Abstract:
Various embodiments relate to a method of performing microbeam radiation therapy on a subject, including: affixing a collimator to the subject at a first location; producing a first high energy radiation fan beam, wherein the width of the first fan beam in a first direction is greater than the width of the first fan beam in a second direction; and moving the subject in the second direction so that the first fan beam irradiates the subject through the collimator to produce first high dose regions alternating with first low dose regions.

Description:
TECHNICAL FIELD 
     Various exemplary embodiments disclosed herein relate generally to low dose-rate radiation for medical and veterinary therapies. Such application is especially useful in treating various cancers and other tumors. 
     BACKGROUND 
     Cancer continues to be one of the foremost health problems. Conventional treatments such as surgery and chemotherapy have been extremely successful in certain cases; in other instances, much less so. Radiation therapy has also exhibited favorable results in many cases, while failing to be completely satisfactory and effective in all instances. An alternative form of radiation therapy, known as microbeam radiation therapy (MRT) may be used to treat certain tumors for which the conventional methods have been ineffective. 
     MRT differs from conventional radiation therapy by employing multiple parallel fan beams of radiation with a narrow dimension or thickness that may be on the order of 10 um to 200 um. The thickness of the microbeams is dependent upon the capacity of tissue surrounding a beam path to support the recovery of the tissue injured by the beam. It has been found that certain types of cells, notably endothelial cells lining blood vessels, have the capacity to migrate over microscopic distances, infiltrating tissue damaged by radiation and reducing tissue necrosis in the beam path. In MRT, sufficient unirradiated or minimally irradiated microscopic zones remain in the normal tissue, through which the microbeams pass, to allow efficient repair of irradiation-damaged tissue. As a result, MRT is fundamentally different from other forms of radiation therapy. 
     In conventional forms of radiation therapy, including the radiosurgical techniques employing multiple convergent beams of gamma radiation, each beam is at least several millimeters in diameter, so that the biological advantage of rapid repair by migrating or proliferating endothelial cells is minimal or nonexistent. Observations of the regeneration of blood vessels following MRT indicate that endothelial cells cannot efficiently regenerate damaged blood vessels over distances on the order of thousands of micrometers (μm). Thus, in view of this knowledge concerning radiation pathology of normal blood vessels, the skilled artisan may select a microbeam thickness as small as 10 μm to 200 μm. Further, the microbeams may include substantially parallel, non-overlapping, planar beams with center-to-center spacing of from about 50 μm to about 500 μm. Also, the beam energies may range from about 30 to several hundred keV. These microbeams result in a dosage profile with peaks and valleys. The radiation dosage in the peaks is large enough to kill the targeted tumor, but also kills healthy cells in the peak dosage areas. The radiation dosage in the valleys is small enough to prevent any damage to cells in the valley dosage areas. 
     A division of a radiation beam into microbeams and the use of a patient exposure plan that provides non-overlapping beams in the tissue surrounding the target tumor allows the non-target tissue to recover from the radiation injury by migration of regenerating endothelial cells of the small blood vessels to the areas in which the endothelial cells have been injured beyond recovery. Therefore, the probability of radiation-induced coagulative necrosis in normal, non-targeted tissue is lowered, which may improve the effectiveness of clinical radiation therapy for deep-seated tumors. The use of microbeams may be of special benefit for deep tumors. 
     Various studies have shown the microbeam tissue-sparing effect for X-ray microbeams. Although other methods and processes are known for radiation therapy, none provides a method for performing radiation therapy while avoiding significant radiation-induced damage to tissues surrounding the target. 
     Present radiation therapies often take many days and weeks of treatment to provide enough radiation to a target tumor. On the other hand, MRT can provide an effectual treatment in single visit. Very high energy radiation may be used with MRT that results in the destruction of tumor tissue while allowing for the regeneration of healthy tissue affected by the microbeam fan beams. 
     Further, MRT provides a method for treating cancerous tumors by using extremely small radiation microbeams increasing the precision and accuracy of radiation therapy. MRT also provides a method of using extremely small microbeams of radiation to unexpectedly produce effective radiation therapy while avoiding significant radiation-induced damage to non-target tissues. 
     A major benefit of MRT is that the microbeams are so narrow that the vasculature of the tissue through which the microbeams pass can repair itself by the infiltration of endothelial cells from surrounding unirradiated tissue. Present knowledge indicates that such infiltration can take place only over distances on the order of less than 500 μm depending on the tissue being irradiated. The dimensions of the microbeams and the configuration of the microbeam array are therefore determinable with reference to the susceptibility of the target tissue and the surrounding tissue to irradiation and the capacities of the various involved tissues to regenerate. 
     U.S. Pat. No. 5,339,247 to Slatkin et al. entitled Method for Microbeam Radiation Therapy provides background related to MRT, and is hereby incorporated by reference for all purposes. 
     SUMMARY 
     Accordingly, there is a need for improved radiation therapies that can quickly yet safely treat patients. Further there is a need to focus radiation doses in desired peak dosage regions will minimizing radiation doses in desired valley dosage regions. 
     A brief summary of various exemplary embodiments is presented. Some simplifications and omissions may be made in the following summary, which is intended to highlight and introduce some aspects of the various exemplary embodiments, but not to limit the scope of the invention. Detailed descriptions of a preferred exemplary embodiment adequate to allow those of ordinary skill in the art to make and use the inventive concepts will follow in the later sections. 
     Various embodiments may also relate to a method of performing microbeam radiation therapy on a subject, including: affixing a collimator to the subject at a first location; producing a first high energy radiation fan beam, wherein the width of the first fan beam in a first direction is greater than the width of the first fan beam in a second direction; and moving the subject in the second direction so that the first fan beam irradiates the subject through the collimator to produce first high dose regions alternating with first low dose regions. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In order to better understand various exemplary embodiments, reference is made to the accompanying drawings wherein: 
         FIG. 1  illustrates a method for producing microbeams using a collimator; 
         FIG. 2  illustrates an embodiment of a MRT system; 
         FIG. 3  illustrates affixing a collimator to the skeleton of a subject; 
         FIG. 4  illustrates affixing a collimator to a subject using a facial mask; 
         FIG. 5  illustrates a pulley system that may help to counter the weight of the collimator; 
         FIG. 6  illustrates another embodiment of a system to counter the weight of the collimator; 
         FIG. 7  illustrates one embodiment of a collimator; and 
         FIG. 8  illustrates another embodiment of a collimator. 
     
    
    
     DETAILED DESCRIPTION 
     Referring now to the drawings, in which like numerals refer to like components or steps, there are disclosed broad aspects of various exemplary embodiments. 
       FIG. 1  illustrates a method for producing microbeams using a collimator. The collimator  105  may include a plurality of parallel slits  115  in a vertical direction. A high energy radiation fan beam  100  that may be very narrow in the vertical direction and wide in the horizontal direction may pass through the collimator  105 . Because the collimator  105  is made of a high Z material, it blocks portions of the of the high energy radiation fan beam  100 . The portion of the high energy radiation fan beam  100  that passes through the slits  115  of the collimator  105  forms the microbeams  110 . The microbeams  110  may be used to treat a subject. Depending upon the vertical height of the fan beam  100  relative to the size of the treatment region, the subject may have to be moved relative to the microbeams  110  in order to irradiate the whole treatment region. It is not possible to move the high energy radiation fan beam  100  because of the massive size of the facility necessary to produce the high energy radiation fan beam  100 . Further, the collimator  105  has been fixed relative to the high energy fan beam  100 . 
     MRT may apply very high energy radiation beams for a very short period of time. One problem with MRT may occur when the subject moves relative to the beam during treatment. This may result in smearing of the peak and valley doses applied to the subject. Effective and safe MRT relies upon valley dose regions where the radiation dose is low enough to prevent any damage to the healthy cells in the valley dose regions. If the subject moves relative to the microbeams  110  during treatment, then the high energy radiation of the microbeams  110  may smear into the valley dose regions resulting in many if not all of the healthy cells along the path of the microbeams  110  being injured beyond recovery. Accordingly there is a need to stabilize and fix the microbeams  110  relative to the subject. 
     The microbeams  110  may be fixed relative to the subject by affixing a collimator to the subject that splits a high energy fan beam  100  into microbeams  110 . In this embodiment, even though the subject may move relative to the high energy fan beam  100 , the collimator moves with the subject, hence the microbeams  115  emanating from the collimator move with the subject as well. This embodiment may prevent the problem described above. 
       FIG. 2  illustrates an embodiment of a MRT system. The MRT system  200  may include a source  205  that produces a high energy fan beam  100 , a beam filtering and limiting system  210 , jaws  215 , a collimator  220 , and a movable platform  225 . A subject  230  may be treated by the MRT system  200 . 
     The source  200  may produce high energy electromagnetic radiation beam such as X-ran or gamma radiation beam. High energy X-ray radiation may be especially beneficial. In any generated photon beam, the photons are produced having a characteristic spectrum of energies. The photon energy of the beams may range of from about 30 keV to about 300 keV. 
     A synchrotron may be used to generate an X-ray beam having practically no divergence and a very high fluence rate. These synchrotron generated X-rays have the potential for projecting sharply defined beam edges deep in the body. This source may be useful for generating X-ray microbeams for radiobiology, radiotherapy, and radiosurgery. A high fluence rate is required to implement MRT because exposure times must be short enough (e.g., less than about 1 second) to avoid the blurring of margins of the irradiated zones of tissue due to body or organ movements. Sharply defined microbeam margins are made possible not only by the high fluence rate and the minimal divergence of the synchrotron beam, but also by the microscopically short ranges in tissue of secondary electrons generated by 50-150 keV synchrotron X-rays. Absorbed doses to nontargeted tissues situated between microbeams may be kept below the threshold for radiation damage in tissues both proximal and distal to the isocentric target, i.e., where the microbeams do not overlap. These factors make it possible to effectively irradiate a target using a field of many well defined, closely spaced microbeams. 
     The radiation beam for producing the microbeam array may be obtained from industrial X-ray generators or from synchrotron beamlines at electron storage rings. The radiation beam may be obtained from a wiggler beam line at an electron storage ring. A conventional “planar” wiggler uses periodic transverse magnetic fields to produce a beam with a rectangular cross-section, typically having a horizontal to vertical beam opening angle ratio on the order of 50:1. In an alternative embodiment, the radiation beam is obtained from a “helical” wiggler, a configuration capable of producing a substantially less anisotropic beam. While a fan beam is discussed in the embodiment below, it is also possible to place the subject to be treated a large distance (i.e., &gt;100 m) from the source  200 , which may allow the X-ray beam from the source to expand enough in both the horizontal and vertical directions so that the beam covers the whole treatment region, and hence, it may not be necessary to move the subject relative to the high energy beam. Further, such beam spreading could be accomplished by two orthogonal wigglers that would spread the beam first in one direction and then in a second orthogonal direction. Such embodiments would not require movement of the subject, but the collimator would still be affixed to the subject as with the previously described embodiments. 
     The beam filtering and limiting system  210  filters and limits the high energy beam  100  for treating the subject  230 . As mentioned above the source may produce a high energy beam with a range of energies. Often only a certain range of energies may be used to treat the subject. Accordingly, various filters made of various materials may be placed in the path of the high energy beam to filter out the undesired energy bands in the high energy beam. Further, spatial limiting may be used to limit the beam to the desired beam size and geometry. This may help to prevent unwanted and unsafe stray radiation from the source  200 . Such spatial limiting may be accomplished, for example, with plates having slits. The plates may be of sufficient thickness and high Z material to block portions of the high energy beam from the source  200 . 
     Jaws  215  further spatially limit the high energy beam  100  that has passed though the filtering and limiting system  210 . The jaws  215  include two jaws that may be made of a material that completely blocks the high energy beam  100 . Because the width of the high energy fan beam typically may be wider than the target region, it may be necessary to limit the width of the fan beam to the width of the target region. Thus, as the subject  230  moves relative to the high energy fan beam  100 , the width of the target region varies. Accordingly, the jaws  215  move to adjust the width of the high energy fan beam  100  to correspond to the width of the target region being irradiated by the high energy fan beam  100 . Prior to the subject being treated using MRT, the target region is very accurately measured, so that during treatment with the high energy fan beam  100 , the width of the beam can be adjusted to correspond the precise desired treatment region. This may prevent the unnecessary irradiation of normal healthy tissue adjacent to the treatment region. 
     The two jaws  215  may be independently controlled so as to adjust the location of edges of the high energy fan beam  100  so that the edges coincide with the edges of the treatment region. Further, actuators that move the jaws  215  may be able to move the jaws  215  quickly enough to adjust the width of the high energy fan beam  100 . The movement of the jaws may be controlled by a controller that receives information relating to the shape and location of the treatment region. Further, the controller may include a processor for controlling the movement of the jaws  215 . Further, while the jaws  215  are shown as spatially independent from the collimator  220 , it is also possible that the jaws  215  may be connected to the collimator or the patient so that it moves with the patient as well. 
     The width adjusted high energy fan beam  100  may irradiate the collimator  220 . As described above with respect to the  FIG. 1 , the collimator  220  may include a plurality of vertical slits. The vertical slits split the high energy fan beam  100  into a plurality of microbeams  110  (as shown in  FIG. 1 ). The collimator  220  may be affixed securely to the subject. Preferably, the collimator  220  is very near the subject  230  or even in contact with the skin of the subject  230 . As a result, the micro beams formed by the collimator  220  are fixed relative to the subject, even if the subject moves. 
     The collimator  220  may be fixed to the skeleton of the subject  220  as shown in  FIG. 3 . The collimator  220  may be attached to the subject  230  using screws  300  or another fastener  300  that may be used to affix items to the skeleton. The collimator may be affixed to the skull as shown in  FIG. 3 , but may also be affixed, for example, to the skull, the hip, the spine, the clavicle, or to bones in the arm or the leg. 
     The collimator  220  may also be affixed to the subject  230  using a facial mask  400  as shown in  FIG. 4 . A facial mask  400  may be placed over the face of the subject  230  and held in place using straps or any other secure method. Then the collimator  220  may be attached to the mask  400 . 
     Further, the collimator  220  may be affixed to the subject  230  by clamping the collimator  220  or a related fixture between the upper and lower jaws of the subject. The subject&#39;s jaws may then be held in place using straps or some other method. 
     Also, a fixture may be used to help affix the collimator  220  to the subject  230 . The fixture may be attached to the face, skeleton, jaw or other stable part of the subject. Then the collimator  220  may be attached to the fixture. 
     It is important to precisely and accurately affix the collimator  220  relative to the target region in the subject  230  that is to be treated. This may be accomplished by affixing the collimator or the fixture to the subject  230  in the desired location. Then a diagnostic test may be performed to verify the alignment of the collimator  230  or fixture with the treatment region. Then the location of the collimator  230  or the fixture may be adjusted, and the diagnostic test repeated. This process may be repeated as many times as needed to achieve the desired alignment accuracy between the collimator  220  and the target region of the subject  230 . 
     The movable platform  225  may hold the subject in a fixed position and then move the subject relative to the high energy fan beam  100 . The movable platform  225  may be any known platform that secures the patient and then allows for very precise movement of the patient relative to the high energy fan beam  100 . 
     Further, the MRT may be conducted in order to accommodate tissue movement in the subject due to the cardiac or respiratory cycle. The on-time of the high energy beam  100  may be synchronized with either the cardiac or the respiratory cycle or both. Each on-time may be limited to a small time interval during the appropriate cycle to avoid the smearing of the extraordinarily precise microbeam effect by movement of the tissue generated by cardiogenic and respiratory pulsation. For example, the on-time of the high energy beam  100  may be limited to the end phase of diastole or the end phase of an exhalation cycle. Other predicable points of these cycles may be used as well. In yet another embodiment, the diagnostic tests performed to characterize the target region or to align the collimator with the target region may be carried out at specific predetermined portion of the cardiac or respiratory cycle. Then the on-time of the high energy beam  100  may be during the same specific predetermined portion of the cardiac or respiratory cycle, and may include one or more on-time periods. The use of compensation for the cardiac and respiratory cycle may depend on the target regions susceptibility to movement due to these cycles. 
     Because such high energy radiation may be used in MRT it is very important to precisely control the dose of radiation applied to the subject  230 . Prior to treatment, a medical physicist may use sophisticated computer tools and modeling to determine the dosage parameters to use during the MRT. In order to evaluate the MRT dosage, a film containing an array of microscopic cell-culture chambers may be used. The film may be placed downstream from the collimator  220  in close proximity to or in contact with the subject&#39;s skin. Those cells behind the radiolucent slits and their similar but minimally irradiated cells in the same film behind the radio-opaque bars of the collimator between its radiolucent slits would indicate, with nearly cell-by-cell spatial resolution, the biologically effective dose received by the skin cells, which are important reference doses for computation by the medical physicist of valley doses in radiosensitive vital normal tissues deep to the skin, proximal and distal to the target region, outlined in diagnostic tests. Such a film may also be placed near the collimator  220  without a subject and irradiated to determine the biological effects of a proposed treatment dosage. 
     While the application of a single MRT dose may be effective to effectively treat a subject, it may also be beneficial to provide multiple treatments from different directions. The treatment directions and doses would be selected to allow the two different sets of microbeams to intersect in the target region. These multiple doses of high energy radiation to the treatment region may increase the effectiveness of the MRT. 
     While the high radiation beam  100  is described as being spread in the horizontal direction, it may be beneficial to spread the beam in the vertical direction or any other direction. Using other beam spreading directions may provide benefits in accurately delivering a dose. Also, if multiple MRT treatments are used, then the ability to spread the high energy beam  100  in various directions may be beneficial. For example, when producing high energy X-rays using a synchrotron, a wiggler may be used to spread the beam in a desired direction. Such a wiggler may be mounted so that it can be rotated around an axis parallel to the high energy beam. As a result the beam may be spread in any desired direction. The rotation of the wiggler may be precisely and accurately controlled to allow the beam to spread as needed to apply the desired radiation dose. 
     Prior research has shown that blanching the subject&#39;s skin during the application of MRT, reduces the damage done to skin cells by MRT. Accordingly, this benefit may be combined with the treatment method and system according the present embodiments. Blanching of the skin may be accomplished by applying pressure to the skin irradiated by the microbeams  110 . Such pressure may be applied by a tightly applying a bandage or bands to the skin. Further, pressure may be applied to the skin by using a bladder placed between the skin of the subject and the collimator  220 . Another method of blanching the skin includes injecting adrenaline into an area near the skin to be blanched. Any other method of blanching the skin may be used as well. 
     Because the collimator  220  may be heavy because of its size and the use of dense materials needed to block the high energy radiation beam  200 , it may be uncomfortable to the subject to support the weight of the collimator  220 . Accordingly, this weight may be offset using a pulley or lever arm system.  FIG. 5  illustrates a pulley system  500  that may help to counter the weight of the collimator  230 . The pulley system  500  may include a pulley  510 , a counter-weight  520 , and a cable  530 . The cable  530  may attach to the collimator  220  and then extend through and over pulley  510  and then attach to the counter-weight  520 . The counter-weight  520  is approximately the same weight as the collimator  220 , so that the effective weight of the collimator  220  on the subject is nearly zero. Further, the pulley may be subject to a small frictional force to minimize the movement of the pulley except when a sufficient force is applied to the cable  530 . 
       FIG. 6  illustrates another embodiment of a system  600  to counter the weight of the collimator  230 . The lever system  600  may include a base  610 , a lever arm  620 , a counter-weight  630 , and gimbal  640 . The base  610  supports the lever arm  620  and allows the lever arm  620  to pivot about a connection point between the base  610  and the lever arm  620 . A counter-weight  630  is attached to one end of the lever arm  630  to counterbalance weight at the gimbal end of the lever arm  630 . The weight of the counter-weight  630  may be selected in order to counter the weight of the collimator  220 . The collimator  220  may be attached to a gimbal  640  at the end of the lever arm  620  opposite the counter-weight  630 . The gimbal allows the collimator  220  be oriented in any needed direction. Other mechanical systems may be used as well to offset the weight of the collimator  220  in order to prevent discomfort to the subject. 
     As described above with respect to  FIG. 1 , the collimator  105  may include alternating radiation translucent regions and radiation opaque regions. The radiation translucent regions may be slits  115  formed in a radiation opaque material. Also, the radiation translucent region may be made of a radiation translucent material that allows the high energy beam  100  to pass through the collimator  105  to form the microbeams  110 . 
       FIG. 7  illustrates one embodiment of a collimator. The collimator  705  may include an enclosure  710 , radiation translucent foils  720 , and radiation opaque liquid  725 . The enclosure  710  may have two substantially parallel opposite sides with grooves  715 . The radiation translucent foils  720  may be mounted in opposite pairs of grooves  715 . All of the radiation translucent foils  720  may be substantially parallel to one another. The radiation translucent foils  720  may be made of aluminum or any other material that is sufficiently radiation translucent. Next a liquid radiation opaque material such as mercury maybe added to the regions in between the radiation translucent foils  720 . Such a collimator  705  would allow for the easy construction of various collimators  705  with various parameters, such as foil height, width, and thickness and the spacing between the foils. 
       FIG. 8  illustrates another embodiment of a collimator. The collimator  805  may include a body  810  and layers  815 . The body may be made of a radiation translucent material such as for example plastic. Plastic has the advantage that it may be easily machined to create slits. The slits may be formed using micromachining techniques. Further, the body  810  may include a machinable side  820 . This machinable side may be machined to conform to specific portion of the subject&#39;s body. This would allow for accurate, stable, and comfortable placement of the collimator  805  in contact with the subject. 
     Although the various exemplary embodiments have been described in detail with particular reference to certain exemplary aspects thereof, it should be understood that the invention is capable of other embodiments and its details are capable of modifications in various obvious respects. As is readily apparent to those skilled in the art, variations and modifications can be affected while remaining within the spirit and scope of the invention. Accordingly, the foregoing disclosure, description, and figures are for illustrative purposes only and do not in any way limit the invention, which is defined only by the claims.