AU2016201333B2 - System for delivering conformal radiation therapy while simultaneously imaging soft tissue - Google Patents

Abstract

Examiner's Abstract AU2016201333 A system and a computer program product comprising a non-transitory machine-readable medium storing instructions that, when executed by at least one programmable processor, cause the at least one programmable processor to perform operations comprising: receiving magnetic resonance imaging data captured by a magnetic resonance imaging system during radiation therapy of a patient during a treatment fraction, the magnetic resonance imaging data acquired at a rate sufficient to capture intra-fraction organ motions; receiving data indicating ionizing radiation doses delivered to the patient; and determining an actual dose deposition in the patient from the magnetic resonance imaging data and the delivered ionizing radiation doses data by summing doses delivered to the patient over at least a portion of the treatment fraction.

Description

2016201333 01 Mar 2016 WO 20.,5/..81842 PCT/US2UU5/....4953

WHILE SI^LTANEOUSLY IMAG^G SOFT TISSUE CROSS-REFERENCE TO RELATED ARPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 60/546,670, which was filed Febniary 20, 2004. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH ORDEVELOPMENT [0002] Not applicable. FIELD OF THE INVENTION [0003] This invention relates to a radiotherapy system and method, more particularly a radiotherapy system and method for rapidly and repeatedly imaging the anatomy of a patient during the moments tirat dose is delivered to the patient during radiation therapy so that the achral ionizing radiation dose delivered to the patient hi portions over a course of many days or weeks may be determined and the therapy may be adjusted to account for any treatment delivery enors caused by organ motions or changes in patient geometty. The magnetic resonance ima^ng method employed in this invention also improves foe soft tissue contiast over the existing χ-ray computed tomography (CT) imaging and may provide additional metabolic and physiological information to improve target delineation and allow for tile monitoring of the response ofthe patient or disease to therapy. BACKGROUND OF THE MENTION [0004] fo tieating disease caused by proliferative tissue disorders sucli as cancer and coronary artery restenosis with radiation, the portions of the patient known to (WP218792;4j 2 wo 2005/081842 PCT/US2l/0٠)4953 2016201333 01 Mar 2016 contain or suspected to contain disease are irradiated. For this purpose, a radiotherapy planning system is used to first acquire planning images of the diseased portion(s) and surrounding regions.

[0005] Radiotherapy planning systems generally include a CT or magnetic resonance imaging (MRI) simulator. CT or MRI radio^aphy is carried out on a single day before the beginning of therapy to acquire a plurality of coregistered sectional 2-D images. These sectional images are combined using known algorithms to produce 3-D images. These 3-D simulation images are displayed and then analyzed to identity the location of regions of suspected disease to be treated, such as a radiographically evident tirmor or regions suspected of microscopic disease spread. These regions to be tieated are called radiotherapy targets. In order to attempt to account for organ motions, he concept of margins and planning target volumes (PTVs) was developed to attempt to irradiate a volume that would hopefillly contain the target during most of he irradiation. PTVs include a geometric mar^n to account for variations in patient geometty or motion. Likewise, the 3-D simulation images are displayed and then analyzed to identify importairt normal anatomy and tissues that may be damaged by foe radiation, such as the spinal cord and lung, to evaluate tire potential impact of radiation on tire fuirction of these tissues. These regions to be spared or protected from excessive radiation are called critical structures or organs at risk and may also include a margin to account for variations in patient geometty or motion. The delivery of radiation therapy is then ttaditionally planned on a single static model of radiotherapy targets and critical structures derived from a single set of CT and/or MRI images. Because the known art does not allow for sinrultaneous imaging and therapy, the patient and all of their internal organs ireed to be repositioned exactly for accurate dose delivery. However, it is known in the art that exactly repositioning the patient even for a single delivety of dose is not possible due to several factors including: the inability to reproduce the patient setup, i.e., the geometry and alignment of foe patient’s body; physiological changes in the patient, such as weight loss or ttrmor growth and shrinkage; and organ motions in the patients including but not limited to breathing motion, cardiac motion, rectal distension, peristalsis, bladder filling, and voluntary muscular motion. Note that the organ motions may occur on rapid time scales such that changes may occur during a single dose delivety (e.g., breathing motion), termed "intra-fraction" organ motions, or they may 3 |WP218752;4) wo 281842لا/5لالا PCT/lJS2005/004953 2016201333 01 Mar 2016 occur ٠η slower time scales such that changes occur in between dose deliveries؛ termed “inter-fraction" organ motions. Much of the curative treatment of patients with cancer outside the CTanium requires the delivered radiation therapy to be fractionated, i.e., the dose is delivered in many fractions. Typically, dose is delivered ئ single 1.8 to 2.2 Gy fi-actions or double 1.2 to 1.5 Gy fractions daily, and delivered during the work week (Monday through Friday)؛ taking 7 to 8 weeks to deliver, e.g., a cumulative dose of 70 to 72 Gy at 2.0 or 1.8 Gy, respectively. A purpose of this invention is to overcome the limitations imposed on radiation therapy by patient setup errors, physiological changes, and botlr infra- and inter-fraction organ motions throughout the many weeks of radiation therapy. Anotlrer purpose is to allow the physician to periodically monitor the response of the patient's disease to the therapy by performing MRI that provides metabolic and physiological information or assessing the growth or shrinkage of gross disease.

[0006] An irradiation field shape is then determined to coincide with an outline of an image of the target’s diseased regions or suspected regions appearing in the planning images. An irradiating angle is determined from sectional images of a wide region including the diseased portion or a fransmitted image, seen from a particular direction, produced by the 3-D simulation images. A fransmitted image seen from the irradiating angle is displayed. The operator then detemines a shape of an irradiation field on the image displayed, and sets an isocenter (reference point) to the irradiation field.

[0007] Optionally, the patient may be positioned relative to a conventional simulator (ortho-voltage χ-ray imaging system that allows portal images to be generated for radiation therapy setirp). An irradiating angle corresponding to the iiradiating angle determined as above is set to the simulator, and an image is generally radiographed on a film through radio^aphy for use as a reference radiograph. Similar digitally reconstnicted radiographs may be produced using CT or MRI simulation software.

[0008] The patient is then positioned and resti'ained relative to a radiation freating apparatus which generally includes a radiation source, typically a linear accelerator. An irradiating angle is set to the frradiating angle determined as above, and film radiography is carried out by emitting radiation from the radiation freating apparatiis. Tlris radiatioir film image is correlated with the above film image acting as the reference radiograph to confirm that the patient has been positioned according to plan as correctly 4 (WP2!8792;4} wo 2005/081842 PCT/US2005/0040S3 2016201333 01 Mar 2016 as possible tefore proceeding with radiotherapy. Some positioning is generally required to place the patient such that the structures in the reference radiograph match the structures in the treatment radio^aph to within a tolerance of 0.2 to 0.5 cm. After acceptable patient positioning is confirmed, radiotherapy is begun.

[0009] Patient sehip errors, physiological changes, and organ motions result in increasing misalignment of the treataent beams relative to he radiotherapy targets and critical structures of a patient as the radiotherapy process proceeds. For years practitioners have been acquiring hard-copy films of the patient using the radiation therapj/ beam, technically referred to as a "port film" to attempt to ensure that the beam position does not significantly vary ftom he original plan. However, the port films acquired are generally only single 2-٥ projection images taken at some predetermined interval during the radiotherapy process (typically 1 week). Port films cannot account for orgarr motion. Additionally, port films do not image soft tissue anatomy with any significant conttast and only provide reliable information on he boney anatomy of he patient. Accordingly, misalignment hformation is only provided at the instants in time in which the port images are laken and may be misleadhg as the boney anatomy and soft tissue anatomy alignment need not conelate and change with time. With appropriate markers in he port image provided, the beam misali^ment may be determined and hen corrected to some limited degree.

[00010] More recently, some have disclosed acquiring tire port images electronically, referred to as electionic portal imaghg. This imaging technique employs solid state semiconductor, schtillator, or liquid ionization chamber array technology to capttrre χ-ray tiansmission radiographs of the patint using tire χ-rays of he linear accelerator or an associated kilovoltage χ-ray unit. As with he hard-copy technique, misalignment data is oirly provided at the instants in time in wlrich the port images are taken. Another recent advance ئ electionic portal imaging includes he use of implanted interstitial radio-opaque markers that attempt to image the location of soft tissues. These procedures are invasive and subject to marker migration. Even rvhen performed with the rapid acquisition of many images, it only finds the motion of discrete points identified by tire radio-opaque markers hside a soft tissue and cannot accourrt for the hie complexities of organ motions and the dosimetiic errors that they cause. Anotlrer recent advance, tlrat creates 3D volumettic image sets from many 2D 5 (WP218792;4) wo 2005/081842 PCT/lJS2005/««4953 2016201333 01 Mar 2016 electronic portal images, is the acquisition of volumetric cone-beam χ-ray CT or helical tomotherapy megavoltage χ-ray CT image set before or after the daily delivery of therapy. While this technology may account for patient setup errors, i.e.5 the geomefty and alignment of the patient's body, physiological changes in the patient, such as weight loss or tnmor grovrth and shrinkage, and inter-fraction organ motions in the patient, such as rectal filling and voiding; it cannot account for inha-fraction organ motions in the patients. Intrafraction organ motions are very important and include, but are not limited to, breathing motion, cardiac motion, rectal gas distension, peristalsis, bladder filling, and voluntary muscular motion.

[00011] Radiation therapy has historically been delivered to large regions of the body including the target volume. While some volume margin is required to account for the possibility of microscopic disease spread, much of the margin is requfred to account for uncertainties in freatment planning and delivery of radiation. Reducing the total volume of tissue irradiated is beneficial, since tiris reduces the amount of normal tissue irradiated and therefore reduces the overall toxicity to the patient fiom radiation therapy. Furthermore, reduction in overall freatment volume may allow dose escalation to the target, thus increasing the probability of tumor control.

[00012] Clinical cobalt (Co٥٥ radioisotope source) therapy units and MV linear accelerators (or linacs) were introduced nearly contemporaneously in the early I950’s. The first two clinical cobalt therapy units were installed nearly simultaneously in October of 1951 in Saskatoon and London, Ontario. The first I linear accelerator installed solely for clinical use was at Hammersmith Hospital, London England in June of 1952. The first patient was freated with this machine ئ August of 1953. These devices soon became widely employed in cancer therapy. The deeply penetrating ionizing photon beams quickly became foe mainstay of radiation therapy, allowing the widespread noninvasive freataent of deep seated tumors. The role of Χ-ray therapy slowly changed witii the advent of these devices from a mainly palliative therapy to a definitive curative therapy. Despite similarities, cobalt units and linacs were always viewed as rival technologies in external beam radiotherapy. This rivalry would result in the eventual dominance of linacs in the United States and Western Europe. The cobalt unit was quite simplistic and was not technically ijnproved si^ificantly over tinre. Of course, the simplicity of the cobalt unit was a cause for some of its appeal; the cobalt 6 )4؛WP21S792) wo 2....5/..81842 l>CI7IIS2005/٧(M953 2016201333 01 Mar 2016 units were very reliable, precise, and required little maintenance and technical expertise to run. Early on, this allowed cobalt therapy to become the most widespread form of external beam therapy. The linac was the more technically intensive device. Accelerating high currents of elections to energies between 4 and 25 MeV to produce beams of bremsstrahlung photons or scattered elections, the linac was a much more versatile machine that allowed more penetrating beams with sharper penumbrae and higher dose rates. As the linac became more reliable, the benefits of having more penetrating photon beams coupled with the addition of election beams was seen as strong enough impetus to replace the existing cobalt units. Cobalt therapy did not die away without some protests and the essence of this debate was capttired in a famous paper in 1986 by Laughlin, Mohan,' and Kutcher which explained the pros and cons of cobalt units with linacs. This was accompanied by an editorial from Suit that pleaded for the continuance and further technical development of cobalt units. The pros of cobalt units and linacs have already been listed. The cons of cobalt units were seen as less penetrating depth dose, larger penumbra due to source size, large surface doses for large fields due to lower energy contamination elections, and mandatory regulatory oversight. The cons for linacs increased with their increasing energy (and hence their difference from a low energy cobalt beam), and were seen to be increased builddown, increased penumbra due to electron tiansport, increased dose to bone (due to increased dose due to pair production), and most inrportantly the production ofphoto-neutions at acceleration potentials ove 10 MV.

00013؛] In the era before intensity modulated radiation therapy (IMRT), the linac held definite advantages over cobalt therapy. The fact that one could produce a very similar beam to cobalt using a 41 linac accelerating potential combined with the linac's ability to produce eitiier election beams or more penetrating photon beams made the linac preferable. When the value of cobalt therapy was being weighed agafost the value linac therapy, radiation fields were only manually developed and were without the benefit of IMRT. As IMRT has developed, the use of higher MV linac accelerating potential beams and election beams have been largely abandoned by the community. This is partly due to the increased concern over neutron production (and increased patient whole body dose) for the increased beam-οη times required by IMRT and the complexity of optimizing election beams, but most importantly because low MV 7 (4؛WP218792) wo 281842لا/5لالا PCT/US2005/0٠)4953 2016201333 01 Mar 2016 photon-beam IMRT could produce treataient plans of excellent quality for all sites of cancer treatment.

[00014] IT presents a culmination of decades of hnproving 3D dose calculations and optimization to the point that we have achieved a high degree of accuracy and precision for static objects. However, there is a fimdamental flaw in our currently accepted paradigm for dose modeling. The problem lies with the fact that patients are essentially dynamic deformable objects that we cannot and will not perfectly reposition for fractioned radiotherapy. Even for one dose delivery, intra-fraction organ motion can cause significant errors. Despite this fact, tire delivery of radiation tlrerapy is traditionally planned on a static model ofradiotlrerapy targets and critical structures. The real probleirr lies in tire fact tlrat outside of the cranium (i.e., excluding tire treatorent of. CNS disease using Stereotactic radiotherapy) radiation therapy needs to be fractionated to be effective, i.e.) it nrust be delivered ئ single 1.8 to 2.2 Gy fractions or doulrle 1.2 to 1.5 Gy fractions daily, and is fractionally delivered during the work week (Monday tlrrough Friday); taking 7 to 8 weeks to deliver a curative dose of 70 to 72 Gy at 2.0 or 1.8 Gy, respectively. This daily fractionation requires the patient and all of their internal organs to be repositioned exactly for accurate dose delivery. This raises arr exfremely inrportant question for radiation therapy: "Of what use is all of the elegant dose computation and optimization we have developed if the targets and critical stmctures move around during the actiral therapy?” Recent critical renews of organ motion studies have summarized the existing literatirre up to 2001 and have shown that tire two most prevalent types of organ-motion: patient set-up errors and organ motions. While si^rificant physiological changes ئ tire patient do occur, e.g., significant tamor shrinkage in head-and-neck cancer is often obse^ed clinically, they have not been well shrdied. Organ motion studies have been further sulrdivided into inter-fraction and intra-fraction organ motion, with the acknowledgement that the tivo cannot be explicitly separated, i.e., infra-fraction motions obviously confound tire clean observation of inter-fraction rrrotions. Data on inter-fi-action nrotion of gynecological hrmors, prostate, bladder, and rectum have been published, as well as data on the infra-fraction movenrent of the liver, diaphragjn, ltidneys, pancreas, lung tumors, and prostate. Many peer-reviewed publications, spanning the two decades prior to publication have demonstrated tire fact that both inter- {4؛WP218792) wo 2005/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 and intra-fraction organ motions may have a significant effect oir radiation therapy dosimetry. This maybe seen in the fact that displacemente between 0.5 and 4.0 cm have been commonly observed in stiidies of less than 50 patients. The mean displacements for many observations of an organ motion may be small, but even an infrequent yet large displacement may significantly altei- the biologically effective dose received by a patient, as it is well accepted that the correct dose per fraction must be maintained to effect himor confrol. In a more focused review of infra-fraction organ motion recently published by Goitein (Seminar in Radiation Oncology 2004 Jan; 14(1):2-9), the importance of dealing with organ motion related dosimetry errors was concisely stated: "... it is incontestable that unacceptably, or at least undesirably, large motions may occur in some patients ..." It was further explained by Goitein that the problem of organ motions has always been a concern in radiation therapy: “We have known that patients move and breathe and that their heaifs beat and their intestines wriggle since radiation was first used in cancer therapy. In not-so-distant decades, our solution was simply to watch all that motion on the simulator’s fluoroscope and then set the field edge wires wide enough that foe target (never mind tliat we could not see it) stayed within the field." [00015] In an attempt to address the limitations imposed on radiation therapy by patient settrp errors, physiological changes, and organ motion throughout the profracted weeks of radiation therapy, the prior art has been advanced to imaging systems capable of acquiring a volumetric CT “snap shot” before and after each delivery of radiation. This new combination of radiation therapy unit witii radiology i.maging equipment has been termed image-guided radiation therapy (IGRT), or preferably image guided IRT (IGIMRT). The prior art has tire potential for removing patient setup errors, slow physiological changes, and inter-fraction organ motions that occur over the extended course of radiation therapy. However, the prior art cannot account for intra-fraction organ motion which is a very significant form of organ motion. The prior art devices are only being used to shift the gross patient position. The prior art cannot capture intra-fraction organ motion and is limited by the speed at which helical or one-beam CT imaging may be performed Secondly, but perhaps equally important, CT imaging adds to the ionizing radiation dose delivered to the patient. It is well known that the 9

(WP218792;4J wo 2٠٠81842ر5لالا PCI /IIS2005/(J(M953 2016201333 01 Mar 2016 incidence of secondary carcinogenesis occurs in regions of low-to-moderate dose and the whole body dose will be increased by the application of many CT image shrdies.

[00016] CT imaging and MRI units were both demonstrated in the I970's. CT imaging was adopted as the "gold standard” for radiation therapy imaging early on due to its intrinsic spatial integrity, wltich comes from the physical process of X-ray attenuation. Despite tlte possibility of spatial distortions occurring in MRI, it is still very ataactive as an imaging modality for radiotherapy as it has a much better soft tissue contrast than CT imaging and the ability to image physiological and metabolic such as chemical titmor signals or oxygenation levels. The MRI artifacts that influence the spatial integrity of the data are related to undesired fluctitations in the magnetic field homogeneity and may be separated into two categories: 1) artifacts due to the scanner such as field inhomogeneities intrinsic to the ma^et design and induced eddy currents due to gradient switching؛ and 2) artifacts due to foe imaging subject, i.e., the inttinsic magnetic susceptibility of tlie patient. Modem MRI units are carefirlly characterized and employ reconstruction algorithms that may effectively eliminate artifacts due to the scanner. At high magnetic field strength, in the range of 1.0-3.0 T, magnetic susceptibility of the patient may produce significant distortions (which are proportional to field strength) that may often be eliminated by first acquiring susceptibility imaging data. Recently, many academic centers have started to employ MRI for radiation tiierapy tteatment planning. Ratiier than dealing with patieirt related artifacts at high field, many radiation therapy centers have employed low field MRI units with 0.2-0.3 T for radiation therapy treatment planning, as these unite diminish patient-susceptibility spatial distortions to insignificant levels. For dealfog with intia-fraction organ motion MRI is highly favorable due to the fact that it is fast enough to tiacli patient motions ئ real-time, has air easily adjustable and orientable field of view, and does not deliver any additional ionizing radiation to the patient which may iircrease the incidence of secondary carcinogenesis. Breath controlled and spirometer-gated fast multi-slice CT has recently been employed ئ an attempt to assess or model intta-fraction breafoing motion by many research groups. Fast, single-slice MRI has also been employed in tire assessment of intra-fraction motions, and dynamic parallel MRI is able to perfomr volumettic intra-fraction motion imaging. MRI holds a definite advantage over CT for fast repetitive imagiirg due to the need for CT imaging to deliver 10 {4؛WP218752) wo 2005/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 increasing doses to the patient. Concerns over increased secondary carcinogenesis due to whole-body dose already exist for IMRT and become significantly worse with the addition of Treated CT imagtog.

[00017] In the prior art, two research groups appear to have simultaneously been attempting to develop a MRI unit integrated with a linac. hi 2001, a patent was filed by Green which teaches an integrated MRI and linac device. 2003 ئ, a group from the University ofUttecht in tlie Netherlands presented their design for an integrated MRI and linac device and has since reported dosimettic computations to test the feasibility of tlieir device. The significant difficulty with integrating a MRI unit with a linac as opposed to a CT imaging unit, is that the malefic field of the MRI unit makes the linac inoperable. It is well known that a charged particle moving at a velocity,؟, in the presence of a magnetic field, B, experiences a Lorentz force given by F = q(vxB). The Lorentz force caused by the MRI unit will not allow elections to be accelerated by the linac as they cannot tiavel in a lfoear path, effectively shutting the linac off. The high radiofrequency (RF) emittance of the linac will also cause problems with tire RF transceiver system of the MRI unit, comrpting the signals required for image reconsttuction and possibly destroying delicate circuitry. The intonation of a linac with a MRI unit is a monumental engineering effort and has not been enabled.

[00018] Intensity modulated radiation therapy (IMRT) is a type of external beajrr tieatnrent tlrat is able to confom radiation to the size, shape and location of a ttrmor. IMRT is a major improvement as conrpared to conveirtional radiation teeatoent. The radiotherapy deliver metlrod of IMRT is torown ئ the art of radiation therapy and is described in a book by Steve Webb ejrtitled "Intensity-Modulated Radiation Therapy" (IOP Publishing, 2001, ISBN 0750306998). This work of Webb is incorporated by reference into the application in its entirety and hereafter referred to as "Webb 2001". The effectiveness of conventional radiation therapy is limited by imperfect targeting of ttrmors and insufficient radiation dosing. Because of these limitations, conventional radiation may expose excessive amounts of healthy tissue to radiation, thus causing negative side-effects or complications. With IMRT, the optimal 3D dose distiibution, as defined by criteria known in the art (Webb 2001), is delivered to the tumor and dose to surrounding healtiiy tissue is minimized. 11 {WP218792:4i wo 2115/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 [00019] In a typical IMRT treataent procedure, the patient undergoes tteatment planning χ-ray CT imaging sinrulation with the possible addition ofMRI simulation or a position emission tomography (PET) shrdy to obtain metabolic information for disease targeting. When scanning takes place, he patient is immobilized in a manner consistent with treatment so that the imaging is completed with the highest degree of accuracy. A radiation oncologist or other affiliated health care professional typically analyzes these images and determines the 3D regions that need to be treated and 3D regions feat need to be spared, such as critical structures, e.g. the spfeal cord and surrounding organs. Based on this analysis, an IMRT treatment plan is developed using large-scale optinrization.

[00020] IMRT relies on two advanced technologies. The first is inverse treatment planning. Through sophisticated algorithms using high speed computers an acceptable treatment plan is determined using an optimization process which is intended to deliver a prescribed unifoim dose to fee tumor while minimizing excessive exposure to surrounding healthy tissue. During inverse planning a large number (e.g. several thousands) of pencil beams or beamlets which comprise the radiation beam are independently targeted to the hrmor or other target structure with high accuracy. Through optimization algorithms the non-uniform intensity distributions of the individual beamlets are determined to attain certain specific clinical objectives.

[00021] The second technology, comprising IMRT generally utilizes multi-leaf collimators (MLC). This technology delivers the treataent plan derived fiom fee inverse treatment planning system. A sepai'ate optimization called leaf sequencing is used to convert the set of beamlet fluences to an equivalent set of leaf motion inshuctions or static apertures with associated fluences. The MLC is typically composed of computer-controlled tangsten leaves that shift to form specific patterns, blocking the radiation beams accordhrg to the intensity profile fiom the treatment plan. As an alternative to MLC delivery, an attenuating filter may also be designed to match the fluence ofbeamlets. The current invention contemplates the fact that MLC delivery is capable of adjusting a delivery rapidly to account for intra-fraction organ motions while an attenuating filter cannot be actively adjusted.

[00022] After the plan is generated and quality confrol checkfeg has been conrpleted, tire patient is immobilized and positioned oir the treatment couch attempting 12 4J؛WP2187S2} wo 2005/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 to produce the positioning performed for the initial χ-ray CT or magnetic resonance imaging. Radiation is then delivered to the patient via the MLC instructions or attenuation filter. This process is then repeated for many work weeks until the prescribed cumulative dose is assumed to be delivered.

[00023] Magnetic resonance imaging (MRI) is an advanced diagnostic imaging procedure that creates detailed images of internal bodily structures without tire use of ionizing radiation, which is used in χ-ray or megavoltage χ-ray CT imaging. The diagnostic imaghrg method of MRI is known in the arts of radiology and radiation tlrerapy and is described in the books by Ε.Μ. Haacke, R.W. Brown, M.R. Thompson, R. Venkatesan entitled Magnetic Resonance Imaging: Physical Principles and Sequence Design (John Wiley & Sons, 1999, ISBN 0-471-35128-8) andbyZ.-Ρ. Liang and P.C. Lauterbur entitied Principles of Magnetic Resonance Imaging: A Si^al Processing Perfective. (IEEE Press 2000, ISBN 0-7803-4723-4). These works of Haacke et al. and Liang and Lauterbur are incorporated by reference into he application in their entirely and hereafter referred to as " Haacke et al. 1999" and "Liang and Lauterbur 2001", respectively. MRI is able to produce detailed images through the use of a powerfirl main magnet, magnetic field gradient system, radiofrequency (RE) fransceiver system, and an image reconstruction conrputer system. Open Magaetic Resonance Imaging (Open MRI) is an advanced form of MRI diagnostic imaging that uses a maiir magnet geometry which does not completely enclose the patient during imaging. MRI is a very atfractive imaging modality for radiotherapy as it has a much better soft tissue contrast than CT imaging and the ability to image physiological and metabolic information such as specfroscopic chemical ttimor signals or oxygenation levels. Many ttacer agents exist and are under development for MRI to improve soft tissue contrast (e.g. Gadopentate dinreglumine for kidney or bowel enhancement, or Gadoterate meglumine for general conttast). Novel conttast agents are currently under development that will allow for the metabolic detection of tumors similar to PET imaging by employing either hyperpolarized liquids containing carbon 13, nittogen 15, or similar stable isotopic agents or paramagnetic niosomes. All oftlrese diagnostic MRI techniques enhance the accurate targeting of disease and help assess response to treatment in radiation therapy. 13 {WP21S792;4} wo 2005/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 [00024] CT scaling for IT treatment planning is performed using I sections (2-3 mm), sometimes after intravenous injection of an iodine-containing contiast medium and filmed at soft tissue and bone window and level settings. It has the advantage of being more widely available, cheaper than magnetic resonance imaging (.1) and it may be calibrated to yield electton density information for tteatment planning. Some patients who cannot be examined by MRI (due to claustrophobia, cardiac pacemaker, aneurism clips, etc.) may be scanned by CT.

[00025] The problem of patient setiip errors, physiological changes, and organ motions during radiotherapy is currently a topic of great interest and significance ئ the field of radiation oncology. It is well blow that the accuracy of conformal radiation therapy is si.ificantly limited by changes in patient mass, location, orientation, articulated geometric configuration, and inter-ftaction and intta-fraction organ motions (e.g. during respiration), both during a single delivery of dose (intraftaction changes, e.g., organ motions such as rectal distension by gas, bladder filling with urine, or tiioracic breathing motion) and between daily dose deliveries (interfraction changes, e.g., physiological changes such as weight gain and ttrmor growth or shrinkage, and patient geometty changes). With the exception of the subject invention, no single effective method is known to account for all of these deviations sinrultaneously during each and every actual dose delivery. Current state-of-the-art imaging technology allows taking 2D and 3D megavoltage and orthovoltage χ-ray CT "snap-shots" of patients before and after radiation delivery or may take time resolved 2D radiographs which have no soft tissue conttast during radiation delivery.

[00026] Great advances have been made in conformal radiation therapy; however, theft true efficacy is not realized without complete real-time imaging guidance and confrol provided by the present invention. By the term "real-thne imaging" we mean repetitive imaging tliat may be acquired fast enough to capture and resolve any intra-fraction organ motions that occiir and result in significant changes in patient geometiy while the dose from the radiation beams are being delivered. The data obtained by real-time ima^ng allows for the determination of the actiial dose deposition in the patient. Tliis is achieved by applying known techniques of deformable registration and - د * to sum the doses delivered to the moving tissues and targets. This data taken over the entire multi-week course of radiotherapy, while the radiation beams are 14 {4؛WP218792} wo 21)1)5/..81842 P( I7٠JS2005/OO4953 2016201333 01 Mar 2016 staking the patient and delivering the d.se) allows foi' the quantitative determination of 3D in vivo dosimetry. Hence, the present invention enables the only effective means of assessing and controlling or eliminating organ motion related dose delivery errors.

SUMMARY OF THE MENTION

[00027] The present invention provides a radiation treatment system including: at least one though possibly more radioisotopic sources to produce ionizing radiation treatment beams, at least one though possibly more MLC or attenuator systems to perform IMRT with the tteatoent beams; a malefic resonance imaging (.1) system that images the target region and surrounding healthy tissue or critical structures simultaneously during delivery of the ionizing radiation; and/or a controller communicably connected to all components. The image data derived ftom he MRI allows for he quantitative assessment of the actual delivered ionizing radiation dose and the ability to reoptimize or replan the tteatment delivety to guide the ionizing radiation delivered by IMRT to the target region more accurately. We now describe a beneficial embodiment of the invention. In this beneficial embodiment, the main magiet Helmlioltz coil pair of an open MRI is desired as a split solenoid so that the patient couch runs through a cylindrical bore ئ the middle of the mallets and the IMRT unit is aimed down the gap between the two selonoidal sections at he patient (FIG. 1 through FIG. 4). In this embodiment, the split solenoidal MRI (015) remains stationary while the shielded co-registered isotopic radiation source with a multi-leaf collimator IMRT unit (020) is rotated axially around the couch on the gantry (025) (note more than one (020) could be beneficially employed). The patient (035) is positioned on the patient couch (030) for simultaneous imaging and tteatoent. The co-registered isotopic radiation source (020) with a multi-leaf collimator contains a radioisotopic source (115) which is collimated with a fixed primary collimator (120), a secondary doubly divergent multileaf collimator (125), and tertiary multi-leaf collimator (130) to block interleaf leakage from the secondary multi-leaf collimator (125) (FIG. 5 through FIG. 7).

[00028] This embodiment is beneficial as it removes the need for rotating the open MRI to provide axial tteatment beam access and it provides a magnetic field along the 15 {4؛jVVP218792 wo 2005/081842 PCT/US2I/004953 2016201333 01 Mar 2016 patient in the cranial-caudal direction, allowing for improved MRI speed using parallel multi-phased array RF transceiver coils for fast image acquisition.

[00029] We now describe additional beneficial embodiments of the process of this invention witlr varying complexity and computational demands. All of these process embodiments could employ any device embodiment. All such process embodiments may include the step of acquiring high resolution dia^ostic quality volumefric MRI data before the daily delivery of radiation and then acquiring real-time MRI data during the radiation delivery where the real-time data may be collected on a different spatial grid or with a diminislred signal-to-noise ratio to improve the speed of acquisition. One beneficial process embodiment would take the MRI data and apply methods known in the art for deformable image registeation and dose calculation to the delivered IT cobalt unit fluences to detemrine the dose delivered to he target and critical strucmres during each delivery fraction. Corrections to the patient's freataent could then be taken to add or subfract delivery fractions to improve tiimor control or reduce side effects, respectively. Along with the dosimeteic assessment, the size and progression of he patient’s disease would also be assessed on a daily basis.

[00030] A second beneficial process embodiment would take the MRI data and perform a reoptimization of the IMRT freatoent plan before each single radiation delivery to improve the accuracy of tire freatoent delivery. This process would be combined with the previous process to assess the dose delivered to the target and critical sfructores during each delivery fraction.

[00031] A third beneficial process embodiment would take the MRI data and perform a reoptimization of the IMRT treatment plan on a beam-by-beam basis before the delivery of each radiation beam in a single radiation delivery to improve the accuracy of the freatment delivery. This process generally includes that the first process to be performed rapidly before each beam delivery.

[00032] A fourth beneficial process embodiment would take the MRI data and perform reoptimization of the IMRT freatment plan on a moment-by-moment basis during the delivery of each part of each radiation beam in a single radiation delivery to improve the accuracy oftlie treafrnent delivery. This process includes that the first process to be performed in real-time substantially simultaneously with the radiation delivery. The present invention contemplates the use of parallel computation 16 4J؛WP218792) wo 2005/081842 PCTUS2M5/٠٠٠٠4i»53 2016201333 01 Mar 2016 employing many computers beneficially connected via a low latency local network or a secure connection on a wide area network may be used to greatly enhance the speed of the algorithms known in the art for MRf image reconstruction, deformable image registration, dose conaputation, andIMRT optimization.

[00033] In another aspect, the present invention also provides a method of applying radiotherapy, having the steps of determining a treatment plan for applying radiotherapy-, obtaining images of a target region within a volume of a subject using a magnetic resonance imaging (MRl) system; irradiating the target and critical structure regions with a treataent beam, wherein the teeatoent beam heats the target region; and continuing to obtain images of the target and critical structure regions during irradiation of the target region; wherein the tteatment plan may be altered during treatment based upon images of the target and critical structure regions obtained during freatment. 17 1WP218792;4> PCT/US2UU5/....4953 2016201333 01 Mar 2016 WO 2....5/..81842

BRIEF DESCRIPTION OF DRAWINGS

[00034] There are shown in the draftings, embodiments which are presently contemplated, it being understood, however, that the invention is not limited to the precise anangements and instrumentalities shown.

[00035] FIG. lisa schematic ofa radiation therapy system including an open ؟lit solenoidal magnetic resonance imaging device (015), a shielded co-registered isotopic radiation source with a multi-leaf collimator (020) (note that more than one 020 could be applied ئ a beneficial embodiment), a gantry (025) for changing the angle of(020), a patient couch (030), and a patient (035) in position for simultaneous imaging and treatment.

[00036] FIG. 2 is a demonstiation of gantiy rotation, where the shielded CO-registered isotopic radiation source with a multi-leaf collimator (020), has been rotated ftom a right lateral beam position to an anterior-posterior beam position.

[00037] FIG. 3 is a top view of the system in FIG. 1.

[00038] FIG. 4 is a side view of the systenr in FIG. 1.

[00039] FIG. 5 is a detailed schematic of the co-re^stered isotopic radiation source witlr a multi-leaf collimatoi' shown as (020) in FIG 1. A radioisotopic source (115), is shown witlr a fixed primary collimator (120), a secondary doubly divergeirt multileaf collimator (125), and tertiary multi-leaf collimator (130) to block interleaf leakage from the secondary multi-leaf collimator (125).

[00040] FIG. 6 is a perspective view of tire secondary doubly divergent multi-leaf collimator (125), and tire tertian multi-leaf collimator (130) to block interleafleakage from the secondary nrulti-leaf collimator (125).

[00041] FIG. 7 is a beams-eye view of the radioisotopic source (115), the secondary doulrly divergent mrrlti-leaf collinrator (125), and tire tertiarj/ multi-leaf 18 (WP2IS752;4( wo 2005/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 collimator (130) to block interleafleakage from the secondary multi-leaf collimator (125).

[00042] FIG. 8 displays axial dose distributions from the single head-and-neck IMRT case planned using tire commissioned cobalt beamlets.

[00043] FIG. 9 displays the DVH data derived from the single head-and-neck IT case planned using the commissioned cobalt beamlets.

[00044] FIG. 10 cobalt beamlets dose disfributions in water with and without a 0.3 Tesla magnetic field.

[00045] FIG. 11 cobalt beamlets dose distributions ئ water and lung with and without a 0.3 Tesla magnetic field.

[00046] FIG. 12 cobalt beamlets dose disfributions in water and air with and without a 0.3 Tesla magnetic field.

DETAILED DESCRIPTION OF THE IN VENTION

[00047] The present invention is more particularly described in the following examples that are intended to be illusfrative only since numerous modifications and variations therein will be apparent to those sliilled in the art. As used in the specification and in the claims, the singular form "a," "an," and "the" may include plural referents unless the context clearly dictates otherwise. Also, as used in the specification and in the claims, the term "comprising" may include the embodiments "consisting of' and "consisting essentially of." [00048] The invention is both a device and a process for performing high temporal-and spatial- resolution magnetic resonance imaging (MRI) of tire anatomy and disease of a patient durhrg intensity modulated radiation therapy (IMRT) to directly measure and coirfrol the highly conformal ionizing radiation dose delivered to the patient. In a beneficial embodiment, this invention combines the technologies of an open MRI that allows for axial access with IMRT radiation beams to the patient, a multileafcollimator or compensating filter-based IMRT delivery system, and cobalt-60 teletherapy radiation source or sources into a single co-registered and gantry mounted system. 19 {WP2!87W;4} wo 20.,5/..81842 PCT/IJS2005/004953 2016201333 01 Mar 2016 [00049] As mentioned, the prior art does not simultaneously image the internal soft tissue anatomy of a person ئ real-time during the delivery of radiation therapy while he beams are steiking the patient. Rather, an image is generated prior to and/or after the radiation delivery, and these images do not reflect any movement and/or natural changes that may occur in the patient during radiation delivery. As such, targeted radiation without the invention described here may not be successfirl if after taking an initial image, the portion of tire body to be heated eitlrer changes in size natirrally, or-changes in location due to the shiffing of the patient prior to treatoent؛ i.e., the occurrence of patient setup errors or errors in the geometry and alignment of the patients anatomy; physiological changes in the patient, such as weiglrt loss or hrmor growrth and shrinkage; and organ motions ئ the patient including but not limited to breathing motion, cardiac motion, rectal distension, peristalsis, bladder filling, and voluntas muscular motion.

[00050] The present invention helps to eliminate all of these problems by perfoming real-tinre MKI of the patient substantially simultaneous to radiation delivery, and tlren readjusting the targeted radiation if the region to be heated suffers from any type ofdosimehic error caused patient setup error, physiological change, and inter-fraction or infra-fraction organ motion. Many actions may be taken including, but not limited to: shifting the patient position to account for changes in size and/or position of targets aird anatomy; stopping heatment altogether to permit additional calculatiorrs to be determined before restarting heatment or allow for the cessation of hansitory motion; adding exha delivery fractions to increase the probability of hrmor conhol or limiting the number of delivery fractions to decrease the probability of side effect; any of the beneficial process embodiments previous described; and reoptimizing tlie IMRT heatinent plan on a variety of time scales, e.g., reoptimization for every delivery, every beam, or every sequent in the IMRT plan is performed..

[00051] A beneficial embodiment of the present invention includes a computer controlled cone-beam cobalt therapy unit, such as a cobalt-60 therapy unit, equipped with a multileaf collinrator or an automated compensating filter system mounted on a rotational gantty along with an orthogonally mounted “Open" MRI unit. As seen in FIG. 1, the IMRT cobalt unit (020) projects its cone-beam geomehy radiation down the center of the opening oftlie axial open MRI unit (015) and the IMRT cobalt unit rotates 20 {4;WP218792؛ wo 2....5/..81842 PCTUS2M5/٠٠٠٠4i»53 2016201333 01 Mar 2016 axially (about the longitudinal (cranial-caudal) axis of the patient) about the patient on a gantry (025). An adjustable treatment couch (030) may be used to support the patient in a stationary position while he ganhy rotates to change the beam angle.

[00052] The present invention uses cobalt teletherapy as the radiation therapy. ١Vhile some IMRT uses a linear electron accelerator for delivering a more penetrating radiation therapy, the accelerator itself produces a freatment beam that is highly variable in regards to he level of radiation emitted. As such, it becomes difficult to accurately detemine he amount of radiation that is being used on the patient and to coordinate the motion of an MLC for IMRT delivery. Gamma-rays are electtoma^etic radiation emitted by the disintegration of a radioactive isotope aird have enough energy to produce ionization in matter, typically from about 100 leV to well over 1 MeV. The most useful gamma-emitting radioactive isotopes for radiological purposes are found to be cobalt (Co 60), fridium (Ir 192), cesium (Cs 137), ytterbium (Yb 169), and thulium (Tm 170). As suclr, the disintegration of a radioactive isotope is a well-known phenomena and, therefore, the radiation emitted by cobalt teletherapy is more consistent and, therefore, easier to calculate in terms of preparing a freatment regimen for a patient.

[00053] Enablement of the present invention’s cobalt IMRT has been demonstrated via computational analysis. Simulations have been performed of IMRT delivery with a commercially available cobalt therapy unit and a ^c. A 3D image-based radiation therapy freatment planning system with a cobalt beamlet model was commissioned and validated using measured' radiochromic film data from a Therafronics lOOOC cobalt tlierapy unit. An isofropic 4x4x4 mm2 dose voxel grid (effectively Shannon-Nyquist limited for y-ray IMRT source penumbra) was generated. This beamlet model was fitted to published data and validated with radiochromic film measurements of lxl cm2 beamlets formed by a Cerrobend block and measured usfog a previously reported methodology. The calculation depths were then determfoed for the same voxels with standard three-dimensional ray-tracing of the structures. Density scaling to the depfos computed was used to better account for tissue heterogeneities ئ foe dose model. The CPLEX, ILOG Concert Technologies indusfrial optimization solver using an implementation of the barrier interior-point mefood with dense column handling for IMRT optimization was used to solve for optimal IMRT plans. Beamlet fluences were 21 {4;1218792أ wo 2....5/..81842 14953ل)ل)/121ا;)ل 2016201333 01 Mar 2016 discretized for each beam angle to 5% levels for leaf sequencing. The resulting plan dose distribution and histograms were computed by summing the dose values weighted by the deliverable discretized intensities. Leaf-transmission leakage intensities were conservatively estimated at 1.7% for otherwise zero intensity beamlets. Finally, standard methods of heuristic leaf-sequencing optimization to create delivery instructions for the tieatinent plans were employed. We adopted the Virginia Medical College simultaneous integrated boost (SIB) target dose-level sclieme as it is the largest maximum to minimum clfoical prescription dose ratio advocated in the literatiire, making it the most difficult dose prescription scheme to satisfy. Head-and-neck IMRT provides an excellent basis for testing IIT optimization for several reasons: 1) there are well defined tieatment goals of sparing salivary glands and other sfructures while maintaining homogeneous target coverage2 ؛) attempting to achieve these goals tests IMRT optimization to its teclinical limits؛ and 3) a large phase i multi-instittitional tiial, the Radiation Therapy Oncology Goup (RT0G)’s Η-0022 Phase Ι/ΙΙ Study ره Conformal and Intensity Modulated Irradiation for Oropharyngeal Cancer, ةةا١ Mvnd a common set of planning criteria. The case examined was run with 7 equispaced beams having International Electrotechnical Commission (IEC) gantry angles of ٥٥, 51., 103., 154., 206°, 257., and 309°. The treatment planning system generated 1,289 beamlets to adequately cover the targets from the seven beam angles, and the 4mm isotropic voxel .id generated 417,560 voxels. Results are shown in FIG 8 and FIG 9. Note that our system normalized plans to ensure 95% coverage of the high dose target. FIG 8 displays axial dose distributions from the single head-and-neck IMRT case planned using the commissioned cobalt beamlets. Excellent target coverage and tissue sparing may be observed. FIG 9 displays the DVH data derived fi-om the leaf sequenced and leakage corrected plan (i.e., deliverable plan) using the 4 mnt voxels and 1 Gy dose bins. The cobalt source based IMRT created an excellent IMRT freatinent plan for a head-and-neck patient. The y-ray IMRT was able to clearly spare the right parotid gland (RFG) and keep the left parotid (LPG) and riglrt submandibular glands (RSMG) under 50% volume at 30 Gy, while covering more than 95% of the target volumes (CTV and GTV) with the prescription dose or hitler. All other structures were below tolerance. The unspecified tissue (SKE4) was lcept below 60 Gy, with less than 3% of the volume above 50 Gy. The optimization model used was the same as 22 !4؛WP2187S2) wo 2005/081842 سسد 2016201333 01 Mar 2016 published in Romeijn et al. and was not modified for the cobalt beams. For sites with larger depths such as prostate and lung it is known in the art that the addition of extra beams or isocenters allows for the creation oftreatarent plans using cobalt IMRT that may achieve the same clinical quality criteria as linac-based IMRT. This enabling demonstration shows that a cobalt therapy unit is capable of providing high quality IMRT.

Enablement of he present invention's dose computation for cobalt IMRT in the presence of the magnetic field has been demonstoated via computational analysis. In addition, by using cobalt teletherapy, the present invention is better able to make calculations based upon foe magnetic .field of the MRI. When the radiation therapy is performed while the patient is stationed within foe MRI, foe magnetic field will cause a slight deflection of the targeted radiation. As such, the calculations used to determine the tieatment regimen need to take this deflection into account. A charged particle moving in a vacuum at a velocity, ٩ in the presence of a magnetic field, !, experiences a Lorentz force given by F :g(vxB). This force is not significant enough to significantly change the physics of foe interactions of ionizing photons and elections with- matter؛ however, it may influence foe overall transport of ionizing elections and hence the resiflting dose distiibution. The impact of magnetic fields on the tiansport of secondly elections has been well studied ئ foe physics literatiire, storting more than 50 years ago. Recent studies have employed Monte Carlo simulation and analytic analysis in an attempt to use a localized magnetic field to help focus or tiap primary or secondary elections to focrease the local dose deposition in the patient. All of these stiidies have examined aligning the direction of the magnetic field lfoes along the direction of the beam axis to laterally confine the election tiansport with the Lorentz force (called "longitudinal” magnetic fields, where the term longittrdinal refers to the beam and not the patient). For high field MRI, with magnetic fields between about 1.5- 3.0 T is known that the initial radius of gyration is small wifo respect to foe MFP of large-angle scattering foteractions for the secondary elections (bremsstiahlung, elastic scatter, and hard collisions) and fois condition j-esults in the desired tiapping or focusfog of the elections. As the elections lose energy tlie radius decreases as it is proportional to 1*1 and, in the absence of large-angle scattering interactions (CSDA) the elections 23 (WP218752;4} PCT/US2U..5/....49S3 2016201333 01 Mar 2016

842إ8لا/5لالا2 WO would follow a spiral with decreasing radius until they stop. Although this spiraling may change foe fluence of elections it is known that it does not produce any significant synchrotron radiation. In the present invention, foe magnetic field must be orthogonal to the radiation beams in 01'der allow parallel MRI for real-time imaging. Recent work has shown that a 1.5 T magnetic field perpendicular to foe lieam axis of a 6MV linac beam may significantly perturb the dose distribution to water for a 6 MV lfoac heamlet. Both to avoid such dose distiibution distortions and to prevent MRI artifacts that could compromise the spatial integrity of foe imaging data, a beneficial embodiment of the present invention uses a low field open MRI design that allows foe magnetic field to be directed along tlie superior-inferior direction of foe patient (see FIG. 1). Single estimates of the radii of gyration for secondary elections from cobalt γ rays indicate that the radii of gyration are much greater than the MFP for large-angle scattering interactions for elections. This is easily understood as the Lorentz force is proportional to the magnitude of the magnetic field, وا , and foe rafous of gyration is inversely proportional to foe magnetic field (104). We have pursued modelfog a beamlet from a cobalt γ-ray source in a slab phantom geometiy using the well-validated Integrated Tiger Series (ITS) Monte Carlo package and its ACCEPTM subroutine for transport in magnetic fields. For the simulations we employed 0.1 MeV election and 0.01 MeV photon transport energy cutoffs, foe standard condensed history energy grid (ETRAN approach), energy stiaggling sampled from Landau distiibutions, mass-collisional stopping powers based on Betlre theory, default electron tiansport substep sizes, and incoherent scattering including binding effect. Three pairs of simulations were run where each pair included the run with and witlrout a 0.3 T uniform magnetic field parallel to tire beam direction. A 2 cm circular cobalt γ-ray beanrlet was modeled on the following geometries: a 30χ30χ30 cm3 water phantom; a 30x30x30 cm3 water phantom with a 10 cm lung density (0.2 g/cc) water slab at 5 cm depth; and a 30x30x30 cm3 water phantonr witlr a 10 cm air density (0.002 g/cc) water slab at 5 cm deptlr. Simula-tions were run with between 30 and 100 million lristories on a Ρ4 1.7 GHz PC for between 8 and 30 hours to obtain less than a percent standard deviation ئ tire estimated doses. The results are displayed in Figures 10-12. FIG. 10 clearly demonstrates tlrat a 0.3 T perpendicular rnriform magnetic field, as would exist ئ a beneficial enrlrodinrent of the current invention will not measurably perturb tire dose distribution in soft tissue 24 4J؛WP2)87S2) wo 20.,5/..81842 PCT/IJS2005/004953 2016201333 01 Mar 2016 or bone. A very usefirl treatment site for the presnt invention will be lung and thorax which contains the most significant tissue lieterogeneities in the body. As seen in FIG. 11, adding a 12 cm lung density (0.2 g/cc) water slab to the phantom causes a very small yet detectable perturbation in the dose at the interfaces of the high and low density regions. These perturbations are small enough to allow acceptable clinical application without correction. In FIG. 12, we finally observe significant perturbations, which exist largely in the low-density and interface regions. This denronshates that air cavities will hold the greatest challenge for accurate dosimetry. However, other than at interfaces with lower density media there should be no sigrificant perturbations in soft tissue and bone (where the MFP shortens even more than soft tissue). This data demonstrates that in a beneficial embodiment of the present invention witlr a low (.2-.5 Tesla) field MRI, dose perhrrbation will be small except inside of air cavities were accurate dosimetty is not required due to an absence of tissue. By using a known radiation soirrce, such as a cobalt teletherapy unit, the amount of deflection may be easily determined if he stiength of tire MRI field is known. However, even if the strength of the field is known, if a linear accelerator is used, the unknown energy spectrum of the radiation makes the calculations much more difficult.

[00054] Alternate sources of radiati on that do not interfere significantly with the operations of the MRI unit such as protons, heavy ions, and neuhons hat are produced by an accelerator or reactor away from tire MRI unit and fransported by beam to patient are also included in tire invention.

[00055] Irr addition, the sfrength of tire MRI field will factor into he calculations and, as a result, the use of open MRIs offers advantages over closed MRIs. In an open MRI, tire strength of the field generated is generally less than the field of a closed MRI. As such, the images resulting from an open MRI have more noise and are not as clear and/or defined as images from a higher field closed .1. However, the sfronger field of the closed MRI causes more ofa deflection of tire radiation freatment than tire weaker field of an open MRI. Accordingly, depending on tire clraracteristics most beneficial to a given freatment regimen, the present invention contemplates tlrat a closed .1 could be used. However, due to ease of calculation and/or the fact tlrat a slightly less clear image during freataent is sufficient for adjusting most freatment regimens, the present invention contemplates that an open MRI of the geometry shown in FIG. 1, is used with 25 {4؛WP218792} wo 2005/081842 PCT/lJS2005/««4953 2016201333 01 Mar 2016 the cobalt teletherapy to eliminate significant dose perturbations, prevent spatial imaging distortions, and allow for fast parallel phased array MRl [00056] By using an open MM and obalt teletherapy, the present invention provides three dimensioiral (3D) imaging of a patient during the radiation therapy. As such, by using the 3D images of the target region and the planning images of the target region a displacement is determined which is updated based upon the continuous 3D images received during the radiotherapy process. Using the infonnation obtained, the patient may then be then hanslated relative to the treatment beam to reduce the displacement during the irradiation process, such as if the measured displacement is outside a predetermined limit. Irradiation may then continue after translation. Alternatively, the treatoent beam may be moved. The translation may occur during tieatarent or treatment may be stopped and tlren translation may occur.

[00057] By using 3D images during treatment and using these images to rapidly position and/or adjust the patient during the radiotherapy process, fteatment accuracy may be substantially improved. If the patient beco'mes misaligned while radiation is being applied, the misalignment may be mitigated through positional adjustment. In addition to possible dose escalation, improved positional accuracy permits tieatment of tomors that are cunently considered not heatable witii radiation using conventional systems. For example, primary spinal cord tamors and spinal cord metastases are typically not treated by conventional radiation systems due to the high accuracy needed to treat lesions in such important fijnctional anatomic regions. The increased precision provided by 3D imaging during heataent makes it feasible to heat these types of tumors, hnprovements are also expected for targets located in the lung, upper thorax, and other regions where inha-ftaction organ motions are known to cause problems with radiotherapy dosimetry.

[00058] 111 air alternative embodiment, the present invention may include a separat guidance system to hack the patient location that may be used to correlate the actual patient position With the imaging information obtained during both planning and radiotherapy. This portion of foe invention may si^ificantly improve foe ease of patient positioning by providing updateable image con-elation and positioning information throughout the patient set-up and heatoent delivery phases, even when the patient is moved to positions that are not perpendicular to the coordinate system of the 26 {؛،؛WP218792} wo 20.,5/..81842 PCT/IS2005/0049S3 2016201333 01 Mar 2016 therapy machine. This ability to monitor patient position at non-coplanar heatment positions may be a significant improvement OVCT conventional radiotherapy systems. In one beneficial embodiment, the guidance system may include an adjustable bed or couch for the patient to be placed upon. In an alternative beneficial embodiment, the guidance system may include a gantiy that permits substantially simultaneous movement of he MRI and the cobalt therapy unit. Some beneficial embodiments include both the gantiy and the adjustable bed or couch.

[00059j The present invention determines the initial radiation tieataent and/or any changes to the treatment regimen based upon the use ofa computer program that takes into account various factors including, but not limited to, tile area of the patient t.o be treated, the strength of the radiation, the stiength of the MRI field, the position of the patient relative to the radiation unit, any chairge in the patient during tieatoent, andor any positional changes necessary oftlie patient and/or the radiation unit during tieatoent. The resulting IMRT is then programmed and tee treatment is started.

[00060} One emliodiment for detennining a tteatnient plan for intensity inodulated radiation tieatinent (IMRT) as used in the present invention focludes the steps of dividing a three dimensional volume ofa patient into a grid of dose voxels, wheein each dose voxel is to receive a prescribed dose of radiation from a plurality ofbeamlets each having a beamlet intensity; and providing a convex programming model witli a convex objective function to optimize radiation delivery. The model is solved to obtain a globally optimal fluence map, the fluence map including beamlet intensities for each of the plurality ofbeamlets. This method is described in ^eater detail in related application U.F. DsclosureNo. 11296.

[00061] in general, the metiiod used for determining a tieatment plan, in one beneficial embodiment, is the interior pofot method and variants tiiereof. This method is beneficial due to its high efficiency and resulting generally short computational times. The interior point method is described in a book by Steven j. Wright entitled "Primal-Dual Interior-Point Methods" (SIAM Publications, 1997, ISBN 089871382Χ), Primal-dual algorithms have emerged as the most beneficial and usefill algorithms from the interior-point class. Wright discloses the major primal-dual algorithms for linear د including path-following algorithms (short- and long-step, predictor- corrector), potential-reduction algorithms, and infeasible-interior-point algorithms. 27 {WP2tS792;4} wo 20.,5/..81842 PCT/US2005/W)4953 2016201333 01 Mar 2016 [00062] Once the treatment plan is determined, the present invention enables the clinician to ensure that the treatment plan is followed. The patient to be treated is placed in the MRL An image of the area to be heated is taken and the MRI continues to transmit a 3٥ image of the area. The heatment plan is input into the cobalt radiation teletherapy unit and heatment commences. During heatment, a continuous image of the area being heated is observed. If the location of the area to be heated changes, such as if the patient moves or the area to be heated changes in size, the present invention either recalculates the heatoent plan and/or adjusts the patient or radiation unit without intenupting treahnent; or the present invention stops heatment, recalculates the heatoent plan, adjusts the patient and/or adjusts the radiation unit before reconrmencing treatment.

[00063] The present invention contemplates multiple process embodiments that nray be used in improving the accuracy of the patient’s tlierapy. One process enrbodiment would take the MRI data and apply methods known in the art for deformable image regishation and dose calculation to he delivered IT cobalt unit fluences to determine the dose delivered to the target and critical structures during each delivery fraction. Corrections to the patient’s treatarent could then be taken to add or subhact delivery fractions to improve hrmor conhol or reduce side effects, respechvely. Along with the dosimetric assessment, the size and progression ofthe patient’s disease would also be assessed on a daily basis.

[00064] A second process embodiment: would take the MRI data and perform a reoptimization ofthe IMRT heatment plan before each single radiation delivery to improve the accuracy ofthe heatment delivery. This process would be combined with the previous process to assess the dose delivered to the target and critical structures during each delivery fraction.

[00065] A third process em١3odiment would take the MRI data and perform a reoptimization ofthe IMRT heatment plan on a beam-by-beam basis before the delivery of each radiation beam in a single radiation delivery to inrprove the accuracy of tire heatment delivery. This process includes that the first process be performed rapidly before eaclr beam delivery.

[00066] A fourth process embodiment would take tire MRI data and perform reoptimization ofthe IMRT heatoent plan on amonrent-by-moment basis during the 28 {4؛WP218792} wo 2005/081842 PCT/IJS2005/004953 2016201333 01 Mar 2016 delivery of each part of each radiation beam in a single radiation delivery to improve the accuracy of he treatment deliver. This process also includes that the first process be performed in real-time simultaneously with the radiation delivery. The present invention contemplates the use of parallel computation employing many computers beneficially connected via a low latency local nefivork or a secure connection on a wide area network may be used to greatly enhance the speed of the algorithms known in the art for MRI image reconstruction, deformable image registration, dose conrputation, and IMRT optimization.

[00067] Reference is now made vdth specific detail to the drawtogs ئ which like reference numerals designate like or equivalent elements throughout the several views, and initially to Figure 1.

[00068] In FIG. 1, the present invention, in one embodiment, shows fee system of the present invention and having an open MRI015 and an IMRT cobalt therapy unit 020. The system also includes a means to perform IMRT in 020, such as an iC or compensation filter unit, and a gantry 025 that may be used for cobalt unit 020 rotation while keeping the MRI 015 stationary. The patient 035 is positional in the system on an adjustable, stationary couch 030.

[00069] FIG. 2 shows the system in use aird wherein the gantry 025 has been rotated approximately 90 de^ees clockwise. As such, the cobalt tlrerapy unit 020 is in position to treat foe patient 035 in one of many selected locations. FIG. 3 is a top view of the system ئ FIG. 1. FIG. 4 is a side view of the system in FIG. 1.

[00070] Although the illustrative embodiments of foe present disclosure have been described herefo with reference to the accompanying drawings and examples, it is to be understood that the disclosure is not limited to those precise embodiments, and various other changes and modifications may be affected therein by one sltilled in the art without departing from the scope of spirit of the disclosure. All such changes and jnodifications are fotended to be focluded witilin the scope of the disclosure as defined by the amended claims. 29

{WP2l8792;4J

Claims (14)

1. Claims:

   1. A computer program product comprising a non-transitory machine-readable medium storing instructions that, when executed by at least one programmable processor, cause the at least one programmable processor to perform operations comprising: receiving magnetic resonance imaging data captured by a magnetic resonance imaging system during radiation therapy of a patient during a treatment fraction, the magnetic resonance imaging data acquired at a rate sufficient to capture intra-fraction organ motions; receiving data indicating ionizing radiation doses delivered to the patient; and determining an actual dose deposition in the patient from the magnetic resonance imaging data and the delivered ionizing radiation doses data by summing doses delivered to the patient over at least a portion of the treatment fraction.
2. 2. The computer program product of claim 1 further comprising determining a reoptimized treatment plan based on the determined actual dose deposition.
3. 3. The computer program product of claim 1 further comprising determining a reoptimized intensity modulated radiation therapy plan based on the determined actual dose deposition.
4. 4. The computer program product of claim 1, wherein the data indicating ionizing radiation doses delivered to the patient is in the form of delivered fluences.
5. 5. The computer program product of claim 1, wherein the data indicating ionizing radiation doses delivered to the patient is in the form of delivered cobalt fluences.
6. 6. The computer program product of claim 1, wherein the magnetic resonance imaging data comprises three dimensional data.
7. 7. A system comprising: a multileaf collimator configured for attenuation of a beam delivering ionizing radiation to a patient during a treatment fraction, the patient having moving tissues during the treatment fraction; a magnetic resonance imaging system configured to acquire magnetic resonance imaging data of patient anatomy fast enough to capture intra-fraction organ motion during the treatment fraction; and a controller configured to determine an actual dose deposition in the patient from the magnetic resonance imaging data and the delivered ionizing radiation by summing doses delivered to the moving tissues of the patient over at least a portion of the treatment fraction.
8. 8. The system of claim 7, wherein the controller is further configured to re-optimize a treatment plan based on the determined actual dose deposition.
9. 9. The system of claim 7, wherein the controller is further configured to stop the delivery of ionizing radiation if the actual dose deposition evidences a dosimetric error.
10. 10. The system of claim 7, wherein the controller and multileaf collimator are configured to rapidly adjust the multileaf collimator to account for intra-fraction organ motions.
11. 11. The system of claim 7, wherein the magnetic resonance imaging system is further configured to monitor the patient’s response to therapy during the treatment fraction.
12. 12. The system of claim 7, wherein the magnetic resonance imaging system is configured to operate at a field strength below 1.0 T.
13. 13. The system of claim 7, wherein the magnetic resonance imaging system is configured to operate at a field strength of between 0.2 and 0.5 T.
14. 14. The system of claim 7, wherein the magnetic resonance imaging data comprises three dimensional data.