Variable collimation for intraoperative minibeam radiation therapy

Abstract

A collimator for minibeam radiation therapy includes a collimator body having a central region and a peripheral region surrounding the central region. A plurality of slits is formed in the central region of the collimator body, with each slit being sized such that a radiation beam impinging on a first surface of the collimator body is collimated into a plurality of radiation minibeams that exit a second surface of the collimator body in a nonuniform dose distribution.

Description

Mayo 2024-364630666.01665VARIABLE COLLIMATION FOR INTRAOPERATIVE MINIBEAM RADIATION THERAPY CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 748,029, filed on January' 22, 2025, and entitled “VARIABLE COLLIMATION FOR INTRAOPERATIVE MINIBEAM RADIATION THERAPY ’ which is herein incorporated by reference in its entirety.BACKGROUND

[0002] Radiation therapy is effective against cancer, but the amount of radiation that can safely be given is limited by the radiation tolerance of surrounding healthy tissues. For many cancers, delivering a high radiation dose would be beneficial, but tumors are often surrounded by critical healthy organs and blood vessels. Administering a high dose of radiation might eradicate the tumor but also cause irreversible harm to healthy tissue, ultimately harming the patient.

[0003] In minibeam radiation therapy (MBRT), a collimator with narrow apertures is attached to the surface of a patient and a radiation beam is delivered onto the collimator to generate a nonuniform dose distribution defined by an alternating pattern of high “peak” x-ray doses immediately adjacent to low dose “valley” regions. Unlike conventional radiation therapy, which uniformly exposes the entire tumor, MBRT uses an array of sub-millimeter wide planar beams of radiation to intentionally deliver a nonuniform dose resulting in several beneficial effects.

[0004] For MBRT to deliver submillimeter wide peak and valley doses, low energy (e.g., kV) x-ray sources are used. Because of the low energy, the radiation does not penetrate deep enough to reach internal organs, such as the pancreas or other deep targets. Additionally, physiological motion and breathing can blur the peaks and valleys of the MBRT treatments.SUMMARY OF THE DISCLOSURE

[0005] It is an aspect of the present disclosure to provide a collimator for minibeam radiation therapy. The collimator includes a collimator body having a thickness extending from a first surface to a second surface. The collimator body includes a central region and a peripheral region surrounding the central region. The first surface of the collimator body is 1QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665substantially flat and the second surface is shaped to conform to an internal anatomy of a patient. A plurality of slits are formed in the central region of the collimator body. The plurality of slits are sized such that a radiation beam impinging on the first surface of the collimator body is collimated into a plurality of radiation minibeams that exit the second surface of the collimator body in a nonuniform dose distribution.

[0006] It is another aspect of the present disclosure to provide a method for intraoperative minibeam radiation therapy. The method includes delivering a first fraction of minibeam radiation to a patient while a variable collimator is coupled to a surface of an internal anatomy of the patient. The first fraction is delivered by impinging a radiation beam on the variable collimator to collimate the radiation beam into a first plurality of radiation minibeams. The variable collimator is in a first configuration during the first fraction. The variable collimator is then adjusted into a second configuration and a second fraction of minibeam radiation is delivered to the patient while the variable collimator is coupled to the surface of the internal anatomy of the patient. The second fraction is delivered by impinging the radiation beam on the variable collimator to collimate the radiation beam into a second plurality of radiation minibeams.

[0007] It is yet another aspect of the present disclosure to provide a method for intraoperative minibeam radiation therapy, in which a fraction of minibeam radiation is delivered to a patient while a variable collimator is coupled to a surface of an internal anatomy of the patient. The fraction of mimbeam radiation is delivered to the patient by impinging a radiation beam on the variable collimator to collimate the radiation beam into a plurality of radiation minibeamsBRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIGS. 1A and IB illustrate a schematic representation of minibeam radiation therapy (MBRT). As shown in FIG. 1 A, in MBRT, a collimator with narrow slits separates the beam into sub-millimeter wide planar beams. As shown in FIG. IB, the result is a nonuniform radiation dose distribution consisting of high dose "peaks" and low dose ’‘valleys”. Because the target is not uniformly irradiated, extremely high doses of radiation can safely be delivered in the “peak” regions allowing for dose escalation far above what can be delivered with conventional radiation treatments.

[0009] FIG. 2 illustrates a schematic representation of intraoperative MBRT (IOMBRT). In IOMBRT, a radiation producing device (shown in orange) is brought close to a 2QB\630666.01665400377480.1Mayo 2024-364630666.01665minibeam collimator with narrow slits (shown in grey) which is secured to a surgical target (shown in green). The minibeam collimator is separate from the radiation device, and attaches directly to the patient inside the surgical cavity. The radiation from the radiation device is then spatially separated into individual narrow minibeams (shown in red) which treat the target. Because the radiation device can be brought very close to the target, the lower energy x-rays needed for IOMBRT are not a limitation as they are in traditional MBRT.

[0010] FIGS. 3A-3C illustrate schematic drawings of circular (FIG. 3A) and rectangular (FIGS. 3B and 3C) minibeam collimators. While a rectangular and circular shape are shown, in principle any shape could be fabricated. The circles at the periphery' of each collimator represent indentations or protrusions that can accommodate additional solid blocking pieces of various shapes to spare healthy tissues.

[0011] FIGS. 4A-4E illustrate side views of example variable collimators in accordance with some examples described in the present disclosure.

[0012] FIGS. 5A-5F shows schematics of interlocking solid blocking element shapes for variable blocking of the minibeam collimator. The solid pieces can be of arbitrary shape and can interlock onto the collimators in well-defined positions with protrusions and indentations to selectively block radiation from regions of healthy tissue while the open slits allow for minibeams of radiation to pass through. FIGS. 5E and 5F illustrate collimator bodies with non-divergent (FIG. 5E) and divergent (FIG. 5F) slits.

[0013] FIG. 6 is a flowchart of an example method for delivering IOMBRT using the variable collimators described in the present disclosure.

[0014] FIG. 7 is a computer rendering showing the shape of a typical pancreas (in green) and the duodenum (in yellow) which is the primary' ‘‘organ at risk"’ (OAR) which limits the amount of radiation that can safely be delivered to the pancreas tumor. The goal of intraoperative minibeam radiation therapy (IOMBRT) would be to irradiate the region indicated by the dashed circle, but spare the duodenum within this region by blocking the radiation. Knowing that anatomy changes from patient to patient, the ability to adapt the location and shape of the irradiated and blocked regions to the specific anatomy of the patient is important.

[0015] FIGS. 8 A and 8B illustrate a schematic demonstration of variable collimator blocking with IOMBRT using a circular tungsten collimator and solid oval tungsten piece to selectively block portions of the duodenum. In FIG. 8A, the intended treatment target is shown outlined with a red dashed line, but the adjacent duodenum above this region should be blocked3QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665from radiation. As shown in FIG. 8B, a circular minibeam collimator can be used with an additional solid oval tungsten piece which blocks the duodenum.

[0016] FIGS. 9 A and 9B illustrate a schematic demonstration of variable collimator blocking with IOMBRT using a rectangular tungsten collimator and solid triangular tungsten piece to selectively block portions of the duodenum. In FIG. 9A, the intended treatment target is shown outlined with a red dashed line, but the adjacent duodenum below this region should be blocked from radiation. As shown in FIG. 9B, a rectangular minibeam collimator can be used with an additional solid triangular tungsten piece which blocks the duodenum in the lower comer.DETAILED DESCRIPTION

[0017] Described here are variable collimators for use with minibeam radiation therapy (MBRT). The variable collimators described in the present disclosure are in particular advantageous for use with intraoperative MBRT (IOMBRT). As one advantage, the variable collimators include interlocking blocking pieces, or elements, that allow for configurable dose distribution shaping during or between fractions of radiation delivery. Additionally, unlike traditional collimators, the variable collimators are designed to be placed into contact with the internal anatomy of a patient (e.g., an internal organ, an internal cavity, etc.) who is undergoing intraoperative radiation therapy.

[0018] In MBRT, a collimator is attached to the surface of a patient, whereas IOMBRT uses a collimator that is attached to the internal organ itself in an intraoperative setting. For MBRT, the radiation often does not penetrate deep enough to reach internal organs, such as the pancreas. Additionally, breathing and physiological motion can blur the peaks and valleys of the MBRT treatments. The variable collimators described in the present disclosure overcome these drawbacks and enable IOMBRT by allow ing for attachment of a collimator directly to the intended target.

[0019] In MBRT, radiation beam is impinged upon a suitable collimator to generate a nonuniform dose distribution defined by an alternating pattern of high “peak” x-ray doses immediately adjacent to low dose “valley” regions, as illustrated in FIGS. 1A and IB. Unlike conventional radiation therapy, which uniformly exposes the entire tumor, MBRT uses an array of sub-millimeter wide planar beams of radiation to intentionally deliver a nonuniform dose resulting in several beneficial effects. Despite only partially irradiating small tumor regions with high doses, extensive animal studies have demonstrated the efficacy of this treatment. A 4QB\630666.01665\100377480.1Mayo 2024-364630666.01665distinct advantage of IOMBRT over current methods is that it allows for the application of MBRT during a surgical procedure, which increases the types and locations of cancers that can be treated with MBRT. Additionally, because the target and healthy tissues are not irradiated uniformly, IOMBRT is expected to be safer and better tolerated than conventional radiation therapy while also allowing for the delivery of a higher dose of radiation.

[0020] Because minibeam radiation employs very narrow beams spaced closely together, the energy of the x-rays used is in the kilovoltage (kV) range. Using higher energy x-rays would eliminate the distinct peak and valley regions due to x-ray scatter. The lower energy x-rays used for minibeam radiation are somewhat of a limitation for traditional MBRT applications, however. For example, these kV x-rays cannot penetrate deeply into tissue, making it challenging to treat through 10—15 cm of abdominal tissue before reaching the pancreas. This problem can be overcome using the systems and methods described in the present disclosure to enable IOMBRT. Minibeam radiation is particularly well-suited for surgical applications where the x-ray source can be positioned directly near or in contact with the target through a surgical cavity. In this context, lower energy x-rays offer an advantage because they deposit the radiation dose directly to the tumor without penetrating deeply beyond the target, as illustrated in FIG. 2. This results in reduced radiation exposure to healthy tissues.

[0021] It will be appreciated that while pancreatic applications are described herein, the systems and methods described in the present disclosure are applicable to a wide variety’ of clinical applications and anatomical sites beyond the pancreas, including other sites in the abdomen, pelvis, rectum, brain, and so forth.

[0022] With reference now to FIGS. 3A-3C, 4A-4E, and 5A-5D, a variable collimator 10 in accordance with some examples includes a collimator body 12 having formed therein a plurality of slits 14. The collimator body 12 extends from a first surface 16 to a second surface 18, thereby defining a thickness 20 of the collimator body 12. In general, the first surface 16 may be a beam-facing surface on which a radiation beam impinges during radiation therapy and the second surface 18 may be a patient-facing surface that is placed into contact with the patient during radiation therapy. In some examples, the thickness 20 is a uniform thickness across the entire collimator body 12. Alternatively, the thickness 20 of the collimator body 12 may be variable. For instance, the thickness 20 may be larger in some portions of the collimator body 12 than others.

[0023] The thickness 20 of the collimator body 12 may be selected from the range of 2.0 mm to 3.0 mm, such as 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.75QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665mm, 2.8 mm, 2.9 mm, or 3.0 mm. Depending on the radiation source and energy used, the thickness 20 of the collimator body 12 may also be selected from the range of 0.5 mm to 2.0 mm, such as 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, or 2.0 mm. Additionally or alternatively, the thickness 20 of the collimator body 12 can be selected between these values, or from a different range of values suitable for shielding radiation. As one non-limiting example, the thickness 20 of the collimator body 12 can be 2.5 mm.

[0024] In some examples, the first surface 16 can be substantially flat whereas the second surface 18 can be contoured or otherwise shaped to conform to the internal anatomy (e.g., an internal organ, an internal canty, or other internal surface) of a patient. When the second surface 18 of the collimator body 12 is contoured or otherwise shaped to conform to the internal anatomy of the patient, the collimator body 12 can be placed into better contact with the patient’s anatomy during radiation therapy, which can improve the accuracy of the dose delivery. The second surface 18 may be contoured or otherwise shaped to have a convex, concave, or arbitrary profile that improves surface contact between the second surface 18 of the collimator body 12 and the internal anatomy of a patient, as illustrated in FIG. 2.

[0025] In some examples, the second surface 18 of the collimator body 12 may be shaped based on the internal anatomy of a particular patient. In other examples, both the first surface 16 and the second surface 18 can be substantially flat and parallel with each other, as illustrated in FIG. 4A. In these instances, the thickness 20 of the collimator body 12 will be uniform. Alternatively, one or both of the first surface 16 and the second surface 18 may be an angled plane that is angled relative to the other, as illustrated in FIGS. 4B. In these instances, the thickness 20 of the collimator body 12 will be nonuniform. The first surface 16 and / or the second surface 18 may be angled about one axis of rotation or multiple different axes of rotation. Additionally or alternatively, the first surface 16 and / or the second surface 18 can have a surface contour or profile that is not flat, such as a convex surface, a concave surface, or another arbitrarily shaped surface profile, as described above and as illustrated in FIGS. 4C-4E.

[0026] The collimator body 12 can have a circular cross-sectional shape, as illustrated in FIG. 3A; a rectangular cross-sectional shape, as illustrated in FIGS. 3B and 3C; or any other suitable cross-sectional shape, including elliptical, oval, polygonal (e.g., hexagonal, octagonal), or irregular / custom shapes designed for specific anatomical targets.6QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665

[0027] In general, the collimator body 12 has a central region 22 and a peripheral region 24. The slits 14 are formed in the central region 22 of the collimator body 12.

[0028] In some examples, a plurality of recesses 26 or indentations are formed in the peripheral region 24 of the collimator body 12. The recesses 26 may be uniformly spaced and / or distributed in the peripheral region 24. Alternatively, one or more of the recesses 26 may be nonuniformly spaced, distributed, or otherwise arranged in the peripheral region 24. For instance, as shown in FIGS. 3B and 3C, the recesses 26 on the long sides of the collimator body 12 are spaced apart with a first spacing, whereas the recesses 26 on the short sides of the collimator body 12 are spaced apart with a second spacing that is different from the first spacing.

[0029] The recesses 26 allow for one or more blocking elements 28 to be removably coupled to the collimator body 12, as illustrated in FIGS. 5A-5D. Each blocking element 28 has one or more protrusions 30 extending away from the bottom surface of the blocking element 28. The protrusions 30 are sized and shaped to be received by the recesses 26 in the peripheral region 24 of the collimator body 12, such that the blocking elements 28 may be removably coupled to the collimator body 12. The protrusions 30, and thus the recesses 26, may have any suitable size or shape that allows for removably coupling the blocking elements 28 to the collimator body 12.

[0030] In some examples, the protrusions 30 and corresponding recesses 26 may have a cylindrical shape, which provides a simple and reliable coupling mechanism that allows for rotational adjustment of the blocking elements 28 about the axis of each protrusion 30. In other examples, the protrusions 30 and corresponding recesses 26 may have a conical shape, which facilitates self-centering alignment during coupling and provides a secure friction fit between the blocking elements 28 and the collimator body 12. In yet other examples, the protrusions 30 and corresponding recesses 26 may have a dovetail shape, which provides a sliding engagement mechanism that securely retains the blocking elements 28 while allowing for precise lateral positioning along the dovetail axis. In still other examples, the protrusions 30 and corresponding recesses 26 may have a T-shaped cross-section, which provides a positive mechanical interlock that resists separation of the blocking elements 28 from the collimator body 12 in directions perpendicular to the insertion axis.

[0031] The blocking elements 28 may have a geometrical shape, as illustrated in FIGS.5B and 5C, or may alternatively have an arbitrary shape, as illustrated in FIG. 5D. In some examples, a blocking element 28 may have a shape that is custom designed for a patient based7QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665on a treatment plan for that patient. More generally, one or more geometrically shaped blocking elements 28 can be used to create arbitrary silhouettes for blocking radiation from impinging on the slits 14. Geometrical shapes for the blocking elements 28 may include squares, rectangles, or other quadrilaterals; triangles; circles, ellipses, semicircles; other polygonal shapes; conic sections or other geometrical shapes; and / or sectors, subsets, or other divisions of such shapes. Blocking elements 28 can be manufactured with the same thickness, or different blocking elements 28 may be manufactured with different thicknesses, such that different thickness blocking elements 28 can be swapped in and out as desired to achieve a planned dose distribution in the patient.

[0032] The blocking elements 28 may have a thickness selected from the range of 2.0 mm to 3.0 mm, such as 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, or 3.0 mm. Depending on the radiation source and energy used, the thickness of the blocking elements 28 may also be selected from the range of 0.5 mm to 2.0 mm, such as 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm. 1.7 mm, 1.8 mm, 1.9 mm, or 2.0 mm. Additionally or alternatively, the thickness of the blocking elements 28 can be selected between these values, or from a different range of values suitable for shielding radiation. As one non-limiting example, the blocking elements 28 can have a thickness of 2.5 mm. As noted above, the blocking elements 28 may have the same thickness as the collimator body 12, or may have a different thickness or thicknesses.

[0033] In some examples, the blocking elements 28 may be configured for partial attenuation rather than complete blocking of the radiation beam. For example, a blocking element 28 may include a mesh structure or may be perforated with a pattern of apertures that allows a controlled fraction of the radiation beam to pass through, thereby providing partial dose delivery to underlying tissue regions. Such mesh or perforated blocking elements 28 can be designed with varying aperture sizes, shapes, and densities to achieve different levels of attenuation. The apertures in mesh or perforated blocking elements 28 may be arranged in regular patterns, such as rectangular grids, hexagonal arrays, or radial patterns, or may be arranged in irregular or randomized patterns to achieve specific dose distribution characteristics. The aperture sizes may range from sub-millimeter dimensions to several millimeters, depending on the desired level of attenuation and the spatial resolution of the dose distribution. In other examples, the blocking elements 28 may have a graduated, wedge-shaped, or otherwise variable thickness profile to create dose gradients across the treatment area. For instance, a blocking element 28 may have a thickness that varies continuously from a first edge8QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665to a second edge, such that radiation passing through thinner portions of the blocking element 28 is attenuated less than radiation passing through thicker portions. Such variable thickness blocking elements 28 can be used to create smooth dose transitions at the boundaries between treated and spared tissue regions. The variable thickness profile may be linear, exponential, sigmoidal, or any other mathematical function selected to achieve a desired dose gradient profile.

[0034] In some other examples, the blocking elements 28 may be stackable, such that multiple blocking elements 28 can be stacked on top of one another to achieve cumulative attenuation effects or to create complex dose distribution profiles. Stackable blocking elements 28 may include complementary features, such as alignment pins, registration marks, or interlocking surfaces, that facilitate precise alignment and secure stacking of multiple blocking elements 28.

[0035] In some examples, multiple collimator bodies 12 may be stacked together to form a stacked collimator assembly. In a stacked collimator assembly, a first collimator body 12 having a first plurality of slits 14 is positioned adjacent to a second collimator body 12 having a second plurality of slits 14, such that the radiation beam passes through both collimator bodies 12 in sequence. The slits 14 in the first collimator body 12 may be oriented at an angle relative to the slits 14 in the second collimator body 12. For example, the slits 14 in the first collimator body 12 may be oriented perpendicular to the slits 14 in the second collimator body 12, such that the slits 14 are at a 90-degree angle relative to one another. Alternatively, the slits 14 in the first collimator body 12 may be oriented at any arbitrary angle relative to the slits 14 in the second collimator body 12, such as 30 degrees, 45 degrees, 60 degrees, or any other angle selected to achieve a desired dose distribution pattern. When the slits 14 in the stacked collimator bodies 12 are oriented at an angle to one another, the resulting radiation pattern comprises a grid or array of discrete radiation beamlets that pass through the intersection points of the overlapping slits 14, rather than the planar minibeams produced by a single collimator body 12. This grid pattern of radiation beamlets can provide enhanced tissue sparing effects compared to planar minibeams in certain applications.

[0036] In a stacked collimator assembly, each collimator body 12 may have a thickness that is less than the thickness required for a single collimator body 12 to provide adequate radiation shielding. For example, each collimator body 12 in a stacked collimator assembly may have a thickness that is approximately half of the total thickness needed for appropriate shielding, such that the combined thickness of the stacked collimator bodies 12 provides the9QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665desired level of radiation attenuation. As a non-limiting example, if a total collimator thickness of 2.5 mm is required for adequate shielding, each collimator body 12 in a two-collimator stack may have a thickness of approximately 1.25 mm. Alternatively, the collimator bodies 12 in a stacked assembly may have different thicknesses from one another, such that the combined thickness provides the desired shielding while allowing for different slit geometries or other characteristics in each collimator body 12. The stacked collimator bodies 12 may be coupled together using alignment features, such as alignment pins, registration marks, magnetic coupling elements, or mechanical fasteners, that ensure precise positioning and alignment of the slits 14 in each collimator body 12 relative to one another. The stacked collimator assembly may be configured such that the relative orientation of the collimator bodies 12 can be adjusted during the intraoperative procedure, allowing the angle between the slits 14 in the first and second collimator bodies 12 to be changed to achieve different dose distribution patterns without removing the collimator assembly from the patient.

[0037] In still other examples, the blocking elements 28 may include integrated fiducial markers that are visible under imaging modalities such as x-ray, computed tomography (CT), or fluoroscopy. Such fiducial markers can facilitate verification of blocking element 28 positioning during treatment setup and can enable real-time monitoring of blocking element 28 position during radiation delivery'. The fiducial markers may be composed of radiopaque materials that are distinguishable from the blocking element 28 material under imaging. The fiducial markers may be embedded within the blocking element 28 material, attached to the surface of the blocking element 28, or formed as distinct features within the blocking element 28 structure. In some examples, the fiducial markers may have known geometric relationships to the edges or other features of the blocking element 28, such that the position and orientation of the blocking element 28 can be determined from the positions of the fiducial markers in an image.

[0038] In addition to the protrusion and recess coupling mechanism described herein, the blocking elements 28 may be removably coupled to the collimator body 12 using alternative coupling mechanisms. For example, the blocking elements 28 may include magnetic elements that magnetically couple to corresponding magnetic elements or ferromagnetic regions on the collimator body 12. As another example, the blocking elements 28 may include snap-fit features that engage with corresponding features on the collimator body 12 to provide a secure yet removable connection. Such alternative coupling mechanisms may be used alone or in combination with the protrusion and recess coupling mechanism.10QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665

[0039] The slits 14 formed in the collimator body 12 are sized such that when a radiation beam impinges on one of the slits 14 at the first surface 16 of the collimator body 12 a corresponding minibeam of radiation exits the slit 14 at the second surface 18 of the collimator body 12. In this way, a single radiation beam impinging on the first surface 16 of the collimator body 12 will create a plurality of minibeams of radiation that exit the second surface 18 of the collimator body 18. The width of each slit can be selected from the range of 0.2 mm to 0.8 mm, such as 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, or 0.8 mm. Additionally or alternatively, the width can be selected between these values, or from a different range of values suitable for generating minibeam radiation patterns. In one nonlimiting example, the width of each slit 14 may be 0.5 mm.

[0040] The slits 14 formed in the collimator body 12 are spaced apart with a slit spacing. As one non-limiting example, the slit spacing may be 1.1 mm center-to-center. Alternatively, the slit spacing may be less than 1.1 mm center-to-center, such as center-to-center spacings of 1.0 mm. 0.9 mm, 0.8 mm, 0.7 mm, and so on. Likewise, in some alternative examples the slit spacing may be greater than 1.1 mm center-to-center, such as center-to-center spacings of 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, and so on. In some examples, the slits 14 may be spaced apart nonuniformly, such that there is a variable density of slits 14 in different parts of the central region 22 of the collimator body 12.

[0041] The slits 14 formed in the collimator body 12 may be configured with different orientations relative to the incident radiation beam. In some examples, the slits 14 are nondivergent slits, meaning that the slits 14 extend through the collimator body 12 in a parallel orientation relative to one another and perpendicular to the first surface 16 and the second surface 18 of the collimator body 12, as illustrated in FIG. 5E. Non-divergent slits 14 have the advantage of simplicity in manufacturing and do not require precise alignment with a specific radiation source geometry. When non-divergent slits 14 are used, the slits 14 do not follow the divergence of the x-ray beam emanating from a point source, and the resulting minibeams exit the second surface 18 of the collimator body 12 in a parallel array.

[0042] In other examples, the slits 14 are divergent slits, meaning that the slits 14 are oriented to follow the divergence of the radiation beam emanating from a radiation source, as illustrated in FIG. 5F. When a radiation beam is produced by a point source or a source with a finite focal spot, the radiation beam diverges as it travels away from the source. Divergent slits 14 are angled such that each slit 14 is aligned with a ray extending from the radiation source focal spot through the collimator body 12. In this configuration, the slits 14 are not parallel to11QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665one another but instead radiate outward from a common focal point corresponding to the location of the radiation source. The angle of each divergent slit 14 relative to a central axis of the collimator body 12 increases with increasing distance from the center of the collimator body 12. For example, a slit 14 located at the center of the central region 22 may be oriented perpendicular to the first surface 16 and the second surface 18, while slits 14 located toward the periphery of the central region 22 are angled outward to align with the diverging rays of the radiation beam. Divergent slits 14 can be beneficial in certain applications where it is desirable to maximize the transmission efficiency of the radiation beam through the collimator body 12. When divergent slits 14 are aligned with the diverging rays of the radiation beam, a greater proportion of the incident radiation passes through the slits 14 rather than being absorbed by the collimator body 12 material between adjacent slits 14. This can result in higher dose rates at the patient surface and more efficient use of the radiation output from the radiation source. Additionally, divergent slits 14 may produce minibeams that are more uniform in intensity across the treatment field, as each slit 14 receives radiation at a more optimal angle of incidence.

[0043] In some examples, the collimator body 12 may include a combination of nondivergent slits 14 and divergent slits 14. For example, slits 14 located in a central portion of the central region 22 may be non-divergent, while slits 14 located toward the periphery' of the central region 22 may be divergent to account for the increased divergence angle of the radiation beam at the edges of the treatment field. In other examples, the collimator body 12 may be designed for use with a specific radiation source having a known source-to-collimator distance and focal spot size, and the divergence angles of the slits 14 may be calculated and manufactured to match the specific geometry of that radiation source.

[0044] The collimator body 12 is made from a material that blocks, mitigates, or otherwise shields radiation. As one example, the collimator body 12 may be composed of tungsten. The tungsten may be substantially pure tungsten (e.g., 99.95% pure tungsten), a tungsten containing alloy, or the like. In other implementations, a radiation shielding material other than tungsten can be used, such as lead or other radiation shielding material suitable for the radiation type (e.g., x-ray, gamma ray, proton, neutron) being used in the radiation therapy application. In most instances, the blocking elements 28 can be composed of the same material as the collimator body 12. In other instances, a blocking element 28 may be composed of a different material than the collimator body 12. This allows for different shielding properties or characteristics to be used by swapping in blocking elements 28 composed of different shielding12QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665materials. For example, a blocking element 28 may be composed of a rare earth oxide, such as SiO2, Li2O, or GeO2. Additionally or alternatively, the collimator body 12 and / or a blocking element 28 may be composed of layers of different radiation shielding materials.

[0045] Referring now to FIG. 6, a flowchart is illustrated as setting forth the steps of an example method for intraoperative minibeam radiation therapy. The method includes arranging a variable collimator on a surface of the internal anatomy of a patient during an intraoperative procedure, as indicated at step 602. The surface of the internal anatomy may be the surface of an internal cavity, an internal organ, or the like.

[0046] With the variable collimator in position, a first fraction of minibeam radiation is delivered to the patient while the variable collimator is coupled to the surface of the internal anatomy of the patient, as indicated at step 604. The first fraction of minibeam radiation is generated by impinging a radiation beam on the variable collimator to collimate the radiation beam into a first plurality of radiation minibeams. The radiation beam may be, for example, an x-ray radiation beam having an x-ray energy' in a kilovolt (kV) energy range.

[0047] During this first fraction, the variable collimator is in a first configuration. For example, the variable collimator may be oriented in a first orientation. As another example, the variable collimator may be configured with no blocking elements 28 coupled to the collimator body 12. As yet another example, the variable collimator may be configured with one or more blocking elements 28 coupled to the collimator body 12 in a first configuration. Based on the configuration of the variable collimator during the first fraction, the first plurality of radiation minibeams define a first nonuniform dose distribution delivered to the patient.

[0048] After the first fraction is delivered, the variable collimator may be adjusted into a second configuration, as indicated at step 606. Adjusting the variable collimator into the second configuration may include changing an orientation of the variable collimator relative to the patient anatomy, adding one or more blocking elements 28 to the collimator body 12, removing one or more blocking elements 28 from the collimator body 12, changing a position of one or more blocking elements 28 on the collimator body 12, changing an orientation of one or more blocking elements 28 on the collimator body, or combinations thereof. Additionally or alternatively, the variable collimator can be kept in the first configuration for the second fraction and may be adjusted into the second configuration in a subsequent fraction (e.g., a third fraction, a fourth fraction, etc.) or may be kept in the first configuration during the entirety of the treatment process.13QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665

[0049] With the variable collimator adjusted into its second configuration, a second fraction of minibeam radiation is delivered to the patient while the variable collimator is coupled to the surface of the internal anatomy of the patient, as indicated at step 608. The second fraction of minibeam radiation is generated by impinging a radiation beam on the variable collimator to collimate the radiation beam into a second plurality of radiation minibeams. During this second fraction, the variable collimator is in its second configuration, as noted above. Based on the configuration of the variable collimator during the second fraction, the second plurality7of radiation minibeams define a second nonuniform dose distribution delivered to the patient, which is different from the first nonuniform dose distribution delivered to the patient during the first fraction.

[0050] A determination is then made at decision block 610 whether the radiation treatment for the patient is complete. If not, the variable collimator may be adjusted as described above into another configuration and another fraction of minibeam radiation delivered to the patient before determining again at decision block 610 whether the radiation treatment for the patient is completed. In some examples, the variable collimator may be adjusted into a different configuration for each fraction of radiation that is delivered. In other examples, the variable collimator may be adjusted between a set number of configurations (e.g., two configurations, three configurations, four configurations, etc.) over a series of a larger number of fractions. In this way. the same configuration may be used for different fractions of radiation. For example, two different configurations of the variable collimator may be used and subsequent fractions of radiation may alternate between the first and second configurations. It will be appreciated by those skilled in the art that various combinations of configurations can be used depending on the intended dose effect and / or treatment plan to be achieved. When the radiation treatment is completed, the variable collimator is removed from the surface of the internal anatomy of the patient as indicated at step 612 and the intraoperative procedure proceeds or is otherwise completed for the patient.

[0051] Higher doses of radiation delivered intraoperatively can improve outcomes, and the normal tissue tolerance associated with minibeam radiation makes it an advantageous treatment method. However, the amount of radiation that is delivered to healthy tissues must still be minimized and the location of these healthy tissues relative to the tumor will vary from patient to patient. Such variability requires that different areas of the minibeam collimator are capable of being blocked to spare healthy tissue. In theory, minibeam collimators can take any shape but the size and spacing of the slits is generally fixed. As described above, in some14QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665examples the size and spacing of the slits can be 0.5 mm and 1.1 mm center-to-center, respectively. The minibeam collimators can be 2.5 mm thick and are made of 99.95% pure tungsten.

[0052] The radiation device used for IOMBRT can produce a uniform beam of radiation that is initially circular or square in shape. As such, it may not conform exactly to the variable patient anatomy as the target and surrounding healthy organs are both likely to be irregularly shaped. The goal of IOMBRT is to irradiate the physician-desired treatment volume, but block the radiation from hitting any surrounding healthy tissue as much as possible.

[0053] In a non-limiting example, the systems and methods described in the present disclosure were implemented for treating a pancreatic cancer tumor. For this example, a schematic representation of a pancreas target (in green), the initially circular radiation field shown by a dashed line, and an adjacent healthy tissue (in yellow) is shown in FIG. 7.

[0054] Simply irradiating the dashed region with the circular collimator shown in FIG.3A would also unnecessarily irradiate the overlapping duodenum. IOMBRT with a variable collimating device can selectively block regions of the duodenum while still treating the pancreas target. This process is illustrated schematically in FIGS. 8 and 9 for circular and rectangular collimators, respectively. In FIG. 8 A, the intended treatment volume of the pancreas is outlined in a red dashed line. The portion of the duodenum (shown in yellow) which is in the upper region of FIG. 8A can be blocked with a solid oval piece of tungsten that interlocks with the circular collimator. This is shown in FIG. 8B. The remaining portion of the pancreas target is then treated with minibeam radiation. Because of the different patient anatomy shown in FIGS. 9A and 9B, a rectangular collimator and triangular blocking piece could be used.

[0055] The variable collimators can be temporarily secured in place w ithin the surgical bed by the surgeon for the treatment. They can be removed after the treatment. Securing the collimator in place over the target is an advantageous component of the systems and methods described in the present disclosure. To mitigate the effects of target motion, the collimator can be affixed directly to the patient. This ensures the integrity of the spatially separated peak and valley doses.

[0056] Because the geometry of the collimators is fixed (i.e., the circular, square, or rectangular shape is known) and the slit size and spacing is held constant (e.g., 0.5 mm wide slits spaced 1.1 mm center-to-center), the radiation dose delivered in all scenarios can be calculated before treatment. This can be done with Monte Carlo dose calculations, which can15QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665subsequently be confirmed with high resolution radiation film dosimetry as part of a commissioning process prior to using the system clinically. Based on this, the desired radiation dose can be quickly calculated and delivered in the operating room. A table of dose calculations could be used manually for treatment, or a computer system which performs the calculation could be created.

[0057] The present disclosure has described one or more preferred examples, and it should be appreciated that many equivalents, alternatives, variations, and modifications, aside from those expressly stated, are possible and within the scope of the invention.16QB\630666.01665\ 100377480.1

Claims

Mayo 2024-364630666.01665CLAIMS1. A collimator for minibeam radiation therapy, comprising:a collimator body having a thickness extending from a first surface to a second surface, the collimator body including a central region and a peripheral region surrounding the central region, wherein the first surface is substantially flat and the second surface is shaped to conform to an internal anatomy of a patient; and a plurality of slits formed in the central region of the collimator body, the plurality of slits being sized such that a radiation beam impinging on the first surface of the collimator body is collimated into a plurality' of radiation minibeams that exit the second surface of the collimator body in a nonuniform dose distribution.

2. The collimator of claim 1 , further comprising a blocking element for removably coupling to the collimator body to block the radiation beam from impinging on a portion of the central region of the collimator body.

3. The collimator of claim 2, further comprising a plurality of recesses formed in the peripheral region of the collimator body, wherein the blocking element is removably coupled to the collimator body via the plurality of recesses.

4. The collimator of claim 3, wherein the blocking element has a thickness extending from a top surface to a bottom surface, the blocking element including a plurality of protrusions extending away from the bottom surface of the blocking element, wherein the blocking element is removably coupled to the collimator body by fitting the plurality of protrusions into at least some of the plurality of recesses in the collimator body.

5. The collimator of claim 2, wherein the collimator body is composed of tungsten.

6. The collimator of claim 5, wherein the blocking element is composed of tungsten.17QB\630666.01665400377480.1Mayo 2024-364630666.016657. The collimator of claim 1, wherein the nonuniform dose distribution comprises a plurality of peaks and a plurality of valleys, wherein each of the plurality of peaks has a higher dose than the plurality of valleys.

8. The collimator of claim 1, wherein each of the plurality of slits have a width of 0.5 mm.

9. The collimator of claim 1 or 8, wherein each of the plurality of slits is spaced apart by 1.1 mm center-to-center.

10. The collimator of claim 1, wherein the thickness of the collimator body is 2.5 mm.

11. The collimator of claim 1 , wherein the collimator body is composed of tungsten.

12. The collimator of claim 1, wherein the second surface of the collimator body is substantially flat.

13. The collimator of claim 12, wherein the second surface of the collimator body is nonparallel with the first surface of the collimator body.

14. A method for intraoperative minibeam radiation therapy, the method comprising:delivering a first fraction of minibeam radiation to a patient while a variable collimator is coupled to a surface of an internal anatomy of the patient by impinging a radiation beam on the variable collimator to collimate the radiation beam into a first plurality of radiation minibeams, wherein the variable collimator is in a first configuration during the first fraction;adjusting the variable collimator into a second configuration; anddelivering a second fraction of minibeam radiation to the patient while the variable collimator is coupled to the surface of the internal anatomy of the patient by18QB\630666.01665400377480.1Mayo 2024-364630666.01665impinging the radiation beam on the variable collimator to collimate the radiation beam into a second plurality of radiation minibeams.

15. The method of claim 14, wherein the radiation comprises x-ray radiation in a kilovoltage (kV) energy range.

16. The method of claim 14, wherein the first plurality of radiation minibeams define a first nonuniform dose distribution caused by the variable collimator being in the first configuration and the second plurality of radiation minibeams define a second nonuniform dose distribution caused by the variable collimator being in the second configuration, wherein the first nonuniform dose distribution is different from the second nonuniform dose distribution.

17. The method of claim 14, wherein adjusting the variable collimator into the second configuration comprises coupling a blocking element to the variable collimator, wherein the blocking element blocks the radiation beam from impinging on a portion of the variable collimator.

18. The method of claim 17, wherein the variable collimator includes a plurality of recesses arranged in a periphery of the variable collimator, the blocking element comprises a plurality of protrusions that match at least some of the plurality of recesses, and coupling the blocking element to the variable collimator comprises fitting the plurality' of protrusions into the plurality of recesses.

19. The method of claim 14, wherein adjusting the variable collimator into the second configuration comprises rotating the variable collimator through a rotation angle.

20. The method of claim 19, wherein the rotation angle is 45 degrees.

21. The method of claim 19, wherein the rotation angle is 90 degrees.

22. A method for intraoperative minibeam radiation therapy, the method comprising:19QB\630666.01665\ 100377480.1Mayo 2024-364630666.01665delivering a fraction of minibeam radiation to a patient while a variable collimator is coupled to a surface of an internal anatomy of the patient by impinging a radiation beam on the variable collimator to collimate the radiation beam into a plurality of radiation minibeams.

23. A collimator for minibeam radiation therapy, comprising:a collimator body having a thickness of about 0.5 mm to about 3.0 mm extending from a first surface to a second surface, the collimator body including a central region and a peripheral region surrounding the central region, wherein the first surface is substantially flat and the second surface is shaped to conform to an internal anatomy of a patient; anda plurality of slits formed in the central region of the collimator body, wherein each of the plurality of slits has a width of about 0.2 mm to about 0.8 mm, and wherein the plurality of slits are spaced apart by about 0.7 mm to about 1.5 mm center-to- center.20QB\630666.01665\ 100377480.1

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