High-resolution three-dimensional dosimetry in clinically relevant volumes utilizing optically stimulated luminescence.

BACKGROUND: The continued development of new radiotherapy techniques requires dosimetry systems that satisfy increasingly rigorous requirements, such as high sensitivity, wide dose range, and high spatial resolution. An emerging requirement is the ability to read out doses in three dimensions (3D) with high precision and spatial resolution. A few dosimetry systems with 3D capabilities are available, but their application in a clinical workflow is limited for various reasons, primarily originating from their chemical nature. The search for a 3D dosimetry system with potential for clinical implementation is thus ongoing. PURPOSE: To demonstrate the capabilities of a novel optically-stimulated-luminescence (OSL)-based 3D dosimetry system capable of measuring radiation doses in clinically relevant volumes. METHODS: A laser-based readout system was used to measure dose distributions delivered by both photons and protons, utilizing the OSL from a 50 × 50 × 50 $50\times 50\times 50$  mm 3 $^3$ YSO:Ce crystal. A homogeneous treatment plan consisting of two opposing photon fields was used to establish an inhomogeneity correction map of the crystal response and demonstrated the accuracy and precision of the system. The crystal was additionally irradiated with a photon treatment plan consisting of three overlapping 10 × 10 $10\times 10$  mm 2 $^2$ fields delivered from different angles, and a proton treatment plan consisting of four pencil beams with energies 90 MeV ( × 2 $\times 2$ ), 115 MeV, and 140 MeV. The system abilities were quantified by comparing the 3D-resolved measurements to Monte Carlo simulations. RESULTS: The dose map reproducibility of the system was found to be within 2% including both statistical and systematic errors. The measurements yielded integrated doses from a volume of 50 × 50 × 40 $50\times 50\times 40$  mm 3 $^3$ with voxel volumes of just 0.28 × 0.28 × 0.50 $0.28\times 0.28\times 0.50$  mm 3 $^3$ . An excellent agreement between the 3D-resolved measurements and the simulations was found for both photon- and proton-irradiation. CONCLUSIONS: The capabilities of the devised system for measuring clinically relevant fields of photons and proton pencil beams within a clinically relevant volume were demonstrated. The system poses as a promising candidate for clinical applications, and enables future research in the field of OSL-based tissue-equivalent 3D dosimetry.

Plan robustness evaluation strategies in whole-pelvic proton therapy for high-risk prostate cancer patients within a randomised clinical trial.

BACKGROUND: Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints. MATERIAL AND METHODS: Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE. RESULTS: Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively. CONCLUSION: The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Risk of second primary cancer from proton arc therapy of pediatric brain tumors.

Proton arc therapy (PAT) is currently explored for clinical implementation, despite its associated low-dose bath. This study therefore aimed at evaluating the risk of radiation-induced second primary cancer (SPC) for PAT in pediatric brain tumor patients. Two brain-specific models for SPC induction were applied in five cases to compare volumetric modulated arc therapy (VMAT), intensity modulated proton therapy (IMPT) and PAT surrogate plans. The PAT integral dose was reduced by a median of 29% compared to VMAT, and 17% compared to IMPT. For both models, the estimated SPC risks were consistently the lowest for PAT.

Proton therapy planning and image-guidance strategies within a randomized controlled trial for high-risk prostate cancer.

The Danish Prostate Cancer Group is launching the randomized trial, PROstate PROTON Trial 1 (NCT05350475), that compares photons and protons to the prostate and pelvic lymph nodes in treatment of high-risk prostate cancer. The aim of the work described in this paper was, in preparation of this trial, to establish a strategy for conventionally fractionated proton therapy of prostate and elective pelvic lymph nodes that is feasible and robust. Proton treatments are image-guided based on gold fiducial markers and on-board imaging systems in line with current practice. Our established proton beam configuration consists of four coplanar fields; two posterior oblique fields and two lateral oblique fields, chosen to minimize range uncertainties associated with penetrating a varying amount of material from both treatment couch and patient body. Proton plans are robustly optimized to ensure target coverage while keeping normal tissue doses as low as is reasonably achievable throughout the course of treatment. Specific focus is on dose to the bowel as a reduction in gastrointestinal toxicity is the primary endpoint of the trial. Strategies have been established using previously treated patients and will be further investigated and evaluated through the ongoing pilot phase of the trial.

Linear energy transfer-inclusive models of brainstem necrosis following proton therapy of paediatric ependymoma.

Background and Purpose: Radiation-induced brainstem necrosis after proton therapy is a severe toxicity with potential association to uncertainties in the proton relative biological effectiveness (RBE). A constant RBE of 1.1 is assumed clinically, but the RBE is known to vary with linear energy transfer (LET). LET-inclusive predictive models of toxicity may therefore be beneficial during proton treatment planning. Hence, we aimed to construct models describing the association between brainstem necrosis and LET in the brainstem. Materials and methods: A matched case-control cohort (n = 28, 1:3 case-control ratio) of symptomatic brainstem necrosis was selected from 954 paediatric ependymoma brain tumour patients treated with passively scattered proton therapy. Dose-averaged LET (LETd) parameters in restricted volumes (L50%, L10% and L0.1cm3, the cumulative LETd) within high-dose thresholds were included in linear- and logistic regression normal tissue complication probability (NTCP) models. Results: A 1 keV/µm increase in L10% to the brainstem volume receiving dose over 54 Gy(RBE) led to an increased brainstem necrosis risk [95% confidence interval] of 2.5 [0.0, 7.8] percentage points. The corresponding logistic regression model had area under the receiver operating characteristic curve (AUC) of 0.76, increasing to 0.84 with the anterior pons substructure as a second parameter. 19 [7, 350] patients with toxicity were required to associate the L10% (D > 54 Gy(RBE)) and brainstem necrosis with 80% statistical power. Conclusion: The established models of brainstem necrosis illustrate a potential impact of high LET regions in patients receiving high doses to the brainstem, and thereby support LET mitigation during clinical treatment planning.

Tissue-specific range uncertainty estimation in proton therapy.

Background and Purpose: Proton therapy is sensitive to range uncertainties, which typically are accounted for by margins or robust optimization, based on tissue-independent uncertainties. However, range uncertainties have been shown to depend on the specific tissues traversed. The aim of this study was to investigate the differences between range margins based on stopping power ratio (SPR) uncertainties which were tissue-specific (applied voxel-wise) or fixed (tissue-independent or composite). Materials and Methods: Uncertainties originating from imaging, computed tomography (CT) number estimation, and SPR estimation were calculated for low-, medium-, and high-density tissues to quantify the tissue-specific SPR uncertainties. Four clinical treatment plans (four different tumor sites) were created and recomputed after applying either tissue-specific or fixed SPR uncertainties. Plans with tissue-specific and fixed uncertainties were compared, based on dose-volume-histogram parameters for both targets and organs-at-risk. Results: The total SPR uncertainties were 7.0% for low-, 1.0% for medium-, and 1.3% for high-density tissues. Differences between the proton plans with tissue-specific and fixed uncertainties were mainly found in the vicinity of the target. Composite uncertainties were found to capture the tissue-specific uncertainties more accurately than the tissue-independent uncertainties. Conclusion: Different SPR uncertainties were found for low-, medium-, and high-density tissues indicating that range margins based on tissue-specific uncertainties may be more exact than the standard approach of using tissue-independent uncertainties. Differences between applying tissue-specific and fixed uncertainties were found, however, a fixed uncertainty might still be sufficient, but with a magnitude that depends on the body region.

Technical note: Temporal and thermal stability of optical response for silicone-based 3D radiochromic dosimeters.

BACKGROUND: Radiochromic silicone-based dosimeters are flexible 3D dosimeters, which at appropriate concentration of leucomalachite green (LMG) and curing agent are dose-rate independent for clinical photon beams. However, their dose response is based on chemical processes that can be influenced by temporal and thermal conditions, impacting measurement stability. PURPOSE: The aim of this study was to investigate the temporal stability of the dose response of radiochromic dosimeters for different curing times and post-irradiation storage temperatures. METHODS: Six cylindrical dosimeters (5 cm diameter, 5 cm length) were produced in a single batch and separated into two groups that were irradiated 72 and 118 h after production. The same photon plan, consisting of two 10 × 1.6 cm2 opposing fields, was delivered to all dosimeters. After irradiation, the dosimeters were separated into three groups, stored at 5°C, 15°C, and 20°C, and read out for five consecutive days. RESULTS: Storage temperature influenced the measurement stability, and changes in the optical response with time differed between irradiated and non-irradiated parts of the dosimeters. The relative change between signal and background was greater than 10% for all measurements performed 24 h or more after irradiation, except for dosimeters stored at 5°C, which changed by 2%-5% after 24 h. The dosimeter temporal stability was not influenced by curing time. CONCLUSIONS: For room temperature storage (15°C and 20°C), readout should take place as soon as possible after irradiation since the background color increased rapidly for both curing times (72 and 118 h), whereas the dosimeters are stored at 5°C, readout can be performed up to 24 h after.

Dose perturbations in proton pencil beam delivery investigated by dynamically deforming silicone-based radiochromic dosimeters.

Objective.Proton therapy with pencil beam delivery enables dose distributions that conform tightly to the shape of a target. However, proton therapy dose delivery is sensitive to motion and deformation, which especially occur in the abdominal and thoracic regions. In this study, the dose perturbation caused by dynamic motion with and without gating during proton pencil beam deliveries were investigated using deformable three-dimensional (3D) silicone-based radiochromic dosimeters.Approach.A spread-out Bragg peak formed by four proton spots with different energies was delivered to two dosimeter batches. All dosimeters were cylindrical with a 50 mm diameter and length. The dosimeters were irradiated stationary while uncompressed and during dynamic compression by sinusoidal motion with peak-to-peak amplitudes of 20 mm in one end of the dosimeter and 10 mm in the other end. Motion experiments were made without gating and with gating near the uncompressed position. The entire experiment was video recorded and simulated in a Monte Carlo (MC) program.Main results.The 2%/2 mm gamma index analysis between the dose measurements and the MC dose simulations had pass rates of 86%-94% (first batch) and 98%-99% (second batch). Compared to the static delivery, the dose delivered during motion had gamma pass rates of 99%-100% when employing gating and 68%-87% without gating in the experiments whereas for the MC simulations it was 100% with gating and 66%-82% without gating.Significance.This study demonstrated the ability of using deformable 3D dosimeters to measure dose perturbations in proton pencil beam deliveries caused by dynamic motion and deformation.

A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy.

BACKGROUND AND PURPOSE: A fixed relative biological effectiveness (RBE) of 1.1 (RBE1.1) is used clinically in proton therapy even though the RBE varies with properties such as dose level and linear energy transfer (LET). We therefore investigated if symptomatic brainstem toxicity in pediatric brain tumor patients treated with proton therapy could be associated with a variable LET and RBE. MATERIALS AND METHODS: 36 patients treated with passive scattering proton therapy were selected for a case-control study from a cohort of 954 pediatric brain tumor patients. Nine children with symptomatic brainstem toxicity were each matched to three controls based on age, diagnosis, adjuvant therapy, and brainstem RBE1.1 dose characteristics. Differences across cases and controls related to the dose-averaged LET (LETd) and variable RBE-weighted dose from two RBE models were analyzed in the high-dose region. RESULTS: LETd metrics were marginally higher for cases vs. controls for the majority of dose levels and brainstem substructures. Considering areas with doses above 54 Gy(RBE1.1), we found a moderate trend of 13% higher median LETd in the brainstem for cases compared to controls (P =.08), while the difference in the median variable RBE-weighted dose for the same structure was only 2% (P =.6). CONCLUSION: Trends towards higher LETd for cases compared to controls were noticeable across structures and LETd metrics for this patient cohort. While case-control differences were minor, an association with the observed symptomatic brainstem toxicity cannot be ruled out.

Optically stimulated luminescence in state-of-the-art LYSO:Ce scintillators enables high spatial resolution 3D dose imaging.

In this contribution, we study the optically stimulated luminescence (OSL) exhibited by commercial [Formula: see text]:Ce crystals. This photon emission mechanism, complementary to scintillation, can trap a fraction of radiation energy deposited in the material and provides sufficient signal to develop a novel post-irradiation 3D dose readout. We characterize the OSL emission through spectrally and temporally resolved measurements and monitor the dose linearity response over a broad range. The measurements show that the [Formula: see text] centers responsible for scintillation also function as recombination centers for the OSL mechanism. The capture to OSL-active traps competes with scintillation originating from the direct non-radiative energy transfer to the luminescent centers. An OSL response on the order of 100 ph/MeV is estimated. We demonstrate the imaging capabilities provided by such an OSL photon yield using a proof-of-concept optical readout method. A 0.1 [Formula: see text] spatial resolution for doses as low as 0.5 Gy is projected using a cubic crystal to image volumetric dose profiles. While OSL degrades the intrinsic scintillating performance by reducing the number of scintillation photons emitted following the passage of ionizing radiation, it can encode highly resolved spatial information of the interaction point of the particle. This feature combines ionizing radiation spectroscopy and 3D reusable dose imaging in a single material.

Towards range-guidance in proton therapy to detect organ motion-induced dose degradations.

Introduction.Internal organ motion and deformations may cause dose degradations in proton therapy (PT) that are challenging to resolve using conventional image-guidance strategies. This study aimed to investigate the potential ofrange guidanceusing water-equivalent path length (WEPL) calculations to detect dose degradations occurring in PT.Materials and methods. Proton ranges were estimated using WEPL calculations. Field-specific isodose surfaces in the planning CT (pCT), from robustly optimised five-field proton plans (opposing lateral and three posterior/posterior oblique beams) for locally advanced prostate cancer patients, were used as starting points. WEPLs to each point on the field-specific isodoses in the pCT were calculated. The corresponding range for each point was found in the repeat CTs (rCTs). The spatial agreement between the resulting surfaces in the rCTs (hereafter referred to as iso-WEPLs) and the isodoses re-calculated in rCTs was evaluated for different dose levels and Hausdorff thresholds (2-5 mm). Finally, the sensitivity and specificity of detecting target dose degradation (V95% < 95%) using spatial agreement measures between the iso-WEPLs and isodoses in the pCT was evaluated.Results. The spatial agreement between the iso-WEPLs and isodoses in the rCTs depended on the Hausdorff threshold. The agreement was 65%-88% for a 2 mm threshold, 83%-96% for 3 mm, 90%-99% for 4 mm, and 94%-99% for 5 mm, across all fields and isodose levels. Minor differences were observed between the different isodose levels investigated. Target dose degradations were detected with 82%-100% sensitivity and 75%-80% specificity using a 2 mm Hausdorff threshold for the lateral fields.Conclusion. Iso-WEPLs were comparable to isodoses re-calculated in the rCTs. The proposed strategy could detect target dose degradations occurring in the rCTs and could be an alternative to a fully-fledged dose re-calculation to detect anatomical variations severely influencing the proton range.

A Novel Nanocomposite Material for Optically Stimulated Luminescence Dosimetry.

Radiotherapy is a well-established and important treatment for cancer tumors, and advanced technologies can deliver doses in complex three-dimensional geometries tailored to each patient's specific anatomy. A 3D dosimeter, based on optically stimulated luminescence (OSL), could provide a high accuracy and reusable tool for verifying such dose delivery. Nanoparticles of an OSL material embedded in a transparent matrix have previously been proposed as an inexpensive dosimeter, which can be read out using laser-based methods. Here, we show that Cu-doped LiF nanocubes (nano-LiF:Cu) are excellent candidates for 3D OSL dosimetry owing to their high sensitivity, dose linearity, and stability at ambient conditions. We demonstrate a scalable synthesis technique producing a material with the attractive properties of a single dosimetric trap and a single near-ultraviolet emission line well separated from visible-light stimulation sources. The observed transparency and light yield of silicone sheets with embedded nanocubes hold promise for future 3D OSL-based dosimetry.