WO2005110495A1 - Biomolecular contrast agents for therapy control in radiation therapy with proton or ion beams - Google Patents

Biomolecular contrast agents for therapy control in radiation therapy with proton or ion beams Download PDF

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Publication number
WO2005110495A1
WO2005110495A1 PCT/EP2005/052252 EP2005052252W WO2005110495A1 WO 2005110495 A1 WO2005110495 A1 WO 2005110495A1 EP 2005052252 W EP2005052252 W EP 2005052252W WO 2005110495 A1 WO2005110495 A1 WO 2005110495A1
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target
bmca
method according
beam
therapy
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PCT/EP2005/052252
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French (fr)
Inventor
Klaus Abraham-Fuchs
Michael Moritz
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Siemens Aktiengesellschaft
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Priority to US84926704A priority Critical
Priority to US10/849,267 priority
Application filed by Siemens Aktiengesellschaft filed Critical Siemens Aktiengesellschaft
Publication of WO2005110495A1 publication Critical patent/WO2005110495A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1048Monitoring, verifying, controlling systems and methods
    • A61N5/1049Monitoring, verifying, controlling systems and methods for verifying the position of the patient with respect to the radiation beam
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0059Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0073Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by tomography, i.e. reconstruction of 3D images from 2D projections
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00Apparatus for radiation diagnosis, e.g. combined with radiation therapy equipment
    • A61B6/48Diagnostic techniques
    • A61B6/481Diagnostic techniques involving the use of contrast agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1085X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
    • A61N2005/1087Ions; Protons
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092Details
    • A61N2005/1098Enhancing the effect of the particle by an injected agent or implanted device
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/10X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N5/1048Monitoring, verifying, controlling systems and methods
    • A61N5/1064Monitoring, verifying, controlling systems and methods for adjusting radiation treatment in response to monitoring
    • A61N5/1065Beam adjustment
    • A61N5/1067Beam adjustment in real time, i.e. during treatment

Abstract

A bio-molecular contrast agent (BMCA) is introduced into a biological organism such that the agent binds or reacts with target tissue within that organism. The BMCA is also signal­giving, allowing control of particle beam therapy by tracking the signal given by BMCA.

Description

BIOMOLECULΛR CONTRAST AGENTS FOR THERAPY CONTROL IN RADIATION THERAPY WITH PROTON OR ION BEAMS BACKGROUND 1. Field of the Invention This invention relates generally to the art of radiation therapy and diagnostic imaging. More specifically, the invention relates to the use of contrast agents in therapy planning and treatment involved in radiation therapy. 2. Related Art In the treatment of cancer and other diseases, therapeutic measures such as particle beam therapy are commonly employed. In particle beam therapy, a beam (or beams) of radiation in the form of electrons, or photons, or more recently, protons, is delivered to a tumor or other target tissue. The dosage of radiation delivered is intended to destroy the tumorous cells or tissues. It is state of the art today that medical imaging techniques such as CT (Computed Tomography), MR (Magnetic Resonance) , PET (Positron Emission Tomography) , optical imaging (ultraviolet/infrared/visible) or ultrasound are used to visualize the target region (most often a tumor) for particle beam therapy. Yet, the medical imaging techniques used for this purpose in many cases cannot reliably differentiate between malign tumors and benign tumors, and

m particular arc not well suited to visualize exactly the borderline between healthy tissue and malign tumors . Thus the therapy control methods today are based on non-optimal medical images, and as a consequence, for the sake of a successful destruction of the tumor, the volume to be irradiated usually is chosen larger than absolutely necessary thereby damaging healthy tissue in the process. Exact positioning and dosage is especially critical n therapies that use proton beams, where the energy is highly concentrated in particular locations due to the well-know Bragg Peak phenomenon . Additionally, it happens in many cases that the images used for therapy planning do not exactly show the location of the target tissue for irradiation during the therapy session, for example because the patient is not positioned exactly in the same way during the imaging and the therapy session, or because the filling of the intestinal tract is different in both sessions, and thus organs are shifted. The composition and relative thickness of fatty tissue, fluids, muscle, and connective tissue in the beam pathway needs to be known, and unfortunately, can change after therapy planning. Recently, artificial or anatomical landmarks are used to control the position of the target tissue . One solution that has been used recently m some

imaging techniques is the introduction of "contrast agents" which enhance the image quality achieved during imaging. To provide diagnostic data, the contrast agent must interfere with the wavelength of radiation used in the imaging, alter the physical properties of the tissue/cell to yield an altered signal or provide the source of radiation itself (as in the case of radio-pharmaceuticals) . Contrast agents are introduced into the body of the patient in either a nonspecific or targeted manner. Non-specific contrast agents diffuse throughout the body such as through the vascular system prior to being metabolized or excreted. Non-specific contrast agents may for instance be distributed through the bloodstream and provide contrast for a tumor with increased vascularization and thus increased blood uptake. Targeted agents bind to or have a specific physical/chemical affinity for particular types of cells, tissues, organs or body compartments, and thus can be more reliable in identifying the correct regions of interest.

Several different targeted contrast agents which bind to particular tissue and then exhibit signal changes based upon state changes in tissues (which are then imaged) are disclosed in international patent application WO 99/17809, entitled "Contrast-Enhanced Diagnostic Imaging Method for Monitoring Interventional Therapies". The methods used today to control the precision of the

irradiation of a target tissue, and to control the success of the irradiation in real-time during the therapy session, are sub-optimal and need to be improved.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates one embodiment of the invention wherein beam positioning is modified based upon a BMCA. Figure 2 illustrates one embodiment of the invention wherein a scan therapy mode is implemented based upon a BMCA. Figure 3 illustrates scan therapy mode irradiation applied to a body of an organism m accordance with one or more embodiments of the invention. Figure 4 illustrates a system utilizing one or more embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION In various aspects of the invention, bio-molecular contrast agents (BMCAs) are introduced into a patient for the purpose of radiation therapy planning and treatment. "BMCA", as the term is used in describing this invention, are at least partially organic contrast agents which have the following properties: 1) they bind to target tissue, cells, and organs, and/or (2) react with metabolic products of the target tissue, cells, and organs by means of highly

specific biochemical reactions (such as body-anti-body mechanisms) . This yields an improved highly precise image of the target region for irradiation. In some embodiments, the invention also uses BMCA that are designed to have certain signal-giving properties as well as having a binding or reactive function. The reactive function can also activate the signal-giving property of the BMCA. These mechanisms help to ensure that the signals used for therapy planning, monitoring and control originate only from the target tissue. Tor instance, fluorescent BMCAs, such as the ones described in U.S. Patent Number 6,083,486, can be used in conjunction with a medical optical imager, like an optical tomograph or a diaphanoscope . As illustrated by the invention such BMCAs and other BMCAs can be adapted for use in therapy planning and real-time, on-line therapy control. One advantage of such BMCAs over conventional contrast agents is that the BMCAs stay immobilized for a longer period within the target tissue, due to the highly specific and stable binding reaction. Thus BMCAs are available for a longer time period to observe/monitor the target region than are conventional contrast agents. BMCAs can also be designed or selected such that their signal-giving property diminishes when the BMCA interacts with the particle beam. The BMCA can thus be "inactivated"

(with respect to its signal-giving property) through irradiation with a particle beam of enough energy. For instance, a fluorescent contrast agent may be inactivated by destroying the fluorescence property of the BMCA which would involve breaking of the functional covalent C-C and/or C-H bindings of the BMCA through irradiation. In some embodiments of the invention, the beam energy, or respectively the irradiation dose, needed to inactivate the signal-giving property of the BMCA is roughly the same energy or dose as needed for successful medical treatment of the target tissue. In this way, two types of information can be derived from the BMCA: the presence of the BMCA through specific binding indicates the target region for treatment . Subsequent diminishing of the signal by destroyed signal- giving properties of the BMCA through the particle beam indicate that the target region has successfully been treated with the particle beam. In one embodiment of the invention, real-time therapy control is achieved through the use of BMCAs which bind to target tissue. The location and geometry of the target tissue can be monitored while irradiation is occurring. Changes in the location and geometry (for instance, the size or extension of the target tissue from a given point) can be fed back to a control system. The signal-giving property

(such as fluorescence, phosphorescence, luminescence, or different spectra or scattering of these) would be constantly measured and stored. The control system would use known or novel image processing techniques upon the obtained signal measurements to determine the precise targeting for the particle beam performing the irradiation. This determination can then be implemented by a particle beam control mechanism which is operated manually or automatically . In yet another embodiment of the invention, a novel scanning therapy mode can be implemented in conjunction with precise particle beam control. A particle beam of a very small diameter (for instance, a few millimeters) can be used to scan sequentially across the target region. The particle beam begins directing energy at an initial location on the target. In one embodiment, the beam scans sequentially in a given direction across the target while monitoring the signal given by the BMCA. The BMCA signal is monitored by a sensing/imaging device and the measurements can be fed to the control system for the particle beam. When the monitored measurements indicate that the BMCA signal is no longer present, there is a high likelihood that the outer edge of the target in the current beam direction (if sequential) has been reached. The particle beam is then given a new initial targeting location which can be, in one

embodiment, directly adjacent to the current location within the target where the sensing/imaging device last received an adequate signal from the BMCA. The particle beam is then redirected to deliver energy toward the new initial targeting location on the target and then moves sequentially in a direction e.g. parallel or identical to the prior direction. BMCA include small molecules and preferably bio- molecules with an affinity or reactivity with the target tissue. lhe affinity to bind or reactivity can be dependent on tissue state or tissue type or both. Bio-molecules are typically biologically derived or synthesized from naturally occurring elements such as ammo acids, peptides, nucleotides and so on. Examples include receptor ligands, saccharides, l pids, nucleic acids, proteins, naturally occurring or genetically engineered anti-bodies . BMCA include those bio-molecules which can bind to proteins m plasma, in the fluid between cells, or n the space between cells . BMCA also includes dyes and other signal generating compounds, as desired. The difference in binding affinity of one bio-molecule versus another can have an effect m the signals that are ultimately received from the BMCA and in the accuracy of the binding to the target tissues. Thus, the specific nature and structure of the BMCA selected for the purpose of therapy control will depend upon which tissue

or tissue component is to be bound. The binding sites for BMCA include such components and tissue as bones, calcified tissues, cancerous tissues, cell membranes, enzymes, fat, certain fluids (such as spinal fluid), proteins etc. BMCAs used m this invention may also include pharmaceutically accepted salts, esters, and derived compounds thereof, including any organic or inorganic acids or bases . S may be accompanied by other agents, such as salts, oils, fats, waxes, emulsifiers, starches, wetting agents which may be used to aid m carrying the BMCAs to the target more rapidly or more securely, or in diffusing the BMCAs into external tissue such as sk n. Figure 1 illustrates one embodiment of the invention wherein beam positioning is modified based upon a BMCA. A bio-molecular contrast agent or agents (BMCA) is introduced into the patient or animal or other organism being treated (block 110) . Methods for introduction of BMCA may be similar to methods used to introduce other contrast agents, such as intravenous or oral and may be targeted or nonspecific (such as those which spread throughout a region of the body) . Other methods specific to BMCA may also be used. The BMCA, once introduced, is allowed to bind to tissues or react with the tissues (block 120) . Thus, a suitable delay after introduction of the BMCA is required. This delay will vary based upon the type of binding or reaction, the type.

size and location of the target tissue, the characteristics/affinity of the BMCA, and so on. The time for allowance should be sufficient to stabilize the BMCA binding or reaction with the target. An imaging technique, such as MR, PET, X-ray, CT or optical imaging, can then be used to locate the initial position and extension of the target tissue (s) (block 130) . The imaging technique will sense the signals given by the BMCA and from a composite reading of all such signals, construct an image. tor example, the imaging technique may involve sensing the fluorescence of BMCA, for instance in BMCA which contain flurochromes, and then illuminating the target tissue region to activate the flurochromes to fluoresce. A CCD imaging device can then be used to translate the detected fluorescence into an image. Also, medical optical imagers such as diaphonoscopes and optical tomographs can be used to construct an image. The exact initial position/location of the target ti ssues can be determined by applying the imaging technique to the region of the body containing the target tissue. In one embodiment of the invention, this can be performed as part of the therapy plan as well. In other embodiments, the imaging technique is used to determine the position/location of the target after the therapy plan has been set and prior to the start of therapy.

Next, the target tissues arc irradiated with the particle/radiation beam (block 135) . The particle therapy beam may deliver any form of radiation including beams comprised of protons, electrons, photons and other ions. The beam of energy is first directed in accordance with both the therapy plan and the initial location determined by the imaging (according to block 130) . The imaging technique (described in reference to block 130) can be used to track the position/location of the target tissue during irradiation as well (block 140) . In one embodiment of the invention, the image obtained prior to the start of therapy in determining the initial tissue location/position is compared with any change in signals (at various locations) from BMCA that are detected. Drastic changes in BMCA signals may be indicative of a change in position/location of the target tissue being irradiated (checked at block 150) . If there is a detected change in position of the target, then the particle beam targeting is modified accordingly (block 160) and the target can be irradiated in accordance with the new position (block 170) . This can especially important in the case of proton particle beam therapy where the Bragg Peak energy must be more precisely located to avoid damage to healthy or non-target tissues that are outside of the therapy plan. Even after adjustment of the particle beam, further changes in position and

location of the target might occur which would need constant monitoring of the BMCA signals (block 140) during irradiation. The control of the particle beam used for irradiation can be achieved by a combination of human-assisted and automated means. The data from the imaging of the BMCA can output corrected position parameters directly to an automated control system and/or a human operator controlling the direction of the particle beam The feedback to the control system of the particle beam or therapy device will allow automation of re-directmg the particle beam as needed. Figure 2 illustrates one embodiment of the invention wherein a scan therapy mode is implemented based upon a BMCA. Scan therapy mode is a form of therapy implemented by a small diameter particle beam which is scanned sequentially along arbitrary paths across the target, in order to precisely irradiate a volume within the boundaries of any arbitrary shape and geometry. This scan therapy mode is advantageously improved according to the invention by using a BMCA n conjunction with it, in that the BMCA signals or the contrast-enhanced BMCA image are used to indicate the area or volume which is to be scanned by the particle beam. The scan therapy mode also allows irradiation m real-time of the tissue without the necessity for a pre-therapy image.

First, a bio-molecular contrast agent or agents (BMCA) is introduced into the patient or animal or other organism being treated (block 210) . Methods for introduction of BMCA may be similar to methods used to introduce other contrast agents, such as intravenous or oral and may be targeted or non-specific (such as those which spread throughout a region of the body) . Other methods specific to BMCA may also be used. The BMCA, once introduced, is allowed to bind to tissues or react with the tissues (block 220) . Thus, a suitable delay after introduction of the BMCA is required. This delay will vary based upon the type of binding or reaction, the type, size and location of the target tissue, the characteristics /af inity of the BMCA, and so on. The time for allowance should be sufficient to stabilize the BMCA binding or reaction with the target. The particle beam is first set to a scan therapy mode (block 230) . In this mode, the beam of energy that impacts the target is only a few millimeters of diameter, or even less, compared with several centimeters, of an ordinary conventional particle therapy beam. In the case of proton beam therapy, such a scan therapy mode is particularly effective because the energy irradiated is concentrated. Again, an initial targeting location is determined (block 240) . The initial targeting location for the scan therapy beam can be by way of a therapy plan and/or real-time

imaging of the current position/location of target tissue. This imaging technique, as discussed above with respect to Figure 1, can utilize a BMCA given signal which is sensed and translated into positional coordinates or into a model or actual image of the target. The initial location is preferably, m one embodiment, representative of the edge or near the edge of the target tissue where the target tissue meets healthy or non-target regions of the patient or subject being treated. The target is irradiated in a sequential fashion using the small scan therapy beam. The target is irradiated using a small diameter particle beam (j.n scan therapy mode) which starts at the determined initial starting location and continues to "scan" across the target tissue, irradiating it along the way (block 250) . The particle therapy beam may deliver any form of radiation including beams comprised of protons, electrons, photons and other ions. The scanning is performed preferably linearly in a given direction, but can also be performed in a patterned- manner such as in a contour pattern (circular or semicircular) or in any arbitrary path as desired. The presence of the target tissue is tracked during irradiation as the energy beam is scanning (block 260) . This tracking may be performed by an imaging technique (for instance, sensing flurochromes and imaging the sensor data) . in some embodiments of the invention, the

scanning particle beam can inactivate the BMCA signal. The reduction in BMCA signal can also be measured as a means of tracking whether the target tissue is still present along the path of the scanning therapy beam. By tracking the presence of the target tissue, there is no need to a priori determine the exact contour and extension of the target tissue. Further, any change in extension or position is automatically accounted for. One key aspect is that the smaller than conventional size (i.e. diameter), when a horizontal slice of beam is considered, allows very fine control of irradiating the target. As long as the presence of the target tissue is still detected (checked at block 270), the scanning therapy particle beam continues to irradiate the target. When the presence of the target tissue is no longer detected, then a ' presumption can be reached that the outer edge of the target tissue in the direction of the scanning therapy beam has been reached and passed. At this point, irradiation by the scanning therapy beam is ceased (block 275) to prevent any other irradiation of potentially healthy or non-target tissues. Since the scan therapy along one row has been completed (a "scan sequence", then the next initial targeting location is determined (block 280) . The next initial targeting location may be adjacent to the ending position of the scanning therapy beam in the

previous sequential scan therapy. By adding or subtracting a fixed or variable quantity to the ending position of the scan therapy beam (ending position of the previous scan sequence) , the new initial targeting location can be determined. The quantity added may be simply the diameter of the scan therapy beam, which would allow a nearly adjacent next scan therapy. For instance, in one embodiment of the invention, the diameter of the scan therapy beam would be added (or subtracted depending on sequence direction) to the ending position of the scan therapy beam in the previous scan sequence. Then, the scan therapy beam can be set to run in the opposite direction of the previous scan sequence, so that the scan therapy beam moves across the target tissue in the other direction. Optionally, a pre-therapy or current real-time image of the target (obtained for instance in conjunction with an imaging technique) can be used in determining the next initial targeting location. In still other embodiments, the next initial targeting location can be set adjacent to the previous initial targeting location such that the scan therapy beam n the next sequence moves in the same or similar direction to the previous sequence. Starting at the new initial targeting location, the scan therapy beam then irradiates the target in a new or same direction as the previous scan sequence (block 290) . Again, as with all scan

sequences, the presence or non-presence of the target tissue is tracked continuously during irradiation (block 260) . Scan sequences can be repeatedly performed until all or substantially all of the target tissue has been irradiated. Figure 3 illustrates scan therapy mode irradiation applied to a body of an organism in accordance with one or more embodiments of the invention. BMCA 390 is delivered into body 360 such that it attracts and binds with or chemically reacts with target tissue 350 but not with healthy tissue (not shown) within body 360. BMCA 390 has a signal-giving property which can be measured and imaged. The combination of the signal-giving property and the tissue binding (or tissue reactive) property allows precise irradiation without reference to a pre-session therapy plan being followed. The radiation therapy system, such as a photon or proton beam therapy system 300 is shown only with respect to the exit nozzle where the scan therapy beam 310 leaves the system and is delivered to the body 360 of a patient . The scan therapy mode of the invention involves a small diameter scan therapy beam 310 which is magnitudes of size smaller than conventional radiation therapy beams. A first initial targeting location 352 is determined on a target tissue 350 within body 360. This location may be determined as the result of one or more processes such as an imaging technique, including the use of bio-molecular

contrast agents to perform the imaging and/or therapy plan based images and markings on body 360 identifying the contours of the target tissue 350 The initial targeting location 352 is preferably near an edge of the target tissue 350. In one embodiment of the invention, a first scan therapy sequence proceeds as follows . After determining the initial targeting location 352, system 300 (or parts thereof) are configured and aligned such that the scan therapy beam 310 is directed at initial targeting location 352. The scan therapy beam 310 stays in place at the first targeting location 352 until the desired dosage (or duration of treatment) is achieved. After the desired dosage/duration of irradiation is achieved, the system 300 is re-configured so that beam 310 is redirected such that it moves in a first direction 312 of scan. This "sequential" scan m the direction 312 across the target tissue 350 continues until the edge of the other side of target tissue 350 is encountered. The edge can be determined by reference to the signal given by BMCA 390. Once the signal given is no longer detected (as the beam 310 is moving along the target 350 in direction 312), then it is likely that the edge of the target tissue 350 in the scan direction 312 has been reached. The BMCA 390 may also have the property of deactivating or decreasing its signal when impacted by the

radiation of the scan therapy beam 310. In one embodiment of the invention, the edge also determines the ending position 353 of the scan therapy sequence. At this point, the beam 310 is discontinued so that it does not irradiate until the beam 310 can be redirected at a new are of the target 350. The ending position 353 can be used to determine the initial targeting location 354 for the next scan therapy sequence. For instance, by adding the diameter of the beam 310 to the ending position 353, the new initial targeting location 354 (which would represent roughly the center of the beam 310 impact area) can be determined. The therapy system 300 would then realign/reposition the beam 310 so that it directs radiation at the new initial targeting location 354. The next scan therapy sequence can then commence by irradiating and directing the beam along a new direction 314 of scanning. The direction 314 would, in this example, be 180 degrees different from (i.e. in the opposite direction as) direction 312 in which the previous scan therapy sequence was commenced. The scan therapy sequence continues until another edge of the target 350 is encountered. In other embodiments of the invention, the next initial targeting location 354 could instead be adjacent to starting location 352, with the scan therapy sequence starting therefrom proceeding m the same direction 312 as the

previous scan therapy sequence. The path of scan therapy sequences, as mentioned before, need not be linear, and can be contoured or even arbitrary if desired. This is possible because the end of the scan therapy sequence is determined by the tracking and analysis of the BMCA signals and not necessarily according to images of the contours, positions, location or extension of the target. Figure 4 illustrates a system utilizing one or more embodiments of the invention. At least a portion of a treatment room 400 is shown which houses a therapy device 450 and bed 405 which positions a patient 410 for treatment by treatment device 450. Treatment device 450 may be a radiation or energy delivery system such as proton or photon particle beam delivery system. Treatment device 450 may include a gantry (pictured but not enumerated) and treatment head 455. Treatment head 455 is responsible primarily for delivering and directing the desired or planned energy to patient 410 m the form of a beam 460, for instance. Treatment head 455 may include a number of different elements include scattering elements, collimators, boluses, refraction/reflection elements, and so on. Generally, in the case of a beam 460 which is composed of particles (such as photons, protons, electrons, neutrons and heavy ions), a particle stream is externally generated and accelerated (by a cyclotron and/or linear accelerator)

and then tho particle stream (or a portion of it) is delivered to treatment head 455. Treatment head 455 can limit or define both the size and shape of the beam 460 as well as the intensity of the beam 460. Treatment head 455 may also contain a nozzle which can be rotated in different axes to deliver the beam 460. Utilizing this nozzle and various elements within the treatment head 455, therapy device 450 can deliver energy into patient 410 at a different incident angle and with varying shape, size and intensity, as desired. A therapy device control system 440 may be employed for the purpose of controlling the various elements of the treatment head 455 and for controlling the level of energy introduced from the externally generated particle source. In accordance with the invention, prior to treatment by treatment device 450, a BMCA is introduced into patient 410. The BMCA is given t me to bind or react to target tissue within the patient 410 to which the beam 460 is to be directed. As mentioned earlier, the target tissues can be initially located using an imaging technique or body marking or similar technique either currently or previously by way of a therapy planning session. The therapy device control system 440 utilizes this initial location information to direct beam 460 towards patient 410. This begins irradiation of the target tissue.

During irradiation, the geometry and location o± the target tissue can be tracked by a sensing system 420. Sensing system 420 will be capable of receiving or detecting the signal emitted by the signal-giving property of the BMCA which is bound to the target tissue within patient 410. Sensing system 420 may be, for example, an optical tomography device or a diaphonoscope which can detect the fluorescence given off the BMCA. The signals emitted by the BMCA may be optical, ultraviolet, infrared, electromagnetic

(in the case of a radio-pharmaceutical BMCA), and so on. Sensing system 420 will be designed/selected m order to detect this signal and transfer this sensor data to decision system 430. Sensing system 420 may also include a source

(not pictured) such as X-ray source in the case of simple X- ray imaging. Sensing system 420 will be able detect the presence and strength of the BMCA signal emitted from patient 410, and responding thereto, generate data which can be utilized m finding the position, location and geometry of the target tissue to which the BMCA is bound. While sensing system 420 is pictured as a non-integrated unit, it can be integrated with the treatment head 455, if desirable, or positioned or integrated anywhere on the therapy device 450 as appropriate. In some embodiments of the invention, the BMCA signal can be inactivated by exposure to beam 460. In such

instances, the sensing system will detect the strength of the BMCA signal as an indication of impaction of beam 460 with the target. In response to data received from sensing system 460, decision system 430 will be able to determine the position, location and/or geometry of the target tissue. Decision system 430 may also have access to a pre-therapy image or images of the target tissue for comparison. Decision system 430 will determine if there is a change in position, location or geometry of the target tissue If there is, and this change s significant enough to affect the therapy plan, then decision system 430 can indicate these changes to the therapy device control system 440. Based upon these changes, the therapy device control system 440 can change the direction or angle of the beam 460 to correspond to the change or variance in the location, position or geometry of the target tissue. The beam 460 can thus be re-targeted or stopped altogether, if necessary, particularly if the sensing system 420 and decision system 430 indicate that the target tissue is no longer present. The decision system 430 may send position/location/geometry information which can then be manually evaluated by an operator handling therapy device control system 440, or the action by the therapy device control system can be automated, whichever is more desired. In other embodiments of the invention, the therapy device control system 440

could modify the position of the patient 410 or the bed 405 in response to decision system 430 indicating a change in target tissue. As mentioned above, some embodiments of the invention involve a novel scan therapy mode of treatment which also involves introduction of a BMCA into patient 410 and binding/reaction thereof to target tissue. Therapy device control system 440 can initially place therapy device 450 into this mode. The treatment head 455 in this mode would limit the diameter of the beam 460 to a few millimeters or whatever desirable size making the energy delivery thereby to patient 410 more precise. The first scan therapy sequence begins at an initial location on the patient 410. The beam 460 irradiates the target at that location and then moves or sweeps in a particular direction or following a particular pattern/path (such as a target tissue contour) . The BMCA signal is tracked by sensing system 420 in a continuous or polled fashion, and thus, where the signal is present, the tissue is deemed to be present. As mentioned, the BMCA signal can be inactivated or activated by the irradiation of beam 460. In this case, the presence or declining strength of the BMCA signal would indicate that target tissue is being irradiated by beam 460. When the sensing system 420 no longer detects a BMCA signal, then the target tissue is no longer present. At that point the

sensing system 420 alerts the decision system 430 to the absence of signal. In response, the decision system 430 would indicate to the therapy device control system 440 to direct the therapy device 450 to terminate the beam 460. In this way, the exact extent of the target tissue need not be known a priori, the scanning therapy beam 460 would discover it by reading the BMCA signal. Once the end of a scan therapy sequence is reached, a new starting location for the beam 460 and a new scan therapy sequence can be determined with the aid of decision system 430 which would position/location information as obtained from a combination of pre-therapy imaging, therapy plan parameters and/or images obtained as a result of interpreting data from sensing system 420. In alternate embodiments of the invention, the BMCA can be seelcted to modify the X-ray radiation absorption properties of the target tissue or m other words, interfere with the wavelengths used in imaging. In such embodiments, the BMCA alters thus the imaging signal and enables better imaging of the BMCA signals (and perhaps more accurate imaging of the target tissue) . The type of BMCA can be selected in accordance with the particular imaging modality (such as ultrasound. X-ray, CT, PET, MRI etc.) sought to be used m or with the sensing system 420. The systems mentioned in the above description

including the sensing system 420, decision system 430 and therapy device control system 440 may be any combination of hardware, software, firmware and the like. Further, all of these systems may be integrated onto the same hardware platform or exist as software modules in a computer system or both. The systems may be distributed in a networked environment as well and may be stand-alone components. One or more of the systems 420, 430 and 440 may be integrated with the therapy device 450 itself, or separate therefrom. Further, any number of these systems 420, 430 and 440 may be physically separated from the therapy device and manually/automatically monitored or controlled. Systems 420, 430 and 440 may utilize or be loaded into processors, storage devices, memories, network devices, communication devices and the like as desired. Sensing system 420 may also contain cameras, sensors, and other active/passive detection and data conversion components, without limitation . In some embodiments of the invention, a novel 3-D scan therapy mode can be implemented in conjunction with precise particle beam control. If the particle beam used is a proton beam, in particular, the depth of energy delivery into the target can be controlled and known more precisely than with other particle beams. This is due to the Bragg Peak phenomenon in which the majority of the energy of the

protons is delivered into the tissue when the protons have slowed down (been "stopped") at a particular depth (the Bragg Peak depth) into the tissue. With other forms of radiation therapy, the energy is distributed m a much more even pattern at all depths of penetration. By utilizing the Bragg Peak phenomenon, it is possible to direct the particle beam at different specific tissue depths. In at least one embodiment of the invention, a two dimensional scan of the tissue is obtained using BMCA to particle beam interaction at a first Bragg Peak depth. Then, repeated two-dimensional scans are performed at successive, different Bragg Peak depths. By combining the two dimensional scans together, a precise three-dimensional therapy scan of the target tissue can be obtained. In one embodiment of the invention, the total depth (thickness) of the target tissue may be determined by a pre-scan using medical imaging techniques such as CT, PET, MRI, Ultrasound, and so on. Based upon this pre-determined depth, a three- dimensional scan therapy may be implemented. In a three- dimensional scan, the energy of the beam would be modified in order to achieve energy delivery (and hence BMCA signal readings) from different depths. In other embodiments of the invention, where the depth of the tissue is not known or cannot be accurately determined (for instance, due to image noise m a optical

imaging system) , then a depth determination mechanism may be implemented. The depth determination mechanism involves the introduction of BMCA which not only is signal-giving, but also signal-reactive . The BMCA is "inactivated" by the particle beam in that the signal given by the BMCA diminishes in strength when irradiated. The particle beam can be directed to irradiate the target tissue at successive Bragg Peak depths. hen the signal diminishes sufficiently at one depth, the BMCA will no longer be active at that depth and allow for the next BMCA signal at the next successive depth to be sensed. The presence and strength of the signal can be detected at the next successive depth by directing the particle beam energy to that depth. When the BMCA signal strength again diminishes significantly at that new depth, then the process can be repeated at further successive depths. When the BMCA signal is no longer present, then the target tissue will be determined to not be present and the depth of the tissue can thereby be established by recording the last depth at which a BMCA signal was detected. This depth determination can be performed as part of pre-therapy or in real-time during therapy itself. Real-time depth determination is possible where the energy dosage required to inactivate the BMCA signal corresponds roughly with the same energy required to destroy the DNA of the target tissue (and hence successfully

complete therapy) . Real-time depth determination eliminates the need for a pre-therapy tissue depth determination. The term "depth" refers to penetration of the target tissue wherein the direction/angle of the beam into the target tissue is fixed, but the level of penetration is variable. Thus, "depth" refers to the tissue thickness when considered in any given direction. While the embodiments of the invention are illustrated in which it is primarily incorporated within a radiation therapy system, almost any type of medical treatment of imaging system may be potential applications for these embodiments. Further, the bio-molecular contrast agents used m various embodiments may be any organic or semi- orgamc compounds which have the desired effect of affinity to certain target tissues/cells to either bind with them or react with them. The examples provided are merely illustrative and not intended to be limiting.

Claims

CLAIMS What is claimed is: 1. A method for controlling a therapy device directing a beam of energy to a target within a biological organism comprising: introducing a bio-molecular contrast agent (BMCA) into said biological organism, said BMCA capable of at least one of binding to said target and reacting with said target, said BMCA capable of also giving detectable signals; irradiating into a first direction toward said target using said beam of energy m accordance with a pre-therapy plan; after said BMCA has bound or reacted to said target, modifying the direction of said beam if said BMCA signals indicate that the position of said target is varied from its position given by said pre-therapy plan.
2. A method according to claim 1 wherein said target is a tissue in a- particular state.
3. A method according to claim 1 further comprising: tracking of said BMCA signals.
4. A method according to claim 3 wherein if said BMCA signals are not detectable, then determining that the target is no longer present .
5. A method according to claim 3 wherein said tracking is performed using an imaging technique, further said BMCA signals are capable of being imaged.
6. A method according to claim 5 wherein said imaging technique is at least one of optical imaging, positron emission tomography, magnetic resonance imaging, X-ray imaging and computed tomography.
7. A method according to claim 1 wherein said BMCA signals include at least one of luorescence, luminescence and phosphorescence .
8. A method according to claim 1 further comprising: utilizing said BMCA signals to detect changes of position of said target.
9. A method according to claim 6 wherein said optical imaging includes detecting at least one of visible, infrared and ultraviolet signals given by said BMCA.
10. A method according to claim 3 wherein if said BMCA signals are not detectable, then determining that the target is has changed state.
11. A method according to claim 1 wherein said beam of energy is composed at least one of proton, photon, heavy ion, neutron and electron particles.
12. A method for controlling a therapy device directing a beam of energy to a target within a biological organism comprising: introducing a bio-molecular contrast agent (BMCA) into said biological organism, said BMCA capable of at least one of binding to said target and reacting with said target, sa d BMCA capable of also giving detectable signals; and after said BMCA has bound or reacted to said target, directing said beam to a region of said target from where the BMCA signal originates.
13. A method for controlling a radiation beam delivery system treating a target with irradiative energy, comprising: introducing a bio-molecular contrast agent (BMCA) into a biological organism, said BMCA capable of at least one of binding to said target and reacting to said target, said BMCA capable of also giving detectable signals; placing said radiation beam delivery system into a scan therapy mode; determining an initial targeting location for a first- scan therapy sequence;
irradiating said target tissue with said system using a small diameter of said radiation beam; directing said radiation beam to move along a first direction of the target starting from said first initial targeting location, said radiation beam irradiating in the path defined by the directing of said beam; and discontinuing irradiating of the target as soon as said BMCA is no longer detected along said path defined by the directing of said beam.
14. A method according to claim 13 wherein the steps of determining, irradiating, directing and discontinuing are repeatedly performed for additional scan therapy sequences .
15. A method according to claim 14 wherein each of said additional scan therapy sequences are targeting different regions of said target than other scan therapy sequences.
16. A method according to claim 14 wherein said additional scan therapy sequences are sufficient to cover the entirety of said target.
17. A method according to claim 14 wherein at least some of said additional scan therapy sequences target the same regions of said target covered by other scan therapy sequences in order to deliver additional irradiative energy thereto.
18. A method according to claim 13 wherein said target is a tissue in a particular state.
19. A method according to claim 13 further comprising: tracking of said target using BMCA signals.
20. A method according to claim 19 wherein if said BMCA signals are not detectable, then determining that the target is not present.
21. A method according to claim 19 wherein said tracking is performed using an imaging technique, further said BMCA signals are capable of being imaged.
22. A method according to claim 21 wherein said imaging technique is at least one of optical, positron emission tomography, magnetic resonance imaging, X-ray imaging and computed tomography.
23. A method for directing a beam of irradiative energy to a target within a biological organism comprising: introducing a bio-molecular contrast agent (BMCA) into said biological organism, said BMCA capable of at least one of binding to said target and reacting with said target, said
BMCA capable of also giving detectable signals; placing said beam nto a scan therapy mode, said beam having a small diameter; after said BMCA has bound or reacted to said target, initially directing said beam to a region of the target from where the BMCA signal originates; and further directing said beam along an arbitrary path of said target n a scan therapy sequence until said BMCA signal is no longer detected.
24. A method according to claim 23 wherein the steps of initially directing and further directing are repeatedly performed for additional scan therapy sequences.
25. A method according to claim 24 wherein each of said additional scan therapy sequences targeting different regions of said target than other scan therapy sequences.
26. A method according to claim 24 wherein said additional scan therapy sequences are sufficient to cover the entirety of said target.
27. A method according to claim 24 wherein at least some of sa d additional scan therapy sequences target the same regions of said target covered by other scan therapy sequences in order to deliver additional irradiative energy thereto.
28. A method according to claim 23 wherein said target is a tissue in a particular state.
29. A method according to claim 23 further comprising: tracking of said target using BMCA signals.
30. A method according to claim 29 wherein if said BMCA signals are not detectable, then determining that the target is not present .
31. A method according to claim 29 wherein said tracking is performed using an imaging technique, further said BMCA signals are capable of being imaged.
32. A method according to claim 31 wherein said imaging technique is at least one of optical, positron emission tomography, magnetic resonance imaging, X-ray imaging and computed tomography.
PCT/EP2005/052252 2004-05-18 2005-05-17 Biomolecular contrast agents for therapy control in radiation therapy with proton or ion beams WO2005110495A1 (en)

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