Peak-to-valley Dose Ratios Research Articles

Proton ARC based LATTICE radiation therapy: feasibility study, energy layer optimization and LET optimization

Objective.LATTICE, a spatially fractionated radiation therapy (SFRT) modality, is a 3D generalization of GRID and delivers highly modulated peak-valley spatial dose distribution to tumor targets, characterized by peak-to-valley dose ratio (PVDR). Proton LATTICE is highly desirable, because of the potential synergy of the benefit from protons compared to photons, and the benefit from LATTICE compared to GRID. Proton LATTICE using standard proton RT via intensity modulated proton therapy (IMPT) (with a few beam angles) can be problematic with poor target dose coverage and high dose spill to organs-at-risk (OAR). This work will develop novel proton LATTICE method via proton ARC (with many beam angles) to overcome these challenges in target coverage and OAR sparing, with optimized delivery efficiency via energy layer optimization and optimized biological dose distribution via linear energy transfer (LET) optimization, to enable the clinical use of proton LATTICE.Approach.ARC based proton LATTICE is formulated and solved with energy layer optimization, during which plan quality and delivery efficiency are jointly optimized. In particular, the number of energy jumps (NEJ) is explicitly modelled and minimized during plan optimization for improving delivery efficiency, while target dose conformality and OAR dose objectives are optimized. The plan deliverability is ensured by considering the minimum-monitor-unit (MMU) constraint, and the plan robustness is accounted for using robust optimization. The biological dose is optimized via LET optimization. The optimization solution algorithm utilizes iterative convex relaxation method to handle the dose-volume constraint and the MMU constraint, with spot-weight optimization subproblems solved by proximal descent method.Main results.ARC based proton LATTCE substantially improved plan quality from IMPT based proton LATTICE, such as (1) improved conformity index (CI) from 0.47 to 0.81 for the valley target dose and from 0.62 to 0.97 for the peak target dose, (2) reduced esophagus dose from 0.68 Gy to 0.44 Gy (a 12% reduction with respect to 2 Gy valley prescription dose) and (3) improved PVDR from 4.15 to 4.28 in the lung case. Moreover, energy layer optimization improved plan delivery efficiency for ARC based proton LATTICE, such as (1) reduced NEJ from 71 to 56 and (2) reduction of energy layer switching time by 65% and plan delivery time by 52% in the lung case. The biological target and OAR dose distributions were further enhanced via LET optimization. On the other hand, proton ARC LATTCE also substantially improved plan quality from VMAT LATTICE, such as (1) improved CI from 0.45 to 0.81 for the valley target dose and from 0.63 to 0.97 for the peak target dose, (2) reduced esophagus dose from 0.59 Gy to 0.38 Gy (a 10.5% reduction with respect to 2 Gy valley prescription dose) and (3) improved PVDR from 3.88 to 4.28 in the lung case.Significance.The feasibility of high-plan-quality proton LATTICE is demonstrated via proton ARC with substantially improved target dose coverage and OAR sparing compared to IMPT, while the plan delivery efficiency for ARC based proton LATTICE can be optimized using energy layer optimization.

Dosimetric impact of intrafraction patient motion on MLC-based 3D-conformal spatially fractionated radiation therapy treatment of large and bulky tumors.

To evaluate the dosimetric impact on spatially fractionated radiation therapy (SFRT) plan quality due to intrafraction patient motion via multi-field MLC-based method for treating large and bulky (≥8cm) unresectable tumors. For large tumors, a cone beam CT-guided 3D conformal MLC-based SFRT method was utilized with 15Gy prescription. An MLC GTV-fitting algorithm provided 1cm diameter apertures with a 2cm center-to-center distance at the isocenter. This generated a highly heterogeneous sieve-like dose distribution within an hour, enabling same-day SFRT treatment. Fifteen previously treated SFRT patients were analyzed (5 head & neck [H&N], 5 chest and lungs, and 5 abdominal and pelvis masses). For each plan, intrafraction motion errors were simulated by incrementally shifting original isocenters of each field in different x-, y-, and z-directions from 1 to 5mm. The dosimetric metrics analyzed were: peak-to-valley-dose-ratio (PVDR), percentage of GTV receiving 7.5Gy, GTV mean dose, and maximum dose to organs-at-risk (OARs). For±1,±2,±3,±4, and±5mm isocenter shifts: PVDR dropped by 3.9%, 3.8%, 4.0%, 4.1%, and 5.5% on average respectively. The GTV(V7.5) remained within 0.2%, and the GTV mean dose remained within 3.3% on average, compared to the original plans. The average PVDR drop for 5mm shifts was 4.2% for H&N cases, 10% for chest and lung, and 2.2% for abdominal and pelvis cases. OAR doses also increased. The maximum dose to the spinal cord increased by up to 17 cGy in H&N plans, mean lung dose (MLD) changed was small for chest/lung, but the bowel dose varied up to 100 cGy for abdominal and pelvis cases. Due to tumor size, location, and characteristics of MLC-based SFRT, isocenter shifts of up to±5mm in different directions had moderate effects on PVDR for H&N and pelvic tumors and a larger effect on chest tumors. The dosimetric impact on OAR doses depended on the treatment site. Site-specific patient masks, Vac-Lok bags, and proper immobilization devices similar to SBRT/SRT setups should be used to minimize these effects.

Clinical Implementation and Dosimetric Evaluation of a Robust Proton Lattice Planning Strategy Using Primary and Robust Complementary Beams

Pencil-beam scanning proton therapy has been considered a potential modality for the 3D form of spatially fractionated radiation therapy called lattice therapy. However, few practical solutions have been introduced in the clinic. Existing limitations include degradation in plan quality and robustness when using single-field versus multifield lattice plans, respectively. We propose a practical and robust proton lattice (RPL) planning method using multifield and evaluate its dosimetric characteristics compared to clinically acceptable photon lattice plans. Seven cases previously treated with photon lattice therapy were used to evaluate a novel RPL planning technique using 2-orthogonal beams: a primary beam (PB) and a robust complementary beam (RCB) that deliver 67% and 33%, respectively, of the prescribed dose to vertices inside the gross target volume (GTV). Only RCB is robustly optimized for setup and range uncertainties. The number and volume of vertices, peak-to-valley dose ratios (PVDRs), and volume of low dose to GTV of proton and photon plans were compared. The RPL technique was then used in the treatment of 2 patients and their dosimetric parameters were reported. The RPL strategy was able to achieve the clinical planning goals. Compared to previously treated photon plans, the average number of vertices increased by 30%, the average vertex volume by 49% (18.2 ± 25.9 cc vs 12.2 ± 14.5 cc, P = .21), and higher PVDR (10.5 ± 4.8 vs 2.5 ± 0.9, P < .005) was achieved. In addition, RPL plans show more conformal dose with less low dose to GTV (V30%, 60.9% ± 7.2% vs 81.6% ± 13.9% and V10%, 88.3% ± 4.5% vs 98.6% ± 3.6% [P < .01]). The RPL plan for 2 treated patients showed PVDRs of 4.61 and 14.85 with vertices-to-GTV ratios of 1.52% and 1.30%, respectively. A novel RPL planning strategy using a pair of orthogonal beams was developed and successfully translated to the clinic. The proposed method can generate better quality plans, a higher number of vertices, and higher PVDRs than currently used photon lattice plans.

Dosimetric characterization for GRID collimator-based spatially fractionated radiation therapy: Dosimetric parameter acquisition and machine interchangeability investigation.

The purpose of this study is to characterize the dosimetric properties of a commercial brass GRID collimator for high energy photon beams including 15 and 10 MV. Then, the difference in dosimetric parameters of GRID beams among different energies and linacs was evaluated. A water tank scanning system was used to acquire the dosimetric parameters, including the percentage depth dose (PDD), beam profiles, peak to valley dose ratios (PVDRs), and output factors (OFs). The profiles at various depths were measured at 100cm source to surface distance (SSD), and field sizes of 10×10 cm2 and 20×20 cm2 on three linacs. The PVDRs and OFs were measured and compared with the treatment planning system (TPS) calculations. Compared with the open beam data, there were noticeable changes in PDDs of GRID fields across all the energies. The GRID fields demonstrated a maximal of 3mm shift in dmax (Truebeam STX, 15MV, 10×10 cm2). The PVDR decreased as beam energy increases. The difference in PVDRs between Trilogy and Truebeam STx using 6MV and 15MV was 1.5%±4.0% and 2.1%±4.3%, respectively. However, two Truebeam linacs demonstrated less than 2% difference in PVDRs. The OF of the GRID field was dependent on the energy and field size. The measured PDDs, PVDRs, and OFs agreed with the TPS calculations within 3% difference. The TPS calculations agreed with the measurements when using 1mm calculation resolution. The dosimetric characteristics of high-energy GRID fields, especially PVDR, significantly differ from those of low-energy GRID fields. Two Truebeam machines are interchangeable for GRID therapy, while a pronounced difference was observed between Truebeam and Trilogy. A series of empirical equations and reference look-up tables for GRID therapy can be generated to facilitate clinical applications.

Abstract PO5-18-05: Assessment of the Potential of Photon mini-GRID Therapy for Pre-operative Partial Breast Cancer Treatment

Abstract Purpose We propose a new spatially fractionated radiation therapy (SFRT) technique, called mini-GRID therapy, to reduce normal tissue toxicities in pre-operative partial breast cancer radiotherapy. Mini-GRID therapy, an optimized implementation of GRID therapy, utilizes very narrow beams (widths ~ 1-2 mm) which significantly increase normal tissue tolerances. The concept, proposed by our team in 2017 [1], has been successfully implemented at Hospital de Santiago de Compostela (Spain) showing excellent results in terms of brain toxicity reduction [2]. Profiting from this remarkable increase in tolerance, this study aims to evaluate the feasibility and efficacy of photon mini-GRID therapy for pre-operative partial breast cancer treatment. Methods Ten unbiased clinical cases were selected for the study, comparing photon mini-GRID therapy with conventional broad beam radiotherapy. Monte Carlo simulations (TOPAS v.3.6) were performed based on the mini-GRID therapy implementation (megavoltage X-rays, Varian flattening-filter-free LINAC) realized at the University Hospital in Santiago de Compostela. A mean dose of 24 Gy was delivered in the PTV using three photon mini-GRID arrays with mini beams of approximately 1.8x1.8 mm² at the isocenter. The study aimed to achieve better tumor coverage than conventional pre-operative radiotherapy while ensuring comparable skin toxicity. Valley doses, determining tissue-sparing effects, were compared against organs-at-risk (OARs) tolerance limits. Results The mini-GRID therapy treatments ensured partial tumor coverage and met the dose tolerance limits for all the considered OARs, the most challenging of all being the skin [3]. Peak-to-valley dose ratio (PVDR) in the skin was higher than 3.5 for all the considered patients. Compared to standard radiotherapy (SRT) plans, mini-GRID therapy significantly reduced mean doses to the lungs, heart, and chest wall in the studied cases. Conclusion In this proof-of-concept study, we evaluated photon mini-GRID therapy with megavoltage X-rays as an alternative treatment approach for pre-operative partial breast cancer irradiation, demonstrating its feasibility and straightforward implementation. Because of its high skin and normal tissue-sparing capacities, photon mini-GRID therapy has great potential to improve pre-operative treatment outcomes. Complementary studies and clinical validation are needed to fully establish the optimal protocols and assess long-term effects, but the results encourage the integration of photon mini-GRID therapy as a promising modality for breast cancer therapy.

β-delayed multiple-particle emitters minibeam radiation therapy: first dosimetric evaluation with Monte Carlo simulations

Radiation therapy, one of the most effective methods for cancer treatment, is still limited by the tolerances of normal tissues surrounding the tumor. Innovative techniques like spatially fractionated radiation therapy (SFRT) have been shown to increase normal tissue dose resistance. Heavy ions also offer high-dose conformity and increased relative biological effectiveness (RBE) when compared to protons and X-rays. The alliance of heavy ions and spatial fractionation of the dose has the potential to further increase the therapeutic index for difficult-to-treat cases today. In particular, the use of β-delayed multiple-particle emitters might further improve treatment response, as it holds the potential to increase high linear energy transfer (LET) decay products in the valleys of SFRT (low-dose regions) at the end of the range. To verify this hypothesis, this study compares β-delayed multiple-particle emitters (8Li, 9C, 31Ar) with their respective stable isotopes (7Li, 12C, 40Ar) to determine possible benefits of β-delayed multiple-particle emitters minibeam radiation therapy (β-MBRT). Monte Carlo simulations were performed using the GATE toolkit to assess the dose distributions of each ion. RBE-weighted dose distributions were calculated and used for the aforementioned comparison. No significant differences were found among carbon isotopes. In contrast, 8Li and 31Ar exhibited improved RBE-weighted dose distributions with an approximately 12–20% increase in the Bragg-peak-to-entrance dose ratio (BEDR) for both peaks and valleys, which favors tissue sparing. Additionally, 8Li and 31Ar exhibited a lower peak-to-valley dose ratio (PVDR) in normal tissues and higher PVDR in the tumor than 7Li and 40Ar. Biological experiments are needed to conclude whether the differences observed make β-delayed multiple-particle emitters advantageous for MBRT.

Dosimetric study for breathing-induced motion effects in an abdominal pancreas phantom for carbon ion mini-beam radiotherapy.

Particle mini-beam therapy exhibits promise in sparing healthy tissue through spatial fractionation, particularly notable for heavy ions, further enhancing the already favorable differential biological effectiveness at both target and entrance regions. However, breathing-induced organ motion affects particle mini-beam irradiation schemes since the organ displacements exceed the mini-beam structure dimensions, decreasing the advantages of spatialfractionation. In this study, the impact of breathing-induced organ motion on the dose distribution was examined at the target and organs at risk(OARs) during carbon ion mini-beam irradiation for pancreaticcancer. As a first step, the carbon ion mini-beam pattern was characterized with Monte Carlo simulations. To analyze the impact of breathing-induced organ motion on the dose distribution of a virtual pancreas tumor as target and related OARs, the anthropomorphic Pancreas Phantom for Ion beam Therapy (PPIeT) was irradiated with carbon ions. A mini-beam collimator was used to deliver a spatially fractionated dose distribution. During irradiation, varying breathing motion amplitudes were induced, ranging from 5to 15mm. Post-irradiation, the 2D dose pattern was analyzed, focusing on the full width at half maximum (FWHM), center-to-center distance (ctc), and the peak-to-valley dose ratio (PVDR). The mini-beam pattern was visible within OARs, while in the virtual pancreas tumor a more homogeneous dose distribution was achieved. Applied motion affected the mini-beam pattern within the kidney, one of the OARs, reducing the PVDR from 3.78 0.12 to 1.478 0.070 for the 15mm motion amplitude. In the immobile OARs including the spine and the skin at the back, the PVDR did not change within 3.4% comparing reference and motionconditions. This study provides an initial understanding of how breathing-induced organ motion affects spatial fractionation during carbon ion irradiation, using an anthropomorphic phantom. A decrease in the PVDR was observed in the right kidney when breathing-induced motion was applied, potentially increasing the risk of damage to OARs. Therefore, further studies are needed to explore the clinical viability of mini-beam radiotherapy with carbon ions when irradiating abdominalregions.

Mini-GRID radiotherapy on the CLEAR very-high-energy electron beamline: collimator optimization, film dosimetry, and Monte Carlo simulations

Objective. Spatially-fractionated radiotherapy (SFRT) delivered with a very-high-energy electron (VHEE) beam and a mini-GRID collimator was investigated to achieve synergistic normal tissue-sparing through spatial fractionation and the FLASH effect. Approach. A tungsten mini-GRID collimator for delivering VHEE SFRT was optimized using Monte Carlo (MC) simulations. Peak-to-valley dose ratios (PVDRs), depths of convergence (DoCs, PVDR ≤ 1.1), and peak and valley doses in a water phantom from a simulated 150 MeV VHEE source were evaluated. Collimator thickness, hole width, and septal width were varied to determine an optimal value for each parameter that maximized PVDR and DoC. The optimized collimator (20 mm thick rectangular prism with a 15 mm × 15 mm face with a 7 × 7 array of 0.5 mm holes separated by 1.1 mm septa) was 3D-printed and used for VHEE irradiations with the CERN linear electron accelerator for research beam. Open beam and mini-GRID irradiations were performed at 140, 175, and 200 MeV and dose was recorded with radiochromic films in a water tank. PVDR, central-axis (CAX) and valley dose rates and DoCs were evaluated. Main results. Films demonstrated peak and valley dose rates on the order of 100 s of MGy/s, which could promote FLASH-sparing effects. Across the three energies, PVDRs of 2–4 at 13 mm depth and DoCs between 39 and 47 mm were achieved. Open beam and mini-GRID MC simulations were run to replicate the film results at 200 MeV. For the mini-GRID irradiations, the film CAX dose was on average 15% higher, the film valley dose was 28% higher, and the film PVDR was 15% lower than calculated by MC. Significance. Ultimately, the PVDRs and DoCs were determined to be too low for a significant potential for SFRT tissue-sparing effects to be present, particularly at depth. Further beam delivery optimization and investigations of new means of spatial fractionation are warranted.

Development and optimisation of grid inserts for a preclinical radiotherapy system and corresponding Monte Carlo beam simulations.

Objective. To develop a physical grid collimator compatible with the X-RAD preclinical radiotherapy system and create a corresponding Monte Carlo (MC) model.Approach. This work presents a methodology for the fabrication of a grid collimator designed for utilisation on the X-RAD preclinical radiotherapy system. Additionally, a MC simulation of the grid is developed, which is compatible with the X-RAD treatment planning system. The grid was manufactured by casting a low melting point alloy, cerrobend, into a silicone mould. The silicone was moulded around a 3D-printed replica of the grid, enabling the production of diverging holes with precise radii and spacing. A MC simulation was conducted on an equivalent 3D grid model and validated using 11 layers of GAFChromic EBT-3 film interspersed in a 3D-printed water-equivalent phantom. A 3D dose distribution was constructed from the film layers, enabling a direct comparison with the MC Simulation.Main results. The film and the MC dose distribution demonstrated a gamma passing rate of 99% for a 1%, 0.5 mm criteria with a 10% threshold applied. The peak-to-valley dose ratio and output factor at the surface were determined to be 20.4 and 0.79, respectively.Significance. The pairing of the grid collimator with a MC simulation can significantly enhance the practicality of grid therapy on the X-RAD. This combination enables further exploration of the biological implications of grid therapy, supported by a knowledge of the complex dose distributions. Moreover, this methodology can be adapted for use in other systems and scenarios.

Virtual-Collimator Based Spatial Dose Modulation for Proton GRID Therapy

Compared to conventional proton therapy, the proton GRID therapy can substantially improve normal tissue protection (with the delivery of spatially-modulated peak-valley dose pattern to normal tissues) while maintaining the tumor control efficacy (with the delivery of uniform dose pattern to tumor targets). The realization of proton GRID often relies on the use of physical collimators to shape the spatial dose distribution. However, the physical collimator may increase neutron dose, decrease delivery efficiency, and limit the freedom for patient positioning. Here we propose a virtual-collimator (VC) method for proton GRID. This new approach can generate peak-to-valley pattern with high peak-to-valley dose ratio (PVDR), without using a physical collimator. The principle behind the VC method to modulate the spatial dose distribution consists of two major steps: (1) the primary beam is essentially halved, i.e., the beamlets are interleaved, so that the organ-at-risk (OAR) plane has the peak-valley dose pattern, while the target plane also has the valley dose; (2) the complementary beam is added with half complementary beamlets to fill in the previously valley-dose positions at the target plane, so that the target dose is uniform, while on the other hand, the complementary beam is angled slightly from the primary beam, so that the OAR still has the peak-valley dose pattern. Moreover, on top of VC, we also utilize sparsity regularization method using total variation and L1 sparsity (TVL1) to further jointly optimize PVDR and dose objectives, namely VC-TVL1. VC and VC-TVL1 were validated in comparison with conventional proton GRID treatment planning method via IMPT ("CONV") and TVL1-based proton GRID treatment planning method without VC ("TVL1"), for a prostate case with single-beam (270° only) or two-beam (90° and 270°) scenarios. As shown in the table, the results show that VC can indeed modulate spatial dose with higher PVDR than CONV or even TVL1. VC had higher spatial modulation frequency with smaller peak-to-peak distance than TVL1. Moreover, VC+TVL1, as the synergy of VC and TVL1, further improved PVDR from VC or TVL1 alone. A new way to deliver proton GRID therapy without a physical collimator is developed using the VC method. The VC method can be synergized with TVL1 optimization algorithm to further jointly optimize PVDR and dose objectives.

Study on Lattice Radiotherapy Treatments (LRT) for Head and Neck Bulky Tumors

Lattice radiotherapy (LRT) exploits various effects of radiation, such as the bystander effect and the abscopal effect, and consists on the administration of high dose fraction in small areas with large tumor masses, helping to solve the problem of treating bulky disease, especially if it is located in a critical anatomical area. The optimization of LRT treatment plans is challenging due to the difficulty to generate spots of high dose within the tumor with consequent high gradient. This study compares the plan dosimetry and delivery time of two delivery techniques VMAT and CyberKnife for LRT treatments of bulky head and neck lesions. Six patients with giant head and neck tumors who received LRT at our institution were included in this study. Target and OARs were contoured following international guidelines; to allow easy identification of the desired high gradient zones, an artificial geometrical lattice structure with spherical vertices was arranged inside the target volume (GTV), and the vertices of the lattice representing the high dose boost volumes (GTVboost) were delineated. The GTVboost and GTV were prescribed to receive 12 Gy and 3 Gy, respectively in a single fraction. Separate VMAT and CyberKnife LRT plans were optimized for each patient with lattice vertex of 0.5 diameter and center-to-center distances of 1.5 cm (LRT1.5) and 3 cm (LRT3). The dose heterogeneity was measured as the peak-to-valley dose ratio (PVDR), with the traditional definition being replaced by the D10/D90 ratio, where D10 and D90 represent the doses covering 10% and 90% of the GTV, respectively. For each plan generated, the treatment delivery time, the monitor units (MU), and the PVDR were assessed. Pre-treatment plan verifications were performed with ArcCheck array and Gafchromics film for VMAT and CyberKnife, respectively, using gamma analysis criteria of 3%-3mm. The mean PVDR obtained for VMAT LRT plans were 2.0 and 2.6 for LRT1.5 and LRT3, respectively, and 3.2 and 4.7, respectively for CyberKnife LRT plans. For each pre-treatment plan dose verification, the gamma passing rate (GPR) was higher than 95.0 %; CyberKnife delivery time and MU were more than 10 times higher than that of VMAT, nevertheless, VMAT had a lower PVDR. The detailed results are shown in the table below. CyberKnife LRT has a strong ability to place the peak dose within the target, generating a higher peak-to-valley dose ratio, however its use is partially invalidated by the long beam delivery times and the resulting high MU number; the use of the VMAT LRT technique allows clinically adequate dosimetry with acceptable delivery times.

Vertex Position Optimization for LATTICE Therapy

LATTICE radiation therapy (RT) aims to deliver 3D heterogenous dose of high peak-to-valley dose ratio (PVDR) to the tumor target, with peak dose at lattice vertices inside the target and valley dose for the rest of the target. In current clinical practice the lattice vertex positions are constant during treatment planning. This work proposes a new LATTICE plan optimization method that can optimize lattice vertex positions as plan variables, which is the first lattice vertex position optimization study to the best of our knowledge. The new LATTICE treatment planning method optimizes lattice vertex positions as well as other plan variables (e.g., photon fluences or proton spot weights), with optimization objectives for target PVDR and organs-at-risk (OAR) sparing. To satisfy mathematical differentiability, the lattice vertices are approximated in sigmoid functions. For geometric feasibility, proper geometry constraints are enforced onto the lattice vertex positions. The lattice vertex position optimization problem is solved by iterative convex relaxation method, where lattice vertex positions and photon/proton plan variables are jointly updated via the Quasi-Newton method. Both photon and proton LATTICE RT were considered, and the optimal lattice vertex positions in terms of plan objectives were found by solving all possible combinations on given discrete positions via heuristic searching based on standard IMRT/IMPT, which served as the ground truth for validating the new LATTICE method ("NEW"). That is, the plan with the smallest optimization objective ("BEST"), the plan with the median optimization objective ("MID"), and the plan with the largest optimization objective ("WORST") were selected as the reference plans to be compared with NEW. The table was for an abdomen case with the large bowel as the OAR, where the parameters are total optimization objective f, the mean valley dose of target Dvalley, the mean peak dose of target Dpeak, PVDR = Dpeak/Dvalley, and the mean dose of large bowel Dbowel. The unit of doses is Gy. The results in the table show that the new method indeed provided the optimal lattice vertex positions with the smallest optimization objective, the largest target PVDR, and the best OAR sparing. A new LATTICE treatment planning method is proposed and validated that can optimize lattice vertex positions as well as other photon or proton plan variables for improving target PVDR and OAR sparing.

A feasibility study of ultra-high dose rate mini-GRID therapy using very-high-energy electron beams for a simulated pediatric brain case

Ultra-high dose rate (UHDR, >40 Gy/s), spatially-fractionated minibeam GRID (mini-GRID) therapy using very-high-energy electrons (VHEE) was investigated using Monte Carlo simulations. Multi-directional VHEE treatments with and without mini-GRID-fractionation were compared to a clinical 6 MV volumetric modulated arc therapy (VMAT) plan for a pediatric glioblastoma patient using dose-volume histograms, volume-averaged dose rates in critical patient structures, and planning target volume D98s. Peak-to-valley dose ratios (PVDRs) and dose rates in organs at risk (OARs) were evaluated due to their relevance for normal-tissue sparing in FLASH and spatially-fractionated techniques. Depths of convergence, defined where the PVDR is first ≤1.1, and depths at which dose rates fall below the UHDR threshold were also evaluated. In a water phantom, the VHEE mini-GRID treatments presented a surface (5 mm depth) PVDR of (51±2) and a depth of convergence of 42 mm at 150 MeV and a surface PVDR of (33±1) with a depth of convergence of 57 mm at 250 MeV. For a pediatric GBM case, VHEE treatments without mini-GRID-fractionation produced 25% and 22% lower volume-averaged doses to OARs compared to the 6 MV VMAT plan and 8/9 and 9/9 of the patient structures were exposed to volume-averaged dose rates >40 Gy/s for the 150 MeV and 250 MeV plans, respectively. The 150 MeV and 250 MeV mini-GRID treatments produced 17% and 38% higher volume-averaged doses to OARs and 3/9 patient structures had volume-averaged dose rates above 40 Gy/s. VHEE mini-GRID plans produced many comparable dose metrics to the clinical VMAT plan, encouraging further optimization.

Lattice position optimization for LATTICE therapy.

LATTICE radiation therapy delivers 3D heterogenous dose of high peak-to-valley dose ratio (PVDR) to the tumor target, with peak dose at lattice vertices inside the target and valley dose for the rest of the target. Although the lattice vertex positions can impact PVDR inside the target and sparing of organs-at-risk (OAR), they are fixed as constants and not optimized during treatment planning in current clinical practice. This work proposes a new LATTICE plan optimization method that can optimize lattice vertex positions during LATTICE treatment planning, which is the first lattice position optimization study to the best of our knowledge. The new LATTICE treatment planning method optimizes lattice vertex positions as well as other plan variables (e.g., photon fluences or proton spot weights), with optimization objectives for target PVDR and OAR sparing. To satisfy mathematical differentiability, the lattice vertices are approximated in sigmoid functions. For geometric feasibility, proper geometry constraints are enforced onto lattice vertex positions. The lattice position optimization problem is solved by iterative convex relaxation (ICR) method and alternating direction method of multipliers (ADMM), and lattice vertex positions and photon/proton plan variables are jointly updated via the Quasi-Newton method. Both photon and proton LATTICE RT were considered, and the optimal lattice vertex positions in terms of plan objectives were found by solving all possible combinations on given discrete positions via exhaustive searching based on standard IMRT/IMPT, which served as the ground truth for validating the new LATTICE method. The results show that the new method indeed provided the optimal lattice vertex positions with the smallest optimization objective, the largest target PVDR, and the best OAR sparing. A new LATTICE treatment planning method is proposed and validated that can optimize lattice vertex positions as well as other photon or proton plan variables for improving target PVDR and OAR sparing.

Monte Carlo study of the free radical yields in minibeam radiation therapy.

Minibeam radiation therapy (MBRT) is a novel technique which has been shown to widen the therapeutic window through significant normal tissue sparing. Despite the heterogeneous dose distributions, tumor control is still ensured. Nevertheless the exact radiobiological mechanisms responsible for MBRT efficacy are not fullyunderstood. Reactive oxygen species (ROS) resulting from water radiolysis were investigated given their implications not only on targeted DNA damage, but also for their role in the immune response and non-targeted cell signalling effects: two potential drivers of MBRTefficacy. Monte Carlo simulations were performed using TOPAS-nBio to carry out the irradiation of a water phantom with beams of protons (pMBRT), photons (xMBRT), 4 He ions (HeMBRT), and 12 C ions (CMBRT). Primary yields at the end of the chemical stage were calculated in spheres of 20 μm diameter, located in the peaks and valleys at various depths up to the Bragg peak. The chemical stage was limited to 1 ns to approximate biological scavenging, and the yield of · OH, H2 O2 , and wasrecorded. Beyond 10 mm, there were no substantial differences in the primary yields between peaks and valleys of the pMBRT and HeMBRT modalities. For xMBRT, there was a lower primary yield of the radical species · OHand at all depths in the valleys compared to the peaks, and a higher primary yield of H2 O2 . Compared to the peaks, the valleys of the CMBRT modality were subject to a higher · OHand yield, and lower H2 O2 yield. This difference between peaks and valleys became more severe in depth. Near the Bragg peak, the increase in the primary yield of the valleys over the peaks was 6% and 4% for · OH and respectively, while there was a decrease in the yield of H2 O2 by 16%. Given the similar ROS primary yields in the peaks and valleys of pMBRT and HeMBRT, the level of indirect DNA damage is expected to be directly proportional to the peak to valley dose ratio (PVDR). The difference in the primary yields implicates a lower level of indirect DNA damage in the valleys compared to the peaks than what would be suggested by the PVDR for xMBRT, and a higher level for CMBRT. These results highlight the notion that depending on the particle chosen, one can expect different levels of ROS in the peaks and valley that goes beyond what would be expected by the macroscopic PVDR. The combination of MBRT with heavier ions is shown to be particularly interesting as the primary yield in the valleys progressively diverges from the level observed in the peaks as the LET increases. While differences in the reported · OH yields of this work implicated the indirect DNA damage, H2 O2 yields particularly implicate non-targeted cell signalling effects, and therefore this work provides a point of reference for future simulations in which the distribution of this species at more biologically relevant timescales could beinvestigated.

Development and characterization of a versatile mini-beam collimator for pre-clinical photon beam irradiation.

Interest in spatial fractionation radiotherapy has exponentially increased over the last decade as a significant reduction of healthy tissue toxicity was observed by mini-beam irradiation. Published studies, however, mostly use rigid mini-beam collimators dedicated to their exact experimental arrangement such that changing the setup or testing new mini-beam collimator configurations becomes challenging andexpensive. In this work, a versatile, low-cost mini-beam collimator was designed and manufactured for pre-clinical applications with X-ray beams. The mini-beam collimator enables variability of the full width at half maximum (FWHM), the center-to-center distance (ctc), the peak-to-valley dose ratio (PVDR), and the source-to-collimator distance (SCD). The mini-beam collimator is an in-house development, which was constructed of 10× 40mm2 tungsten or brass plates. These metal plates were combined with 3D-printed plastic plates that can be stacked together in the desired order. A standard X-ray source was used for the dosimetric characterization of four different configurations of the collimator, including a combination of plastic plates of 0.5, 1, or 2mm width, assembled with 1 or 2mm thick metal plates. Irradiations were done at three different SCDs for characterizing the performance of the collimator. For the SCDs closer to the radiation source, the plastic plates were 3D-printed with a dedicated angle to compensate for the X-ray beam divergence, making it possible to study ultra-high dose rates of around 40Gy/s. All dosimetric quantifications were performed using EBT-XD films. Additionally, in vitro studies with H460 cells were carriedout. Characteristic mini-beam dose distributions were obtained with the developed collimator using a conventional X-ray source. With the exchangeable 3D-printed plates, FWHM and ctc from 0.52 to 2.11mm, and from 1.77 to 4.61mm were achieved, with uncertainties ranging from 0.01% to 8.98%, respectively. The FWHM and ctc obtained with the EBT-XD films are in agreement with the design of each mini-beam collimator configuration. For dose rates in the order of several Gy/min, the highest PVDR of 10.09 ± 1.08 was achieved with a collimator configuration of 0.5mm thick plastic plates and 2mm thick metal plates. Exchanging the tungsten plates with the lower-density metal brass reduced the PVDR by approximately 50%. Also, increasing the dose rate to ultra-high dose rates was feasible with the mini-beam collimator, where a PVDR of 24.26 ± 2.10 was achieved. Finally, it was possible to deliver and quantify mini-beam dose distribution patterns in vitro. With the developed collimator, we achieved various mini-beam dose distributions that can be adjusted according to the needs of the user in regards to FWHM, ctc, PVDR and SCD, while accounting for beam divergence. Therefore, the designed mini-beam collimator may enable low-cost and versatile pre-clinical research on mini-beamirradiation.

Treatment Planning of Bulky Tumors Using Pencil Beam Scanning Proton GRID Therapy.

To compare spatially fractionated radiation therapy (GRID) treatment planning techniques using proton pencil-beam-scanning (PBS) and photon therapy. PBS and volumetric modulated arc therapy (VMAT) GRID plans were retrospectively generated for 5 patients with bulky tumors. GRID targets were arranged along the long axis of the gross tumor, spaced 2 and 3 cm apart, and treated with a prescription of 18 Gy. PBS plans used 2- to 3-beam multiple-field optimization with robustness evaluation. Dosimetric parameters including peak-to-edge ratio (PEDR), ratio of dose to 90% of the valley to dose to 10% of the peak VPDR(D90/D10), and volume of normal tissue receiving at least 5 Gy (V5) and 10 Gy (V10) were calculated. The peak-to-valley dose ratio (PVDR), VPDR(D90/D10), and organ-at-risk doses were prospectively assessed in 2 patients undergoing PBS-GRID with pretreatment quality assurance computed tomography (QACT) scans. PBS and VMAT GRID plans were generated for 5 patients with bulky tumors. Gross tumor volume values ranged from 826 to 1468 cm3. Peak-to-edge ratio for PBS was higher than for VMAT for both spacing scenarios (2-cm spacing, P = .02; 3-cm spacing, P = .01). VPDR(D90/D10) for PBS was higher than for VMAT (2-cm spacing, P = .004; 3-cm spacing, P = .002). Normal tissue V5 was lower for PBS than for VMAT (2-cm spacing, P = .03; 3-cm spacing, P = .02). Normal tissue mean dose was lower with PBS than with VMAT (2-cm spacing, P = .03; 3-cm spacing, P = .02). Two patients treated using PBS GRID and assessed with pretreatment QACT scans demonstrated robust PVDR, VPDR(D90/D10), and organs-at-risk doses. The PEDR was significantly higher for PBS than VMAT plans, indicating lower target edge dose. Normal tissue mean dose was significantly lower with PBS than VMAT. PBS GRID may result in lower normal tissue dose compared with VMAT plans, allowing for further dose escalation in patients with bulky disease.

Maximization of Peak-to-Valley Dose Ratio and Normal-Tissue Survival Fraction for Proton Minibeam Radiation Therapy

<h3>Purpose/Objective(s)</h3> Proton minibeam radiation therapy (pMBRT) is a novel proton modality of spatially fractionated RT (SFRT). pMBRT can reduce the radiation damage to normal tissues via biological dose sparing of high peak-to-valley dose ratio (PVDR). This work will develop a new pMBRT treatment planning method that jointly optimizes the plan quality and maximizes the PVDR. <h3>Materials/Methods</h3> The new optimization method simultaneously maximizes the normal-tissue PVDR and optimizes the dose distribution at tumor targets and organs-at-risk (OAR). The PVDR maximization is through the joint total variation (TV) and L1 regularization with respect to the normal-tissue dose. That is, at beam-eye-view projected dose slices of several depths for each beam angle, the TV of dose is maximized, corresponding to the PVDR maximization, while the L1 of dose is minimized, corresponding to the minimization of the OAR dose and maximization of survival fraction (SF). <h3>Results</h3> The new IMPT method with TV and L1 regularization (TVL1) was validated in comparison with the conventional IMPT method (CONV) for pMBRT on several clinical cases. The results show that TVL1 provided larger PVDR and SF than CONV for biological sparing of normal tissues, with preserved plan quality in terms of physical dose distribution. <h3>Conclusion</h3> A new pMBRT treatment planning method is developed that can optimize and improve normal-tissue PVDR and SF, by incorporating TV and L1 dose regularization into IMPT.

TVL1-IMPT: Optimization of Peak-to-Valley Dose Ratio Via Joint Total-Variation and L1 Dose Regularization for Spatially Fractionated Pencil-Beam-Scanning Proton Therapy

Proton minibeam radiation therapy (pMBRT) is a novel proton modality of spatially fractionated RT. pMBRT can reduce the radiation damage to normal tissues via biological dose sparing of high peak-to-valley dose ratio (PVDR). This work will develop a new spatially fractionated IMPT treatment planning method for pMBRT that jointly optimizes the plan quality and maximizes the PVDR. The new optimization method simultaneously maximizes the normal-tissue PVDR and optimizes the dose distribution at tumor targets and organs at risk. The PVDR maximization is through the joint total variation (TV) and L1 regularization with respect to the normal-tissue dose. That is, the beam-eye view projects dose slices of several depths for each beam angle; the TV of dose is maximized, corresponding to the PVDR maximization; and the L1 of dose is minimized, corresponding to the minimization of the organs-at-risk dose and maximization of survival fraction (SF). The new IMPT method with TV and L1 regularization was validated in comparison with the conventional IMPT method for pMBRT in several clinical cases. The results show that TVL1 provided larger PVDR and SF than the conventional IMPT method for biological sparing of normal tissues, with preserved plan quality in terms of physical dose distribution. A new spatially fractionated IMPT treatment planning method was developed for pMBRT that can optimize and improve normal-tissue PVDR and SF by incorporating TV and L1 dose regularization with properly chosen regularization parameters into IMPT.

Monte Carlo optimization of a GRID collimator for preclinical megavoltage ultra-high dose rate spatially-fractionated radiation therapy

Objective. A 2-dimensional pre-clinical SFRT (GRID) collimator was designed for use on the ultra-high dose rate (UHDR) 10 MV ARIEL beamline at TRIUMF. TOPAS Monte Carlo simulations were used to determine optimal collimator geometry with respect to various dosimetric quantities. Approach. The GRID-averaged peak-to-valley dose ratio (PVDR) and mean dose rate of the peaks were investigated with the intent of maximizing both values in a given design. The effects of collimator thickness, focus position, septal width, and hole width on these metrics were found by testing a range of values for each parameter on a cylindrical GRID collimator. For each tested collimator geometry, photon beams with energies of 10, 5, and 1 MV were transported through the collimator and dose rates were calculated at various depths in a water phantom located 1.0 cm from the collimator exit. Main results. In our optimization, hole width proved to be the only collimator parameter which increased both PVDR and peak dose rates. From the optimization results, it was determined that our optimized design would be one which achieves the maximum dose rate for a PVDR at 10 MV. Ultimately, this was achieved using a collimator with a thickness of 75 mm, 0.8 mm septal and hole widths, and a focus position matched to the beam divergence. This optimized collimator maintained the PVDR of 5 in the phantom between water depths of 0–10 cm at 10 MV and had a mean peak dose rate of at 0–1 cm depth. Significance. We have investigated the impact of various GRID-collimator design parameters on the dose rate and spatial fractionation of 10, 5, and 1 MV photon beams. The optimized collimator design for the 10 MV ultra-high dose rate photon beam could become a useful tool for radiobiology studies synergizing the effects of ultra-high dose rate (FLASH) delivery and spatial fractionation.