Search Results (53)

Background: Osteosarcoma remains a biologically complex and clinically challenging malignancy, with survival gains plateauing despite decades of multimodal therapy incorporating surgery and cytotoxic chemotherapy. Unlike cancers in which mutation-centric precision oncology has yielded transformative advances, osteosarcoma is characterized by profound structural variation, copy number alteration dominance, and dynamic clonal evolution, limiting the effectiveness of single-target approaches. These realities motivate alternative strategy-level frameworks that better align treatment selection with evolving disease behavior. Methods: This narrative educational review synthesizes contemporary evidence from osteosarcoma biology, radiobiology, and translational oncology to propose a state-based framework for integrating radiotherapy—particularly stereotactic body radiotherapy (SBRT/SABR) and spatially fractionated radiotherapy (SFRT)—into osteosarcoma management and clinical trial design. Rather than relying solely on static anatomic stage, this framework emphasizes clinically actionable, time-varying state variables, including disease burden patterns (localized, oligometastatic, polymetastatic), tempo of progression, prior systemic response, and feasibility of complete local control. Results: Within this context, radiotherapy is presented not only as a local control modality but also as a hypothesis-generating biologic intervention, capable of perturbing tumor vasculature, inflammatory signaling, innate DNA-sensing pathways, and immune/myeloid programs in a dose-, fractionation-, and spatial-distribution-dependent manner. The review critically examines both the potential opportunities (e.g., local eradication, immune modulation) and limitations (e.g., rarity of abscopal responses, risk of unintended systemic signaling) of radiobiotherapy combinations, emphasizing the need for cautious interpretation and prospective validation. Conclusions: Finally, the article outlines practical implications for state-stratified, biomarker-embedded clinical trials, highlighting endpoints beyond conventional response criteria, including circulating tumor DNA dynamics, immune and myeloid signatures, and long-term patterns of disease progression. Overall, this review frames radiobiotherapy as an educational and investigational paradigm intended to support rational hypothesis generation, multidisciplinary decision-making, and learning-oriented trial designs in osteosarcoma, rather than as definitive clinical guidance. Full article

Background: Neoadjuvant partial breast irradiation using stereotactic body radiotherapy (SBRT) has emerged as a strategy to induce tumor and immune responses in early-stage, low-risk breast cancer. While prior studies have demonstrated encouraging response rates and evidence of immune modulation, the optimal radiotherapy regimen for immune priming remains unclear. SIGNAL 2.0 is a randomized phase II trial designed to compare the biological and immunological impact of a single-fraction versus three-fraction neoadjuvant SBRT. Materials and Methods: Sixty-one postmenopausal patients ≥ 50 years with unifocal, hormone positive, node-negative invasive ductal carcinoma < 3 cm were randomized 1:1 to receive either 21 Gy in one fraction or 30 Gy in three fractions, delivered to the tumor in the prone position. Core biopsies were collected pre-SBRT and 14–20 days post-SBRT at the time of surgery. Immune markers were assessed using tumor-infiltrating lymphocyte (TIL) scoring, NanoString nCounter PanCancer Immune Profiling, and NanoString GeoMx Digital Spatial Profiling (DSP). Results: Available tumor samples from 47 patients underwent paired tissue analysis. Three-fraction SBRT induced 200 differentially expressed genes, including enrichment of pathways related to adaptive immune activation, with significant increases in expression levels of macrophages, dendritic cells, neutrophils and CD8 T-cells. Proteomic profiling also identified a significant increase in the expression levels of neutrophils, Treg cells, macrophages, and NK cells in the tumor microenvironment of the samples from patients receiving the three-fraction regimen. Conclusions: Neoadjuvant SBRT induces measurable immune activation, with three-fraction regimens generating more extensive transcriptional, proteomic, and cellular immune changes than a single fraction. Three-fraction neoadjuvant SBRT may provide superior immune priming, providing a foundation for future trials integrating neoadjuvant radiotherapy with immunomodulatory therapies. Full article

Spatially fractionated radiotherapy with X-ray minibeams (x-MBRT) aims to increase normal-tissue tolerance by delivering alternating high- and low-dose regions. We provide a Monte Carlo-based framework to design and optimize multi-slit collimators, quantifying how geometry and material govern peak–valley modulation. A validated digital twin of the SmART X-RAD225Cx irradiator was implemented in TOPAS/Geant4. Various x-MBRT collimators were simulated with parallel or divergent slits. The parameter space covered a slit width w (0.1–0.9 mm), center-to-center spacing CTC (1–3 mm), thickness T (1–5 mm), and acceptance angle θ. Dose was scored in a 2 × 2 × 2 cm³ water phantom at a 1 cm depth. For fixed w/CTC, peak-valley dose ratio PVDR increases with larger CTC via an increase in peak dose, with the valley dose nearly constant. Peak transmission saturated at θ ≈ 3°, indicating minimal benefit from larger acceptance. Divergent slits yielded flatter lateral profiles but higher valley doses than parallel slits, reducing PVDR around the central axis. This Monte Carlo study provides insights for optimizing collimator geometries in x-MBRT using small-animal irradiators, informing the design of more effective collimation systems to enhance treatment precision and normal-tissue sparing. Full article

Objectives: This study aimed to evaluate the setup accuracy and intrafractional geometric stability of surface-guided radiation therapy (SGRT) under frameless immobilization in lung cancer radiotherapy and to assess its clinical utility in a relatively large patient cohort. Materials and Methods: A total of 678 treatment fractions from 52 patients with primary non-small cell lung cancer (NSCLC), treated between October 2024 and November 2025, were retrospectively analyzed. Patient setup was performed using SGRT with the Identify system, and cone-beam computed tomography (CBCT) served as the reference for internal target localization Intrafractional setup displacements, center-of-mass (COM) shifts, residual setup errors, and intrafractional clinical target volume (CTV) variations were evaluated. Spatial agreement between planned and intrafractional tumor volumes was quantified using the Dice Similarity Coefficient (DSC). Results: The mean CBCT-based intrafractional shifts were −0.01 mm (vertical), 0.03 mm (longitudinal), and 0.01 mm (lateral), indicating negligible systematic errors. The greatest variability was observed in the longitudinal direction (standard deviation, 1.32 mm), with a maximum displacement of 4.58 mm. COM-based analysis demonstrated near-zero mean displacements in all directions, with standard deviations ranging from 0.01 to 0.02 mm. DSC values ranged from 0.91 to 0.98, with a mean of 0.96, indicating excellent spatial agreement between planned and intrafractional tumor volumes. Residual setup errors were predominantly within ±1 mm, and the mean intrafractional CTV volume change was minimal (0.27 cm³). Conclusions: SGRT-based frameless lung cancer radiotherapy demonstrated high setup accuracy and robust intrafractional geometric stability. Although slightly greater variability was observed in the longitudinal direction, overall positional deviations and volumetric changes remained within clinically acceptable limits. These findings support the feasibility of integrating SGRT with CBCT-guided radiotherapy and suggest potential benefits for workflow efficiency and planning target volume margin optimization. Full article

Introduction: Lattice Radiation Therapy (LRT) is an evolving spatially fractionated radiation therapy (SFRT) technique that delivers heterogeneous dose distributions to large and radioresistant tumors. The literature highlights LRT’s potential for effective tumor debulking, palliation, and immune modulation. Effective LRT planning is crucial for maximizing tumor control while minimizing toxicity to organs at risk (OARs). The process involves defining the size, spacing, and arrangement of high-dose vortexes within the GTV. Traditionally, this has been a manual and time-consuming process, prone to inter-planner variability in vortex placement. Recent research has focused on developing automated or semi-automated tools to address these challenges, enhancing planning standardization. We aimed to systematically review for the first time the available scientific evidence of automated planning tools of vortexes for Lattice Radiotherapy and to assess the efficacy of such tools for standardizing Lattice Radiotherapy delivery. Methods: A systematic review of available studies in PubMed, Web of Science, and Scopus, including the terms “Lattice radiation therapy and (automated or optimized)”. Only LRT clinical planning reports published in English and with access to the full accepted text were considered eligible. This study was conducted in accordance with the PRISMA guidelines and was registered on the PROSPERO platform (CRD420251108024). Results: A total of 82 articles were found. Twenty articles fulfilled all inclusion criteria. Automated treatment planning tools have significantly improved the efficiency, consistency, and scalability of LRT planning, addressing limitations of manual planning. In conclusion, LRT should be planned to use automated tools to improve wide clinical standardization and implementation. Full article

Radiotherapy (RT) is a standard treatment for lung cancer; however, radiation-induced toxicities such as pneumonitis and fibrosis limit dose escalation and tumor control. Therefore, improved RT approaches are needed. This study investigated the radiation response of human ex vivo normal lung tissue using the three-dimensional EpiAlveolar™ model. Tissue models were irradiated with broad-beam (BB) and two spatially fractionated microbeam radiation therapy (MRT) dose metrics: equivalent uniform dose (MRT-EUD) and valley dose (MRT-valley). Our findings show that ex vivo lung tissue is able to tolerate peak doses of 36 Gy following MRT-EUD. On day 21, models effectively repaired significant DNA double-strand break (DSB) damage seen in the MRT-EUD-irradiated peak regions. In contrast, persistent unresolved DSBs were detected in MRT-valley-irradiated models 21 days post irradiation. Prolonged culture time resulted in cell loss and a reduction in epithelial cell layers. A significant upregulation of the pro-inflammatory cytokine IL6 was observed in both BB and MRT-EUD groups at 21 days. Fibrotic collagen deposition was detected in one BB-irradiated model but was absent in remaining BB- and MRT-treated tissues. Further investigation is required to clarify the potential and suitability of EpiAlveolar™ models for studying radiation-induced lung injury. Full article

This review explores the transformative role of three-dimensional (3D) printing in radiation therapy for cancer treatment, emphasizing its potential to deliver patient-specific, cost-effective, and sustainable medical devices. The integration of 3D printing enables rapid fabrication of customized boluses, compensators, immobilization devices, and GRID collimators tailored to individual anatomical and clinical requirements. Comparative analysis reveals that additive manufacturing surpasses conventional machining in design flexibility, lead time reduction, and material efficiency, while offering significant cost savings and recyclability benefits. Case studies demonstrate that 3D-printed GRID collimators achieve comparable dosimetric performance to traditional devices, with peak-to-valley dose ratios optimized for spatially fractionated radiation therapy. Furthermore, emerging applications of artificial intelligence (AI) in conjunction with 3D printing promise automated treatment planning, generative device design, and real-time quality assurance, and are paving the way for adaptive and intelligent radiotherapy solutions. Regulatory considerations, including FDA guidelines for additive manufacturing, are discussed to ensure compliance and patient safety. Despite challenges such as material variability, workflow standardization, and large-scale clinical validation, evidence indicates that 3D printing significantly enhances therapeutic precision, reduces toxicity, and improves patient outcomes. This review underscores the synergy between 3D printing and AI-driven innovations as a cornerstone for next-generation radiation oncology, offering a roadmap for clinical adoption and future research. Full article

Radiotherapy (RT) is currently among the standard treatments for lung cancer. However, in vitro studies have revealed that irradiation can increase lung cancer cell motility. This way, RT could potentially enhance the malignancy of solid tumors post-treatment, promoting metastasis. Therefore, there is a continued need to continue evolving RT modalities into safer and more effective treatments. The present study compares the impact of the broad beam (BB) and the spatially fractionated modality of microbeam radiation therapy (MRT) on the motility of A549 lung cancer cells. Our data corroborates previous findings that showed BB irradiation is a promoter of cell motility. For MRT, however, we observed a prevention of cellular migration. A significant reduction in NF-κB expression was observed only when A549 cells were irradiated with MRT, indicating a potential mechanism behind these findings. Finally, our data supports potential issues regarding MRT irradiation of key components of the tumor microenvironment, such as fibroblasts. Co-culturing A549 cells with MRT-irradiated MRC-5 lung fibroblasts led to increased tumor cell invasion, not observed when the fibroblasts received BB irradiation. Full article

Background and clinical Significance: The management of head and neck squamous cell carcinoma in elderly patients is a clinical scenario that is currently under debate. Case Presentation: Patients over 65 years old are particularly vulnerable, and the administration of curative oncological care is challenging. Furthermore, such treatment has the potential to be extremely toxic. Spatially fractionated radiation therapy (SFRT) is a radiotherapy modality that offers a promising approach for treating tumors. This method involves the delivery of a spatially modulated dose, resulting in highly non-uniform dose distributions. This leads to the generation of peaks and valleys of doses within a target volume. In this case study, a patient with an ulcerating lesion on the right cheek was treated with a two-phase radiotherapy regimen. The purpose of the first procedure was to stimulate the immunogenicity of the tumor microenvironment. In the second part of the procedure, standard fractionated irradiation was delivered with curative aim. Conclusions: The clinical response indicates that this combination of high-dose “localized” and low-dose irradiation can produce immunological effects with an acceptable toxicity profile. Full article

Spatially fractionated radiotherapy (SFRT) is emerging as a powerful tool in cancer therapy for patients who are ineligible for treatment with clinically established irradiation techniques. Microbeam radiotherapy (MRT) is characterized by spatial dose fractionation in the micrometre range. This presents challenges in both treatment planning and dosimetry. While a dosimetry system with a spatial resolution of 10 µm and an option for real-time readout already exists, this system can only record dose in a very small volume. Thus, we are exploring dosimetry in an N-isopropylacrylamide (NIPAM) gel as an option for 3D dose visualization and, potentially, also three-dimensional dosimetry in larger volumes. In the current study, we have recorded the geometric patterns of single- and multiport irradiation with microbeam arrays in NIPAM gel. Data for 3D dose distribution was acquired in a 7T small animal MRI scanner. We found that the resolution of the gel is well suited for a detailed 3D visualization of microbeam patterns even in complex multiport geometries, similar to that of radiochromic film, which is well established for recording 2D dose distribution in MRT. The results suggest that a dose–response calibration is required for reliable quantitative dosimetry. Full article

Purpose: This paper aims to calculate the gross tumor volume (GTV) receiving low radiation doses in patients submitted to “metabolism-guided” lattice radiation therapy and relative possible implications with clinical outcomes. Material and Methods: We reviewed plans for treating voluminous masses via “metabolism-guided” LATTICE-01 irradiation. The aim was to deliver high-dose radiation to spherical deposits (vertices) within a bulky tumor mass. These were placed at tumor areas with differing PET metabolism. We evaluated the relationships between GTV volumes and dose-volumetric histograms (mean, maximum, minimum, and % GTV received 0.5, 1, 2, 3 Gy). Results: Sixty-two plans of treatment met the inclusion criteria as established. The median GTV volume was 315.9 cc (range = 10.54–2605.9 cc). A median of two Vertices was allocated within the GTVs (range 1–9) and were planned to receive a dose of ≥10 Gy/1 fraction (median 12 Gy, range 10–15 Gy). Median V3Gy percentage was 51.58% (range 2–100%), median V2Gy percentage was 67.80% (range 1.60–100%), median V1Gy percentage was 83.70% (range 0.80–100%), and median V0.5Gy percentage was 88.49% (range 17.60–100%). Conclusions: In the present series, we performed a dosimetric evaluation of the GTV’s volume exposed to low doses during the metabolic guided lattice irradiation process. Combining high- and low-dose radiotherapy based on a spatially fractionated (LATTICE) approach could reactivate the immune system against cancer cells. These observations could be useful for planning prospective studies on immunotherapy combined with the lattice technique. Full article

Background: Lattice Radiation Therapy (LRT), a spatially fractionated stereotactic radiotherapy (SBRT) technique, has shown promising results in the palliative treatment of large tumors. The focus of our first analysis of 56 lesions ≥7 cm was on the extent of shrinkage following palliative LRT (mean 50%) and assessment of its effect duration (: mean 6 months). Herewith we present an updated analysis of our single-center LRT cohort, with a focus on LRT outcome across diagnoses and applied LRT regimens. Methods: We assessed the clinical outcome following LRT in 66 patients treated for 81 lesions between 01.2022 and 05.2025. LRT protocols included simultaneous integrated boost (sib-) LRT in 49 lesions (5 × 4–5 Gy to the entire mass with sib of 9–13 Gy to lattice vertices). Alternatively mainly in pre-irradiated and/or very large lesions—a single-fraction stereotactic LRT (SBRT-LRT) of 1 × 20 Gy to vertices only was delivered to 26 lesions. In six cases with modest response to single fraction SBRT-LRT, the sib-LRT schedule was added 4–8 weeks later. Results: The median age was 68 years (18–93). Main tumor locations were abdomino-pelvic (n = 34) and thoracic (n = 17). Histopathological diagnoses included carcinoma (n = 34), sarcoma (n = 31), and melanoma (n = 16). 31% of all lesions have been previously irradiated. 73% of cases underwent concurrent or peri-LRT systemic therapy. The mean/median overall survival (OS) time of the cohort was 7.6/4.6 months (0.4–40.2), 11.9/5.8 months in 16/66 alive, and 6.4/4.3 months in deceased patients, respectively. 82% of symptomatic patients reported immediate subjective improvement (PROM), with a lifelong response duration in most cases. Progressive disease (PD: >10% increase in initial volume) was found in 9%, stable disease (SD +/−10% of initial volume) in 19% of scanned lesions, and shrinkage (>10% reduction in initial volume) in 75%, with a mean/median tumor volume reduction of 51/60%. The extent of shrinkage was found to be 11–30%/31–60%/61–100% in 38/24/38% of lesions. Response rates (PD, SD, shrinkage) following the two applied LRT regimens, as well as those related to sarcoma and carcinoma diagnoses, were found to be comparable. Treatment tolerance was excellent (G0-1). Conclusions: Palliative LRT provides rapid subjective relief in ~80% of symptomatic patients. Radiologic shrinkage was stated in 75% of FU-scanned lesions, with a lifelong effect duration in most patients. LRT was found effective across histologies, with a similar extent of shrinkage in carcinoma and sarcoma following 1F SBRT- and 5F sib-LRT regimens, respectively. Full article

The results of radiotherapy in patients with primary malignant brain tumors are extremely dissatisfactory: the overall survival after a diagnosis of glioblastoma is typically less than three years. The development of spatially fractionated radiotherapy techniques could help to improve this bleak prognosis. In order to develop technical equipment and organ-specific therapy plans, dosimetry studies as well as radiobiology studies are conducted. Although perfect spheres are considered optimal phantoms by physicists, this does not reflect the wide variety of head sizes and shapes in our patient community. Depth from surface and X-ray dose absorption by tissue between dose entry point and target, two key parameters in medical physics planning, are largely determined by the shape and thickness of the skull bone. We have, therefore, designed and produced a biomimetic tool to correlate measured technical dose and biological response in human cancer cells: a brain phantom, produced from tissue-equivalent materials. In a first pilot study, utilizing our phantom to correlate technical dose measurements and metabolic response to radiation in human cancer cell lines, we demonstrate why an anthropomorphic phantom is preferable over a simple spheroid phantom. Full article

Radiotherapy (RT) has undergone transformative advancements since its inception over a century ago. This review highlights the most promising and impactful innovations shaping the current and future landscape of RT. Key technological advances include adaptive radiotherapy (ART), which tailors treatment to daily anatomical changes using integrated imaging and artificial intelligence (AI), and advanced image guidance systems, such as MR-LINACs, PET-LINACs, and surface-guided radiotherapy (SGRT), which enhance targeting precision and minimize collateral damage. AI and data science further support RT through automation, improved segmentation, dose prediction, and treatment planning. Emerging biological and targeted therapies, including boron neutron capture therapy (BNCT), radioimmunotherapy, and theranostics, represent the convergence of molecular targeting and radiotherapy, offering personalized treatment strategies. Particle therapies, notably proton and heavy ion RT, exploit the Bragg peak for precise tumor targeting while reducing normal tissue exposure. FLASH RT, delivering ultra-high dose rates, demonstrates promise in sparing normal tissue while maintaining tumor control, though clinical validation is ongoing. Spatially fractionated RT (SFRT), stereotactic techniques and brachytherapy are evolving to treat challenging tumor types with enhanced conformality and efficacy. Innovations such as 3D printing, Auger therapy, and hyperthermia are also contributing to individualized and site-specific solutions. Across these modalities, the integration of imaging, AI, and novel physics and biology-driven approaches is redefining the possibilities of cancer treatment. This review underscores the multidisciplinary and translational nature of modern RT, where physics, engineering, biology, and informatics intersect to improve patient outcomes. While many approaches are in various stages of clinical adoption and investigation, their collective impact promises to redefine the therapeutic boundaries of radiation oncology in the coming decade. Full article

Spatially fractionated radiotherapy (SFRT) offers a promising approach for debulking large tumors by delivering high-dose radiation to a fraction of the tumor volume. However, the complex tumor microenvironment necessitates models beyond traditional 2D cultures and resource-intensive animal studies for SFRT investigations. Three-dimensional (3D) scaffold-based models with an adequate cross-sectional area have emerged as uniquely suited platforms to bridge this gap, by providing a more realistic platform for GRID-based SFRT research. In this study, we employed a 3D co-culture scaffold model to dissect the contributions of the radiation-induced bystander effect, abscopal effect, and immune system response on clonogenic survival following GRID irradiation. MDA-MB-231 breast cancer cells were seeded on commercial 3D scaffolds and irradiated at a 20 Gy peak dose using lead grids with three- and six-hole patterns, exposing ~12.8% and 25.7% of the scaffold area, respectively. An assessment of reproductive cell survival revealed a significant bystander effect, as the survival was notably lower than predicted based solely on the directly irradiated fraction. Evidence of an abscopal effect was observed by culturing non-irradiated cells in media exposed to GRID irradiation. Furthermore, a co-culture with allogeneic peripheral blood mononuclear cells (PBMCs) modulated clonogenic survival, with an additive effect observed when combined with SFRT. These findings underscore the presence of a bystander effect in GRID radiotherapy and indicate an abscopal immune component, particularly with the three-hole GRID configuration. This study established the utility of in vitro 3D co-culture scaffolds as an effective model system for elucidating complex SFRT-mediated biological responses. Full article