Semi-automated vertex placement for lattice radiotherapy and dosimetric verification using 3D polymer gel dosimetry.

PURPOSE: To evaluate the feasibility of an open-source, semi-automated, and reproducible vertex placement tool to improve the efficiency of lattice radiotherapy (LRT) planning. We used polymer gel dosimetry with a Cone Beam CT (CBCT) readout to commission this LRT technique. MATERIAL AND METHODS: We generated a volumetric modulated arc therapy (VMAT)-based LRT plan on a 2 L NIPAM polymer gel dosimeter using our Eclipse Acuros version 15.6 AcurosXB beam model, and also recalculated the plan with a pre-clinical Acuros v18.0 dose calculation algorithm with the enhanced leaf modelling (ELM). With the assistance of the MAAS-SFRThelper software, a lattice vertex diameter of 1.5 cm and center-to-center spacing of 3 cm were used to place the spheres in a hexagonal, closed packed structure. The verification plan included four gantry arcs with 15°, 345°, 75°, 105° collimator angles. The spheres were prescribed 20 Gy to 50% of their combined volume. The 6 MV Flattening Filter Free beam energy was used to deliver the verification plan. The dosimetric accuracy of the LRT delivery was evaluated with 1D dose profiles, 2D isodose maps, and a 3D global gamma analysis. RESULTS: Qualitative comparisons between the 1D dose profiles of the Eclipse plan and measured gel showed good consistency at the prescription dose mark. The average diameter measured 13.3 ± 0.2 mm (gel for v15.6), 12.6 mm (v15.6 plan), 13.1 ± 0.2 mm (gel for v18.0), and 12.3 mm (v18.0 plan). 3D gamma analysis showed that all gamma pass percent were > 95% except at 1% and 2% at the 1 mm distance to agreement criteria. CONCLUSION: This study presents a novel application of gel dosimetry in verifying the dosimetric accuracy of LRT, achieving excellent 3D gamma results. The treatment planning was facilitated by publicly available software that automatically placed the vertices for consistency and efficiency.

Comparison of treatment planning approaches for spatially fractionated irradiation of deep tumors.

PURPOSE: The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. METHODS: Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. RESULTS: The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). CONCLUSION: Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

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.

Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

Partial-Volume Irradiation of Murine Tumors.

Radiotherapy is a widely used approach for cancer treatment. However, delivering a single high dose of radiation to bulky tumors can be challenging due to the toxicities induced in the surrounding healthy tissue. To overcome this issue, a nonuniform high dose can be delivered using partial-volume tumor irradiation or spatially fractionated radiotherapy (SFRT). Moreover, SFRT has the potential to induce a stronger antitumor immune response compared to traditional radiotherapy due to the preservation of immune cells in the unirradiated tumor regions. There are several SFRT approaches, including GRID therapy, three-dimensional GRID therapy (LATTICE), microbeam radiation therapy (MRT), and Stereotactic Body Radiation Therapy for PArtial Tumor irradiation targeting exclusively the HYpoxic segment (SBRT-PATHY). The following protocol describes partial-volume tumor irradiation, a technique that enables dose delivery to only a part of the tumor in mice using an X-ray generator and collimators of different dimensions that limit the size of the irradiation field.

Spatially fractionated GRID radiation potentiates immune-mediated tumor control.

BACKGROUND: Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success. METHODS: We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after 2 Gy × 35 whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling. RESULTS: In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control. CONCLUSION: This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.

A novel treatment planning method via scissor beams for uniform-target-dose proton GRID with peak-valley-dose-ratio optimization.

BACKGROUND: Proton spatially fractionated RT (SFRT) can potentially synergize the unique advantages of using proton Bragg peak and SFRT peak-valley dose ratio (PVDR) to reduce the radiation-induced damage for normal tissues. Uniform-target-dose (UTD) proton GRID is a proton SFRT modality that can be clinically desirable and conveniently adopted since its UTD resembles target dose distribution in conventional proton RT (CONV). However, UTD proton GRID is not used clinically, which is likely due to the lack of an effective treatment planning method. PURPOSE: This work will develop a novel treatment planning method using scissor beams (SB) for UTD proton GRID, with the joint optimization of PVDR and dose objectives. METHODS: The SB method for spatial dose modulation in normal tissues with UTD has two steps: (1) a primary beam (PB) is halved with interleaved beamlets, to generate spatial dose modulation in normal tissues; (2) a complementary beam (CB) is added to fill in previously valley-dose positions in the target to generate UTD, while the CB is angled slightly from the PB, to maintain spatial dose modulation in normal tissues. A treatment planning method with PVDR optimization via the joint total variation and L1 (TVL1) regularization is developed to jointly optimize PVDR and dose objectives. The plan optimization solution is obtained using an iterative convex relaxation algorithm. RESULTS: The new methods SB and SB-TVL1 were validated in comparison with CONV. Compared to CONV of relatively homogeneous dose distribution, SB had modulated spatial dose pattern in normal tissues with UTD and comparable plan quality. Compared to SB, SB-TVL1 further maximized PVDR, with comparable dose-volume parameters. CONCLUSIONS: A novel SB method is proposed that can generate modulated spatial dose pattern in normal tissues to achieve UTD proton GRID. A treatment planning method with PVDR optimization capability via TVL1 regularization is developed that can jointly optimize PVDR and dose objectives for proton GRID.

Comprehensive dosimetric commissioning of proton minibeam radiotherapy on a single gantry proton system.

Background: Proton minibeam radiation therapy (pMBRT) can deliver spatially fractionated dose distributions with submillimeter resolution. These dose distributions exhibit significant heterogeneity in both depth and lateral directions. Accurate characterization of pMBRT doses requires dosimetry devices with high spatial resolution and a wide dynamic range. Furthermore, the dependency of dosimetric measurements on Linear Energy Transfer (LET), as observed in conventional proton therapy, is also present in pMBRT depth dose measurements. Purpose: This work demonstrates the process of performing comprehensive dosimetric measurements to characterize the pMBRT collimator on a clinical single-gantry proton machine, utilizing commercially available dosimetry devices. Methods: The minibeam collimator is designed to be mounted on the clinical nozzle as a beam-modifying accessory. Three collimators, each with a slit opening of 0.4 mm, are thoroughly evaluated. The center-to-center (c-t-c) distances of the slits for these collimators are 2.8 mm, 3.2 mm, and 4.0 mm, respectively. High spatial resolution dosimetry devices are essential for PMBRT dose characterizations. To meet this requirement, two-dimensional (2D) dose measurement devices, Gafchromic films, are used to measure lateral profiles at various depths. Films are also used for depth dose profile measurements in solid water. Additionally, high-resolution point dose detectors, microDiamond, and Razor diode detectors are employed for lateral profile measurements at various depths. Percent depth dose (PDD) measurements of pMBRT in solid water, with various proton energies, collimators, and air gaps, are performed using Gafchromic films. The film's LET dependency for proton beams is corrected to ensure accurate pMBRT PDD measurements. The Monte Carlo simulation tool TOPAS is utilized to compare and validate all experimental measurements. Results: At depths where LET is not a concern, film dose measurements were consistent with microDiamond and Razor diode point measurements. The point detectors need to be orientated with the thin side aligned to the incoming beam. Comparison of the lateral dose profiles extracted from TOPAS simulations, films, microDiamond, and Razor diode detectors shows a passing rate exceeding 98% in 1D gamma analysis at 3% 0.1 mm criteria.However, when the microDiamond detector is orientated to face the pMBRT beam, its spatial resolution may not be sufficient to capture the peak and valley dose accurately. Nevertheless, an accuracy within 2% can still be achieved when comparing the average dose. The PDD measurements show that the peak valley dose ratio (PVDR) of pMBRT can be altered at different depths with different air gaps using the same collimator or different collimators of different c-t-c distances. Conclusion: Our study demonstrates that comprehensive dose measurements for pMBRT can be conducted using standard clinical dose measurement devices. These measurements are indispensable for guiding and ensuring accurate dose reporting in pre-clinical studies using the pMBRT technique.

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.

BACKGROUND: 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. PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Novel unconventional radiotherapy techniques: Current status and future perspectives - Report from the 2nd international radiation oncology online seminar.

•Improvement of therapeutic ratio by novel unconventional radiotherapy approaches.•Immunomodulation using high-dose spatially fractionated radiotherapy.•Boosting radiation anti-tumor effects by adding an immune-mediated cell killing.

Salvage LATTICE radiotherapy for a growing tumour despite conventional radio chemotherapy treatment of lung cancer.

A 40-year-old patient with cT4cN1M0 squamous cell lung cancer of the upper right lobe received preoperative induction chemotherapy. Systemic induction treatment failed to reverse tumour growth with the addition of conventional radiotherapy (RT). A salvage lattice RT boost of 12 Gy was administered immediately to increase the dose to the tumour. Conventional RT was resumed at the planned dose of 60 Gy. The tumour shrank rapidly, and the patient was surged. The postoperative pathology remained ypT0ypN0 status.

Lattice Radiation Therapy in clinical practice: A systematic review.

Purpose: Lattice radiation therapy (LRT) is an innovative type of spatially fractionated radiation therapy. It aims to increase large tumors control probability by administering ablative doses without an increased toxicity. Considering the rising number of positive clinical experiences, the objective of this work is to evaluate LRT safety and efficacy. Method: Reports about LRT clinical experience were identified with a systematic review conducted on four different databases (namely, Medline, Embase, Scopus, and Cochrane Library) through the August 2022. Only LRT clinical reports published in English and with the access to the full manuscript text were considered as eligible. The 2020 update version PRISMA statement was followed. Results: Data extraction was performed from 12 eligible records encompassing 7 case reports, 1 case series, and 4 clinical studies. 81 patients (84 lesions) with a large lesion ranging from 63.2 cc to 3713.5 cc were subjected to exclusive, hybrid, and metabolism guided LRT. Excluding two very severe toxicity with a questionable relation with LRT, available clinical experience seem to confirm LRT safety. When a complete response was not achieved 3-6 months after LRT, a median lesion reduction approximately ≥50 % was registered. Conclusion: This systematic review appear to suggest LRT safety, especially for exclusive LRT. The very low level of evidence and the studies heterogeneity preclude drawing definitive conclusions on LRT efficacy, even though an interesting trend in terms of lesions reduction has been described.

Feasibility Study of 3D-VMAT-Based GRID Therapy.

Background: Spatially fractionated radiotherapy (GRID) could effectively de-bulk tumor volumes for shallow and deep-seated locally advanced tumors. A new treatment planning method using the three-dimensional-volumetric modulated arc therapy (VMAT) technique combined with a novel, software-generated, virtual GRID block (VGB) was developed which allows better conformity plans (VMAT-GRID) and maintain the GRID dosimetric characteristics. The dosimetric metrics calculated via the valley/peak ratio (Dmin/Dmax), D90/D10, gross tumor volume (GTV) mean dose (Dmean), GTV equivalent uniform dose (EUD), and normal tissue maximum dose. Methods: Twenty-five patients with tumor volumes ranging between 71.6 cc and 4683 cc at various tumor sites were retrospectively studied. The prescription was 20 Gy to the maximum point of GTV in a single fraction, and the VMAT-GRID plan was generated using 6 MV/10 MV flattening-filter-free beams. Results: The optimized VGB was designed with the median center-to-center distance of 27 mm, and 9 mm for the median diameter of the opening area in this study. These 2 values can be used to design any optimized VGB, the final VGB may be modified to generate a patient-specific VGB. The median GTV mean dose was 918 (877- 938) cGy, and the median GTV EUD dose was 818 (597-916) cGy. In terms of dose inhomogeneity, the median valley-to-peak dose ratio was 0.07 (0.02-0.26); and the median ratio of D90/D10 was 0.70 (0.38-0.94). For the organ-at-risk doses, there was a rapid dose drop-off in the normal tissue area immediately adjacent to the target, and the maximum global doses were all located inside the GTV. Conclusion: Our results indicated that the VMAT-GRID planning approach could successfully deliver dose with acceptable GRID dose metric while sparing the normal tissue especially in the region near the target due to the rapid dose drop-off and restricting maximum dose inside the target.

LITE SABR M1: A phase I trial of Lattice stereotactic body radiotherapy for large tumors.

PURPOSE: Stereotactic body radiotherapy (SBRT) is an attractive treatment option for patients with metastatic and/or unresectable tumors, however its use is limited to smaller tumors. Lattice is a form of spatially fractionated radiotherapy that may allow safe delivery of ablative doses to bulky tumors. We previously described Lattice SBRT, which delivers 20 Gy in 5 fractions with a simultaneous integrated boost to 66.7 Gy in a defined geometric arrangement (Lattice boost). The goal of this study was to prospectively evaluate the acute toxicity and quality of life (QoL) of patients with large tumors (>5 cm) treated with Lattice SBRT. METHODS: This was a single-arm phase I trial conducted between October 2019 and August 2020. Patients with tumors > 4.5 cm were eligible. Lattice SBRT was delivered every other day. The primary outcome was the rate of 90-day treatment-associated (probably or definitely attributable) grade 3 + acute toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Other outcomes included changes in patient reported toxicity and QoL inventories, GTV, and peripheral blood cytokines. RESULTS: Twenty patients (22 tumors) were enrolled. Median GTV was 579.2 cc (range: 54.2-3713.5 cc) in volume and 11.1 cm (range: 5.6-21.4 cm) in greatest axial diameter. Fifty percent of tumors were in the thorax, 45% abdomen/pelvis, and 5% extremity. There was no likely treatment-associated grade 3 + toxicity in the 90-day period (acute and sub-acute). There was one case of grade 4 toxicity possibly associated with Lattice SBRT. CONCLUSIONS: This phase I study met its primary endpoint of physician reported short-term safety. An ongoing phase II clinical trial of Lattice SBRT will evaluate late safety and efficacy of this novel technique.

Prospect of radiotherapy technology development in the era of immunotherapy.

Radiotherapy (RT) is one of the important modalities for cancer treatments. Mounting evidence suggests that the host immune system is involved in the tumor cell killing during RT, and future RT technology development should aim to minimize radiation dose to the immune system while maintaining a sufficient dose to the tumor. A brief history of RT technology development is first summarized. Three RT technologies, namely FLASH RT, proton therapy, and spatially fractionated RT (SFRT), are singled out for the era of immunotherapy. Besides the technical aspects, the mechanism of FLASH effect is discussed, which is likely the combined results of the recombination effect, oxygen depletion effect and immune sparing effect. The proton therapy should have the advantage of causing much less immune damage in comparison to X-ray based RT due to the Bragg peak. However, the relative biological effectiveness (RBE) uncertainty and range uncertainty may hinder the translation of this advantage into clinical benefit. Research approaches to overcome these two technical hurdles are discussed. Various SFRT approaches and their application are reviewed. These approaches are categorized as single-field 1D/2D SFRT, multi-field 3D SFRT and quasi-3D SFRT techniques. A 3D SFRT approach, which is achieved by placing the Bragg peak of a proton 2D SFRT field in discrete depths, may have special potential because all 3 technologies (FLASH RT, proton therapy and SFRT) may be used in this approach.

Investigating spatial fractionation and radiation induced bystander effects: a mathematical modelling approach.

Radiation induced bystander effects (RIBEs) have been shown to cause death in cells receiving little or no physical dose. In standard radiotherapy, where uniform fields are delivered and all cells are directly exposed to radiation, this phenomenon can be neglected. However, the role of RIBEs may become more influential when heterogeneous fields are considered. Mathematical modelling can be used to determine how these heterogeneous fields might influence cell survival, but most established techniques account only for the direct effects of radiation. To gain a full appreciation of how non-uniform fields impact cell survival, it is also necessary to consider the indirect effects of radiation. In this work, we utilise a mathematical model that accounts for both the direct effects of radiation on cells and RIBEs. This model is used to investigate how spatially fractionated radiotherapy plans impact cell survivalin vitro. These predictions were compared to survival in normal and cancerous cells following exposure to spatially fractionated plans using a clinical linac. The model is also used to explore how spatially fractionated radiotherapy will impact tumour controlin vivo. Results suggest that spatially fractionated plans are associated with higher equivalent uniform doses than conventional uniform plans at clinically relevant doses. The model predicted only small changes changes in normal tissue complication probability, compared to the larger protection seen clinically. This contradicts a central paradigm of radiotherapy where uniform fields are assumed to maximise cell kill and may be important for future radiotherapy optimisation.

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy.

Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the "oxygen-guided radiation therapy" (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.

A Multi-Scale and Multi-Technique Approach for the Characterization of the Effects of Spatially Fractionated X-ray Radiation Therapies in a Preclinical Model.

The purpose of this study is to use a multi-technique approach to detect the effects of spatially fractionated X-ray Microbeam (MRT) and Minibeam Radiation Therapy (MB) and to compare them to seamless Broad Beam (BB) irradiation. Healthy- and Glioblastoma (GBM)-bearing male Fischer rats were irradiated in-vivo on the right brain hemisphere with MRT, MB and BB delivering three different doses for each irradiation geometry. Brains were analyzed post mortem by multi-scale X-ray Phase Contrast Imaging-Computed Tomography (XPCI-CT), histology, immunohistochemistry, X-ray Fluorescence (XRF), Small- and Wide-Angle X-ray Scattering (SAXS/WAXS). XPCI-CT discriminates with high sensitivity the effects of MRT, MB and BB irradiations on both healthy and GBM-bearing brains producing a first-time 3D visualization and morphological analysis of the radio-induced lesions, MRT and MB induced tissue ablations, the presence of hyperdense deposits within specific areas of the brain and tumor evolution or regression with respect to the evaluation made few days post-irradiation with an in-vivo magnetic resonance imaging session. Histology, immunohistochemistry, SAXS/WAXS and XRF allowed identification and classification of these deposits as hydroxyapatite crystals with the coexistence of Ca, P and Fe mineralization, and the multi-technique approach enabled the realization, for the first time, of the map of the differential radiosensitivity of the different brain areas treated with MRT and MB. 3D XPCI-CT datasets enabled also the quantification of tumor volumes and Ca/Fe deposits and their full-organ visualization. The multi-scale and multi-technique approach enabled a detailed visualization and classification in 3D of the radio-induced effects on brain tissues bringing new essential information towards the clinical implementation of the MRT and MB radiation therapy techniques.

Spatially fractionated radiotherapy (SFRT) targeting the hypoxic tumor segment for the intentional induction of non-targeted effects: An in silico study to exploit a new treatment paradigm.

INTRODUCTION: The possibility of intentionally triggering non targeted effects (NTEs) using spatially fractionated radiotherapy (SFRT) alone or combined with immunotherapy is an intriguing and fascinating area of research. Among different techniques for SFRT, stereotactic body radiotherapy targeting exclusively the central hypoxic segment of bulky tumors, (SBRT-PATHY) might trigger immunogenic cell death more efficiently. This in silico study aims to identify the best possible dosimetric trade-off for prescribing SFRT with volumetric modulated arc (VMAT) based stereotactic radiotherapy (SRT). MATERIAL AND METHODS: Eight spherical volumes defined "Gross Tumor Volumes" (GTVs) were generated with diameters of 3-10 cm (with incremental steps of 1 cm), simulating tumor lesions. The inner third part of each GTV (GTVcentral) was selected to simulate the central hypoxic area and a ring structure was derived around it to simulate the tumor periphery (GTVperipheral). Volumetric modulated arc radiation treatment (VMAT) plans were calculated to deliver a single fraction of 10 Gy to each GTVcentral with different dose prescription methods: target mean and isodose driven (40, 50, 60, 70, 80 and 90%).The volume of GTVperipheral receiving less than 2 Gy was recorded as dosimetric performance indicator. RESULTS: 56 possible dosimetric scenarios were analyzed. The largest percentage of GTVperipheral spared from the dose of 2 Gy was achieved with dose prescription methods to the 70% isodose line for lesions smaller than 6 cm (range 42.9-48.4%) and to the target mean for larger ones (range 52.9-64.5%). CONCLUSIONS: Optimizing the dose prescription method may reduce the dose to tumor periphery in VMAT-based SFRT, thus potentially sparing tumor infiltrating immune cells. The optimal method may vary according to the size of the lesion. This should be taken into account when designing prospective trials using SFRT.