Metrology for advanced radiotherapy using particle beams with ultra-high dose rates.

Dosimetry of ultra-high dose rate beams is one of the critical components which is required for safe implementation of FLASH radiotherapy (RT) into clinical practice. In the past years several national and international programmes have emerged with the aim to address some of the needs that are required for translation of this modality to clinics. These involve the establishment of dosimetry standards as well as the validation of protocols and dosimetry procedures. This review provides an overview of recent developments in the field of dosimetry for FLASH RT, with particular focus on primary and secondary standard instruments, and provides a brief outlook on the future work which is required to enable clinical implementation of FLASH RT.

Recent developments in absolute dosimetry for FLASH radiotherapy.

Ultra-high dose-rate (UHDR) irradiations, known as FLASH radiotherapy (RT), rely on delivery of therapeutic doses at instantaneous dose-rates several orders of magnitude higher than those currently used in conventional radiotherapy. It has been shown that such an extremely short delivery of radiation leads to remarkable reduction of normal tissue toxicity with respect to conventional dose-rate RT. However, dosimetry at UHDRs is complicated and it is essential to understand the effects that will influence detector response. To date, FLASH RT research has been focused on finding pragmatic solutions that allow the use of UHDR beams in the research setting, but there has been limited focus on absolute dosimetry utilizing primary and secondary standard devices. However, very recently, the data on existing standard dosimeters and novel solutions which could serve as secondary standard devices in UHDR dosimetry started emerging. This review provides an overview of the studies that have been conducted employing calorimeters and innovative solutions utilizing ionization chambers.

Characterization of Inorganic Scintillator Detectors for Dosimetry in Image-Guided Small Animal Radiotherapy Platforms.

The purpose of the study was to characterize a detection system based on inorganic scintillators and determine its suitability for dosimetry in preclinical radiation research. Dose rate, linearity, and repeatability of the response (among others) were assessed for medium-energy X-ray beam qualities. The response's variation with temperature and beam angle incidence was also evaluated. Absorbed dose quality-dependent calibration coefficients, based on a cross-calibration against air kerma secondary standard ionization chambers, were determined. Relative output factors (ROF) for small, collimated fields (≤10 mm × 10 mm) were measured and compared with Gafchromic film and to a CMOS imaging sensor. Independently of the beam quality, the scintillator signal repeatability was adequate and linear with dose. Compared with EBT3 films and CMOS, ROF was within 5% (except for smaller circular fields). We demonstrated that when the detector is cross-calibrated in the user's beam, it is a useful tool for dosimetry in medium-energy X-rays with small fields delivered by Image-Guided Small Animal Radiotherapy Platforms. It supports the development of procedures for independent "live" dose verification of complex preclinical radiotherapy plans with the possibility to insert the detectors in phantoms.

Monte Carlo modelling of a prototype small-body portable graphite calorimeter for ultra-high dose rate proton beams.

Background and purpose: Accurate dosimetry in Ultra-High Dose Rate (UHDR) beams is challenging because high levels of ion recombination occur within ionisation chambers used as reference dosimeters. A Small-body Portable Graphite Calorimeter (SPGC) exhibiting a dose-rate independent response was built to offer reduced uncertainty on secondary standard dosimetry in UHDR regimes. The aim of this study was to quantify the effect of the geometry and material properties of the device on the dose measurement. Materials and methods: A detailed model of the SPGC was built in the Monte Carlo code TOPAS (v3.6.1) to derive the impurity and gap correction factors, kimp and kgap. A dose conversion factor, DwMC/DgMC, was also calculated using FLUKA (v2021.2.0). These factors convert the average dose to its graphite core to the dose-to-water for a 249.7 MeV mono-energetic spot-scanned clinical proton beam. The effect of the surrounding Styrofoam on the dose measurement was examined in the simulations by substituting it for graphite. Results: The kimp and kgap correction factors were 0.9993 ± 0.0002 and 1.0000 ± 0.0001, respectively when the Styrofoam was not substituted, and 1.0037 ± 0.0002 and 0.9999 ± 0.0001, respectively when substituted for graphite. The dose conversion factor was calculated to be 1.0806 ± 0.0001. All uncertainties are Type A. Conclusions: Impurity and gap correction factors, and the dose conversion factor were calculated for the SPGC in a FLASH proton beam. Separating out the effect of scatter from Styrofoam insulation showed this as the dominating correction factor, amounting to 1.0043 ± 0.0002.

Absolute dosimetry for FLASH proton pencil beam scanning radiotherapy.

A paradigm shift is occurring in clinical oncology exploiting the recent discovery that short pulses of ultra-high dose rate (UHDR) radiation-FLASH radiotherapy-can significantly spare healthy tissues whilst still being at least as effective in curing cancer as radiotherapy at conventional dose rates. These properties promise reduced post-treatment complications, whilst improving patient access to proton beam radiotherapy and reducing costs. However, accurate dosimetry at UHDR is extremely complicated. This work presents measurements performed with a primary-standard proton calorimeter and derivation of the required correction factors needed to determine absolute dose for FLASH proton beam radiotherapy with an uncertainty of 0.9% (1[Formula: see text]), in line with that of conventional treatments. The establishment of a primary standard for FLASH proton radiotherapy improves accuracy and consistency of the dose delivered and is crucial for the safe implementation of clinical trials, and beyond, for this new treatment modality.

Roadmap for precision preclinical x-ray radiation studies.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.

Ultrahigh dose rate pencil beam scanning proton dosimetry using ion chambers and a calorimeter in support of first in-human FLASH clinical trial.

PURPOSE: To provide ultrahigh dose rate (UHDR) pencil beam scanning (PBS) proton dosimetry comparison of clinically used plane-parallel ion chambers, PTW (Physikalisch-Technische Werkstaetten) Advanced Markus and IBA (Ion Beam Application) PPC05, with a proton graphite calorimeter in a support of first in-human proton FLASH clinical trial. METHODS: Absolute dose measurement intercomparison of the plane-parallel plate ion chambers and the proton graphite calorimeter was performed at 5-cm water-equivalent depth using rectangular 250-MeV single-layer treatment plans designed for the first in-human FLASH clinical trial. The dose rate for each field was designed to remain above 60 Gy/s. The ion recombination effects of the plane-parallel plate ion chambers at various bias voltages were also investigated in the range of dose rates between 5 and 60 Gy/s. Two independent model-based extrapolation methods were used to calculate the ion recombination correction factors ks to compare with the two-voltage technique from most widely used clinical protocols. RESULTS: The mean measured dose to water with the proton graphite calorimeter across all the predefined fields is 7.702 ± 0.037 Gy. The average ratio over the predefined fields of the PTW Advanced Markus chamber dose to the calorimeter reference dose is 1.002 ± 0.007, whereas the IBA PPC05 chamber shows ∼3% higher reading of 1.033 ± 0.007. The relative differences in the ks values determined from between the linear and quadratic extrapolation methods and the two-voltage technique for the PTW Advanced Markus chamber are not statistically significant, and the trends of dose rate dependence are similar. The IBA PPC05 shows a flat response in terms of ion recombination effects based on the ks values calculated using the two-voltage technique. Differences in ks values for the PPC05 between the two-voltage technique and other model-based extrapolation methods are not statistically significant at FLASH dose rates. Some of the ks values for the PPC05 that were extrapolated from the three-voltage linear method and the semiempirical model were reported less than unity possibly due to the charge multiplication effect, which was negligible compared to the volume recombination effect in FLASH dose rates. CONCLUSIONS: The absolute dose measurements of both PTW Advanced Markus and IBA PPC05 chambers are in a good agreement with the National Physical Laboratory graphite calorimeter reference dose considering overall uncertainties. Both ion chambers also demonstrate good reproducibility as well as stability as reference dosimeters in UHDR PBS proton radiotherapy. The dose rate dependency of the ion recombination effects of both ion chambers in cyclotron generated PBS proton beams is acceptable and therefore, both chambers are suitable to use in clinical practice for the range of dose rates between 5 and 60 Gy/s.

Eigencolor radiochromic film dosimetry.

PURPOSE: The goal of this work is to propose a new multichannel method correcting for systematic thickness disturbances and to evaluate its precision in relevant radiation dosimetry applications. METHODS: The eigencolor ratio technique is introduced and theoretically developed to provide a method correcting for thickness disturbances. The method is applied to EBT3 GafchromicTM film irradiated with cobalt-60 and 6 MV photon beams and digitized with an Epson 10000XL photo scanner. Dose profiles and output factors of different field sizes are measured and analyzed. Variance analysis of the previous method of Bouchard et al. ["On the characterization and uncertainty analysis of radiochromic film dosimetry" Med Phys. 2009;36:1931-1946] is adapted to the new approach. Uncertainties are predicted for relevant applications. RESULTS: Results show that systematic disturbances attributed to thickness variations are efficiently corrected. The method is shown efficient to identify and correct for dark spots which cause systematic errors in single-channel distributions. Applications of the method in the context of relative dosimetry yields standard uncertainties ranging between 0.8% and 1.9%, depending on the region of interest (ROI) size and the film irradiation. Variance analysis predicts that uncertainty levels between 0.3% and 0.6% are achievable with repeated measurements. Uncertainties are found to vary with absorbed dose and ROI size. CONCLUSIONS: The proposed multichannel method is efficient for accurate dosimetry, reaching uncertainty levels comparable to previous publications with EBT film. The method is also promising for applications beyond clinical QA, such as machine characterization and other advanced dosimetry applications.

Evaluation of a micro ionization chamber for dosimetric measurements in image-guided preclinical irradiation platforms.

Image-guided small animal irradiation platforms deliver small radiation fields in the medium energy x-ray range. Commissioning of such platforms, followed by dosimetric verification of treatment planning, are mostly performed with radiochromic film. There is a need for independent measurement methods, traceable to primary standards, with the added advantage of immediacy in obtaining results. This investigation characterizes a small volume ionization chamber in medium energy x-rays for reference dosimetry in preclinical irradiation research platforms. The detector was exposed to a set of reference x-ray beams (0.5-4 mm Cu HVL). Leakage, reproducibility, linearity, response to detector's orientation, dose rate, and energy dependence were determined for a 3D PinPoint ionization chamber (PTW 31022). Polarity and ion recombination were also studied. Absorbed doses at 2 cm depth were compared, derived either by applying the experimentally determined cross-calibration coefficient at a typical small animal radiation platform 'user's' quality (0.84 mm Cu HVL) or by interpolation from air kerma calibration coefficients in a set of reference beam qualities. In the range of reference x-ray beams, correction for ion recombination was less than 0.1%. The largest polarity correction was 1.4% (for 4 mm Cu HVL). Calibration and correction factors were experimentally determined. Measurements of absorbed dose with the PTW 31022, in conditions different from reference were successfully compared to measurements with a secondary standard ionization chamber. The implementation of an End-to-End test for delivery of image-targeted small field plans resulted in differences smaller than 3% between measured and treatment planning calculated doses. The investigation of the properties and response of a PTW 31022 small volume ionization chamber in medium energy x-rays and small fields can contribute to improve measurement uncertainties evaluation for reference and relative dosimetry of small fields delivered by preclinical irradiators while maintaining the traceability chain to primary standards.

Development and Implementation of an End-To-End Test for Absolute Dose Verification of Small Animal Preclinical Irradiation Research Platforms.

PURPOSE: Lack of standardization and inaccurate dosimetry assessment in preclinical research is hampering translational opportunities for new radiation therapy interventions. The aim of this work was to develop and implement an end-to-end dosimetry test for small animal radiation research platforms to monitor and help improve accuracy of dose delivery and standardization across institutions. METHODS AND MATERIALS: The test is based on a bespoke zoomorphic heterogeneous mouse and WT1 Petri dish phantoms with alanine as a reference detector. Alanine measurements within the mouse phantom were validated with Monte Carlo simulations at 0.5 mm Cu x-ray reference beam. Energy dependence of alanine in medium x-ray beam qualities was taken into consideration. For the end-to-end test, treatment plans considering tissue heterogeneities were created in Muriplan treatment planning systems (TPS) and delivered to the phantoms at 5 institutions using Xstrahl's small animal irradiation platforms. Mean calculated dose to the pellets were compared with alanine measured dose. RESULTS: Monte Carlo simulations and in phantom alanine measurements in NPL's reference beam were in excellent agreement, validating the experimental approach. At 1 institute, initial measurements showed a larger than 12% difference between calculated and measured dose caused by incorrect input data. The physics data used by the calculation engine were corrected, and the TPS was recommissioned. Subsequent end-to-end test measurements showed differences <5%. With an anterior field, 4 of the participating institutes delivered dose within 5% to both phantoms. CONCLUSIONS: An end-to-end dosimetry test was developed and implemented for dose evaluation in preclinical irradiation with small animal irradiation research platforms. The test was capable of detecting treatment planning commissioning errors and highlighted critical elements in dose calculation. Absolute dosimetry with alanine in relevant preclinical irradiation conditions showed reasonable levels of accuracy compared with TPS calculations. This work provides an independent and traceable dosimetric validation in preclinical research involving small animal irradiation.

The influence of lack of reference conditions on dosimetry in pre-clinical radiotherapy with medium energy x-ray beams.

Despite well-established dosimetry in clinical radiotherapy, dose measurements in pre-clinical and radiobiology studies are frequently inadequate, thus undermining the reliability and reproducibility of published findings. The lack of suitable dosimetry protocols, coupled with the increasing complexity of pre-clinical irradiation platforms, undermines confidence in preclinical studies and represents a serious obstacle in the translation to clinical practice. To accurately measure output of a pre-clinical radiotherapy unit, appropriate Codes of Practice (CoP) for medium energy x-rays needs to be employed. However, determination of absorbed dose to water (Dw) relies on application of backscatter factor (Bw) employing in-air method or carrying out in-phantom measurement at the reference depth of 2 cm in a full backscatter (i.e. 30 × 30 × 30 cm3) condition. Both of these methods require thickness of at least 30 cm of underlying material, which are never fulfilled in typical pre-clinical irradiations. This work is focused on evaluation the effects of the lack of recommended reference conditions in dosimetry measurements for pre-clinical settings and is aimed at extending the recommendations of the current CoP to practical experimental conditions and highlighting the potential impact of the lack of correct backscatter considerations on radiobiological studies.

An open source heterogeneous 3D printed mouse phantom utilising a novel bone representative thermoplastic.

The lack of rigorous quality standards in pre-clinical radiation dosimetry has renewed interest in the development of anthropomorphic phantoms. Using 3D printing customisable phantoms can be created to assess all parts of pre-clinical radiation research: planning, image guidance and treatment delivery. We present the full methodology, including material development and printing designs, for the production of a high spatial resolution, anatomically realistic heterogeneous small animal phantom. A methodology for creating and validating tissue equivalent materials is presented. The technique is demonstrated through the development of a bone-equivalent material. This material is used together with a soft-tissue mimicking ABS plastic filament to reproduce the corresponding structure geometries captured from a CT scan of a nude mouse. Air gaps are used to represent the lungs. Phantom validation was performed through comparison of the geometry and x-ray attenuation of CT images of the phantom and animal images. A 6.6% difference in the attenuation of the bone-equivalent material compared to the reference standard in softer beams (0.5 mm Cu HVL) rapidly decreases as the beam is hardened. CT imaging shows accurate (sub-millimetre) reproduction of the skeleton (Distance-To-Agreement 0.5 mm ± 0.4 mm) and body surface (0.7 mm ± 0.5 mm). Histograms of the voxel intensity profile of the phantom demonstrate suitable similarity to those of both the original mouse image and that of a different animal. We present an approach for the efficient production of an anthropomorphic phantom suitable for the quality assurance of pre-clinical radiotherapy. Our design and full methodology are provided as open source to encourage the pre-clinical radiobiology community to adopt a common QA standard.

Evaluation of a pixelated large format CMOS sensor for x-ray microbeam radiotherapy.

PURPOSE: Current techniques and procedures for dosimetry in microbeams typically rely on radiochromic film or small volume ionization chambers for validation and quality assurance in 2D and 1D, respectively. Whilst well characterized for clinical and preclinical radiotherapy, these methods are noninstantaneous and do not provide real time profile information. The objective of this work is to determine the suitability of the newly developed vM1212 detector, a pixelated CMOS (complementary metal-oxide-semiconductor) imaging sensor, for in situ and in vivo verification of x-ray microbeams. METHODS: Experiments were carried out on the vM1212 detector using a 220 kVp small animal radiation research platform (SARRP) at the Helmholtz Centre Munich. A 3 x 3 cm2 square piece of EBT3 film was placed on top of a marked nonfibrous card overlaying the sensitive silicon of the sensor. One centimeter of water equivalent bolus material was placed on top of the film for build-up. The response of the detector was compared to an Epson Expression 10000XL flatbed scanner using FilmQA Pro with triple channel dosimetry. This was also compared to a separate exposure using 450 µm of silicon as a surrogate for the detector and a Zeiss Axio Imager 2 microscope using an optical microscopy method of dosimetry. Microbeam collimator slits with range of nominal widths of 25, 50, 75, and 100 µm were used to compare beam profiles and determine sensitivity of the detector and both film measurements to different microbeams. RESULTS: The detector was able to measure peak and valley profiles in real-time, a significant reduction from the 24 hr self-development required by the EBT3 film. Observed full width at half maximum (FWHM) values were larger than the nominal slit widths, ranging from 130 to 190 µm due to divergence. Agreement between the methods was found for peak-to-valley dose ratio (PVDR), peak to peak separation and FWHM, but a difference in relative intensity of the microbeams was observed between the detectors. CONCLUSIONS: The investigation demonstrated that pixelated CMOS sensors could be applied to microbeam radiotherapy for real-time dosimetry in the future, however the relatively large pixel pitch of the vM1212 detector limit the immediate application of the results.

The European Joint Research Project UHDpulse - Metrology for advanced radiotherapy using particle beams with ultra-high pulse dose rates.

UHDpulse - Metrology for advanced radiotherapy using particle beams with ultra-high pulse dose rates is a recently started European Joint Research Project with the aim to develop and improve dosimetry standards for FLASH radiotherapy, very high energy electron (VHEE) radiotherapy and laser-driven medical accelerators. This paper gives a short overview about the current state of developments of radiotherapy with FLASH electrons and protons, very high energy electrons as well as laser-driven particles and the related challenges in dosimetry due to the ultra-high dose rate during the short radiation pulses. We summarize the objectives and plans of the UHDpulse project and present the 16 participating partners.

Development of an anatomically correct mouse phantom for dosimetry measurement in small animal radiotherapy research.

Significant improvements in radiotherapy are likely to come from biological rather than technical optimization, for example increasing tumour radiosensitivity via combination with targeted therapies. Such paradigms must first be evaluated in preclinical models for efficacy, and recent advances in small animal radiotherapy research platforms allow advanced irradiation protocols, similar to those used clinically, to be carried out in orthotopic models. Dose assessment in such systems is complex however, and a lack of established tools and methodologies for traceable and accurate dosimetry is currently limiting the capabilities of such platforms and slowing the clinical uptake of new approaches. Here we report the creation of an anatomically correct phantom, fabricated from materials with tissue-equivalent electron density, into which dosimetry detectors can be incorporated for measurement as part of quality control (QC). The phantom also allows training in preclinical radiotherapy planning and cross-institution validation of dose delivery protocols for small animal radiotherapy platforms without the need to sacrifice animals, with high reproducibility. Mouse CT data was acquired and segmented into soft tissue, bone and lung. The skeleton was fabricated using 3D printing, whilst lung was created using computer numerical control (CNC) milling. Skeleton and lung were then set into a surface-rendered mould and soft tissue material added to create a whole-body phantom. Materials for fabrication were characterized for atomic composition and attenuation for x-ray energies typically found in small animal irradiators. Finally cores were CNC milled to allow intracranial incorporation of bespoke detectors (alanine pellets) for dosimetry measurement.

Challenges of dosimetry of ultra-short pulsed very high energy electron beams.

Very high energy electrons (VHEE) in the range from 100 to 250MeV have the potential of becoming an alternative modality in radiotherapy because of their improved dosimetric properties compared with 6-20MV photons generated by clinical linear accelerators (LINACs). VHEE beams have characteristics unlike any other beams currently used for radiotherapy: femtosecond to picosecond duration electron bunches, which leads to very high dose per pulse, and energies that exceed that currently used in clinical applications. Dosimetry with conventional online detectors, such as ionization chambers or diodes, is a challenge due to non-negligible ion recombination effects taking place in the sensitive volumes of these detectors. FLUKA and Geant4 Monte Carlo (MC) codes have been employed to study the temporal and spectral evolution of ultrashort VHEE beams in a water phantom. These results are complemented by ion recombination measurements employing an IBA CC04 ionization chamber for a 165MeV VHEE beam. For comparison, ion recombination has also been measured using the same chamber with a conventional 20MeV electron beam. This work demonstrates that the IBA CC04 ionization chamber exhibits significant ion recombination and is therefore not suitable for dosimetry of ultrashort pulsed VHEE beams applying conventional correction factors. Further study is required to investigate the applicability of ion chambers in VHEE dosimetry.

Standards and Methodologies for Characterizing Radiobiological Impact of High-Z Nanoparticles.

Research on the application of high-Z nanoparticles (NPs) in cancer treatment and diagnosis has recently been the subject of growing interest, with much promise being shown with regards to a potential transition into clinical practice. In spite of numerous publications related to the development and application of nanoparticles for use with ionizing radiation, the literature is lacking coherent and systematic experimental approaches to fully evaluate the radiobiological effectiveness of NPs, validate mechanistic models and allow direct comparison of the studies undertaken by various research groups. The lack of standards and established methodology is commonly recognised as a major obstacle for the transition of innovative research ideas into clinical practice. This review provides a comprehensive overview of radiobiological techniques and quantification methods used in in vitro studies on high-Z nanoparticles and aims to provide recommendations for future standardization for NP-mediated radiation research.