Patent Publication Number: US-8995608-B2

Title: Compact microbeam radiation therapy systems and methods for cancer treatment and research

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of and claims priority to U.S. patent application Ser. No. 12/688,425 filed Jan. 15, 2010, which claims the benefit of and priority to U.S. Provisional Application No. 61/205,240, filed Jan. 16, 2009, the entire disclosures of which are herein incorporated by reference. 
    
    
     GOVERNMENT INTEREST 
     This invention was made with government support under Grant Nos. U54 CA 119343 and 1R21 CA 118351-01 awarded by the National Cancer Institute. The government has certain rights in the invention. 
    
    
     TECHNICAL FIELD 
     The subject matter disclosed herein relates generally to radiotherapy systems and methods. More particularly, the subject matter disclosed herein relates to microbeam radiotherapy systems and methods for cancer treatment and research. Microbeam Radiotherapy (MRT) radiation can be characterized by its microscopically discrete spatial radiation distribution (beam width is less than 1 millimeter and beam separation is several millimeters) and ultra-high dose rate (10 Gy/s or higher). 
     BACKGROUND 
     The fundamental challenge of radiotherapy is to treat cancer patients effectively and safely. Current radiotherapy systems and methods provide excellent benefits for patients with early stage and radiosensitive cancers, but these benefits diminish for patients with radioresistant tumors (e.g., brain or pancreas cancers) and patients with late stage tumors. For these patients, the radiation needed to eradicate the tumor can cause intolerable or fatal radiation damage. This is especially the case for pediatric patients, whose rapidly developing normal tissues are often more radiosensitive than their tumors, and who therefore cannot tolerate radiotherapy that would be curative for adults with the same disease. As a result, normal tissue collateral damage is a major limitation in current radiotherapy, preventing effective radiotherapy treatments for cancer patients of a young age, patients with central nerve system cancers, radioresistant cancers, and late stage cancer with large tumors. These cancer patients currently have a poor prognosis. 
     Microbeam Radiotherapy (MRT) is a unique form of radiation that has shown an extraordinary ability to eradicate tumors while sparing normal tissue in numerous animal studies. MRT utilizes multiple narrow but well separated x-ray planar beams (i.e., “microbeams”) and delivers radiation at extremely high dose rate. MRT radiation differs from conventional radiotherapy radiations in two aspects: dose spatial discreteness and dose temporal rate. In conventional therapy, the dose rate is about 100 times lower and the dose distribution is microscopically continuous in space. The current solution, which is not always effective, is to use multiple treatments at 2 Gy per treatment. In contrast, animal studies have shown that single treatments at a dose level of several hundred Gy (e.g., about 10 2  Gy or greater) can eradicate a tumor while sparing normal tissue, including developing tissue in the central nervous system. 
     There are currently two hypotheses for the mechanism by which MRT can provide tumor eradication while sparing normal tissue. First, it is believed that tumor microvasculature does not repair itself well while normal tissue does. Second, there appears to be a bystander effect wherein unirradiated tumor cells die with irradiated tumor cells through cell-cell signaling (See, e.g., D. Slatkin et al.,  Proc. Natl. Acac. Sci. USA, Vol  92, pp 8783-8787, 1995). However, the underlying mechanism of MRT is still poorly understood. Nonetheless, MRT is extremely attractive for human application as the key challenge of radiotherapy has been how to eradicate tumors with minimal collateral damage to the host normal tissue. 
     Unfortunately, however, MRT requires that x-rays with an extremely high dose rate (e.g., on the order of 100 Gy/s or higher) are needed to irradiate tissues in a fraction of a second to assure minimal broadening of the micro slices due to movement of the target. This dose rate is several orders of magnitude higher than what is typically used for conventional radiation therapy. 
     Existing x-ray tube technologies today cannot provide a MRT dose distribution and dose rate as the MRT dose rate can be thousands of times that of state-of-art radiotherapy machines (˜5 Gy/min). The high dose rate is thought to be important for minimizing the broadening (due to the object motion) of the tens of micron wide microbeam required during irradiation of live objects. A conventional x-ray tube comprises a metal filament (cathode) which emits electrons when it is resistively heated to over 1000° C. and a metal target (anode) that emits x-ray when bombarded by the accelerated electrons. The spatial resolution of an x-ray source is determined by the size of the focal spot which is the area on the x-ray anode that receives the electron beam. Because of the high operating temperature and power consumption, essentially all current commercial x-ray tubes are single-pixel devices where x-ray radiations are emitted from single focal spots on the anodes. The heat load of the anode limits the maximum x-ray flux of an x-ray tube. To generate the small MRT beam size at the ultrahigh dose rate using the current x-ray technology would require an ultrahigh electron beam density and heat load that are beyond physical possibility. For instance, the state-of-art high-power x-ray tube operating at ˜100 kW delivers only about 1-10 cGy/s at patient with ˜0.6 m source-object distance 
     As a result, due to this high required dose rate, MRT has thus far been studied exclusively using synchrotron radiation, for instance at the National Synchrotron Light Source (NSLS) in the United States and at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. Therefore, in order to speed up the research that may advance the promising cancer treatment for potential human application, there is a need for compact, non-synchrotron source MRT systems and associated methods that can be widely available for cancer centers for preclinical research and clinical application. 
     SUMMARY 
     In accordance with this disclosure, compact, non-synchrotron source MRT systems and methods for microbeam radiotherapy are provided. In one aspect, a method for microbeam radiation therapy is provided. The method can comprise positioning a distributed x-ray source array about a target to be irradiated, the x-ray source array comprising a plurality of carbon-nanotube field emission x-ray sources, and simultaneously generating a plurality of x-ray microbeams from the plurality of carbon-nanotube field emission x-ray sources. 
     In another aspect, a microbeam radiotherapy system is provided. The system can comprise a distributed x-ray source array comprising a plurality of carbon-nanotube field emission x-ray sources, each of the x-ray sources being positioned to direct x-rays towards a common focus, a microbeam array collimation, a positioning device for aligning a target with the plurality of x-ray microbeams, and a control system in communication with each of the plurality of x-ray sources in the distributed x-ray source array for simultaneous generation of a plurality of x-ray microbeams from the plurality of x-ray sources. 
     Although some of the aspects of the subject matter disclosed herein have been stated hereinabove, and which are achieved in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying drawings as best described hereinbelow. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The features and advantages of the present subject matter will be more readily understood from the following detailed description which should be read in conjunction with the accompanying drawings that are given merely by way of explanatory and non-limiting example, and in which: 
         FIG. 1A  is a side view of microbeam radiotherapy of a target within an object; 
         FIG. 1B  is a graphical representation of the dose rate distribution across the x-ray microbeam of  FIG. 1A ; 
         FIG. 2  is an image of a horizontal histological section of the hindbrain of a rat irradiated using a method for microbeam radiotherapy; 
         FIG. 3  is a schematic diagram of a field emission x-ray source for use with a microbeam radiotherapy system according to an embodiment of the presently disclosed subject matter; 
         FIG. 4  is a schematic diagram of a field emission x-ray source for use with a microbeam radiotherapy system according to another embodiment of the presently disclosed subject matter; 
         FIG. 5  is a top plan view of a microbeam radiotherapy system according to an embodiment of the presently disclosed subject matter; 
         FIG. 6  is a top plan view of a microbeam radiotherapy system arranged in a ring-shaped array according to an embodiment of the presently disclosed subject matter; 
         FIG. 7  is a top plan view of a microbeam radiotherapy system arranged in a polygonal array according to an embodiment of the presently disclosed subject matter; 
         FIG. 8  is a side view of microbeam radiotherapy of a target within an object according to an embodiment of the presently disclosed subject matter; and 
         FIG. 9  is a flow chart for a method for microbeam radiotherapy according to an embodiment of the presently disclosed subject matter. 
     
    
    
     DETAILED DESCRIPTION 
     A traditional x-ray source generates x-ray radiation from a small area on the x-ray anode (“focal spot”) that receives electrons. The local temperature on the anode can reach over 1500° C. when it is bombarded by the high energy electrons. The maximum x-ray dose can be limited by the heat load that can be tolerated by the anode, which is also related to the size of the focal spot. For instance, a clinical linear accelerator (LINAC) can deliver a dose of only about 5 Gy/min. In contrast, the present subject matter provides compact, non-synchrotron source MRT devices, systems, and methods that can utilize multiple separated, narrow x-ray planar or line beams to deliver radiation at a comparatively higher dose rate. The MRT devices, systems, and methods can be used, for example, for cancer treatment for humans including brain tumors and for intra-operative radiation therapy. It is also envisioned that MRT devices, systems, and methods as disclosed herein can be used for cancer research in animal models. 
     As discussed above, MRT differs from conventional radiotherapy techniques in both dose spatial discreteness and dose temporal rate. Specifically, referring to  FIGS. 1A and 1  B, rather than a single, broad beam that provides a substantially continuous dose distribution across the beam width, devices, systems, and methods for MRT produce a plurality of x-ray microbeams MB each having a beam width on the order of about 1 mm or smaller. As can be seen in  FIG. 2 , a sample irradiated using an MRT method can be identified by a plurality of distinct x-ray beam paths. The plurality of microbeams MB can be directed toward a target T (e.g., a tumor), which can be contained within an object O. 
     A second feature that differentiates MRT from conventional radiotherapy is the comparatively high temporal dose rate. Previously disclosed systems and methods for MRT produce x-ray using a high energy synchrotron or a conventional X-ray tube source, but each of these options has significant drawbacks as discussed above. In contrast, the presently-disclosed subject matter provides that comparatively high temporal dose rates sufficient for MRT can be achieved using a spatially distributed x-ray source array composed of a plurality of individual x-ray sources that can be positioned about object O. 
     In one aspect of the presently disclosed subject matter, the spatially distributed x-ray source array can be based on a carbon nanotube (CNT) distributed x-ray source array technology. For example, CNT field emitters are disclosed in U.S. Pat. No. 6,876,724, titled “Large-Area Individually Addressable Multi-Beam X-Ray System and Method of Forming Same”; U.S. Pat. No. 6,850,595, titled “X-Ray Generating Mechanism Using Electron Field Emission Cathode”; and U.S. Pat. No. 6,553,096, titled “X-Ray Generating Mechanism Using Electron Field Emission Cathode”, the disclosures of which are incorporated by reference herein in their entireties. 
     Exemplary configurations for a field emission x-ray source are illustrated in  FIGS. 3 and 4 . In the exemplary configurations shown, a field emission x-ray source  100  can comprise a field emission cathode structure  110 , such as, for example, a nanostructure or carbon nanotube film on a conducting substrate. A gate electrode  120  (e.g., a high melting temperature metal grid) can be positioned above cathode  110  such that applying a voltage between cathode  110  and gate electrode  120  can cause electrons to be field emitted from cathode  110 , for example as an electron beam EB, and directed towards an anode  130  for generation of an x-ray beam. X-ray source  100  can further comprise a focusing electrode  140  for focusing electron beam EB before it reaches anode  130 , thereby reducing the size of the focal spot on anode  130 . 
     The system can further comprise a microbeam collimator  150 , shown in  FIG. 3 , which can be positioned in the path of the emitted x-ray beam to allow only selected x-ray microbeams MB having a defined beam thickness d to be transmitted, thereby defining the irradiation area. In one embodiment shown in  FIG. 5 , for example, collimator  150  can produce fan-beam x-ray radiation with a narrow beam width (e.g., having a beam width of between about 0.01 mm and 1 mm). As a result, a thin-slice of target T can be irradiated by x-ray microbeams MB. To minimize the damage to the normal tissues, the fan-beam angle θ (i.e., the spread of the fan-beam) can also be collimated such that the x-ray radiation covers primarily the region occupied by target T. In addition, the system can also comprise a radiochromic film (e.g., Gafchromic XR-QA) positioned between each x-ray source  100  and target T. In this configuration, x-ray microbeam MB can be generated with significantly higher dose rate than what is used in clinical treatment. In another arrangement, the system can comprise a multi-slit microbeam collimator or a plurality of collimators  150 , shown in  FIG. 4 , which can likewise be positioned in the path of the emitted x-ray beam. This arrangement can create a plurality of non-overlapping (e.g., parallel) x-ray microbeams MB emitted from each of x-ray sources  100 . 
     To achieve the high dose rate required by MRT, a plurality of x-ray sources  100  can be assembled in a distributed x-ray source array  200  as shown in  FIG. 5 . Each x-ray source  100  can be a distinct element, with an independent cathode  110  and anode  130 , which can be operated independently or in combination with other of the plurality of x-ray sources  100 . Alternatively, x-ray source array  200  can comprise an anode ring and an opposing cathode ring inside a vacuum container. In this alternative configuration, cathode ring and anode ring can be operated collectively to produce x-ray radiation from the anode ring and irradiate target T within object O. 
     In either arrangement, x-ray source array  200  functions as a distributed x-ray source. Instead of using one parallel x-ray beam delivering the radiation from one direction or two orthogonal beam arrays (i.e., as done in the experiments performed at the synchrotron sources), x-ray source array  200  surrounds target T to be irradiated. In this way, x-ray radiation can be delivered from multiple directions to a common focus to increase the amount of radiation received at target T without increasing the amount of radiation received at any intervening portion of object O outside of target T. In addition, each of the plurality of x-ray sources  100  can be arranged such that x-ray microbeams MB from one of x-ray sources  100  irradiate a first portion of target T, x-ray microbeams MB from a second of x-ray sources  100  irradiate a second portion of target T different from the first portion, and so on. For instance, referring to  FIG. 8 , a first set of x-ray microbeams MB can irradiate target T along a plurality of parallel radiation planes while a separate set of x-ray microbeams, designated MB′ in  FIG. 8 , can irradiate target T along radiation planes that are interleaved with the radiation planes of the first set of x-ray microbeams MB. In this way, the x-ray radiation at target T has a substantially continuous dose distribution even though each individual x-ray microbeam MB does not. 
     As a result, by distributing the x-ray power over a large area surrounding target T, x-ray source array  200  can generate micro-planar x-ray beams with dose rates at target T that are sufficient for MRT. For example, x-ray source array  200  can generate dose rates on the order of about 0.1 to 100 Gy/sec, or it can generate much higher dose rates on the order of 500 Gy/sec. Meanwhile, portions of object O outside of target T only receive x-ray radiation from a single x-ray microbeam MB (or group of microbeams) rather than the combined radiation at the common focus, and thus the dose rate for these intervening portions can be much lower. 
     X-ray source array  200  can be configured to be in any of a variety of geometries, such as a ring, an arc, a polygon, or a linear array. For instance, in one configuration shown in  FIG. 6 , x-ray source array  200  can have a ring-shaped structure. Object  0  can be positioned inside the ring structure, with target T at a focus of the plurality of x-ray sources  100 , and a plurality of x-ray microbeams can thereby be emitted from multiple locations along a circumference of the ring towards target T. In another configuration shown in  FIG. 7 , x-ray source array  200  can have a polygonal structure with multiple segments, each segment essentially operating as a linear x-ray source array. Although the ring-shaped array and polygonal array configurations shown in the figures only have x-ray sources  100  on a portion of x-ray source array  200 , it should be understood by those having skill in the art that x-ray sources  100  can be positioned about the entirety of x-ray source array  200  to more fully distribute the emitted x-ray microbeams MB about target T. 
     Compared to conventional x-ray tubes that typically generate x-rays from a small area on the x-ray anode, therefore, x-ray source array  200  distributes the power over a larger area and/or to multiple focal points on the x-ray anode so that a high dose rate can be achieved. Primarily because of the limitations of the heat load of the x-ray anode, a current state-of-art commercial thermionic x-ray tube can be operated at around 100 kW at an effective focal spot size of 1×1 mm (after reflection). This is insufficient for the dose rate required for MRT. Specifically, previous study of MRT indicates that a dose rate in the order of 100 Gy/sec can be effective, but achieving such dose rates has previously only been possible using a synchrotron source. In the present systems and methods, however, x-ray microbeams MB can be generated around the circumference of a ring- or polygon-shaped anode structure and directed towards target T. By distributing the power over a large area, a much higher x-ray dose can be achieved without generating excessive heat loads at any one x-ray anode. Further, through the use of carbon-nanotube-based field emission x-ray sources  100 , the size of the x-ray focal spot can be reduced compared to prior art devices (i.e., less than 1×1 mm). 
     Further, a system for microbeam radiotherapy can comprise a controller  210  that can set the treatment parameters, including the dose to be delivered, the dwell time, the width of the x-ray radiation plane, and the spacing between adjacent radiation planes. In addition, the system can also comprise a patient bed for supporting the patient undergoing radiotherapy (i.e., object O) and a positioning device  220  that can align target T with the radiation field. For instance, the alignment of x-ray source array  200  can be performed using an x-ray computed tomography (CT) scanner  222  (e.g., a dynamic micro-CT) in connection with positioning device  220 . CT scanner  222  can identify the location of target T, as well as any peripheral structures of object O (e.g., normal tissue surrounding a tumor), and positioning device  220  can then be used to align target T with a focus of microbeams MB. 
     In another aspect of the presently disclosed subject matter, a method for microbeam radiotherapy is provided. The method can comprise positioning distributed x-ray source array  200  about target T to be irradiated (e.g., a tumor within a medical patient), x-ray source array  200  comprising a plurality of carbon-nanotube field emission x-ray sources  100 , and simultaneously generating a plurality of x-ray microbeams MB from the plurality of carbon-nanotube field emission x-ray sources  100 . X-ray source array  200  can be structured such that x-ray microbeams MB can be generated from the plurality of field emission x-ray sources  100  at different locations on x-ray source array  200 . X-ray sources  100  can be switched to deliver x-ray microbeams MB to either one or several parallel radiation planes on target T in a short time. A treatment planning program can be used to determine the radiation dose, the width of the x-ray beam, the spacing between the x-ray radiation planes, and the exposure time, each of which can be controlled by a controller  220  in communication with x-ray source array  200 . 
     To generate multiple and parallel irradiation planes, either object O in which target T is contained or x-ray source array  200  can be translated after each exposure to a sequence of positions within a small interval, and x-ray source array  200  can be operated to irradiate target T after each translation. The process can be repeated until the entire area of target T is irradiated. In this way, x-ray source array  200  can deliver x-ray radiation to target T with the dose being distributed in alternating high and low dose planes. 
     The steps for an exemplary process according to this method are shown in  FIG. 9 . Specifically, a method for microbeam radiotherapy can comprise identifying a region of interest (ROI) for irradiation (e.g., target T), and aligning the ROI with a radiation field. For instance, aligning the ROI can comprise positioning object O on a patient bed and aligning the region of interest of object O to be irradiated, such as a tumor (i.e., target T), with a focus of x-ray microbeams MB. For example, a positioning device  220  discussed above can be used to align target T with the radiation field. This alignment can be facilitated by first locating target T within object O. As discussed above, this locating can be accomplished using an imaging device, such as an x-ray computed tomography scanner  222 . It can be further advantageous to monitor the location of target T during the course of treatment. For example, physiological motions of object O generally or target T specifically can be monitored, and the operation of x-ray source array  200  can be synchronized with such physiological motions, which can minimize blurring of the irradiation field due to the motions. Once the ROI has been aligned, the method can further comprise determining a dose, width, and spacing of the radiation plane generated by x-ray source array  200 , and irradiating the ROI. As discussed above, either object O or x-ray source array  200  can be translated by a predetermined distance, and the irradiation process can be repeated until the entire ROI is irradiated. 
     In summary, compact systems and methods are disclosed that can generate spatially discrete x-ray microbeams with planar and other geometries with high dose rate for microbeam therapy. Such microbeam radiotherapy systems and methods can provide can be used for human cancer treatment such as human external beam treatment, intra-operative radiation therapy, brachytherapy, and for preclinical cancer research on animal cancer models. 
     The present subject matter can be embodied in other forms without departure from the spirit and essential characteristics thereof. The embodiments described therefore are to be considered in all respects as illustrative and not restrictive. Although the present subject matter has been described in terms of certain preferred embodiments, other embodiments that are apparent to those of ordinary skill in the art are also within the scope of the present subject matter.