernels on Zeff and Rho measured in DECT. MATERIALS AND METHODS: An anthropomorphic head phantom including five probes of known composition was scanned under three tube-voltage combinations in DECT: Sn140/100 kV, 140/80 kV and Sn140/80 kV with incremented radiation doses. Raw data were reconstructed with four reconstruction kernels (I30, I40, I50, and I70). Rho and Zeff were measured for each probe for all possible combinations of scan and reconstruction parameters. RESULTS: DECT-based Rho and Zeff closely approached the reference values with a mean and maximum error of 1.7% and 6.8%, respectively. Rho was lower for 140/80 kV compared with Sn140/100 kV and Sn140/80 kV with differences being 0.009. Zeff differed among all tube voltages with the most prominent difference being 0.28 between 140/80 kV and Sn140/100 kV. Zeff was lower in I70 compared with those of I30 and I40 with a difference of 0.07. Varying radiation dose yielded a variation of 0.0002 in Rho and 0.03 in Z, both considered negligible in practice. CONCLUSION: DECT comprises a feasible method for the extraction of material-specific information. Slight variations should be taken into account when different radiation doses, photon energies, and kernels are applied; however, they are considered small and in practice not crucial for an effective tissue differentiation.

Increase of the transmission and emittance acceptance through a cyclotron-based proton therapy gantry.

PURPOSE: In proton therapy, the gantry, as the final part of the beamline, has a major effect on beam intensity and beam size at the isocenter. Most of the conventional beam optics of cyclotron-based proton gantries have been designed with an imaging factor between 1 and 2 from the coupling point (CP) at the gantry entrance to the isocenter (patient location) meaning that to achieve a clinically desirable (small) beam size at isocenter, a small beam size is also required at the CP. Here we will show that such imaging factors are limiting the emittance which can be transported through the gantry. We, therefore, propose the use of large beam size and low divergence beam at the CP along with an imaging factor of 0.5 (2:1) in a new design of gantry beam optics to achieve substantial improvements in transmission and thus increase beam intensity at the isocenter. METHODS: The beam optics of our gantry have been re-designed to transport higher emittance without the need of any mechanical modifications to the gantry beamline. The beam optics has been designed using TRANSPORT, with the resulting transmissions being calculated using Monte Carlo simulations (BDSIM code). Finally, the new beam optics have been tested with measurements performed on our Gantry 2 at PSI. RESULTS: With the new beam optics, we could maximize transmission through the gantry for a fixed emittance value. Additionally, we could transport almost four times higher emittance through the gantry compared to conventional optics, whilst achieving good transmissions through the gantry (>50%) with no increased losses in the gantry. As such, the overall transmission (cyclotron to isocenter) can be increased by almost a factor of 6 for low energies. Additionally, the point-to-point imaging inherent to the optics allows adjustment of the beam size at the isocenter by simply changing the beam size at the CP. CONCLUSION: We have developed a new gantry beam optics which, by selecting a large beam size and low divergence at the gantry entrance and using an imaging factor of 0.5 (2:1), increases the emittance acceptance of the gantry, leading to a substantial increase in beam intensity at low energies. We expect that this approach could easily be adapted for most types of existing gantries.

Beam properties within the momentum acceptance of a clinical gantry beamline for proton therapy.

PURPOSE: Energy changes in pencil beam scanning proton therapy can be a limiting factor in delivery time, hence, limiting patient throughput and the effectiveness of motion mitigation techniques requiring fast irradiation. In this study, we investigate the feasibility of performing fast and continuous energy modulation within the momentum acceptance of a clinical beamline for proton therapy. METHODS: The alternative use of a local beam degrader at the gantry coupling point has been compared with a more common upstream regulation. Focusing on clinically relevant parameters, a complete beam properties characterization has been carried out. In particular, the acquired empirical data allowed to model and parametrize the errors in range and beam current to deliver clinical treatment plans. RESULTS: For both options, the local and upstream degrader, depth-dose curves measured in water for off-momentum beams were only marginally distorted (γ(1%, 1 mm) > 90%) and the errors in the spot position were within the clinical tolerance, even though increasing at the boundaries of the investigated scan range. The impact on the beam size was limited for the upstream degrader, while dedicated strategies could be required to tackle the beam broadening through the local degrader. Range correction models were investigated for the upstream regulation. The impaired beam transport required a dedicated strategy for fine range control and compensation of beam intensity losses. Our current parameterization based on empirical data allowed energy modulation within acceptance with range errors (median 0.05 mm) and transmission (median -14%) compatible with clinical operation and remarkably low average 27 ms dead time for small energy changes. The technique, tested for the delivery of a skull glioma treatment, resulted in high gamma pass rates at 1%, 1 mm compared to conventional deliveries in experimental measurements with about 45% reduction of the energy switching time when regulation could be performed within acceptance. CONCLUSIONS: Fast energy modulation within beamline acceptance has potential for clinical applications and, when realized with an upstream degrader, does not require modification in the beamline hardware, therefore, being potentially applicable in any running facility. Centers with slow energy switching time can particularly profit from such a technique for reducing dead time during treatment delivery.

Assessment of Radiation-Induced Optic Neuropathy in a Multi-Institutional Cohort of Chordoma and Chondrosarcoma Patients Treated with Proton Therapy.

Radiation-induced optic neuropathy (RION) is a rare side effect following radiation therapy involving the optic structures whose onset is, due to the low amount of available data, challenging to predict. We have analyzed a multi-institutional cohort including 289 skull-base cancer patients treated with proton therapy who all received >45 GyRBE to the optic apparatus. An overall incidence rate of 4.2% (12) was observed, with chordoma patients being at higher risk (5.8%) than chondrosarcoma patients (3.2%). Older age and arterial hypertension, tumor involvement, and repeated surgeries (>3) were found to be associated with RION. Based on bootstrapping and cross-validation, a NTCP model based on age and hypertension was determined to be the most robust, showing good classification ability (AUC-ROC 0.77) and calibration on our dataset. We suggest the application of this model with a threshold of 6% to segment patients into low and high-risk groups before treatment planning. However, further data and external validation are warranted before clinical application.

A new emittance selection system to maximize beam transmission for low-energy beams in cyclotron-based proton therapy facilities with gantry.

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.

Investigating the potential of proton therapy for hypoxia-targeted dose escalation in non-small cell lung cancer.

BACKGROUND: Hypoxia is known to be prevalent in solid tumors such as non-small cell lung cancer (NSCLC) and reportedly correlates with poor prognostic clinical outcome. PET imaging can provide in-vivo hypoxia measurements to support targeted radiotherapy treatment planning. We explore the potential of proton therapy in performing patient-specific dose escalation and compare it with photon volumetric modulated arc therapy (VMAT). METHODS: Dose escalation has been calibrated to the patient specific tumor response of ten stage IIb-IIIb NSCLC patients by combining HX4-PET imaging and radiobiological modelling of oxygen enhancement ratio (OER) to target variable tumor hypoxia. In a dose-escalation-by-contour approach, escalated dose levels were simulated to the most hypoxic region of the primary target and its effectiveness in improving loco-regional tumor control was assessed. Furthermore, the impact on normal tissue of proton treatments including dose escalation was evaluated in comparison to the normal tissue complication probability (NTCP) of conventional VMAT plans. RESULTS: Ignoring regions of tumor hypoxia can cause overestimation of TCP values by up to 10%, which can effectively be recovered on average to within 0.9% of the nominal TCP, using patient-specific dose escalations of up to 22% of the prescribed dose to PET defined hypoxic regions. Despite such dose escalations, the use of protons could also simultaneously reduce mean doses to the heart (- 14.3 GyRBE), lung (- 8.3 GyRBE), esophagus (- 6.9 GyRBE) and spinal cord (- 3.8 Gy) compared to non-escalated VMAT plans. These reductions are predicted to lead to clinically relevant decreases in NTCP for radiation-induced pneumonitis (- 11.3%), high grade heart toxicity (- 7.4%) and esophagitis (- 7.5%). CONCLUSIONS: This study suggests that the administration of proton therapy for dose escalation to patient specific regions of tumor hypoxia in the treatment of NSCLC can mitigate TCP reduction due to hypoxia-induced radio resistance, while simultaneously reducing NTCP levels even when compared to non-escalated treatments delivered with state-of-the-art photon techniques.

Experimental validation of daily adaptive proton therapy.

Anatomical changes during proton therapy require rapid treatment plan adaption to mitigate the associated dosimetric impact. This in turn requires a highly efficient workflow that minimizes the time between imaging and delivery. At the Paul Scherrer Institute, we have developed an online adaptive workflow, which is specifically designed for treatments in the skull-base/cranium, with the focus set on simplicity and minimizing changes to the conventional workflow. The dosimetric and timing performance of this daily adaptive proton therapy (DAPT) workflow has been experimentally investigated using an in-house developed DAPT software and specifically developed anthropomorphic phantom. After a standard treatment preparation, which includes the generation of a template plan, the treatment can then be adapted each day, based on daily imaging acquired on an in-room CT. The template structures are then rigidly propagated to this CT and the daily plan is fully re-optimized using the same field arrangement, DVH constraints and optimization settings of the template plan. After a dedicated plan QA, the daily plan is delivered. To minimize the time between imaging and delivery, clinically integrated software for efficient execution of all online adaption steps, as well as tools for comprehensive and automated QA checks, have been developed. Film measurements of an end-to-end validation of a multi-fraction DAPT treatment showed high agreement to the calculated doses. Gamma pass rates with a 3%/3 mm criteria were >92% when comparing the measured dose to the template plan. Additionally, a gamma pass rate >99% was found comparing measurements to the Monte Carlo dose of the daily plans reconstructed from the logfile, accumulated over the delivered fractions. With this, we experimentally demonstrate that the described adaptive workflow can be delivered accurately in a timescale similar to a standard delivery.

Non-invasive recognition of eye torsion through optical imaging of the iris pattern in ocular proton therapy.

The introduction of non-invasive imaging techniques such as MRI imaging for treatment planning and optical eye tracking for in-room eye localization would obviate the requirement of clips implantation for many patients undergoing ocular proton therapy. This study specifically addresses the issue of torsional eye movement detection during patient positioning. Non-invasive detection of eye torsion is performed by measuring the iris pattern rotations using a beams eye view optical camera. When handling images of patients to be treated using proton therapy, a number of additional challenges are encountered, such as changing eye position, pupil dilatation and illumination. A method is proposed to address these extra challenges while also compensating for the effect of cornea distortion in eye torsion computation. The accuracy of the proposed algorithm was evaluated against corresponding measurement of eye torsion using the clips configuration measured on x-ray images. This study involves twenty patients who received ocular proton therapy at Paul Scherrer Institute and it is covered by ethical approval (EKNZ 2019-01987).