UNASSIGNED: Locally advanced bulky unresectable head neck cancer causes significant tumor mass effects, leading to severe symptoms. This study aims to report the safety and outcomes in patients undergoing Lattice spatially fractionated radiotherapy (Lattice SFRT) for locally advanced bulky unresectable head and neck cancer.
UNASSIGNED: Patients with bulky head and neck cancer received Lattice SFRT between June 2022 and June 2023. Lattice SFRT was administered in 2-3 fractions of 12 Gy (Gy) using 6-megavolt (MV) photon beams through a multileaf collimator (MLC) based on VMAT technology. The primary endpoints were symptomatic and tumor response rates. Secondary endpoints were overall survival, local control, and acute and late toxicity rates.
UNASSIGNED: 19 consecutive patients meeting the study criteria were identified, predominantly with squamous cell carcinoma histology. The median patient age was 62 years (range 39-79 years), and the median tumor volume was 208 cc (cc) (range 48-701 cc). All patients completed radiotherapy. Among all investigated patients, 16 of 19 (84.2 %) patients achieved an objective response, including 10 individuals achieved a partial response (PR), with 3 of them exhibiting regression exceeding 75 %. 17 patients showed symptom improvement to varying degrees. Acute toxicity of Radiation Therapy Oncology Group (RTOG) grade 1 or higher occurred in 5 patients, while no grade 3 adverse events was observed.
UNASSIGNED: Lattice SFRT proves to be a viable treatment option for the palliative management of bulky head and neck cancer. In the palliative setting, Lattice SFRT offers timely symptom relief, enhancing patient quality of life. Treatment toxicity remains within an acceptable range. Continued optimization of Lattice SFRT delivery and patient selection can benefit from further data on the feasibility and efficacy of this radiation modality.

OBJECTIVE: Lattice radiation therapy (LRT) alternates regions of high and low doses inside the tumour. Whilst this technique reported positive results in tumour size reduction, optimal lattice parameters are still unknown. We introduce an automated LRT planning method personalised to tumour shape and designed to allow investigation of lattice geometry.
METHODS: Patients with retroperitoneal sarcoma were considered for inclusion. Automation was performed with the Eclipse Scripting Application Interface (v16, Varian Medical Systems, Palo Alto). By iterating over vertex size (V) and centre-to-centre distance (D), vertices were segmented within the gross tumour volume (GTV) in an alternating square pattern. Iterations stopped when the number of inserted vertices was contained between a prespecified lower and upper bound. Forty sets of lattices were considered, produced by varying V and D in five lower/upper bound pairs. Best-scoring sets were determined with a score favouring the maximization of GTV dose uniformity and heterogeneity whilst minimizing the maximum dose to organs at risk.
RESULTS: Fifty patients with tumour volumes between 150 cm3 and 10,000 cm3 were included. Best-scoring sets were characterised by a low number of vertices (<15). Based on the best-scoring set, the predicted parameters to use for new patients were V = 0.19 (GTV volume)1/3 and D = 2V, in centimetres. The number of vertices (N) to insert in the GTV can be estimated with N ≤ (24 × 3% GTV volume)/(4πV3).
CONCLUSIONS: The automated LRT treatment planning personalised to tumour size allows investigation of lattice geometry over a large range of GTV volumes.

Spatially fractionated radiotherapy (SFRT) techniques have undergone transformative evolution, encompassing physical GRID therapy, MLC-based grids, virtual TOMO GRIDs, and 3-dimensional high-dose lattices. Historical roots trace back to Alban Köhler\'s pioneering Spatially fractionated grid therapy (SFGRT), utilizing physical grids for dose modulation. Technological innovations introduced multi-leaf collimators (MLCs), enabling adaptable spatial fractionation and a shift to the broader term \"SFRT.\" Physics and dosimetry-based studies have demonstrated the feasibility of computerized treatment planning and identified the potential to minimize the peripheral dose while using such high-dose therapy. Meanwhile, 3-dimensional high-dose lattices showed enhanced precision. The meticulous placement of high-dose volumetric spheres enables a reduction in the volume of high-dose spills. Advancements in 3-dimensional lattices through intensity-modulated radiotherapy and volumetric modulated arc therapy (VMAT) techniques offer enhanced therapeutic options. A database of SFRT studies identified 723 articles. This review shows the trajectory of SFRT from traditional grids to MLC-based approaches, virtual TOMO GRIDs, and innovative 3-dimensional lattices. Technological innovations, dosimetric advancements, and clinical feasibility have underscored the continual progress in refining spatially fractionated radiotherapy. The integration of MLCs and lattice techniques has demonstrated improved therapeutic outcomes, solidifying their relevance in modern radiation therapy protocols. Research has yet to reveal a clear correlation between treatment outcomes and dosimetric parameters. Additional investigations are necessary to assess the impact of various dosimetric parameters, such as EUD, peak-to-valley ratio (PVDR), D5%, D10%, D20%, D90%, etc., on the effectiveness of treatments.

OBJECTIVE: The highly heterogeneous dose delivery of spatially fractionated radiation therapy (SFRT) is a profound departure from standard radiation planning and reporting approaches. Early SFRT studies have shown excellent clinical outcomes. However, prospective multi-institutional clinical trials of SFRT are still lacking. This NRG Oncology/American Association of Physicists in Medicine working group consensus aimed to develop recommendations on dosimetric planning, delivery, and SFRT dose reporting to address this current obstacle toward the design of SFRT clinical trials.
METHODS: Working groups consisting of radiation oncologists, radiobiologists, and medical physicists with expertise in SFRT were formed in NRG Oncology and the American Association of Physicists in Medicine to investigate the needs and barriers in SFRT clinical trials.
RESULTS: Upon reviewing the SFRT technologies and methods, this group identified challenges in several areas, including the availability of SFRT, the lack of treatment planning system support for SFRT, the lack of guidance in the physics and dosimetry of SFRT, the approximated radiobiological modeling of SFRT, and the prescription and combination of SFRT with conventional radiation therapy.
CONCLUSIONS: Recognizing these challenges, the group further recommended several areas of improvement for the application of SFRT in cancer treatment, including the creation of clinical practice guidance documents, the improvement of treatment planning system support, the generation of treatment planning and dosimetric index reporting templates, and the development of better radiobiological models through preclinical studies and through conducting multi-institution clinical trials.

Spatially Fractionated Radiation Therapy (SFRT) is a form of radiotherapy that delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of under dosage. SFRT types can be defined by how the heterogeneous pattern of radiation is obtained. Immune checkpoint inhibitors (ICIs) have been approved for various malignant tumors and are widely used to treat patients with metastatic cancer. The efficacy of ICI monotherapy is limited due to the \"cold\" tumor microenvironment. Fractionated radiotherapy can achieve higher doses per fraction to the target tumor, and induce immune activation (immodulate tumor immunogenicity and microenvironment). Therefore, coupling ICI therapy and fractionated radiation therapy could significantly improve the outcome of metastatic cancer. This review focuses on both preclinical and clinical studies that use a combination of radiotherapy and ICI therapy in cancer.

Lattice radiation therapy (LRT) is an advanced treatment approach specifically designed for massive tumors. It aims to deliver high-dose regions within tumors while ensuring the safety of the surrounding dose-limiting organs at risk (OAR). This case report introduces two unique clinical cases: a 63-year-old male diagnosed with a massive non-small cell lung cancer (NSCLC) tumor and a 61-year-old male with an inoperable recurrent left-sided adrenal mass intricately surrounded by dose-limiting bowel structures. Both patients underwent LRT to enhance tumor control and maintain less toxicity. Notably, both patients displayed a significant tumor volume reduction accompanied by minimal adverse effects during the 12-month follow-up period. While these initial results suggest that LRT may be effective and safe for treating large tumors, further investigation through exhaustive research and multicenter trials is necessary to fully understand and determine the specifics of lattice radiation therapy techniques.

BACKGROUND: Lattice radiation therapy (LRT) alternates regions of high and low doses within the target. The heterogeneous dose distribution is delivered to a geometrical structure of vertices segmented inside the tumor. LRT is typically used to treat patients with large tumor volumes with cytoreduction intent. Due to the geometric complexity of the target volume and the required dose distribution, LRT treatment planning demands additional resources, which may limit clinical integration.
OBJECTIVE: We introduce a fully automated method to (1) generate an ordered lattice of vertices with various sizes and center-to-center distances and (2) perform dose optimization and calculation. We aim to report the dosimetry associated with these lattices to help clinical decision-making.
METHODS: Sarcoma cancer patients with tumor volume between 100 cm3 and 1500 cm3 who received radiotherapy treatment between 2010 and 2018 at our institution were considered for inclusion. Automated segmentation and dose optimization/calculation were performed by using the Eclipse Scripting Application Programming Interface (ESAPI, v16, Varian Medical Systems, Palo Alto, USA). Vertices were modeled by spheres segmented within the gross tumor volume (GTV) with 1 cm/1.5 cm/2 cm diameters (LRT-1 cm/1.5 cm/2 cm) and 2 to 5 cm center-to-center distance on square lattices alternating along the superior-inferior direction. Organs at risk were modeled by subtracting the GTV from the body structure (body-GTV). The prescription dose was that 50% of the vertice volume should receive at least 20 Gy in one fraction. The automated dose optimization included three stages. The vertices optimization objectives were refined during optimization according to their values at the end of the first and second stages. Lattices were classified according to a score based on the minimization of body-GTV max dose and the maximization of GTV dose uniformity (measured with the equivalent uniform dose [EUD]), GTV dose heterogeneity (measured with the GTV D90%/D10% ratio), and the number of patients with more than one vertex inserted in the GTV. Plan complexity was measured with the modulation complexity score (MCS). Correlations were assessed with the Spearman correlation coefficient (r) and its associated p-value.
RESULTS: Thirty-three patients with GTV volumes between 150 and 1350 cm3 (median GTV volume = 494 cm3 , IQR = 272-779 cm3 were included. The median time required for segmentation/planning was 1 min/21 min. The number of vertices was strongly correlated with GTV volume in each LRT lattice for each center-to-center distance (r > 0.85, p-values < 0.001 in each case). Lattices with center-to-center distance = 2.5 cm/3 cm/3.5 cm in LRT-1.5 cm and center-to-center distance = 4 cm in LRT-1 cm had the best scores. These lattices were characterized by high heterogeneity (median GTV D90%/D10% between 0.06 and 0.19). The generated plans were moderately complex (median MCS ranged between 0.19 and 0.40).
CONCLUSIONS: The automated LRT planning method allows for the efficacious generation of vertices arranged in an ordered lattice and the refinement of planning objectives during dose optimization, enabling the systematic evaluation of LRT dosimetry from various lattice geometries.

Lattice is a 3-dimensional spatially fractionated radiotherapy that uses a distribution of high-doses, similar to spheres at vertices of a 3D network or matrix. These vertices that receive the high-dose are called peaks, while the rest of the target volume that receives a lower dose, is called the valley. This study aims to verify the technical feasibility for Spatially Fractionated Radiation Therapy treatment using the Lattice technique performed with VMAT at the National Cancer Institute José Alencar Gomes da Silva - INCA, Unit I. Ten patient cases were selected, with gross tumor volumes ranging from 90 to 1734 cc. A literature review was carried out to determine the geometry, the distribution of peaks and the peak to valley dose ratio that will be used in the Lattice technique plans. The dose distributions in the targets and organs at risk of the Lattice plans were clinically compared with the plans without the peaks. A configuration of spheres with diameter of 1.2 cm, separated center-to-center by 3 cm and with a prescription of 14 Gy in a single dose at these peaks was estabilished, while the valley had a prescription of 25 Gy in 5 fractions. Despite the increase in the prescribed equivalent dose in 2 Gy fractions from 40 Gy to 79.3 Gy, the median increase in doses to the OARs was 2.7%, with a maximum increase of 14.7%. The quality control of the plans was approved through the gamma analysis of the measurements performed with the Varian EPID. These findings demonstrate the technical feasibility of SFRT using the lattice technique with VMAT, and suggest that it may provide an effective delivery of high radiation therapy doses to tumors while minimizing the damage to surrounding healthy tissues.

This article tells the story of a medical physicist\'s journey to understand SFRT which started by accident more than 15 years ago. For decades, clinical application and preclinical research have shown that spatially fractionated radiation therapy (SFRT) can achieve a magically high therapeutic index. However, only recently, SFRT received well-deserved attention from mainstream radiation oncology. Today, our understanding of SFRT remains limited, which significantly hinders the advancement of SFRT for patient care. In this article, the author intends to shed some light on several important but unanswered SFRT research questions, including what is the essence of SFRT, which dosimetric parameters have clinical relevance and which do not, how does SFRT spare normal tissue but not tumor, and why radiobiological models developed for conventional radiation therapy may not be suitable for SFRT.

UNASSIGNED: To report a case of large extremity soft tissue sarcoma (2933 cc), safely treated with a novel approach of interdigitating high-dose LATTICE radiation therapy (LRT) with standard radiation therapy as a neoadjuvant treatment to surgery.
UNASSIGNED: Four sessions of high-dose LRT were delivered in a weekly interval, interdigitated with standard radiation therapy. The LRT plan consisted of 15 high-dose vertices receiving a dose >12 Gy per session, with 2-3 Gy to the peripheral margin of the tumor. The patient underwent surgical excision 2 months after the new regimen of induction radiation therapy.
UNASSIGNED: The patient tolerated the radiation therapy regimen well. The post-operative assessment revealed a negative surgical margin and over 95% necrosis of the total tumor volume. The post-surgical wound complication was mitigated by outpatient wound care. Interdigitating multiple sessions of high-dose LATTICE radiation treatments with standard neoadjuvant radiation therapy as a neoadjuvant therapy for soft tissue sarcoma was feasible and did not incur additional toxicity in this clinical case. A phase-I/II trial will be conducted to further evaluate the toxicity and efficacy of the new treatment strategy with the intent to increase the rate of pathologic necrosis, which has been shown to positively correlate with the overall survival.