An International Consensus on the Design of Prospective Clinical–Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer

Amendola, Beatriz E.; Mahadevan, Anand; Suárez, José; Griffin, Robert J.; Wu, Xiaodong; Pérez, Naipy; Hippe, Daniel S.; Simone, Charles B.; Mohiuddin, Majid; Mohiuddin, Mohammed; Snider, J.W.; Zhang, Hualin; Le, Quynh‐Thu; Mayr, Nina A.

doi:10.3390/cancers14174267

Cited by 12 publications

(2 citation statements)

References 39 publications

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“…Since the 1950's, SFRT has been used primarily in the palliative setting (14), or for debulking large tumors prior to conventional radiation, concomitant chemoradiotherapy, or surgery (15)(16)(17)(18). Current clinical use of SFRT focuses on single ablative doses (> 15 𝐺𝑦) prior to conventional whole tumor / whole field RT (WTRT) (19,20) , which may obliterate the immune-activating features of SFRT. Recent insights into both pro-and anti-tumor immunological consequences of radiation warrant a novel look at SFRT: radiation-shielded areas may create immune reservoirs that are additionally promoted by the release of immune-stimulatory cytokines in adjacent unshielded sites.…”

Section: Introductionmentioning

confidence: 99%

Spatially Fractionated GRID radiation potentiates immune-mediated tumor control

Bekker,

Obertopp,

Redler

et al. 2024

Preprint

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Background Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed ‘hot’ tumor beds, or ‘cold’ immune deserts with low levels of infiltration. The pre-treatment immune state of the TIME is associated with treatment outcome; immunologically hot tumors generally exhibit better responses to radio- and immunotherapy than cold 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 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. Only explicit consideration of radiation-induced antitumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is only successful with radiation-induced antitumor 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 antitumor 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.

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Section: Introductionmentioning

confidence: 99%

Spatially Fractionated GRID radiation potentiates immune-mediated tumor control

Bekker,

Obertopp,

Redler

et al. 2024

Preprint

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“…This has been followed by the establishment of GRID, Lattice, Microbeam and FLASH Radiation Therapy Working Groups. As a group, they have published a white paper on GRID RT (16) and developed consensus on the design of clinical trials in spatially fractionated radiotherapy (17,18). More recently, the RSS has also opened a patient registry to incorporate GRID RT and LRT data to better understand the delivery techniques and outcomes.…”

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confidence: 99%

Lattice radiotherapy: where less is more?

Wang

Ong

2022

Ann Palliat Med

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We read with great interest the case report by Iori et al. who treated a large sarcomatoid lung cancer with lattice radiotherapy (LRT) (1). The authors reported good radiological response and patient reported symptom relief. We commend their efforts in implementing this emerging radiotherapy technique at their centre. We hope that this case report raises awareness and interest in the implementation of LRT in other institutions.LRT derived its basis from grid radiotherapy (GRID RT), where a wide radiation beam is passively filtered through a heavy metal block to deliver radiation in beamlets. This technique was popularized in the 1990s by Mohiuddin et al., with patients experiencing good clinical response despite partial irradiation of tumours, albeit at high doses (2). There were subsequently many pre-clinical and clinical studies exploring different aspects of GRID RT (3-5). However, the use of GRID RT remains limited to few centres worldwide. Possible reasons include difficulties with commissioning and delivering treatment with a GRID block or multileaf-collimator. As GRID RT is delivered as a static field, treating deep seated tumours may be difficult without unnecessary risk to adjacent organs at risk.Since the initial reports from Mohiuddin et al, we have seen technological advances in radiotherapy equipment and techniques over the past few decades. The early 2000s have seen the advent of intensity modulated radiotherapy that enabled us to deliver radiation via dose painting. Radiation techniques have also evolved with time and ablative doses can now be delivered via stereotactic body radiotherapy (SBRT). However, the lesions treatable with SBRT is often limited by size.So how do we marry the learnings of GRID RT and SBRT in the treatment of large tumours? LRT may be a potential solution. In essence, LRT takes dose painting to the extreme by delivering precise SBRT-like doses to spherical sub-volumes termed vertices, spread out within the tumour whilst simultaneously covering the entire tumour to a lower dose. In two recently reported studies, namely the LITE-SABR-M1 trial (6) as well as the LATTICE_01 study (7), we now have good clinical evidence supporting the use of this emerging radiotherapy technique.The LITE-SABR-M1 trial was a single-arm phase I trial conducted between October 2019 and August 2020 on 22 patients with tumours >4.5 cm. LRT technique was as described in the accompanying case report, except that the vertices received 66.7 Gy instead of 50 Gy. Importantly, concurrent systemic therapy was not allowed and a 2 week washout period was recommended before and after LRT. The authors reported a good safety profile with no treatment related grade 3 or more toxicity noted in the acute period. Patients also reported improvements in anxiety, depression, pain interferences, physical global health and physical function. Whilst not the primary endpoint, good radiological tumour responses were also

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