A simple calibration routine for small inorganic scintillation detectors for in vivo dosimetry during brachytherapy.

BACKGROUND: In vivo dosimetry (IVD) is rarely performed in brachytherapy (BT), allowing potential dose misadministration to go unnoticed. This study presents a clinical routine-calibration method of detectors for IVD in high (HDR) and pulsed dose rate (PDR) Ir-192 BT. PURPOSE: To evaluate the dosimetric precision and feasibility of an in-clinic calibration routine of detectors for IVD in afterloading BT. METHODS: Calibrations were performed in a PMMA phantom with two needles inserted 20 mm apart. The source was loaded in one of the needles at 15 dwells for 10 s. The detector was placed in the other needle, and its signal was recorded. The mean signal at each dwell position was fitted to the expected dose rate with the calibration factor and the detector's longitudinal position being free parameters. The method was tested with an inorganic scintillation detector using one Ir-192 FlexiSource HDR and two Ir-192 GammaMedPlus PDR sources and followed by validation measurements in water. RESULTS: The standard measurement uncertainty (k = 1) of the calibration factor in absolute terms (Gy/s) was 3.2/3.4% for the HDR/PDR source. The uncertainty was dominated by source strength uncertainty, and the precision of the method was <1%. The mean ± 1SD of the difference in measured and expected dose rate during validation was 1.5 ± 4.7% (HDR) and 0.0 ± 4.1% (PDR) with a positional uncertainty in the setup of 0.33/0.23 mm (HDR/PDR) (k = 1). CONCLUSION: A precise and feasible in-clinic calibration method for IVD and source strength consistency tests in BT was presented.

Establishing a fingerprinting method for fast catheter identification in HDR brachytherapy in vivo dosimetry.

PURPOSE: To use quantities measurable during in vivo dosimetry to build unique channel identifiers, that enable detection of brachytherapy errors. MATERIALS AND METHODS: Treatment plan of 360 patients with prostate cancer who underwent high-dose-rate brachytherapy (range, 16-25 catheters; mean, 17) were used. A single point virtual dosimeter was placed at multiple positions within the treatment geometry, and the source-dosimeter distance and dwell time were determined for each dwell position in each catheter. These values were compared across all catheters, dwell position by dwell position, simulating a treatment delivery. A catheter was considered uniquely identified if, for a given dwell position, no other catheters had the same measured values. The minimum number of dwell positions needed to identify a specific catheter and the optimal dosimeter location uniquely were determined. The radial (r) and vertical (z) dimensions of the source-dosimeter distance were also examined for their utility in discriminating catheters. RESULTS: Using a virtual dosimeter with no uncertainties, all catheters were identified in 359 of the 360 cases with 9 dwell position measurements. When only the dwell time were measured, all catheters were uniquely identified after 1 dwell position. With a 2-mm spatial accuracy (r,z), all catheters were identified in 94% of the plans. Simultaneous measurement of source-dosimeter distance and dwell time ensured full catheter identification in all plans ranging from 2 to 6 dwell positions. The number of dwell positions needed to uniquely identify all catheters was lower when the distance from the implant center was higher. CONCLUSIONS: The most efficient fingerprinting approach involved combining source-dosimeter distance (i.e., source tracking) and dwell time. The further the dosimeter is placed from the center of the implant the better it can uniquely identify catheters.

Proton FLASH: Impact of Dose Rate and Split Dose on Acute Skin Toxicity in a Murine Model.

PURPOSE: Preclinical studies have shown a preferential normal tissue sparing effect of FLASH radiation therapy with ultra-high dose rates. The aim of the present study was to use a murine model of acute skin toxicity to investigate the biologic effect of varying dose rates, time structure, and introducing pauses in the dose delivery. METHODS AND MATERIALS: The right hind limbs of nonanaesthetized mice were irradiated in the entrance plateau of a pencil beam scanning proton beam with 39.3 Gy. Experiment 1 was with varying field dose rates (0.7-80 Gy/s) without repainting, experiment 2 was with varying field dose rates (0.37-80 Gy/s) with repainting, and in experiment 3, the dose was split into 2, 3, 4, or 6 identical deliveries with 2-minute pauses. In total, 320 mice were included, with 6 to 25 mice per group. The endpoints were skin toxicity of different levels up to 25 days after irradiation. RESULTS: The dose rate50, which is the dose rate to induce a response in 50% of the animals, depended on the level of skin toxicity, with the higher toxicity levels displaying a FLASH effect at 0.7-2 Gy/s. Repainting resulted in higher toxicity for the same field dose rate. Splitting the dose into 2 deliveries reduced the FLASH effect, and for 3 or more deliveries, the FLASH effect was almost abolished for lower grades of toxicity. CONCLUSIONS: The dose rate that induced a FLASH effect varied for different skin toxicity levels, which are characterized by a differing degree of sensitivity to radiation dosage. Conclusions on a threshold for the dose rate needed to obtain a FLASH effect can therefore be influenced by the dose sensitivity of the used endpoint. Splitting the total dose into more deliveries compromised the FLASH effect. This can have an impact for fractionation as well as for regions where 2 or more FLASH fields overlap within the same treatment session.

In vivo dosimetry with an inorganic scintillation detector during multi-channel vaginal cylinder pulsed dose-rate brachytherapy: Dosimetry for pulsed dose-rate brachytherapy.

Background and purpose: In vivo dosimetry is not standard in brachytherapy and some errors go undetected. The aim of this study was to evaluate the accuracy of multi-channel vaginal cylinder pulsed dose-rate brachytherapy using in vivo dosimetry. Materials and methods: In vivo dosimetry data was collected during the years 2019-2022 for 22 patients (32 fractions) receiving multi-channel cylinder pulsed dose-rate brachytherapy. An inorganic scintillation detector was inserted in a cylinder channel. Each fraction was analysed as independent data sets. In vivo dosimetry-based source-tracking was used to determine the relative source-to-detector position. Measured dose was compared to planned and re-calculated source-tracking based doses. Assuming no change in organ and applicator geometry throughout treatment, the planned and source-tracking based dose distributions were compared in select volumes via γ-index analysis and dose-volume-histograms. Results: The mean ± SD planned vs. measured dose deviations in the first pulse were 0.8 ± 5.9 %. In 31/32 fractions the deviation was within the combined in vivo dosimetry uncertainty (averaging 9.7 %, k = 2) and planning dose calculation uncertainty (1.6 %, k = 2). The dwell-position offsets were < 2 mm for 88 % of channels, with the largest being 5.1 mm (4.0 mm uncertainty, k = 2). 3 %/2 mm γ pass-rates averaged 97.0 % (clinical target volume (CTV)), 100.0 % (rectum), 99.9 % (bladder). The mean ± SD deviation was -1. 1  ± 2.9 % for CTV D98, and -0.2 ± 0.9 % and -1.2 ± 2.5 %, for bladder and rectum D2cm3 respectively, indicating good agreement between intended and delivered dose. Conclusions: In vivo dosimetry verified accurate and stable dose delivery in multi-channel vaginal cylinder based pulsed dose-rate brachytherapy.

Spread-out Bragg peak FLASH: quantifying normal tissue toxicity in a murine model.

Objective: A favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model. Material/Methods: Radiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment. Results: Comparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4). Conclusion: Full dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Monte Carlo characterization of high atomic number inorganic scintillators for in vivo dosimetry in 192 Ir brachytherapy.

BACKGROUND: There is increased interest in in vivo dosimetry for 192 Ir brachytherapy (BT) treatments using high atomic number (Z) inorganic scintillators. Their high light output enables construction of small detectors with negligible stem effect and simple readout electronics. Experimental determination of absorbed-dose energy dependence of detectors relative to water is prevalent, but it can be prone to high detector positioning uncertainties and does not allow for decoupling of absorbed-dose energy dependence from other factors affecting detector response . PURPOSE: To investigate which measurement conditions and detector properties could affect their absorbed-dose energy dependence in BT in vivo dosimetry. METHODS: We used a general-purpose Monte Carlo (MC) code PENELOPE for the characterization of high-Z inorganic scintillators with the focus on ZnSe ( Z ¯ = 32 $\bar{Z}=32$ ) Z. Two other promising media CsI ( Z ¯ = 54 $\bar{Z}=54$ ) and Al2 O3 ( Z ¯ = 11 $\bar{Z}=11$ ) were included for comparison in selected scenarios. We determined absorbed-dose energy dependence of crystals relative to water under different scatter conditions (calibration phantom 12 × 12 × 30 cm3 , characterization phantoms 20 × 20 × 20 cm3 , 30 × 30 × 30 cm3 , 40 × 40 × 40 cm3 , and patient-like elliptic phantom 40 × 30 × 25 cm3 ). To mimic irradiation conditions during prostate treatments, we evaluated whether the presence of pelvic bones and calcifications affect ZnSe response. ZnSe detector design influence was also investigated. RESULTS: In contrast to low-Z organic and medium-Z inorganic scintillators, ZnSe and CsI media have substantially greater absorbed-dose energy dependence relative to water. The response was phantom-size dependent and changed by 11% between limited- and full-scatter conditions for ZnSe, but not for Al2 O3 . For a given phantom size, a part of the absorbed-dose energy dependence of ZnSe is caused not due to in-phantom scatter but due to source anisotropy. Thus, the absorbed-dose energy dependence of high-Z scintillators is a function of not only the radial distance but also the polar angle. Pelvic bones did not affect ZnSe response, whereas large and intermediate size calcifications reduced it by 9% and 5%, respectively, when placed midway between the source and the detector. CONCLUSIONS: Unlike currently prevalent low- and medium-Z scintillators, high-Z crystals are sensitive to characterization and in vivo measurement conditions. However, good agreement between MC data for ZnSe in the present study and experimental data for ZnSe:O by Jørgensen et al. (2021) suggests that detector signal is proportional to the average absorbed dose to the detector cavity. This enables an easy correction for non-TG43-like scenarios (e.g., patient sizes and calcifications) through MC simulations. Such information should be provided to the clinic by the detector vendors.

3D dose reconstruction based on in vivo dosimetry for determining the dosimetric impact of geometric variations in high-dose-rate prostate brachytherapy.

INTRODUCTION: In vivo dosimetry (IVD) can be used for source tracking (ST), i.e., estimating source positions, during brachytherapy. The aim of this study was to exploit IVD-based ST to perform 3D dose reconstruction for high-dose-rate prostate brachytherapy and to evaluate the robustness of the treatments against observed geometric variations. MATERIALS AND METHODS: Twenty-three fractions of high-dose-rate prostate brachytherapy were analysed. The treatment planning was based on MRI. Time-resolved IVD was performed using a fibre-coupled scintillator. ST was retrospectively performed using the IVD measurements. The ST identified 2D positional shifts of each treatment catheter and thereby inferred updated source positions. For each fraction, the dose was recalculated based on the source-tracked catheter positions and compared with the original plan dose using differences in dose volume histogram indices. RESULTS: Of 352 treatment catheters, 344 had shifts of less than 5 mm. Shifts between 5 and 10 mm were observed for 3 catheters, and shifts greater than 10 mm for 2 catheters. The ST failed for 3 catheters. The maximum relative difference in clinical target volume (prostate + 3 mm isotropic margin) D90% was 5%. In one fraction, the bladder D2cm3 dose increased by 18% (1.4 Gy) due to a single source position being inside the bladder rather than nearby as planned. The max increase in urethra dose was 1.5 Gy (15%). CONCLUSION: IVD-based 3D dose reconstruction for high-dose-rate prostate brachytherapy is feasible. The dosimetric impact of the observed catheter shifts was limited. Dose reconstruction can therefore aid in determining the dosimetric impact of geometric variations and errors in brachytherapy.

Pencil beam scanning proton FLASH maintains tumor control while normal tissue damage is reduced in a mouse model.

PURPOSE: Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model. METHODS AND MATERIALS: Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63 Gy/s field dose rate, 244 MeV) or FLASH (71-89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60 Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation. RESULTS: TCD50 (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD50 (dose for 50% of mice displaying moist desquamation) of <40.1 Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD50 (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14). CONCLUSIONS: FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis.

3D source tracking and error detection in HDR using two independent scintillator dosimetry systems.

PURPOSE: The aim of this study is to perform three-dimensional (3D) source position reconstruction by combining in vivo dosimetry measurements from two independent detector systems. METHODS: Time-resolved dosimetry was performed in a water phantom during HDR brachytherapy irradiation with 192 Ir source using two detector systems. The first was based on three plastic scintillator detectors and the second on a single inorganic crystal (CsI:Tl). Brachytherapy treatments were simulated in water under TG-43U1 conditions, including a HDR prostate plan. Treatment needles were placed in distances covering a range of source movement of 120 mm around the detectors. The distance from each dwell position to each scintillator was determined based on the measured dose rates. The three distances given by the mPSD were recalculated to a position along the catheter (z) and a distance radially away from the mPSD (xy) for each dwell position (a circumference around the mPSD). The source x, y, and z coordinates were derived from the intersection of the mPSD's circumference with the sphere around the ISD based on the distance to this detector. We evaluated the accuracy of the source position reconstruction as a function of the distance to the source, the most likely location for detector positioning within a prostate volume, as well as the capacity to detect positioning errors. RESULTS: Approximately 4000 source dwell positions were tracked for eight different HDR plans. An intersection of the mPSD torus and the ISD sphere was observed in 77.2% of the dwell positions, assuming no uncertainty in the dose rate determined distance. This increased to 100% if 1σ search regions were added. However, only 73(96)% of the expected dwell positions were found within the intersection band for 1(2) σ uncertainties. The agreement between the source's reconstructed and expected positions was within 3 mm for a range of distances to the source up to 50 mm. The experiments on a HDR prostate plan, showed that by having at least one of the detectors located in the middle of the prostate volume, reduces the measurement deviations considerably compared to scenarios where the detectors were located outside of the prostate volume. The analysis showed a detection probability that, in most cases, is far from the random detection threshold. Errors of 1(2) mm can be detected in ranges of 5-25 (25-50) mm from the source, with a true detection probability rate higher than 80%, while the false probability rate is kept below 20%. CONCLUSIONS: By combining two detector responses, we enabled the determination of the absolute source coordinates. The combination of the mPSD and the ISD in vivo dosimetry constitutes a promising alternative for real-time 3D source tracking in HDR brachytherapy.

Accuracy of an in vivo dosimetry-based source tracking method for afterloading brachytherapy - A phantom study.

PURPOSE: To report on the accuracy of an in vivo dosimetry (IVD)-based source tracking (ST) method for high dose rate (HDR) prostate brachytherapy (BT). METHODS: The ST was performed on a needle-by-needle basis. A least square fit of the expected to the measured dose rate was performed using the active dwell positions in the given needle. Two fitting parameters were used to determine the position of each needle relative to the IVD detector: radial (away or toward the detector) and longitudinal (along the axis of the treatment needle). The accuracy of the ST was assessed in a phantom where the geometries of five HDR prostate BT treatments previously treated at our clinic were reproduced. For each of the five treatment geometries, one irradiation was performed with the detector placed in the middle of the implant. Furthermore, four additional irradiations were performed for one of the geometries where the detector was retracted caudally in four steps of 10-15 mm and up to 12 mm inferior of the most inferior active dwell position, which represented the prostate apex. The time resolved dose measurements were retrieved at a rate of 20 Hz using a detector based on an Al2 O3 :C radioluminescence crystal, which was placed inside a standard BT needle. Individual calibrations of the detector were performed prior to each of the nine irradiations. RESULTS: Source tracking could be applied in all needles across all nine irradiations. For irradiations with the detector located in the middle region of the implant (a total of 89 needles), the mean ± standard deviation (SD, k = 1) accuracy was -0.01 mm ± 0.38 mm and 0.30 mm ± 0.38 mm in the radial and longitudinal directions, respectively. Caudal retraction of the detector did not lead to reduced accuracy as long as the detector was located superior to the most inferior active dwell positions in all needles. However, reduced accuracy was observed for detector positions inferior to the most inferior active dwell positions which corresponded to detector positions in and inferior to the prostate apex region. Detector positions in the prostate apex and 12 mm inferior to the prostate resulted in mean ± SD (k = 1) ST accuracy of 0.7 mm ± 1 mm and 2.8 mm ± 1.6 mm, respectively, in radial direction, and -1.7 mm ± 1 mm and -2.1 mm ± 1.1 mm, respectively, in longitudinal direction. The largest deviations for the configurations with those detector positions were 2.6 and 5.4 mm, respectively, in the radial direction and -3.5 and -3.8 mm, respectively, in the longitudinal direction. CONCLUSION: This phantom study demonstrates that ST based on IVD during prostate BT is adequately accurate for clinical use. The ST yields submillimeter accuracy on needle positions as long as the IVD detector is positioned superior to at least one active dwell position in all needles. Locations of the detector inferior to the prostate apex result in decreased ST accuracy while detector locations in the apex region and above are advantageous for clinical applications.

A high-Z inorganic scintillator-based detector for time-resolved in vivo dosimetry during brachytherapy.

PURPOSE: High-dose rate (HDR) and pulsed-dose rate (PDR) brachytherapy would benefit from an independent treatment verification system to monitor treatment delivery and to detect errors in real time. This paper characterizes and provides an uncertainty budget for a detector based on a fiber-coupled high-Z inorganic scintillator capable of performing time-resolved in vivo dosimetry during HDR and PDR brachytherapy. METHOD: The detector was composed of a detector probe and an optical reader. The detector probe consisted of either a 0.5 × 0.4 × 0.4 mm3 (HDR) or a 1.0 × 0.4 × 0.4 mm3 (PDR) cuboid ZnSe:O crystal glued onto an optical-fiber cable. The outer diameter of the detector probes was 1 mm, and fit inside standard brachytherapy catheters. The signal from the detector probe was read out at 20 Hz by a photodiode and a data acquisition device inside the optical reader. In order to construct an uncertainty budget for the detector, six characteristics were determined: (1) temperature dependence of the detector probe, (2) energy dependence as a function of the probe-to-source position in 2D (determined with 2 mm resolution using a robotic arm), (3) the signal-to-noise ratio (SNR), (4) short-term stability over 8 h, and (5) long-term stability of three optical readers and four probes used for in vivo monitoring in HDR and PDR treatments over 21 months (196 treatments and 189 detector calibrations, and (6) dose-rate dependence. RESULTS: The total uncertainty of the detector at a 20 mm probe-to-source distance was < 5.1% and < 5.8% for the HDR and PDR versions, respectively. Regarding the above characteristics, (1) the sensitivity of the detector decreased by an average of 1.4%/°C for detector probe temperatures varying from 22 to 37°C; (2) the energy dependence of the detector was nonlinear and depended on both probe-to-source distance and the angle between the probe and the brachytherapy source; (3) the median SNRs were 187 and 34 at a 20 mm probe-to-source distance for the HDR and PDR versions, respectively (corresponding median source activities of 4.8 and 0.56 Ci, respectively); (4) the detector response varied by 0.6% in 11 identical irradiations over 8 h; (5) the sensitivity of the four detector probes decreased systematically by 0-1.2%/100 Gy of dose delivered to the probes, and random fluctuations of 4.8% in the sensitivity were observed for the three probes used in PDR and 1.9% for the probe used in HDR; and (6) the detector response was linear with dose rate. CONCLUSION: ZnSe:O detectors can be used effectively for in vivo dosimetry and with high accuracy for HDR and PDR brachytherapy applications.

In vivo dosimetry in brachytherapy: Requirements and future directions for research, development, and clinical practice.

Brachytherapy can deliver high doses to the target while sparing healthy tissues due to its steep dose gradient leading to excellent clinical outcome. Treatment accuracy depends on several manual steps making brachytherapy susceptible to operational mistakes. Currently, treatment delivery verification is not routinely available and has led, in some cases, to systematic errors going unnoticed for years. The brachytherapy community promoted developments in in vivo dosimetry (IVD) through research groups and small companies. Although very few of the systems have been used clinically, it was demonstrated that the likelihood of detecting deviations from the treatment plan increases significantly with time-resolved methods. Time-resolved methods could interrupt a treatment avoiding gross errors which is not possible with time-integrated dosimetry. In addition, lower experimental uncertainties can be achieved by using source-tracking instead of direct dose measurements. However, the detector position in relation to the patient anatomy remains a main source of uncertainty. The next steps towards clinical implementation will require clinical trials and systematic reporting of errors and near-misses. It is of utmost importance for each IVD system that its sensitivity to different types of errors is well understood, so that end-users can select the most suitable method for their needs. This report aims to formulate requirements for the stakeholders (clinics, vendors, and researchers) to facilitate increased clinical use of IVD in brachytherapy. The report focuses on high dose-rate IVD in brachytherapy providing an overview and outlining the need for further development and research.