Hybrid ultra-high and conventional dose rate treatments with electrons and photons for the clinical transfer of FLASH-RT to deep-seated targets: A treatment planning study.

PURPOSE: This study explores the dosimetric feasibility and plan quality of hybrid ultra-high dose rate (UHDR) electron and conventional dose rate (CDR) photon (HUC) radiotherapy for treating deep-seated tumours with FLASH-RT. METHODS: HUC treatment planning was conducted optimizing a broad UHDR electron beam (between 20-250 MeV) combined with a CDR VMAT for a glioblastoma, a pancreatic cancer, and a prostate cancer case. HUC plans were based on clinical prescription and fractionation schemes and compared against clinically delivered plans. Considering a HUC boost treatment for the glioblastoma consisting of a 15-Gy-single-fraction UHDR electron boost supplemented with VMAT, two scenarios for FLASH sparing were assessed using FLASH-modifying-factor-weighted doses. RESULTS: For all three patient cases, HUC treatment plans demonstrated comparable dosimetric quality to clinical plans, with similar PTV coverage (V95% within 0.5 %), homogeneity, and critical OAR-sparing. At the same time, HUC plans delivered a substantial portion of the dose to the PTV (Dmedian of 50-69 %) and surrounding tissues at UHDR. For the HUC boost treatment of the glioblastoma, the first FLASH sparing scenario showed a moderate FLASH sparing magnitude (10 % for D2%,PTV) for the 15-Gy UHDR electron boost, while the second scenario indicated a more substantial sparing of brain tissues inside and outside the PTV (32 % for D2%,PTV, 31 % for D2%,Brain). CONCLUSIONS: From a planning perspective, HUC treatments represent a feasible approach for delivering dosimetrically conformal UHDR treatments, potentially mitigating technical challenges associated with delivering conformal FLASH-RT for deep-seated tumours. While further research is needed to optimize HUC fractionation and delivery schemes for specific patient cohorts, HUC treatments offer a promising avenue for the clinical transfer of FLASH-RT.

Validation of MLC leaf open time calculation methods for PSQA in adaptive radiotherapy with tomotherapy units.

BACKGROUND: Treatment delivery safety and accuracy are essential to control the disease and protect healthy tissues in radiation therapy. For usual treatment, a phantom-based patient specific quality assurance (PSQA) is performed to verify the delivery prior to the treatment. The emergence of adaptive radiation therapy (ART) adds new complexities to PSQA. In fact, organ at risks and target volume re-contouring as well as plan re-optimization and treatment delivery are performed with the patient immobilized on the treatment couch, making phantom-based pretreatment PSQA impractical. In this case, phantomless PSQA tools based on multileaf collimator (MLC) leaf open times (LOTs) verifications provide alternative approaches for the Radixact® treatment units. However, their validity is compromised by the lack of independent and reliable methods for calculating the LOT performed by the MLC during deliveries. PURPOSE: To provide independent and reliable methods of LOT calculation for the Radixact® treatment units. METHODS: Two methods for calculating the LOTs performed by the MLC during deliveries have been implemented. The first method uses the signal recorded by the build-in detector and the second method uses the signal recorded by optical sensors mounted on the MLC. To calibrate the methods to the ground truth, in-phantom ionization chamber LOT measurements have been conducted on a Radixact® treatment unit. The methods were validated by comparing LOT calculations with in-phantom ionization chamber LOT measurements performed on two Radixact® treatment units. RESULTS: The study shows a good agreement between the two LOT calculation methods and the in-phantom ionization chamber measurements. There are no notable differences between the two methods and the same results were observed on the different treatment units. CONCLUSIONS: The two implemented methods have the potential to be part of a PSQA solution for ART in tomotherapy.

Sensitivity of automated and manual treatment planning approaches to contouring variation in early-breast cancer treatment.

PURPOSE: One of the advantages of integrating automated processes in treatment planning is the reduction of manual planning variability. This study aims to assess whether a deep-learning-based auto-planning solution can also reduce the contouring variation-related impact on the planned dose for early-breast cancer treatment. METHODS: Auto- and manual plans were optimized for 20 patients using both auto- and manual OARs, including both lungs, right breast, heart, and left-anterior-descending (LAD) artery. Differences in terms of recalculated dose (ΔDrcM,ΔDrcA) and reoptimized dose (ΔDroM,ΔDroA) for manual (M) and auto (A)-plans, were evaluated on manual structures. The correlation between several geometric similarities and dose differences was also explored (Spearman's test). RESULTS: Auto-contours were found slightly smaller in size than manual contours for right breast and heart and more than twice larger for LAD. Recalculated dose differences were found negligible for both planning approaches except for heart (ΔDrcM=-0.4 Gy, ΔDrcA=-0.3 Gy) and right breast (ΔDrcM=-1.2 Gy, ΔDrcA=-1.3 Gy) maximum dose. Re-optimized dose differences were considered equivalent to recalculated ones for both lungs and LAD, while they were significantly smaller for heart (ΔDroM=-0.2 Gy, ΔDroA=-0.2 Gy) and right breast (ΔDroM =-0.3 Gy, ΔDroA=-0.9 Gy) maximum dose. Twenty-one correlations were found for ΔDrcM,A (M=8,A=13) that reduced to four for ΔDroM,A (M=3,A=1). CONCLUSIONS: The sensitivity of auto-planning to contouring variation was found not relevant when compared to manual planning, regardless of the method used to calculate the dose differences. Nonetheless, the method employed to define the dose differences strongly affected the correlation analysis resulting highly reduced when dose was reoptimized, regardless of the planning approach.

Very high-energy electron therapy as light-particle alternative to transmission proton FLASH therapy - An evaluation of dosimetric performances.

PURPOSE: Clinical translation of FLASH-radiotherapy (RT) to deep-seated tumours is still a technological challenge. One proposed solution consists of using ultra-high dose rate transmission proton (TP) beams of about 200-250 MeV to irradiate the tumour with the flat entrance of the proton depth-dose profile. This work evaluates the dosimetric performance of very high-energy electron (VHEE)-based RT (50-250 MeV) as a potential alternative to TP-based RT for the clinical transfer of the FLASH effect. METHODS: Basic physics characteristics of VHEE and TP beams were compared utilizing Monte Carlo simulations in water. A VHEE-enabled research treatment planning system was used to evaluate the plan quality achievable with VHEE beams of different energies, compared to 250 MeV TP beams for a glioblastoma, an oesophagus, and a prostate cancer case. RESULTS: Like TP, VHEE above 100 MeV can treat targets with roughly flat (within ± 20 %) depth-dose distributions. The achievable dosimetric target conformity and adjacent organs-at-risk (OAR) sparing is consequently driven for both modalities by their lateral beam penumbrae. Electron beams of 400[500] MeV match the penumbra of 200[250] MeV TP beams and penumbra is increased for lower electron energies. For the investigated patient cases, VHEE plans with energies of 150 MeV and above achieved a dosimetric plan quality comparable to that of 250 MeV TP plans. For the glioblastoma and the oesophagus case, although having a decreased conformity, even 100 MeV VHEE plans provided a similar target coverage and OAR sparing compared to TP. CONCLUSIONS: VHEE-based FLASH-RT using sufficiently high beam energies may provide a lighter-particle alternative to TP-based FLASH-RT with comparable dosimetric plan quality.

Construction and dosimetric characterization of a motorized scanning-slit system for electron FLASH experiments.

BACKGROUND: Beam scanning is a useful technique for the treatment of large tumors when the primary beam size is limited, which is the case with radiation beams used in FLASH radiotherapy. PURPOSE: To optimize beam scanning as a dose delivery method for FLASH radiotherapy, it is necessary to first understand the effects of beam scanning on the FLASH effect. To do so, biological FLASH experiments need to be done using defined beam parameters with beam scanning and compared to the situation without beam scanning. In this regard, we propose implementation of a simple slit scanning system with an electron FLASH beam to obtain a scanned radiation field that closely resembles a static field. METHODS: A pulsed electron linear accelerator (linac) was used in combination with a scanning slit system in order to simulate a scanned electron beam. Three configurations that produced homogeneous lateral profiles and high enough doses per pulse for FLASH experiments were established. The optimal scanning parameters were found for each configuration by examining the flatness of the obtained lateral dose profiles. Using the optimal scanning parameters, the scanned FLASH beams were dosimetrically characterized and compared to non-scanned open field beam. RESULTS: A final electron FLASH beam scanning configuration was found for a 1 mm wide slit at a distance of 350 mm from the linac and a 2 mm wide slit at distances of 350 and 490 mm from the linac. The lateral profiles for these final configurations were found to have a homogeneity that is comparable to the open field profiles. The percentage depth dose (PDD) values found for these final configurations closely matched (by a few percentage) the PDD of the open field beam. CONCLUSIONS: Three electron FLASH beam scanning configurations achieved by the motorized slit system were found to produce radiation fields similar to a non-scanned open field electron beam. These final configurations can therefore be used in future biological FLASH experiments to compare to non-scanned beam experiments in order to optimize beam scanning as a technique permitting the treatment of larger tumors with FLASH radiotherapy.

Comparison of volumetric modulated arc therapy and helical tomotherapy for prostate cancer using Pareto fronts.

BACKGROUND: Studies comparing different radiotherapy treatment techniques-such as volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT)-typically compare one treatment plan per technique. Often, some dose metrics favor one plan and others favor the other, so the final plan decision involves subjective preferences. Pareto front comparisons provide a more objective framework for comparing different treatment techniques. A Pareto front is the set of all treatment plans where improvement in one criterion is possible only by worsening another criterion. However, different Pareto fronts can be obtained depending on the chosen machine settings. PURPOSE: To compare VMAT and HT using Pareto fronts and blind expert evaluation, to explain the observed differences, and to illustrate limitations of using Pareto fronts. METHODS: We generated Pareto fronts for twenty-four prostate cancer patients treated at our clinic for VMAT and HT techniques using an in-house script that controlled a commercial treatment planning system. We varied the PTV under-coverage (100% - V95%) and the rectum mean dose, and fixed the mean doses to the bladder and femoral heads. In order to ensure a fair comparison, those fixed mean doses were the same for the two treatment techniques and the sets of objective functions were chosen so that the conformity indexes of the two treatment techniques were also the same. We used the same machine settings as are used in our clinic. Then, we compared the VMAT and HT Pareto fronts using a specific metric (clinical distance measure) and validated the comparison using a blinded expert evaluation of treatment plans on these fronts for all patients in the cohort. Furthermore, we investigated the observed differences between VMAT and HT and pointed out limitations of using Pareto fronts. RESULTS: Both clinical distance and blind treatment plan comparison showed that VMAT Pareto fronts were better than HT fronts. VMAT fronts for 10 and 6 MV beam energy were almost identical. HT fronts improved with different machine settings, but were still inferior to VMAT fronts. CONCLUSIONS: That VMAT Pareto fronts are better than HT fronts may be explained by the fact that the linear accelerator can rapidly vary the dose rate. This is an advantage in simple geometries that might vanish in more complex geometries. Furthermore, one should be cautious when speaking about Pareto optimal plans as the best possible plans, as their calculation depends on many parameters.

Clinical implementation of deep learning-based automated left breast simultaneous integrated boost radiotherapy treatment planning.

Background and purpose: Automation in radiotherapy treatment planning aims to improve both the quality and the efficiency of the process. The aim of this study was to report on a clinical implementation of a Deep Learning (DL) auto-planning model for left-sided breast cancer. Materials and methods: The DL model was developed for left-sided breast simultaneous integrated boost treatments under deep-inspiration breath-hold. Eighty manual dose distributions were revised and used for training. Ten patients were used for model validation. The model was then used to design 17 clinical auto-plans. Manual and auto-plans were scored on a list of clinical goals for both targets and organs-at-risk (OARs). For validation, predicted and mimicked dose (PD and MD, respectively) percent error (PE) was calculated with respect to manual dose. Clinical and validation cohorts were compared in terms of MD only. Results: Median values of both PD and MD validation plans fulfilled the evaluation criteria. PE was < 1% for targets for both PD and MD. PD was well aligned to manual dose while MD left lung mean dose was significantly less (median:5.1 Gy vs 6.1 Gy). The left-anterior-descending artery maximum dose was found out of requirements (median values:+5.9 Gy and + 2.9 Gy, for PD and MD respectively) in three validation cases, while it was reduced for clinical cases (median:-1.9 Gy). No other clinically significant differences were observed between clinical and validation cohorts. Conclusion: Small OAR differences observed during the model validation were not found clinically relevant. The clinical implementation outcomes confirmed the robustness of the model.

Influence of optimisation parameters on directly deliverable Pareto fronts explored for prostate cancer.

PURPOSE: In inverse radiotherapy treatment planning, the Pareto front is the set of optimal solutions to the multi-criteria problem of adequately irradiating the planning target volume (PTV) while reducing dose to organs at risk (OAR). The Pareto front depends on the chosen optimisation parameters whose influence (clinically relevant versus not clinically relevant) is investigated in this paper. METHODS: Thirty-one prostate cancer patients treated at our clinic were randomly selected. We developed an in-house Python script that controlled the commercial treatment planning system RayStation to calculate directly deliverable Pareto fronts. We calculated reference Pareto fronts for a given set of objective functions, varying the PTV coverage and the mean dose of the primary OAR (rectum) and fixing the mean doses of the secondary OARs (bladder and femoral heads). We calculated the fronts for different sets of objective functions and different mean doses to secondary OARs. We compared all fronts using a specific metric (clinical distance measure). RESULTS: The in-house script was validated for directly deliverable Pareto front calculations in two and three dimensions. The Pareto fronts depended on the choice of objective functions and fixed mean doses to secondary OARs, whereas the parameters most influencing the front and leading to clinically relevant differences were the dose gradient around the PTV, the weight of the PTV objective function, and the bladder mean dose. CONCLUSIONS: Our study suggests that for multi-criteria optimisation of prostate treatments using external therapy, dose gradient around the PTV and bladder mean dose are the most influencial parameters.

3D-conformal very-high energy electron therapy as candidate modality for FLASH-RT: A treatment planning study for glioblastoma and lung cancer.

BACKGROUND: Pre-clinical ultra-high dose rate (UHDR) electron irradiations on time scales of 100 ms have demonstrated a remarkable sparing of brain and lung tissues while retaining tumor efficacy when compared to conventional dose rate irradiations. While clinically-used gantries and intensity modulation techniques are too slow to match such time scales, novel very-high energy electron (VHEE, 50-250 MeV) radiotherapy (RT) devices using 3D-conformed broad VHEE beams are designed to deliver UHDR treatments that fulfill these timing requirements. PURPOSE: To assess the dosimetric plan quality obtained using VHEE-based 3D-conformal RT (3D-CRT) for treatments of glioblastoma and lung cancer patients and compare the resulting treatment plans to those delivered by standard-of-care intensity modulated photon RT (IMRT) techniques. METHODS: Seven glioblastoma patients and seven lung cancer patients were planned with VHEE-based 3D-CRT using 3 to 16 coplanar beams with equidistant angular spacing and energies of 100 and 200 MeV using a forward planning approach. Dose distributions, dose-volume histograms, coverage (V95% ) and homogeneity (HI98% ) for the planning target volume (PTV), as well as near-maximum doses (D2% ) and mean doses (Dmean ) for organs-at-risk (OAR) were evaluated and compared to clinical IMRT plans. RESULTS: Mean differences of V95% and HI98% of all VHEE plans were within 2% or better of the IMRT reference plans. Glioblastoma plan dose metrics obtained with VHEE configurations of 200 MeV and 3-16 beams were either not significantly different or were significantly improved compared to the clinical IMRT reference plans. All OAR plan dose metrics evaluated for VHEE plans created using 5 beams of 100 MeV were either not significantly different or within 3% on average, except for Dmean for the body, Dmean for the brain, D2% for the brain stem, and D2% for the chiasm, which were significantly increased by 1, 2, 6, and 8 Gy, respectively (however below clinical constraints). Similarly, the dose metrics for lung cancer patients were also either not significantly different or were significantly improved compared to the reference plans for VHEE configurations with 200 MeV and 5 to 16 beams with the exception of D2% and Dmean to the spinal canal (however below clinical constraints). For the lung cancer cases, the VHEE configurations using 100 MeV or only 3 beams resulted in significantly worse dose metrics for some OAR. Differences in dose metrics were, however, strongly patient-specific and similar for some patient cases. CONCLUSIONS: VHEE-based 3D-CRT may deliver conformal treatments to simple, mostly convex target shapes in the brain and the thorax with a limited number of critical adjacent OAR using a limited number of beams (as low as 3 to 7). Using such treatment techniques, a dosimetric plan quality comparable to that of standard-of-care IMRT can be achieved. Hence, from a treatment planning perspective, 3D-conformal UHDR VHEE treatments delivered on time scales of 100 ms represent a promising candidate technique for the clinical transfer of the FLASH effect.

Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models: A Systematic Analysis.

PURPOSE: Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect," also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. METHODS AND MATERIALS: A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. RESULTS: We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. CONCLUSIONS: The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.

The general-purpose Geant4 Monte Carlo toolkit and its Geant4-DNA extension to investigate mechanisms underlying the FLASH effect in radiotherapy: Current status and challenges.

FLASH radiotherapy is a promising approach to cancer treatment that offers several advantages over conventional radiotherapy. With this novel technique, high doses of radiation are delivered in a short period of time, inducing the so-called FLASH effect - a phenomenon characterized by healthy tissue sparing without alteration of tumor control. The mechanisms behind the FLASH effect remain unknown. One way to approach this problem is to gain insight into the initial parameters that can distinguish FLASH from conventional irradiation by simulating particle transport in aqueous media using the general-purpose Geant4 Monte Carlo toolkit and its Geant4-DNA extension. This review article discusses the current status of Geant4 and Geant4-DNA simulations to investigate mechanisms underlying the FLASH effect, as well as the challenges faced in this research field. One of the primary challenges is to accurately simulate the experimental irradiation parameters. Another challenge is the temporal extension of the simulations. This review also focuses on two hypotheses to explain the FLASH effect - namely the oxygen depletion hypothesis and the inter-track interactions hypothesis - and discusses how the Geant4 toolkit can be used to investigate them. The aim of this review is to provide an overview of Geant4 and Geant4-DNA simulations for FLASH radiotherapy and to highlight the challenges that need to be overcome in order to better study the FLASH effect.

Independent Reproduction of the FLASH Effect on the Gastrointestinal Tract: A Multi-Institutional Comparative Study.

FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used.

Dosimetry in the lungs of α-particles (210Po) and ß-particles (210Pb) present in the tobacco smoke of conventional cigarettes and heated tobacco products.

Tobacco products contain radioactive 210Pb and 210Po which can be transferred from the filler to the mainstream smoke. When inhaled, they can contribute to the radioactive dose to the lungs and are suspected to significantly contribute to lung cancer from smoking. Currently, no data are available on the radioactive risk of the heated tobacco products (HTP). However, due to the relatively high heat involved in some of these devices, there are concerns about the volatility of polonium particles. Here we used data on the 210Po and 210Pb content in tobacco smoke along with biokinetic and dosimetric models to compute the effective dose induced by conventional smoking and by using an HTP device (PMI IQOS system). Results show that conventional smoking of one pack per day induces a dose to the lung of about 0.3 mSv/year. This dose decreases by a factor of ten (0.03 mSv/year) for the IQOS system. However, this dose reduction is not obtained by specific countermeasures but by the fact that the IQOS system heats only 15% of the tobacco filler to the target temperature of 330 °C. When heated homogeneously to 300 °C, both conventional and Heets (IQOS) cigarettes release about 80% of the 210Po from the tobacco, leading to similar doses to lungs.

The minimal FLASH sparing effect needed to compensate the increase of radiobiological damage due to hypofractionation for late-reacting tissues.

PURPOSE: Normal tissue (NT) sparing by ultra-high dose rate (UHDR) irradiations compared to conventional dose rate (CONV) irradiations while being isotoxic to the tumor has been termed "FLASH effect" and has been observed when large doses per fraction (d ≳ 5 Gy) have been delivered. Since hypofractionated treatment schedules are known to increase toxicities of late-reacting tissues compared to normofractionated schedules for many clinical scenarios at CONV dose rates, we developed a formalism based on the biologically effective dose (BED) to assess the minimum magnitude of the FLASH effect needed to compensate the loss of late-reacting NT sparing when reducing the number of fractions compared to a normofractionated CONV treatment schedule while remaining isoeffective to the tumor. METHODS: By requiring the same BED for the tumor, we derived the "break-even NT sparing weighting factor" WBE for the linear-quadratic (LQ) and LQ-linear (LQ-L) models for an NT region irradiated at a relative dose r (relative to the prescribed dose per fraction d to the tumor). WBE was evaluated numerically for multiple values of d and r, and for different tumor and NT α/ß-ratios. WBE was compared against currently available experimental data on the magnitude of the NT sparing provided by the FLASH effect for single fraction doses. RESULTS: For many clinically relevant scenarios, WBE decreases steeply initially for d > 2 Gy for late-reacting tissues with (α/ß)NT ≈ 3 Gy, implying that a significant NT sparing by the FLASH effect (between 15% and 30%) is required to counteract the increased radiobiological damage experienced by late-reacting NT for hypofractionated treatments with d < 10 Gy compared to normofractionated treatments that are equieffective to the tumor. When using the LQ model with generic α/ß-ratios for tumor and late-reacting NT of (α/ß)T  = 10 Gy and (α/ß)NT  = 3 Gy, respectively, most currently available experimental evidence about the magnitude of NT sparing by the FLASH effect suggests no net NT sparing benefit for hypofractionated FLASH radiotherapy (RT) in the high-dose region when compared with WBE . Instead, clinical indications with more similar α/ß-ratios of the tumor and dose-limiting NT toxicities [i.e., (α/ß)T  ≈ (α/ß)NT ], such as prostate treatments, are generally less penalized by hypofractionated treatments and need consequently smaller magnitudes of NT sparing by the FLASH effect to achieve a net benefit. For strongly hypofractionated treatments (>10-15 Gy/fraction), the LQ-L model predicts, unlike the LQ model, a larger WBE suggesting a possible benefit of strongly hypofractionated FLASH RT, even for generic α/ß-ratios of (α/ß)T  = 10 Gy and (α/ß)NT  = 3 Gy. However, knowledge on the isoeffect scaling for high doses per fraction (≳10 Gy/fraction) and its modeling is currently limited and impedes accurate and reliable predictions for such strongly hypofractionated treatments. CONCLUSIONS: We developed a formalism that quantifies the minimal NT sparing by the FLASH effect needed to compensate for hypofractionation, based on the LQ and LQ-L models. For a given hypofractionated UHDR treatment scenario and magnitude of the FLASH effect, the formalism predicts if a net NT sparing benefit is expected compared to a respective normofractionated CONV treatment.

Design and validation of a dosimetric comparison scheme tailored for ultra-high dose-rate electron beams to support multicenter FLASH preclinical studies.

BACKGROUND AND PURPOSE: We describe a multicenter cross validation of ultra-high dose rate (UHDR) (>= 40 Gy/s) irradiation in order to bring a dosimetric consensus in absorbed dose to water. UHDR refers to dose rates over 100-1000 times those of conventional clinical beams. UHDR irradiations have been a topic of intense investigation as they have been reported to induce the FLASH effect in which normal tissues exhibit reduced toxicity relative to conventional dose rates. The need to establish optimal beam parameters capable of achieving the in vivo FLASH effect has become paramount. It is therefore necessary to validate and replicate dosimetry across multiple sites conducting UHDR studies with distinct beam configurations and experimental set-ups. MATERIALS AND METHODS: Using a custom cuboid phantom with a cylindrical cavity (5 mm diameter by 10.4 mm length) designed to contain three type of dosimeters (thermoluminescent dosimeters (TLDs), alanine pellets, and Gafchromic films), irradiations were conducted at expected doses of 7.5 to 16 Gy delivered at UHDR or conventional dose rates using various electron beams at the Radiation Oncology Departments of the CHUV in Lausanne, Switzerland and Stanford University, CA. RESULTS: Data obtained between replicate experiments for all dosimeters were in excellent agreement (±3%). In general, films and TLDs were in closer agreement with each other, while alanine provided the closest match between the expected and measured dose, with certain caveats related to absolute reference dose. CONCLUSION: In conclusion, successful cross-validation of different electron beams operating under different energies and configurations lays the foundation for establishing dosimetric consensus for UHDR irradiation studies, and, if widely implemented, decrease uncertainty between different sites investigating the mechanistic basis of the FLASH effect.

Normal Tissue Sparing by FLASH as a Function of Single-Fraction Dose: A Quantitative Analysis.

PURPOSE: The FLASH effect designates normal tissue sparing by ultra-high dose rate (UHDR) compared with conventional dose rate irradiation without compromising tumor control. Understanding the magnitude of this effect and its dependency on dose are essential requirements for an optimized clinical translation of FLASH radiation therapy. In this context, we evaluated available experimental data on the magnitudes of normal tissue sparing provided by the FLASH effect as a function of dose, and followed a phenomenological data-driven approach for its parameterization. METHODS AND MATERIALS: We gathered available in vivo data of normal tissue sparing of conventional (CONV) versus UHDR single-fraction doses and converted these to a common scale using isoeffect dose ratios, hereafter referred to as FLASH-modifying factors (FMF= (DCONV/DUHDR)|isoeffect). We then evaluated the suitability of a piecewise linear function with 2 pieces to parametrize FMF × DUHDR as a function of dose DUHDR. RESULTS: We found that the magnitude of FMF generally decreases (ie, sparing increases) as a function of single-fraction dose, and that individual data series can be described by the piecewise linear function. The sparing magnitude appears organ-specific, and pooled skin-reaction data followed a consistent trend as a function of dose. Average FMF values and their standard deviations were 0.95 ± 0.11 for all data <10 Gy, 0.92 ± 0.06 for mouse gut data between 10 and 25 Gy, and 0.96 ± 0.07 and 0.71 ± 0.06 for mammalian skin-reaction data between 10 and 25 Gy and >25 Gy, respectively. CONCLUSIONS: The magnitude of normal tissue sparing by FLASH increases with dose and is dependent on the irradiated tissue. A piecewise linear function can parameterize currently available individual data series.

Commissioning and validation of RayStation treatment planning system for CyberKnife M6.

BACKGROUND: RaySearch (AB, Stockholm) has released a module for CyberKnife (CK) planning within its RayStation (RS) treatment planning system (TPS). PURPOSE: To create and validate beam models of fixed, Iris, and multileaf collimators (MLC) of the CK M6 for Monte Carlo (MC) and collapsed cone (CC) algorithms in the RS TPS. METHODS: Measurements needed for the creation of the beam models were performed in a water tank with a stereotactic PTW 60018 diode. Both CC and MC models were optimized in RS by minimizing the differences between the measured and computed profiles and percentage depth doses. The models were then validated by comparing dose from the plans created in RS with both single and multiple beams in different phantom conditions with the corresponding measured dose. Irregular field shapes and off-axis beams were also tested for the MLC. Validation measurements were performed using an A1SL ionization chamber, EBT3 Gafchromic films, and a PTW 1000 SRS detector. Finally, patient-specific QAs with gamma criteria of 3%/1 mm were performed for each model. RESULTS: The models were created in a straightforward manner with efficient tools available in RS. The differences between computed and measured doses were within ±1% for most of the configurations tested and reached a maximum of 3.2% for measurements at a depth of 19.5-cm. With respect to all collimators and algorithms, the maximum averaged dose difference was 0.8% when considering absolute dose measurements on the central axis. The patient-specific QAs led to a mean result of 98% of points fulfilling gamma criteria. CONCLUSIONS: We created both CC and MC models for fixed, Iris, and MLC collimators in RS. The dose differences for all collimators and algorithms were within ±1%, except for depths larger than 9 cm. This allowed us to validate both models for clinical use.

Technical note: Validation of an ultrahigh dose rate pulsed electron beam monitoring system using a current transformer for FLASH preclinical studies.

PURPOSE: The Oriatron eRT6 is a linear accelerator (linac) used in FLASH preclinical studies able to reach dose rates ranging from conventional (CONV) up to ultrahigh (UHDR). This work describes the implementation of commercially available beam current transformers (BCTs) as online monitoring tools compatible with CONV and UHDR irradiations for preclinical FLASH studies. METHODS: Two BCTs were used to measure the output of the Oriatron eRT6 linac. First, the correspondence between the set nominal beam parameters and those measured by the BCTs was checked. Then, we established the relationship between the total exit charge (measured by BCTs) and the absorbed dose to water. The influence of the pulse width (PW) and the pulse repetition frequency (PRF) at UHDR was characterized, as well as the short- and long-term stabilities of the relationship between the exit charge and the dose at CONV and UHDR. RESULTS: The BCTs were able to determine consistently the number of pulses, PW, and PRF. For fixed PW and pulse height, the exit charge measured from BCTs was correlated with the dose, and linear relationships were found with uncertainties of 0.5 % and 3 % in CONV and UHDR mode, respectively. Short- and long-term stabilities of the dose-to-charge ratio were below 1.6 %. CONCLUSIONS: We implemented commercially available BCTs and demonstrated their ability to act as online beam monitoring systems to support FLASH preclinical studies with CONV and UHDR irradiations. The implemented BCTs support dosimetric measurements, highlight variations among multiple measurements in a row, enable monitoring of the physics parameters used for irradiation, and are an important step for the safety of the clinical translation of FLASH radiation therapy.

Comparison of ultra-high versus conventional dose rate radiotherapy in a patient with cutaneous lymphoma.

A patient with a cutaneous lymphoma was treated on the same day for 2 distinct tumors using a 15 Gy single electron dose given in a dose rate of 0.08 Gy/second versus 166 Gy/second. Comparing the two treatments, there was no difference for acute reactions, late effects at 2 years and tumor control.