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Published in final edited form as: Semin Radiat Oncol. 2024 Jul;34(3):276–283. doi: 10.1016/j.semradonc.2024.04.002

Spatially Fractionated Radiotherapy in the Era of Immunotherapy

Matthew T McMillan *, Atif J Khan *, Simon N Powell *, John Humm †, Joseph O Deasy †, Adriana Haimovitz-Friedman *,#
PMCID: PMC12013776  NIHMSID: NIHMS2070190  PMID: 38880536

Abstract

Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and a resulting systemic immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies.

INTRODUCTION

Classical radiation oncology dogma is grounded in the principle that radiotherapy exerts its cytotoxic anti-tumor effects through the induction and lack of repair of lethal DNA damage, and consequently an effective radiotherapy treatment requires the delivery of a high radiotherapy dose to the full tumor volume. The ICRU report 62 codified this belief into a paradigm that extends the treatment margin to account for any peri-tumoral occult disease as well as a setup margin. In practice, there are tradeoffs with normal tissue constraints such as those recommended in the QUANTEC reports (Marks 2010). Spatially fractionated radiotherapy (SFRT) is a promising treatment technique characterized by an inhomogeneous intra-tumoral dose distribution alternating between dose peaks and valleys. SFRT upends traditional radiobiological dogma through leveraging favorable immunomodulatory aspects of radiotherapy to achieve tumor control exceeding expectations based on the sum of predicted lethal DNA damage to tumor.

The Therapeutic Index & the “Rs” of Radiotherapy

A universal principle guiding radiotherapy decision making is the therapeutic index, which is the ratio between the radiotherapy dose that induces unacceptable normal tissue toxicity (tolerance dose) and the dose that achieves an acceptable tumor control probability. The corresponding therapeutic window is the difference between the tumor control dose and (usually higher) tolerance dose.

Efforts to widen this therapeutic window have historically involved variations in fractionation as well as continuous efforts to improve disease and dose co-localization via improvements in imaging and dose delivery technologies. The primary radiobiological rationale for fractionation changes (prior to the move to hypofractionation) centered on the canonical “four R’s” of radiotherapy (i.e., DNA Repair, Redistribution of cells in the cell cycle, Repopulation, and Reoxygenation of hypoxic areas), first codified by Rodney Withers in 1975 (Withers 1975). In the 1980s, Steel and colleagues identified a “fifth R”, intrinsic radiosensitivity (Steel, McMillan, and Peacock 1989). The ‘five Rs’ were largely derived through in vitro experiments, such as clonogenic survival assays. In comparison, the ability to hypo-fractionate treatments has been driven by improvements in disease and dose localization for small target volumes where high doses are well tolerated. More recently, a “sixth R” (i.e., Reactivation of the antitumor immune response) (Boustani et al. 2019), has been described to account for the role of the immune system in radiation-induced tumor control. Although much is currently unknown about the ‘sixth R,’ it is likely an integral component of SFRT’s local and systemic therapeutic effects.

Radiotherapy as an Immunomodulator: The Role of Dose, Fractionation, and Target biology

Radiotherapy can be used as an immunomodulator, but the therapeutic context and desired immunological changes are critical considerations, given that different radiotherapy dose and fractionation combinations generate distinct immune phenotypes which are slowly being unraveled.

Short-course low-dose radiotherapy (LD-RT) (e.g., 0.5 to 2.0Gy x 4 fractions) has been reported to promote vascular and stromal normalization – as well as the release of chemokines – with a subsequent increase in tumor-infiltrating T cells and natural killer cells (Herrera et al. 2022; Patel et al. 2021; Barsoumian et al. 2020; Chen 2021). Furthermore, short-course LD-RT downregulates immunosuppressive TGF-β in the tumor microenvironment and promotes macrophage repolarization from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype (Monjazeb et al. 2021; Schoenfeld et al. 2022).

Although short courses of tumor-directed low-dose radiotherapy are immunostimulatory, long courses of conventionally fractionated low-dose radiotherapy or chemoradiotherapy (e.g., 2.0Gy x 30 fractions) are often immunosuppressive due to several factors, including: repeated killing of circulating immune cells, disruption of vasculature, chronic interferon signaling, and frequent inclusion of tumor-draining lymph nodes in the treatment field (Galluzzi 2023). The latter is particularly relevant in studies combining long-course conventionally fractionated radiotherapy with immune checkpoint blockade (ICB). The tumor-draining lymph nodes are a key site for the priming of naive T cells to tumor neoantigens. Furthermore, ICB induces T cell proliferation in the tumor-draining lymph nodes (Prokhnevska et al. 2023; Huang et al. 2022; Buchwald et al. 2020). Proliferating T cells are more sensitive to radiotherapy-induced damage (Pawlik and Keyomarsi 2004) and preclinical work has shown that administering anti-PD-1 pre-RT, as opposed to post-RT, is associated with increased CD8+ T cell damage and apoptosis, as well as reduced abscopal effects (Wei et al. 2021). These data could potentially explain the failure of all randomized trials combining conventional radiotherapy with elective nodal irradiation and concurrent ICB. (“LBA5 Primary Results of the Phase III KEYNOTE-412 Study: Pembrolizumab (pembro) with Chemoradiation Therapy (CRT) vs Placebo plus CRT for Locally Advanced (LA) Head and Neck Squamous Cell Carcinoma (HNSCC)” 2022; Lee et al. 2021; Tao et al. 2023; Monk et al. 2023). Alternatively, every successful randomized trial combining conventionally fractionated radiotherapy with ICB administered anti-PD-1/PD-L1 sequentially (Antonia et al. 2017; Zhou et al. 2022; Kelly et al. 2021). Nevertheless, more work is necessary to clarify this point, namely pre-RT ICB always fails, post-RT is sometimes successful.

In contrast to long-course conventionally fractionated RT, sub-ablative radiotherapy (e.g., 8Gy x 3 fractions) increases tumor MHC class I/II expression and generates robust type I interferon responses, which leads to enhanced antigen-presenting cell activity, immune priming, T cell clonal expansion, and T cell effector function (Altorki et al. 2021; Darragh et al. 2022; Formenti et al. 2018). Preclinical work demonstrated that sub-ablative immunomodulatory radiotherapy might be preferable compared to higher doses of radiotherapy per fraction (e.g., >12Gy per fraction) given that the higher doses may lead to homeostatic upregulation of three prime repair exonuclease 1 (TREX1) with subsequent degradation of cytosolic double-stranded DNA (i.e., the innate immune stimulus). Supporting clinical evidence for this hypothesis was reported in a trial of SBRT (30 to 50Gy over 3 to 5 fractions) plus pembrolizumab for advanced solid tumors; patients with increased TREX1 expression after SBRT were associated with disease progression (Luke et al. 2020).

A potential benefit of sub-ablative immunomodulatory radiotherapy identified in preclinical studies is the ability to stimulate abscopal responses through increased intercellular adhesion molecule 1 (ICAM-1) expression in CD8+ T cells and endothelial cells in spatially distinct unirradiated tumor; this leads to both increased activation and infiltration of CD8+ T cells into unirradiated tumor (Zhao et al. 2021; Markovsky et al. 2019).

Higher, ablative radiotherapy doses (e.g., 3-5 x 10Gy) can eliminate immunosuppressive tumor-resident immune cells (e.g., regulatory T cells) and induce immunogenic cell death via the release of damage-associated molecular patterns (e.g., high mobility group box 1 protein, extracellular ATP, and calreticulin on the cell surface) and tumor neoantigens, leading to innate inflammatory signaling, immune priming, T cell clonal expansion, and T cell chemotaxis to the tumor microenvironment. (Phillips et al. 2020; Tang et al. 2017; Spurr et al. 2022; Chang et al. 2023; Monjazeb et al. 2023; Luke et al. 2020). Ablative doses also cause endothelial cell damage, which can impair tumor vascular supply and limit extravasation of immune cells into the tumor microenvironment (Torok et al. 2019; Rodríguez-Barbeito et al. 2019). Radiation also induces endoplasmic reticulum stress through ROS. ER stress is known to result in the translocation of calreticulin to the cell membrane, possibly leading to NK immune stimulation Sen Santara S) Balancing this, however, is at least some suppressive impact of radiation in high dose areas on pro-stimulatory cell types.

Given that LD-RT and high-dose radiotherapy (i.e., sub-ablative immunomodulatory radiotherapy or ablative radiotherapy) act through complementary mechanisms to stimulate antitumor immunity, clinical trials have used combinations of LD-RT and high-dose radiotherapy to target spatially distinct metastases in patients receiving ICB. Early work suggesting enhanced responses to ICB when combining high-dose RT and low-dose RT were seen in a clinical trial of ipilimumab plus liver- or lung-metastasis-directed SBRT for advanced solid tumors (Welsh et al. 2019). Investigators anecdotally noted that many responding tumors received low-dose RT (i.e., 5-10Gy), and tumors in the same patient that did not receive low-dose RT did not respond. This led to an exploratory analysis which showed a >50% decrease in tumor volume was seen in 31% of lesions that received low-dose radiation (i.e., 5-10Gy typically over 4 fractions) versus only 5% of lesions that did not receive any radiation (p=0.009).

A subsequent randomized trial of patients on ICB for predominantly metastatic melanoma or lung cancer compared high-dose RT to a single site versus high-dose RT to one site plus low-dose RT to several other lesions (Patel et al. 2021). Compared to high-dose RT alone, the combination of high-dose RT plus low-dose RT was associated with a trend towards a higher overall response rate (26% vs 13%) and increased overall survival (median 16.7 vs 9.6mo). Additionally, comparing the lesions irradiated with low-dose RT to the non-irradiated lesions from the high-dose RT alone cohort demonstrated significantly improved lesion-specific responses for the lesions receiving low-dose RT (53% vs 11%). Furthermore, translational studies showed lesions receiving low-dose RT had increased infiltration of CD8+ T cells, CD4+ T cells, and natural killer cells.

Delivering Both Low- and High-Dose RT to the Same Tumor with SFRT

SFRT represents an approach to deliver effectively low-dose RT and high-dose RT in a single target volume through intensity modulation. This is particularly attractive given the complementary mechanisms of short-course low-dose and high-dose radiotherapy. Two-dimensional GRID therapy can be considered the precursor to SFRT. Grid therapy was initially tested as a ‘last option’ approach to cytoreduce bulky tumors while sparing a larger volume of surrounding normal tissue. GRID therapy uses blocks or multi-leaf collimators to deliver a wave-like pattern of radiation alternating between high-dose ‘peaks’ (e.g., 20Gy) and low-dose ‘valleys’ (e.g., ~1Gy) (Billena and Khan 2019). The high-dose ‘peaks’ ablate microvasculature, as well as immunosuppressive tumor-resident immune cells and tumor cells, leading to catastrophic tumor DNA damage, immunogenic cell death, innate inflammatory signaling, and spillage of tumor neoantigens into the tumor microenvironment. Cytokines secreted from neighboring high-dose regions and scatter radiation delivered to low-dose ‘valleys’ (e.g., 1Gy) can induce bystander cell death, and remodel the tumor microenvironment through normalization of stroma and vasculature, decreased secretion of immunosuppressive TGF-β, increased secretion of T cell attracting chemokines (e.g., CXCL9), and repolarization of immunosuppressive macrophages to an immunostimulatory phenotype. These changes facilitate the migration of cytotoxic immune cells to intra-tumoral low-dose ‘valley’ regions and adjacent high-dose ‘peak’ regions. The changes in the low-dose ‘valleys’ also facilitate the migration of antigen-presenting cells to the border of high-dose regions where they can collect neoantigens of ablated tumor cells and migrate to nearby tumor-draining lymph nodes where they prime naive T cells to tumor neoantigens.

Lattice-SFRT is a newer approach that delivers SFRT in three dimensions with alternating high-dose and low-dose spheres within the tumor. Lattice is an attractive option given its ability to reduce toxicity to superficial tissues and minimize peak doses delivered to proximal organs at risk. With the ability to deliver a more homogeneous immunomodulatory low-dose both to tumor regions between high-dose spheres, lattice could theoretically optimize the spatial distribution of high-dose peaks and low-dose valleys while also increasing the volume of tumor receiving low-dose radiotherapy; thereby, maximizing stromal and vascular normalization and subsequent infiltration of cytotoxic effects and antigen presenting cells.

Preclinical Studies of SFRT

The mechanisms mediating local and distant (i.e., abscopal) responses to SFRT have been investigated across a variety of preclinical studies for decades. This review will highlight more recent studies investigating mechanisms of SFRT-induced tumor control. In the low-dose valley regions of a SFRT treatment field, a common finding is radiation-induced bystander effects.(Cho et al. 2023; Rogers et al. 2022; Autsavapromporn et al. 2013). In two preclinical murine models (i.e., SCK mammary carcinoma and SCCVII squamous cell carcinoma), Asur and colleagues compared cells directly irradiated with 10Gy versus bystander cells that received ~1Gy scatter dose from two-dimensional SFRT (i.e., GRID RT) or unirradiated cells receiving conditioned media from irradiated cells (Asur et al. 2012). The bystander cells demonstrated increased expression of genes involved in DNA repair, cell cycle arrest, and apoptosis immediately after exposure and at four hours post exposure. Furthermore, bystander cells experienced a 50% decrease in cell survival compared to sham controls.

Kanagavelu and colleagues investigated both local and distant effects of partial- or full-volume irradiation (20Gy x1 fraction) using a Lewis lung carcinoma (LLC) murine model (Kanagavelu et al. 2014). Tumors were implanted in the bilateral flanks of mice and only one flank tumor underwent partial- or full-volume irradiation. The partial-volume irradiation treatment groups consisted of radiotherapy delivered to two 10% vertices, one 20% vertex, or one 50% vertex. The best local control was observed in mice who received full-volume irradiation or partial-volume irradiation to two 10% vertices. Maximal tumor control in the unirradiated flank was observed in mice who received partial-volume irradiation consisting of two 10% vertices or one 50% vertex.

A later study using murine 67NR (breast orthotopic tumor) and LLC models investigated the mechanism underlying tumor responses to partial-volume irradiation (Markovsky et al. 2019) 67NR murine orthotopic breast tumors received either full-volume irradiation or partial-volume irradiation to 50% of the tumor volume using a 2 x 2 cm collimator on a microirradiator. Tumor growth control was comparable with partial volume and full-volume irradiation (10Gy, 15Gy, or 20Gy) in immunocompetent mice; however, athymic nude mice demonstrated inferior tumor control when receiving partial-volume irradiation compared to full-volume irradiation. Given the importance of an intact immune system for generating similar disease control with partial-volume irradiation, the authors investigated the immune compartment in irradiated and unirradiated tumor segments. They subsequently identified a significant influx of CD8+ T cells into the unirradiated segment of the tumors 24 hours after receiving partial volume irradiation (10Gy x1 fraction), and there was inferior tumor control in partially irradiated tumors when mice were treated with a CD8+ T cell depleting antibody.

Markovsky et al. investigated the effect of precisely irradiating half tumors in preclinical intact-immune system murine models using 67NR breast and Lewis lung carcinoma (LLC) murine cell lines (Markovsky 2019). Given partial-volume irradiation’s significant dependency on CD8+ T cells for its therapeutic effects, Markovsky et al investigated the source of CD8+ T cells that influx the unirradiated half of partially irradiated tumors. They discovered that ICAM-1 surface expression (a key regulator of immune responses; Bui 2020) was significantly increased following irradiation, for both partial-volume irradiation and full-volume irradiation. However, a larger increase in ICAM-1 expression was observed in the unirradiated tumor segments of partially irradiated tumors. Administration of an anti-ICAM antibody significantly impaired CD8+ T cell extravasation into the unirradiated segment of partially irradiated (10Gy x1) tumors and diminished tumor control in partially irradiated tumors. The importance of CD8+ T cells and ICAM-1 expression for tumor control after partial-volume irradiation was confirmed using the less immunogenic murine LLC model as well.

To investigate the source of CD8+ T cells infiltrating the unirradiated tumor segment, Markovsky et al administered FTY720, which sequesters cytotoxic T lymphocytes to secondary lymphoid compartments (Pinschewer et al. 2000), and demonstrated that CD8+ T cells infiltrating the unirradiated segment shortly after partial volume irradiation likely originated from the tumor irradiated segment. Despite the early infiltration of CD8+ T cells after FTY720 and partial-volume irradiation, egress of cytotoxic T lymphocytes from the tumor-draining lymph nodes was impaired, and rapid tumor growth continued after a delay of approximately one week later. A later study using a syngeneic p53/MCA transplant sarcoma model was unable to demonstrate similar tumor control with half-irradiation (15Gy x1) compared to full-volume irradiation (15Gy x1 fraction), (Johnson et al. 2022). There are likely differences in tumor immunogenicity, radiosensitivity, transplant tumor microenvironment, and innate inflammatory signaling that explain the discrepant findings.

A recent study investigated mechanisms underlying anti-tumor immunity after partial-volume irradiation to determine if there was histology-specific variability in innate inflammatory signaling (Mathieu et al. 2023). Using 67NR (breast tumor) and murine LLC models, Mathieu et al delivered radiotherapy to 50% or 100% of the tumor volume using a 2 x 2 cm collimator. In the 67NR model, partial-volume irradiation significantly upregulated canonical cGAS/STING signaling compared to full-volume irradiation. In the LLC model, the immune response associated with partial-volume irradiation acted through a noncanonical tumor ATM-dependent, host-STING-dependent, and cGAS-independent pathway. This study underscored how components of the DNA damage response and innate inflammatory signaling contribute to partial-volume irradiation-induced anti-tumor immunity in a histology-specific manner.

Clinical Studies of SFRT

Modern clinical studies of SFRT range from the early work of Mohiuddin with GRID therapy in the 1990s to recent clinical trials featuring lattice and partial-volume irradiation. The historical clinical experience with SFRT has been extensively described in prior reviews (Billena and Khan 2019; Lukas et al. 2023). This review will focus on several contemporary clinical trials and large retrospective experiences, as well as ongoing clinical trials.

Partial volume tumor irradiation was evaluated in a single-center phase l trial (NCT02608385) of stereotactic body radiotherapy (SBRT) (30-50Gy to 2-4 metastases over 3-5 fractions) followed by pembrolizumab for advanced solid tumors (Luke et al. 2018, 2020). SBRT was only prescribed to a maximum tumor volume of 65 cc, so 18 of 68 patients (21/139 metastases) received partial volume irradiation. Treated metastasis control (i.e., local control of irradiated metastases) was 89.5% at one-year, and was associated with increased survival. Tumors that received partial volume irradiation achieved similar local control compared to tumors receiving full-volume irradiation (p=0.24). For the irradiated lesions, the partial and complete response rates were 30% and 5%, respectively. The out-of-field (i.e., abscopal) lesion response rate was 13%. Response rates were similar between patients who receive full- and partial-volume irradiation.

Given the limited sample size in the initial analysis,(Luke et al. 2020) the University of Chicago group recently reported an updated and expanded study. Combining the original study population with an expansion cohort of advanced solid tumor patients receiving SBRT plus pembrolizumab, they compared 51 patients receiving full-volume irradiation versus 46 patients receiving partial-volume irradiation (Korpics et al. 2023). The most common tumor histologies in the partial-volume irradiation and full-volume irradiation cohorts were colorectal cancer (22%) and head and neck cancer (20%), respectively. The median tumor volume for the 62 metastases that received partial-volume irradiation and 157 metastases that received full-volume irradiation were 138 cc and 8 cc, respectively.

Although the full-volume irradiation cohort had a significantly higher median tumor volume covered by the prescription dose (75% vs 49%) or 90% of the prescription dose (99% vs 82%) compared to the partial-volume irradiation cohort, the one-year local failure was 13% and 5% for partial-volume irradiation and full-volume irradiation, respectively (p=0.08). Notably, 71% of local failure events occurred in the liver, and a larger proportion of the tumors receiving partial-volume irradiation were located in the liver compared to the full-volume irradiation tumors (36% vs 18%). This is a relevant confounder given that local failures were more common after SBRT for liver metastases compared to other sites of metastasis in SABR-COMET 2,(Palma et al. 2020) and ICB is significantly less effective in patients with liver metastases compared to other sites of metastatic disease (Yu et al. 2021; Cohen et al. 2023; Tumeh et al. 2017; Chen et al. 2023). When accounting for the site of metastasis as a confounder, Korpics et al no longer identified a trend toward worse local control with partial-volume irradiation (p=0.41). The lack of success of immunotherapy in the liver may also be due to the unique role of liver cells in inducing immune tolerance (Li 2013).

While Luke et al’s work evaluated partial-volume irradiation in the setting of ICB, a recent phase I study, LITE SABR M1 (NCT04133415), evaluated 5-fraction lattice radiotherapy monotherapy using volumetric modulated arc therapy for 20 patients with advanced bulky tumors (i.e., >4.5 cm) (Duriseti et al. 2022). Patients underwent a four-dimensional simulation CT and the iGTV was isotropically expanded by 5 to 10 mm to generate a PTV_2000cGy. Within a 1 cm contraction of the GTV, 1.5 cm diameter lattice spheres (i.e., PTV_6670cGy) were arranged in a regular pattern alternating with 1.5 cm diameter PTV_2000cGy spheres (Kavanaugh et al. 2022). The study achieved its primary endpoint of safety with no likely treatment-associated grade ≥3 toxicities within 90 days of treatment (Duriseti et al. 2022). Most tumors were located in the thorax (59%) and the median GTV was 579 cc. At first post-treatment imaging (median 1.8 mo post lattice SBRT), all irradiated tumors had decreased in size (median 24% decrease, range 2.4-91.7%). At the second follow-up imaging study (median 4.5 mo post lattice SBRT), all but one irradiated tumor had decreased in size with a median decrease of 47.4%. As a follow-up to their phase I study, Duriseti and colleagues reported an ongoing phase II study is investigating lattice SBRT for sarcomas (NCT04553471),(Duriseti et al. 2022).

The largest clinical experience of modern SFRT to date was presented at the ASTRO 2022 annual meeting.(“Spatially Fractionated Radiation Therapy in the Modern Era: The Mayo Clinic Experience” 2022). The Mayo Clinic’s retrospective cohort consisted of 126 patients and 129 treatment courses. Lesions were most commonly located in the thorax (38%) and the most common tumor histology was sarcoma (33%). The most common SFRT dose was 20Gy (85%) with VMAT vertices (84%). Follow-up palliative or definitive external beam radiotherapy was received by 80% of patients. At one-year, local control was 83% and grade ≥3 toxicity was 13%.

An ongoing clinical trial at Memorial Sloan-Kettering Cancer Center (NCT05837767) is assessing lattice radiotherapy in patients with ≥2 advanced extracranial solid tumors (one with a GTV ≥100 cc) amenable to radiotherapy. The site of disease with a GTV ≥100 cc will receive lattice radiotherapy (21 to 25Gy x1 fraction), and the other tumor will receive SBRT (i.e., 9Gy x 3 fractions). There are two primary endpoints in the study: (i) 12-wk overall response rate (per RECIST v1.1) in the lattice radiotherapy-treated lesion on imaging and (ii) changes in the expression of predefined RNA seq signatures of immune infiltration in pre- and post-biopsies from lattice radiotherapy-treated and stereotactic body radiotherapy-treated lesions.

A phase I trial at Washington University (NCT05831579) is investigating palliative GRID RT for tumors ≥4.5 cm using intensity-modulated proton therapy to deliver 20Gy x 3 fractions with an integrated dose of 6Gy x 3 fractions to the planning target volume. It will assess the following co-primary endpoints: (i) the rate of treatment-related acute toxicity (i.e., from treatment start until day 90) and (ii) the rate of treatment-related late toxicity (i.e., from day 91 until 12 months).

Another phase I trial at Washington University (NCT04098887) is assessing lattice SBRT for localized unresectable or metastatic conventional type chondrosarcoma. Radiotherapy is prescribed to 20Gy in 5 fractions delivered every other day with a lattice simultaneous integrated boost to 66.7Gy in 5 fractions. The primary endpoint of the study is the incidence of treatment-related grade ≥3 non-hematologic adverse events within 90 days of starting radiotherapy.

Other Considerations

Although most of this review has been dedicated to discussing the immunostimulatory effects of SFRT and related tumor control, it is critical to not overlook the potential for reduced toxicity with SFRT approaches. In Korpics et al’s expanded analysis of SBRT plus pembrolizumab for advanced solid tumors, in addition to achieving comparable local control, partial-volume irradiation was associated with significantly fewer dose-limiting toxicities compared to patients who received full-volume irradiation (12% vs 2%, p=0.03) (Korpics et al. 2023). Additionally, SFRT for 20 patients using highly conformal lattice radiotherapy in LITE SABR M1 was associated with no likely treatment-related grade ≥3 toxicities – despite treating 1.5 cm diameter lattice spheres geometrically arranged in extremely large tumors (median GTV 579 cc) to 66.7Gy over 5 fractions.

The reduced toxicity associated with SFRT not only applies in the context of sparing standard organs at risk but also reducing the integral radiotherapy dose delivered to circulating peripheral lymphocytes. Although intra-tumoral T cells are more radioresistant – secondary to TGF-β-mediated reprogramming (Arina et al. 2019) – circulating/lymphoid tissue T cells are extremely sensitive to radiotherapy with apoptosis seen even after exposure to doses as low as 0.125Gy (Heylmann et al. 2021). Radiation-related lymphopenia is associated with a poor prognosis across numerous solid tumor histologies,(Lin et al. 2019; Abravan et al. 2020; Davuluri et al. 2017; Chadha et al. 2017) and it is associated with worse response to immunotherapy (Jing et al. 2022). By limiting the size of treatment fields, SFRT may limit hematological toxicity as well, thus resulting in a better clinical outcome.

A potential approach for maximizing sparing of circulating lymphocytes and organs at risk is the delivery of SFRT using ultra-high dose rates (≥ 40Gy per second, i.e., FLASH SFRT). By delivering radiotherapy in milliseconds – rather than over several minutes – a smaller fraction of circulating peripheral lymphocytes is exposed to radiotherapy. FLASH radiotherapy might also potentiate the immunostimulatory effects of SFRT as it has been shown to decrease immunosuppressive TGF-β signaling,(Cunningham et al. 2021) preserve microvasculature to promote immune cell infiltration,(Kim et al. 2021) and preferentially facilitate tumor infiltration with CD8+ T cells and immunostimulatory M1 macrophages (Shukla et al. 2023).

Future Directions

SBRT-PATHY

A novel SFRT approach under investigation is SBRT PArtial Tumor irRT of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY). The hypoxic segment is identified using PET and contrast-enhanced CT, and it is defined as the hypovascularized and hypometabolic junctional zone between the central necrotic and peripheral hypervascularized and hypermetabolic tumor segment (Tubin, Popper, and Brcic 2019; Tubin et al. 2020). Retrospective analyses and correlative studies of SBRT-PATHY suggest that selectively targeting the hypoxic tumor segment and sparing surrounding normoxic tumor and proximal organs at risk (including circulating lymphocytes) induces robust local and abscopal clinical responses (Tubin, Popper, and Brcic 2019; Tubin et al. 2020, 2022). A similar approach, termed “metabolism-guided lattice,” has also generated impressive clinical responses (Ferini et al. 2022).

Microbeam and Minibeam SFRT

Two of the more intriguing SFRT approaches, microbeam radiotherapy (MRT) and minibeam radiotherapy (MBRT), have predominantly been tested in preclinical settings due to technical challenges; however, their ability to induce strong immune responses and spare normal tissue with an impressive therapeutic index – despite using very high peak doses – make them an attractive option for further development (Bertho et al. 2023; Yang et al. 2019; Prezado et al. 2018; Lamirault et al. 2020). MRT and MBRT deliver an array of parallel 50-100 μm and 0.5-1 mm beamlets, respectively (Prezado 2022). The space between beams is approximately 200-400 μm and 1-4 mm for MRT and MBRT, respectively. In rat and murine models, MRT can delivery very high peak doses (400-600Gy) with remarkable normal tissue sparing.(Fernandez-Palomo et al. 2020) However, MRT has several limitations: (i) it requires low kilovoltage energies to avoid scattering which limits the ability to treat non-superficial tumors; (Prezado 2022) (iii) requires extremely high dose rates to avoid blurring by cardiosynchronous pulsations of peak and valley patterns (Manchado de Sola et al. 2018). Consequently, it must be administered at large 3rd generation synchrotrons capable of meeting these technical requirements.

Despite these limitations, a dose escalation clinical trial of MRT for canines recently reported outcomes for the first canine treated with three-dimensional conformal synchrotron x-ray MRT treatment (Adam et al. 2022). The canine had a spontaneous deep-seated glioma and was treated with 50 μm wide beams (400 μm of space between beams) with each beam delivering 20 to 25Gy to the PTV as peak doses and ~1Gy as valley doses at high dose rates (i.e., 5500Gy/s). At 3 months post MRT, the tumor had decreased in size by 87% with cessation of pre-MRT seizures and significant improvement in quality of life per canine owner survey.

MBRT is closer to clinical implementation than MRT given that its beam widths do not require delivery at a synchrotron, and it can more easily target deeper seated tumors using technology such as particle therapy. A recent trial of 16 canines with de novo brain tumors randomized dogs to either an SRS (9Gy x 3 fractions) or MBRT (mean dose 26Gy) treatment arm (Kundapur et al. 2022; “New Kid on the Block- Mini Beam Radiation Treatment- Final Report of a Randomized Phase III Study of Treating Canine Denovo Brain Tumors” 2019). In the MBRT arm, complete pathologic remission was detected in 71% of dogs versus no remissions in the SRS treatment arm. In the MBRT group, structural damage was not seen in the beam path outside of the target region; alternatively, in the SRS cohort, treatment-related damage was noted. The favorable therapeutic index of MBRT and its potential for widespread application make it an appealing therapy to take to human trials.

CONCLUSION

Spatially fractionated radiotherapy (SFRT) may facilitate clinical translation of radiation immunostimulatory effects. Despite defying radiobiological canon, SFRT often induces exceptional clinical responses, and modern three-dimensional SFRT delivery (i.e., lattice) could further enhance the normal tissue-sparing and safety of this treatment approach and may have a significant effect on metastatic lesions. Ongoing clinical trials continue to investigate different SFRT approaches alone and in combination with immunotherapies.

Footnotes

Conflict of interest: None.

REFERENCES

  1. Abravan Azadeh, Faivre-Finn Corinne, Kennedy Jason, McWilliam Alan, and van Herk Marcel. 2020. “Radiotherapy-Related Lymphopenia Affects Overall Survival in Patients with Lung Cancer.” Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 15 (10): 1624–35. [DOI] [PubMed] [Google Scholar]
  2. Adam Jean-François, Balosso Jacques, Bayat Sam, Berkvens Paul, Berruyer Gilles, Bräuer-Krisch Elke, Brochard Thierry, et al. 2022. “Toward Neuro-Oncologic Clinical Trials of High-Dose-Rate Synchrotron Microbeam Radiation Therapy: First Treatment of a Spontaneous Canine Brain Tumor.” International Journal of Radiation Oncology, Biology, Physics 113 (5): 967–73. [DOI] [PubMed] [Google Scholar]
  3. Altorki Nasser K., McGraw Timothy E., Borczuk Alain C., Saxena Ashish, Port Jeffrey L., Stiles Brendon M., Lee Benjamin E., et al. 2021. “Neoadjuvant Durvalumab with or without Stereotactic Body Radiotherapy in Patients with Early-Stage Non-Small-Cell Lung Cancer: A Single-Centre, Randomised Phase 2 Trial.” The Lancet Oncology 22 (6): 824–35. [DOI] [PubMed] [Google Scholar]
  4. Antonia Scott J., Villegas Augusto, Daniel Davey, Vicente David, Murakami Shuji, Hui Rina, Yokoi Takashi, et al. 2017. “Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.” The New England Journal of Medicine 377 (20): 1919–29. [DOI] [PubMed] [Google Scholar]
  5. Arina Ainhoa, Beckett Michael, Fernandez Christian, Zheng Wenxin, Pitroda Sean, Chmura Steven J., Luke Jason J., et al. 2019. “Tumor-Reprogrammed Resident T Cells Resist Radiation to Control Tumors.” Nature Communications 10 (1): 3959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Asur Rajalakshmi S., Sharma Sunil, Chang Ching-Wei, Penagaricano Jose, Kommuru Indira M., Moros Eduardo G., Corry Peter M., and Griffin Robert J.. 2012. “Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells.” Radiation Research 177 (6): 751–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Autsavapromporn Narongchai, Suzuki Masao, Funayama Tomoo, Usami Noriko, Plante Ianik, Yokota Yuichiro, Mutou Yasuko, et al. 2013. “Gap Junction Communication and the Propagation of Bystander Effects Induced by Microbeam Irradiation in Human Fibroblast Cultures: The Impact of Radiation Quality.” Radiation Research 180 (4): 367–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Barsoumian Hampartsoum B., Ramapriyan Rishab, Younes Ahmed I., Caetano Mauricio S., Menon Hari, Comeaux Nathan I., Cushman Taylor R., et al. 2020. “Low-Dose Radiation Treatment Enhances Systemic Antitumor Immune Responses by Overcoming the Inhibitory Stroma.” Journal for Immunotherapy of Cancer 8 (2). 10.1136/jitc-2020-000537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bertho Annaig, Iturri Lorea, Brisebard Elise, Juchaux Marjorie, Gilbert Cristèle, Ortiz Ramon, Sebrie Catherine, et al. 2023. “Evaluation of the Role of the Immune System Response After Minibeam Radiation Therapy.” International Journal of Radiation Oncology, Biology, Physics 115 (2): 426–39. [DOI] [PubMed] [Google Scholar]
  10. Billena Cole, and Khan Atif J.. 2019. “A Current Review of Spatial Fractionation: Back to the Future?” International Journal of Radiation Oncology, Biology, Physics 104 (1): 177–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Boustani Jihane, Grapin Mathieu, Laurent Pierre-Antoine, Apetoh Lionel, and Mirjolet Céline. 2019. “The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response.” Cancers 11 (6). 10.3390/cancers11060860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Buchwald Zachary S., Nasti Tahseen H., Lee Judong, Eberhardt Christiane S., Wieland Andres, Im Se Jin, Lawson David, Curran Walter, Ahmed Rafi, and Khan Mohammad K.. 2020. “Tumor-Draining Lymph Node Is Important for a Robust Abscopal Effect Stimulated by Radiotherapy.” Journal for Immunotherapy of Cancer 8 (2). 10.1136/jitc-2020-000867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bui TM, Wiesolek HL, Sumagin R. ICAM-1: A master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis. J Leukoc Biol [Internet]. 2020. Sep;108(3):787–799. Available from: 10.1002/JLB.2MR0220-549R [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chadha Awalpreet S., Liu Guan, Chen Hsiang-Chun, Das Prajnan, Minsky Bruce D., Mahmood Usama, Delclos Marc E., et al. 2017. “Does Unintentional Splenic Radiation Predict Outcomes After Pancreatic Cancer Radiation Therapy?” International Journal of Radiation Oncology, Biology, Physics 97 (2): 323–32. [DOI] [PubMed] [Google Scholar]
  15. Chang Joe Y., Lin Steven H., Dong Wenli, Liao Zhongxing, Gandhi Saumil J., Gay Carl M., Zhang Jianjun, et al. 2023. “Stereotactic Ablative Radiotherapy with or without Immunotherapy for Early-Stage or Isolated Lung Parenchymal Recurrent Node-Negative Non-Small-Cell Lung Cancer: An Open-Label, Randomised, Phase 2 Trial.” Lancet 402 (10405): 871–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chen Z, Wu Z, Muluh TA, Fu S, Wu J. Effect of low-dose total-body radiotherapy on immune microenvironment. Transl Oncol [Internet]. 2021. Aug 1;14(8):101118. Available from: https://www.sciencedirect.com/science/article/pii/S1936523321001108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chen Eric X., Loree Jonathan M., Titmuss Emma, Jonker Derek J., Kennecke Hagen F., Berry Scott, Couture Felix, et al. 2023. “Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial.” JAMA Network Open 6 (12): e2346094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Cho Young-Bin, Yoon Nara, Suh John H., and Scott Jacob G.. 2023. “Radio-Immune Response Modelling for Spatially Fractionated Radiotherapy.” Physics in Medicine and Biology 68 (16). 10.1088/1361-6560/ace819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Cohen Romain, Raeisi Morteza, Shi Qian, Chibaudel Benoist, Yoshino Takayuki, Zalcberg John Raymond, Adams Richard, et al. 2023. “Prognostic Value of Liver Metastases in Colorectal Cancer Treated by Systemic Therapy: An ARCAD Pooled Analysis.” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 41 (16_suppl): 3554–3554. [Google Scholar]
  20. Cunningham Shannon, McCauley Shelby, Vairamani Kanimozhi, Speth Joseph, Girdhani Swati, Abel Eric, Sharma Ricky A., et al. 2021. “FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice.” Cancers 13 (5). 10.3390/cancers13051012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Darragh Laurel B., Knitz Michael M., Hu Junxiao, Clambey Eric T., Backus Jennifer, Dumit Andrew, Samedi Von, et al. 2022. “A Phase I/Ib Trial and Biological Correlate Analysis of Neoadjuvant SBRT with Single-Dose Durvalumab in HPV-Unrelated Locally Advanced HNSCC.” Nature Cancer 3 (11): 1300–1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Davuluri Rajayogesh, Jiang Wen, Fang Penny, Xu Cai, Komaki Ritsuko, Gomez Daniel R., Welsh James, et al. 2017. “Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy.” International Journal of Radiation Oncology, Biology, Physics 99 (1): 128–35. [DOI] [PubMed] [Google Scholar]
  23. Duriseti Sai, Kavanaugh James A., Szymanski Jeff, Huang Yi, Basarabescu Franco, Chaudhuri Aadel, Henke Lauren, et al. 2022. “LITE SABR M1: A Phase I Trial of Lattice Stereotactic Body Radiotherapy for Large Tumors.” Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 167 (February): 317–22. [DOI] [PubMed] [Google Scholar]
  24. Ferini Gianluca, Parisi Silvana, Lillo Sara, Viola Anna, Minutoli Fabio, Critelli Paola, Valenti Vito, et al. 2022. “Impressive Results after ‘Metabolism-Guided’ Lattice Irradiation in Patients Submitted to Palliative Radiation Therapy: Preliminary Results of LATTICE_01 Multicenter Study.” Cancers 14 (16). 10.3390/cancers14163909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fernandez-Palomo Cristian, Fazzari Jennifer, Trappetti Verdiana, Smyth Lloyd, Janka Heidrun, Laissue Jean, and Djonov Valentin. 2020. “Animal Models in Microbeam Radiation Therapy: A Scoping Review.” Cancers 12 (3). 10.3390/cancers12030527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Formenti Silvia C., Rudqvist Nils-Petter, Golden Encouse, Cooper Benjamin, Wennerberg Erik, Lhuillier Claire, Vanpouille-Box Claire, et al. 2018. “Radiotherapy Induces Responses of Lung Cancer to CTLA-4 Blockade.” Nature Medicine 24 (12): 1845–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Galluzzi L, Aryankalayil MJ, Coleman CN, Formenti SC. Emerging evidence for adapting radiotherapy to immunotherapy. Nat Rev Clin Oncol [Internet]. nature.com; 2023. Aug;20(8):543–557. Available from: 10.1038/s41571-023-00782-x [DOI] [PubMed] [Google Scholar]
  28. Herrera Fernanda G., Ronet Catherine, de Olza Maria Ochoa, Barras David, Crespo Isaac, Andreatta Massimo, Corria-Osorio Jesus, et al. 2022. “Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.” Cancer Discovery 12 (1): 108–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Heylmann Daniel, Ponath Viviane, Kindler Thomas, and Kaina Bernd. 2021. “Comparison of DNA Repair and Radiosensitivity of Different Blood Cell Populations.” Scientific Reports 11 (1): 2478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Huang Qizhao, Wu Xia, Wang Zhiming, Chen Xiangyu, Wang Lisha, Lu Yijun, Xiong Dan, et al. 2022. “The Primordial Differentiation of Tumor-Specific Memory CD8 T Cells as Bona Fide Responders to PD-1/PD-L1 Blockade in Draining Lymph Nodes.” Cell 185 (22): 4049–66.e25. [DOI] [PubMed] [Google Scholar]
  31. Jing Wang, Xu Ting, Wu Lirong, Lopez Pablo B., Grassberger Clemens, Ellsworth Susannah G., Mohan Radhe, et al. 2022. “Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab after Concurrent Chemoradiotherapy for NSCLC.” JTO Clinical and Research Reports 3 (9): 100391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Johnson Timothy R., Bassil Alex M., Williams Nerissa T., Brundage Simon, Kent Collin L., Palmer Greg, Mowery Yvonne M., and Oldham Mark. 2022. “An Investigation of kV Mini-GRID Spatially Fractionated Radiation Therapy: Dosimetry and Preclinical Trial.” Physics in Medicine and Biology 67 (4). 10.1088/1361-6560/ac508c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kanagavelu Saravana, Gupta Seema, Wu Xiaodong, Philip Sakhi, Wattenberg Max M., Hodge James W., Couto Mariluz D., Chung Kristina D., and Ahmed Mansoor M.. 2014. “In Vivo Effects of Lattice Radiation Therapy on Local and Distant Lung Cancer: Potential Role of Immunomodulation.” Radiation Research 182 (2): 149–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kavanaugh James A., Spraker Matthew B., Duriseti Sai, Basarabescu Franco, Price Alex, Goddu Murty, Knutson Nels, Prusator Michael, Robinson Clifford, and Mazur Thomas. 2022. “LITE SABR M1: Planning Design and Dosimetric Endpoints for a Phase I Trial of Lattice SBRT.” Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 167 (February): 172–78. [DOI] [PubMed] [Google Scholar]
  35. Kelly Ronan J., Ajani Jaffer A., Kuzdzal Jaroslaw, Zander Thomas, Van Cutsem Eric, Piessen Guillaume, Mendez Guillermo, et al. 2021. “Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.” The New England Journal of Medicine 384 (13): 1191–1203. [DOI] [PubMed] [Google Scholar]
  36. Kim Young-Eun, Gwak Seung-Hee, Hong Beom-Ju, Oh Jung-Min, Choi Hyung-Seok, Kim Myeoung Su, Oh Dawit, et al. 2021. “Effects of Ultra-High Doserate FLASH Irradiation on the Tumor Microenvironment in Lewis Lung Carcinoma: Role of Myosin Light Chain.” International Journal of Radiation Oncology, Biology, Physics 109 (5): 1440–53. [DOI] [PubMed] [Google Scholar]
  37. Korpics Mark C., Onderdonk Benjamin E., Dadey Rebekah E., Hara Jared H., Karapetyan Lilit, Zha Yuanyuan, Karrison Theodore G., et al. 2023. “Partial Tumor Irradiation plus Pembrolizumab in Treating Large Advanced Solid Tumor Metastases.” The Journal of Clinical Investigation 133 (10). 10.1172/JCI162260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kundapur V, Mayer M, Auer RN, Alexander A, Weibe S, Pushie MJ, and Cranmer-Sargison G. 2022. “Is Mini Beam Ready for Human Trials? Results of Randomized Study of Treating De-Novo Brain Tumors in Canines Using Linear Accelerator Generated Mini Beams.” Radiation Research 198 (2): 162–71. [DOI] [PubMed] [Google Scholar]
  39. Lamirault Charlotte, Valérie Doyère, Juchaux Marjorie, Pouzoulet Frederic, Labiod Dalila, Dendale Remi, Patriarca Annalisa, et al. 2020. “Short and Long-Term Evaluation of the Impact of Proton Minibeam Radiation Therapy on Motor, Emotional and Cognitive Functions.” Scientific Reports 10 (1): 13511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. “LBA5 Primary Results of the Phase III KEYNOTE-412 Study: Pembrolizumab (pembro) with Chemoradiation Therapy (CRT) vs Placebo plus CRT for Locally Advanced (LA) Head and Neck Squamous Cell Carcinoma (HNSCC).” 2022. Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO 33 (September): S1399. [Google Scholar]
  41. Lee Nancy Y., Ferris Robert L., Psyrri Amanda, Haddad Robert I., Tahara Makoto, Bourhis Jean, Harrington Kevin, et al. 2021. “Avelumab plus Standard-of-Care Chemoradiotherapy versus Chemoradiotherapy Alone in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3 Trial.” The Lancet Oncology 22 (4): 450–62. [DOI] [PubMed] [Google Scholar]
  42. Li F, Tian Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol [Internet]. 2013. Jul;10(4):292–302. Available from: 10.1038/cmi.2013.7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lin Alexander J., Gang Margery, Rao Yuan James, Campian Jian, Daly Mackenzie, Gay Hiram, Oppelt Peter, et al. 2019. “Association of Posttreatment Lymphopenia and Elevated Neutrophil-to-Lymphocyte Ratio With Poor Clinical Outcomes in Patients With Human Papillomavirus-Negative Oropharyngeal Cancers.” JAMA Otolaryngology-- Head & Neck Surgery 145 (5): 413–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Lukas Lauren, Zhang Hualin, Cheng Karen, and Epstein Alan. 2023. “Immune Priming with Spatially Fractionated Radiation Therapy.” Current Oncology Reports, November. 10.1007/s11912-023-01473-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Luke Jason J., Lemons Jeffrey M., Karrison Theodore G., Pitroda Sean P., Melotek James M., Zha Yuanyuan, Al-Hallaq Hania A., et al. 2018. “Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients with Advanced Solid Tumors.” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 36 (16): 1611–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Luke Jason J., Onderdonk Benjamin E., Bhave Sandeep R., Karrison Theodore, Lemons Jeffrey M., Chang Paul, Zha Yuanyuan, et al. 2020. “Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 26 (24): 6437–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Manchado de Sola Francisco, Vilches Manuel, Prezado Yolanda, and Lallena Antonio M.. 2018. “Impact of Cardiosynchronous Brain Pulsations on Monte Carlo Calculated Doses for Synchrotron Micro- and Minibeam Radiation Therapy.” Medical Physics 45 (7): 3379–90. [DOI] [PubMed] [Google Scholar]
  48. Markovsky Ela, Budhu Sadna, Samstein Robert M., Li Hongyan, Russell James, Zhang Zhigang, Drill Esther, et al. 2019. “An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models.” International Journal of Radiation Oncology, Biology, Physics 103 (3): 697–708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, Bentzen SM, Nam J, Deasy JO. Use of normal tissue complication probability models in the clinic. International Journal of Radiation Oncology* Biology* Physics. 2010. Mar 1;76(3):S10–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Mathieu Mickael, Budhu Sadna, Nepali Prerna R., Russell James, Powell Simon N., Humm John, Deasy Joseph O., and Haimovitz-Friedman Adriana. 2023. “Activation of STING in Response to Partial-Tumor Radiation Exposure.” International Journal of Radiation Oncology, Biology, Physics 117 (4): 955–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Monjazeb Arta M., Daly Megan E., Luxardi Guillaume, Maverakis Emanual, Merleev Alexander A., Marusina Alina I., Borowsky Alexander, et al. 2023. “Atezolizumab plus Stereotactic Ablative Radiotherapy for Medically Inoperable Patients with Early-Stage Non-Small Cell Lung Cancer: A Multi-Institutional Phase I Trial.” Nature Communications 14 (1): 5332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Monjazeb Arta M., Giobbie-Hurder Anita, Lako Ana, Thrash Emily M., Brennick Ryan C., Kao Katrina Z., Manuszak Claire, et al. 2021. “A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 27 (9): 2470–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Monk Bradley J., Toita Takafumi, Wu Xiaohua, Limón Juan C. Vázquez, Tarnawski Rafal, Mandai Masaki, Shapira-Frommer Ronnie, et al. 2023. “Durvalumab versus Placebo with Chemoradiotherapy for Locally Advanced Cervical Cancer (CALLA): A Randomised, Double-Blind, Phase 3 Trial.” The Lancet Oncology 24 (12): 1334–48. [DOI] [PubMed] [Google Scholar]
  54. “New Kid on the Block- Mini Beam Radiation Treatment- Final Report of a Randomized Phase III Study of Treating Canine Denovo Brain Tumors.” 2019. International Journal of Radiation Oncology*Biology*Physics 105 (3): 683–84. [Google Scholar]
  55. Palma David A., Olson Robert, Harrow Stephen, Gaede Stewart, Louie Alexander V., Haasbeek Cornelis, Mulroy Liam, et al. 2020. “Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial.” Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 38 (25): 2830–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Patel Roshal R., He Kewen, Barsoumian Hampartsoum B., Chang Joe Y., Tang Chad, Verma Vivek, Comeaux Nathan, et al. 2021. “High-Dose Irradiation in Combination with Non-Ablative Low-Dose Radiation to Treat Metastatic Disease after Progression on Immunotherapy: Results of a Phase II Trial.” Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 162 (September): 60–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Pawlik Timothy M., and Keyomarsi Khandan. 2004. “Role of Cell Cycle in Mediating Sensitivity to Radiotherapy.” International Journal of Radiation Oncology, Biology, Physics 59 (4): 928–42. [DOI] [PubMed] [Google Scholar]
  58. Phillips Ryan, Shi William Yue, Deek Matthew, Radwan Noura, Lim Su Jin, Antonarakis Emmanuel S., Rowe Steven P., et al. 2020. “Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial.” JAMA Oncology 6 (5): 650–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Pinschewer DD, Ochsenbein AF, Odermatt B, Brinkmann V, Hengartner H, and Zinkernagel RM. 2000. “FTY720 Immunosuppression Impairs Effector T Cell Peripheral Homing without Affecting Induction, Expansion, and Memory.” Journal of Immunology 164 (11): 5761–70. [DOI] [PubMed] [Google Scholar]
  60. Prezado Yolanda. 2022. “Divide and Conquer: Spatially Fractionated Radiation Therapy.” Expert Reviews in Molecular Medicine 24 (January): e3. [Google Scholar]
  61. Prezado Yolanda, Jouvion Gregory, Patriarca Annalisa, Nauraye Catherine, Guardiola Consuelo, Juchaux Marjorie, Lamirault Charlotte, et al. 2018. “Proton Minibeam Radiation Therapy Widens the Therapeutic Index for High-Grade Gliomas.” Scientific Reports 8 (1): 16479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Prokhnevska Nataliya, Cardenas Maria A., Valanparambil Rajesh M., Sobierajska Ewelina, Barwick Benjamin G., Jansen Caroline, Moon Adriana Reyes, et al. 2023. “CD8 T Cell Activation in Cancer Comprises an Initial Activation Phase in Lymph Nodes Followed by Effector Differentiation within the Tumor.” Immunity 56 (1): 107–24.e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Rodríguez-Barbeito Pedro, Díaz-Botana Pablo, Gago-Arias Araceli, Feijoo Manuel, Neira Sara, Guiu-Souto Jacobo, López-Pouso Óscar, Gómez-Caamaño Antonio, and Pardo-Montero Juan. 2019. “A Model of Indirect Cell Death Caused by Tumor Vascular Damage after High-Dose Radiotherapy.” Cancer Research 79 (23): 6044–53. [DOI] [PubMed] [Google Scholar]
  64. Rogers Linda Joanne, Harley Juliette Cornelia, McKenzie David Robert, and Suchowerska Natalka. 2022. “Radiation Responses of Cancer and Normal Cells to Split Dose Fractions with Uniform and Grid Fields: Increasing the Therapeutic Ratio.” International Journal of Radiation Biology 98 (9): 1424–31. [DOI] [PubMed] [Google Scholar]
  65. Schoenfeld Jonathan D., Giobbie-Hurder Anita, Ranasinghe Srinika, Kao Katrina Z., Lako Ana, Tsuji Junko, Liu Yang, et al. 2022. “Durvalumab plus Tremelimumab Alone or in Combination with Low-Dose or Hypofractionated Radiotherapy in Metastatic Non-Small-Cell Lung Cancer Refractory to Previous PD(L)-1 Therapy: An Open-Label, Multicentre, Randomised, Phase 2 Trial.” The Lancet Oncology 23 (2): 279–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Sen Santara S, Lee DJ, Crespo Â, Hu JJ, Walker C, Ma X, Zhang Y, Chowdhury S, Meza-Sosa KF, Lewandrowski M, Zhang H, Rowe M, McClelland A, Wu H, Junqueira C, Lieberman J. The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells. Nature [Internet]. 2023. Apr;616(7956):348–356. Available from: 10.1038/s41586-023-05912-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Shukla Samriddhi, Saha Taniya, Rama Nihar, Acharya Anusha, Le Tien, Bian Fenghua, Donovan Johnny, et al. 2023. “Ultra-High Dose-Rate Proton FLASH Improves Tumor Control.” Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 186 (109741): 109741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. “Spatially Fractionated Radiation Therapy in the Modern Era: The Mayo Clinic Experience.” 2022. International Journal of Radiation Oncology*Biology*Physics 114 (3): S86. [Google Scholar]
  69. Spurr Liam F., Martinez Carlos A., Kang Wenjun, Chen Mengjie, Zha Yuanyuan, Hseu Robyn, Gutiontov Stanley I., et al. 2022. “Highly Aneuploid Non-Small Cell Lung Cancer Shows Enhanced Responsiveness to Concurrent Radiation and Immune Checkpoint Blockade.” Nature Cancer 3 (12): 1498–1512. [DOI] [PubMed] [Google Scholar]
  70. Steel GG, McMillan TJ, and Peacock JH. 1989. “The 5Rs of Radiobiology.” International Journal of Radiation Biology 56 (6): 1045–48. [DOI] [PubMed] [Google Scholar]
  71. Tang Chad, Welsh James W., de Groot Patricia, Massarelli Erminia, Chang Joe Y., Hess Kenneth R., Basu Sreyashi, et al. 2017. “Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells.” Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 23 (6): 1388–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Tao Y, Biau J, Sun XS, Sire C, Martin L, Alfonsi M, Prevost JB, et al. 2023. “Pembrolizumab versus Cetuximab Concurrent with Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck Unfit for Cisplatin (GORTEC 2015-01 PembroRad): A Multicenter, Randomized, Phase II Trial.” Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO 34 (1): 101–10. [DOI] [PubMed] [Google Scholar]
  73. Torok Jordan A., Oh Patrick, Castle Katherine D., Reinsvold Michael, Ma Yan, Luo Lixia, Lee Chang-Lung, and Kirsch David G.. 2019. “Deletion of in Tumor but Not Endothelial Cells Improves Radiation Response in a Primary Mouse Model of Lung Adenocarcinoma.” Cancer Research 79 (4): 773–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Tubin Slavisa, Fossati Piero, Carlino Antonio, Martino Giovanna, Gora Joanna, Stock Markus, and Hug Eugen. 2022. “Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety.” Cancers 14 (9). 10.3390/cancers14092232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Tubin Slavisa, Gupta Seema, Grusch Michael, Popper Helmuth H., Brcic Luka, Ashdown Martin L., Khleif Samir N., et al. 2020. “Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY).” Cancers 13 (1). 10.3390/cancers13010050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Tubin Slavisa, Popper Helmut H., and Brcic Luka. 2019. “Novel Stereotactic Body Radiation Therapy (SBRT)-Based Partial Tumor Irradiation Targeting Hypoxic Segment of Bulky Tumors (SBRT-PATHY): Improvement of the Radiotherapy Outcome by Exploiting the Bystander and Abscopal Effects.” Radiation Oncology 14 (1): 21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Tumeh Paul C., Hellmann Matthew D., Hamid Omid, Tsai Katy K., Loo Kimberly L., Gubens Matthew A., Rosenblum Michael, et al. 2017. “Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC.” Cancer Immunology Research 5 (5): 417–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Wei Joyce, Montalvo-Ortiz Welby, Yu Lola, Krasco Amanda, Ebstein Sarah, Cortez Czrina, Lowy Israel, Murphy Andrew J., Sleeman Matthew A., and Skokos Dimitris. 2021. “Sequence of αPD-1 Relative to Local Tumor Irradiation Determines the Induction of Abscopal Antitumor Immune Responses.” Science Immunology 6 (58). 10.1126/sciimmunol.abg0117. [DOI] [PubMed] [Google Scholar]
  79. Welsh James W., Tang Chad, de Groot Patricia, Naing Aung, Hess Kenneth R., Heymach John V., Papadimitrakopoulou Vassiliki A., et al. 2019. “Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.” Cancer Immunology Research 7 (12): 1903–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Withers H. Rodney. 1975. “The Four R’s of Radiotherapy.” In Advances in Radiation Biology, edited by Lett John T. and Adler Howard, 5:241–71. Elsevier. [Google Scholar]
  81. Yang Yuqing, Swierczak Agnieszka, Ibahim Mohammad, Paiva Premila, Cann Leonie, Stevenson Andrew W., Crosbie Jeffrey C., Anderson Robin L., and Rogers Peter A. W.. 2019. “Synchrotron Microbeam Radiotherapy Evokes a Different Early Tumor Immunomodulatory Response to Conventional Radiotherapy in EMT6.5 Mammary Tumors.” Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 133 (April): 93–99. [DOI] [PubMed] [Google Scholar]
  82. Yu Jiali, Green Michael D., Li Shasha, Sun Yilun, Journey Sara N., Choi Jae Eun, Rizvi Syed Monem, et al. 2021. “Liver Metastasis Restrains Immunotherapy Efficacy via Macrophage-Mediated T Cell Elimination.” Nature Medicine 27 (1): 152–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Zhao Yang, Zhang Ting, Wang Yanpu, Lu Dehua, Du Jinhong, Feng Xun, Zhou Haoyi, et al. 2021. “ICAM-1 Orchestrates the Abscopal Effect of Tumor Radiotherapy.” Proceedings of the National Academy of Sciences of the United States of America 118 (14). 10.1073/pnas.2010333118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Zhou Qing, Chen Ming, Jiang Ou, Pan Yi, Hu Desheng, Lin Qin, Wu Gang, et al. 2022. “Sugemalimab versus Placebo after Concurrent or Sequential Chemoradiotherapy in Patients with Locally Advanced, Unresectable, Stage III Non-Small-Cell Lung Cancer in China (GEMSTONE-301): Interim Results of a Randomised, Double-Blind, Multicentre, Phase 3 Trial.” The Lancet Oncology 23 (2): 209–19. [DOI] [PubMed] [Google Scholar]

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