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.

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.

Validation of Monte Carlo dose calculation algorithm for CyberKnife multileaf collimator.

PURPOSE: To commission and evaluate the Monte Carlo (MC) dose calculation algorithm for the CyberKnife equipped with a multileaf collimator (MLC). METHODS: We created a MC model for the MLC using an integrated module of the CyberKnife treatment planning software (TPS). Two parameters could be optimized: the maximum energy and the source full width at half-maximum (FWHM). The optimization was performed by minimizing the differences between the measured and the MC calculated tissue phantom ratios and profiles. MLC plans were calculated in the TPS with the MC algorithm and irradiated on different phantoms. The dose was measured using an A1SL ionization chamber and EBT3 Gafchromic films, and then compared to the TPS dose to obtain dose differences (ΔD). Finally, patient-specific quality assurances (QA) were performed with global gamma index criteria of 3%/1 mm. RESULTS: The maximum energy and source FWHM showing the best agreement with measurements were 6.4 MeV and 1.8 mm. The output factors calculated with these parameters gave an agreement within ±1% with measurements. The ΔD showed that MC model systematically underestimated the dose with an average of -1.5% over all configurations tested. For depths deeper than 12 cm, the ΔD increased, up to -3.0% (maximum at 15.5 cm depth). CONCLUSIONS: The MC model for MLC of CyberKnife is clinically acceptable but underestimates the delivered dose by an average of -1.5%. Therefore, we recommend using the MC algorithm with the MLC only in heterogeneous regions and for shallow-seated tumors.

Hypofractionated FLASH-RT as an Effective Treatment against Glioblastoma that Reduces Neurocognitive Side Effects in Mice.

PURPOSE: Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses. EXPERIMENTAL DESIGN: Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT. RESULTS: The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens. CONCLUSIONS: The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT.See related commentary by Huang and Mendonca, p. 662.

Optimization of Alanine Measurements for Fast and Accurate Dosimetry in FLASH Radiation Therapy.

FLASH radiation therapy (FLASH-RT) reference dosimetry to obtain traceability, repeatability and stability of irradiations cannot be performed with conventional dosimetric methods, such as monitor chambers or ionization chambers. Until now, only passive dosimeters have provided the necessary dosimetric data. Alanine dosimetry is accurate; however, to be used for FLASH-RT in biological experiments and for clinical transfer to humans, the reading time needs to be reduced, while preserving a maximum deviation to the reference of ±2%. Optimization of alanine dosimetry was based on the acquisition of electron paramagnetic resonance (EPR) spectra with a Bruker spectrometer. Reading parameters such as the conversion time, the number of scans, the time constant, the microwave power and the modulation amplitude of the magnetic field were optimized as a trade-off between the signal-to-noise ratio (SNR) and the reading time of one measurement using the reference 10.1 Gy alanine pellet. After optimizing the parameters, we compared the doses measured with alanine pellets up to 100 Gy with the reference doses, and then determined the number of measurements necessary to get a difference lower than ±2%. A low-dose alanine pellet of 4.9 Gy was also measured to evaluate the quality of the optimization for doses lower than 10 Gy. The optimization of the Bruker default parameters made it possible to reduce the reading time for one measurement from 5.6 to 2.6 min. That reduction was not at the cost of the SNR because it was kept comparable to the default parameters. Three measurements were enough to obtain a maximum dose deviation to the reference of 1.8% for the range of 10-100 Gy. The total reading time for the three measurements was 7.8 min (3 × 2.6 min). For lower doses such as 4.9 Gy, three measurements led to a deviation greater than 5%. By increasing the number of measurements to five, the average difference to the reference dose was reduced to less than 5% with a total reading time increased to 13.0 min. For doses between 10 Gy and 100 Gy, the optimized acquisition parameters made it possible to keep the average differences between the reference and the measured doses below ±2%, for a reading time of 7.8 min. This enabled an accurate and fast dose determination for biological preparations as part of FLASH-beam irradiations.

Dosimetric and preparation procedures for irradiating biological models with pulsed electron beam at ultra-high dose-rate.

PURPOSE: Preclinical studies using a new treatment modality called FLASH Radiotherapy (FLASH-RT) need a two-phase procedure to ensure minimal uncertainties in the delivered dose. The first phase requires a new investigation of the reference dosimetry lying outside the conventional metrology framework from national metrology institutes but necessary to obtain traceability, repeatability, and stability of irradiations. The second consists of performing special quality assurance procedure prior to irradiation. MATERIALS AND METHODS: The Oriatron eRT6 (PMB-Alcen, France) is an experimental high dose-per-pulse linear accelerator, delivering a 6 MeV pulsed electron beam with mean dose-rates, ranging from a few Gy/min up to thousands of Gy/s. Absolute dosimetry is investigated with alanine, thermo-luminescent dosimeters (TLD) and radiochromic films as well as an ionization chamber for relative stability. The beam characteristic and dosimetry are prepared for three different setups. RESULTS: A cross-check between alanine, films and TLD revealed a dose agreement within 3% for dose-rates between 0.078 Gy/s and 1050 Gy/s, showing that these dosimeters are suitable for absolute dosimetry for FLASH-RT. In absence of appropriate setup dependent corrections, active dosimetry can reveal dose deviations up to 15% of the prescribed dose. These differences reduce to less than 3% when our dosimetric procedure is applied. CONCLUSION: We developed procedures to accurately irradiate biological models. Our method is based on validated absolute dosimeters and extends their use to routine FLASH irradiations. We reached an agreement of 3% between the delivered and prescribed dose and developed the requirements needed for workflows of preclinical and clinical studies.

Precision analysis and optimization in phase decorrelation OCT velocimetry.

Quantitative flow velocimetry in Optical Coherence Tomography is used to determine both the axial and lateral flow component at the level of individual voxels. The lateral flow is determined by analyzing the statistical properties of reflected electro-magnetic fields for repeated measurements at (nearly) the same location. The precision or statistical fluctuation of the quantitative velocity estimation depends on the number of repeated measurements and the method to determine quantitative flow velocity. In this paper, both a method to determine quantitative flow velocity and a model for the prediction of the statistical fluctuations of velocity estimations are developed to analyze and optimize the estimation precision for phase-based velocimetry methods. The method and model are validated by phantom measurements in a bulk scattering medium as well as in intralipid solution in a capillary. Based on the model, the number of repeated measurements to achieve a certain velocimetry precision is predicted.