Abstract:
A treatment schedule for radiopharmaceuticals is developed by collecting a volumetric history of tissue uptake in identified volumes of interest using emitted-radiation scans and relating this data to a treatment-radiopharmaceutical to develop a quantitatively accurate radiation treatment schedule of delivery amounts and delivery times of the treatment-radiopharmaceutical. This data may also be used to model biological effective dose and to prepare augmenting external radiation beam treatment schedules.

Description:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0001]    This invention was made with United States government support awarded by the following agency:
       NIH CA014520, CA109656       
 
         [0003]    The United States government has certain rights in this invention. 
     
    
     BACKGROUND OF THE INVENTION 
       [0004]    The invention relates generally to methods and apparatus for the treatment of tumors using radiopharmaceuticals and, in particular, to a system for the computerized scheduling of the administration of such radiopharmaceuticals. 
         [0005]    Radiopharmaceuticals include materials that may “target” specific tissues to deliver radioactive materials to those targeted tissues. Such radiopharmaceuticals generally combine a radioactive component such as a radionuclide with a tracer component exhibiting selective uptake in target tissue. Such radiopharmaceuticals allow imaging or treatment of specific tissues in the body after a generalized introduction of the radiopharmaceutical to the body, for example, by injection into the bloodstream. 
         [0006]    When such radiopharmaceuticals are used for radiation therapy, the quantity and timing of the administration of the radiopharmaceutical must provide a radiation dose to the tissue sufficient to kill tumor cells and the radiation dose must be sustained for a time period related to the reproduction rate of tumor cells. While the selective uptake of radiopharmaceuticals may concentrate the radioactive component in the target tissue, the selectivity of such mechanisms is not perfect and accordingly the quantity and timing of the administration of the radiopharmaceuticals must also be limited to reduce toxicity to healthy-tissues that exhibit some uptake of the radiopharmaceutical. 
         [0007]    Selecting the appropriate quantity and timing for administration of a radiopharmaceutical may be approximated by using a model of a “standard man” or extrapolation from animal models such as rodents to humans. Differences between animals and humans and even among humans make such determinations imprecise at best. 
       SUMMARY OF THE INVENTION 
       [0008]    The present invention provides a system for precisely tailoring the quantity and timing of the administration of a radiopharmaceutical to a particular patient. In one embodiment, the invention takes advantage of an analogous biological behavior between certain imaging and therapeutic radiopharmaceuticals. The imaging-radiopharmaceutical may be used to prepare “time activity curves” describing the uptake of the radiopharmaceutical in different designated volumes of interest using SPECT, PET or similar imaging modalities. The volumes of interest may be selected to include a target tissue and sensitive healthy-tissue. The collected time activity curves then form the basis for a model indicating uptake of a treatment-radiopharmaceutical. This model yields a precise, patient-specific treatment schedule for administering the radiopharmaceutical accommodating constraints such as minimum radiation dose-rate and healthy-tissue toxicity. This two-step technique can provide sufficient precision to make practical the combination of radiopharmaceutical treatment with other radiation treatment techniques such as external-beam radiotherapy. 
         [0009]    Specifically then, the present invention permits the development of a treatment schedule for a treatment-radiopharmaceutical by using a three-dimensional data set recording a history of tissue uptake of an imaging-radiopharmaceutical in at least one volume of interest. This history of tissue (such as a time activity curve or TAC) shows the time during which the imaging-radiopharmaceutical is active in the volume of interest and may be used to prepare a treatment schedule for the treatment-radiopharmaceutical, the latter having similar uptake characteristics as the imaging-radiopharmaceutical. The treatment schedule provides a set of pharmaceutical delivery amounts and delivery times for the treatment-radiopharmaceutical. 
         [0010]    It is thus a feature of at least one embodiment of the invention to employ current imaging technologies to provide quantitative guidance for therapeutic radiopharmaceuticals tailored for an individual patient. 
         [0011]    The system may receive a desired treatment radiation dose-rate and the treatment schedule may determine radiopharmaceutical delivery amounts and delivery times to provide the desired treatment radiation dose-rate in the volume of interest. 
         [0012]    It is thus a feature of at least one embodiment of the invention to use radiopharmaceutical imaging systems to develop an uptake model for that patient that may then be manipulated to produce an accurate treatment schedule. 
         [0013]    In one embodiment, the invention deduces an active time of the imaging-radiopharmaceutical in at least two volumes of interest and the desired treatment radiation dose-rate is received for a first volume of interest and a toxicity limit is received for the second volume of interest. The delivery amount and delivery time of the treatment schedule is calculated to maximize a time period when the radiation dose-rate in the first volume of interest is no less than the desired treatment radiation dose-rate under the condition that the radiation dose-rate in the second volume of interest be no greater than the toxicity limit. 
         [0014]    It is thus a feature of at least one embodiment of the invention to accurately model uptake and clearing time differences among tissue, particularly between treated and healthy-tissue, to provide the ability to make accurate trade-offs between tumor treatment and toxicity to healthy-tissue. 
         [0015]    The invention may provide, in one embodiment, an augmenting radiation dose map for external-beam radiotherapy to augment a radiation dose in the first volume of interest when a desired treatment radiation dose-rate cannot be achieved under the condition that the radiation dose-rate in the second volume of interest is no greater than the toxicity limit. 
         [0016]    It is thus a feature of at least one embodiment of the invention to promote a synergistic combination of external-beam radiotherapy and targeted radiopharmaceuticals by providing an improved model of radiopharmaceutical-induced radiation dose consistent with the accuracy provided by external-beam radiotherapy. 
         [0017]    A library of toxicity limits for organs may be provided and the input volumes of interest may be organ names for the volumes of interest to automatically deduce the toxicity limits. 
         [0018]    It is thus a feature of at least one embodiment of the invention to permit the treatment planner to identify volumes of interest as particular organs in order to provide for automatic optimization of delivery amount and delivery times for the radiopharmaceutical. 
         [0019]    The system may determine the delivery amounts and delivery times by using a linear superposition of the active times of the imaging-radiopharmaceutical. 
         [0020]    It is thus a feature of at least one embodiment of the invention to provide a highly versatile method of treatment planning for radiopharmaceuticals that allows a single imaging experiment to be used to construct a wide variety of different possible treatment plans. 
         [0021]    The system may receive from a physician or other user a desired radiation dose map of the first volume of interest indicating the desired radiation dose in that volume of interest during a particular time. A cumulative radiation dose map of the first volume of interest may then be produced from the three-dimensional data set to compute a difference radiation dose therebetween for external radiation beam treatment. 
         [0022]    It is thus a feature of at least one embodiment of the invention to address the problem of tumor hypoxia, or limited blood flow in some regions of a tumor, through the use of external-beam radiotherapy. The ability to treat the margins of the tumor with radiopharmaceuticals complements the ability of external-beam radiotherapy to treat a tumor center. The hypoxia introduces an increase oxygen enhancement ratio which has to be compensated for through increased radiation dose, thus combined therapies. 
         [0023]    In one embodiment, the invention may compute an achievable external radiation beam radiation dose and iteratively correct the difference between radiation dose and the treatment schedule to provide a desired radiation dose to the first volume. 
         [0024]    It is thus a feature of at least one embodiment of the invention to accommodate the physical limitations of external-beam radiotherapy by compensating with the radiopharmaceutical radiation dose and vice versa. 
         [0025]    The imaging-radiopharmaceutical will typically be different from the treatment-radiopharmaceutical and accordingly the invention may include the step of correcting the active time schedule for the imaging-radiopharmaceutical to reflect an active time schedule of the treatment-radiopharmaceutical. This correction may change radiation dose-rate within the first and second volumes, for example reflecting different half-lives of different radionuclides, while preserving relative uptake between the first and second volumes. 
         [0026]    It is thus a feature of at least one embodiment of the invention to permit imaging-radiopharmaceuticals to be used to develop precise models of the behavior of treatment-radiopharmaceuticals before the treatment-radiopharmaceuticals are used. 
         [0027]    The imaging-radiopharmaceutical may be identical to the treatment-radiopharmaceutical with the exception of a radioactive isotope. 
         [0028]    It is thus an object of the invention to test the same targeting mechanism that will be used with the treatment-radiopharmaceutical. 
         [0029]    These particular features and advantages may apply to only some embodiments falling within the claims and thus do not define the scope of the invention. 
     
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         [0030]      FIG. 1  is a schematic overview of the process implemented by the present invention; 
           [0031]      FIG. 2  is a flow chart of the steps of the present invention as may be implemented in whole or in part on one or more electronic computers; 
           [0032]      FIG. 3  is a graph showing a time activity curve collected using an imaging-radiopharmaceutical for two volumes of interest; 
           [0033]      FIG. 4  is a graph showing development of a treatment plan for a treatment-radiopharmaceutical using the time activity curves of  FIG. 3  as model elements; and 
           [0034]      FIG. 5  is graphical representations of a desired radiation dose map and an actual radiation dose map produced by administration of the radiopharmaceutical, the difference providing a dose map for an augmenting external-beam radiation treatment plan. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
       [0035]    Referring now to  FIG. 1 , the present invention provides a two-step process for the administration of a treatment-radiopharmaceutical having an imaging phase  10  followed by a treatment phase  12 . 
         [0036]    In one embodiment, the imaging phase  10  uses a combination SPECT/CT or PET/CT machine  14 . Such a machine employs a conventional CT gantry  16  together with area gamma sensors  18  to provide a set of spatially aligned tomographic x-ray images  20  and corresponding tomographic emitted-radiation images  22  typically taken along a transverse (“x-y”) cross-sectional plane through the patient  24 . Tomographic x-ray images  20  and tomographic emitted-radiation images  22  displaced along the anterior-posterior (“z”) axis complete a three-dimensional data scan used by the present invention producing a volumetric CT image set  30  and a volumetric emitted-radiation image set  28 . 
         [0037]    Contemporaneously with the CT scan, the patient  24  may be injected with a radiopharmaceutical  26 , for example, NM404 tagged with an imaging radionuclide I124. A description of this radiopharmaceutical  26  is found in U.S. patent application 2005/0196339 entitled: “Phospholipid Analogs As Diapeutic Agents and Methods Thereof”, published Sep. 8, 2005, naming the present inventor and hereby incorporated by reference. This particular radiopharmaceutical  26  emits gamma rays compatible with SPECT imaging. 
         [0038]    As will be understood from the following discussion, the present invention is not limited to this particular radiopharmaceutical  26  or this particular radionuclide. Accordingly, the tomographic emitted-radiation images  22  may be collected using other radiopharmaceutical and with other imaging modalities, for example PET. 
         [0039]    The collection of data of the volumetric emitted-radiation image set  28  continues for a period of time sufficient for the pharmacokinetic properties of the radiopharmaceutical  26  to be determined. Typically this period will be long enough for the radiopharmaceutical  26  to be taken up into the targeted tissue of the patient  24  and expelled from the body or to be exhausted by half-life decay. This time period will often span many days and, accordingly, the patient  24  may return to the hospital or clinic on a periodic basis for acquisition of each volumetric emitted-radiation image set  28 . Periodically in this process, a new volumetric CT image set  30  may be obtained (or selected tomographic x-ray images  20 ) to, permit accurate alignment of the volumetric emitted-radiation image sets  28  with earlier and later data using the higher resolution CT data. 
         [0040]    While the preferred embodiment employs x-ray CT data, it will be appreciated that other imaging modalities may be used in this capacity or that the volumetric emitted-radiation image set  28  may be used alone without a separate data set for alignment or volume definition as will be described below. 
         [0041]    At the conclusion of this process a model data set  33  will have been collected including multiple volumetric CT image sets  30  and multiple volumetric emitted-radiation image sets  28 . Referring also to  FIG. 2 , when the model data set  33  has been collected, as indicated by process block  32 , it may be loaded in a workstation  34 , for example, a free standing personal computer or a workstation associated with the SPECT/CT machine  14  or (as shown) associated with an external-beam radiation therapy machine  40 . The workstation  34  will preferably be of a type that can execute commercially available treatment planning software. 
         [0042]    As is generally understood the art, such workstations  34  may include one or more processors  36  communicating with memory  38  by means of an internal bus  41 . The memory  38  may hold a program  42  implementing one or more steps of the present invention as well as data libraries, as will be described. The bus  41  may communicate with an interface  44  providing for graphics display on monitor  46  and the entry of data through keyboard  48  or the like. The interface  44  may also provide data to the external-beam radiation therapy machine  40  or receive data (not depicted) from the SPECT/CT machine  14 . 
         [0043]    Referring now to  FIGS. 2 and 3 , the model data set  33  may be loaded into memory  38  and displayed using conventional techniques to allow volumes of interest (VOIs) within the tissue to be identified with respect to the CT images. For example, a first tumor volume of interest  50  (tumor VOI) and an adjacent healthy-tissue volume of interest  52  (healthy-tissue VOI) may be identified. This identification describes a three-dimensional volume and may be performed, for example, by the reviewing of successive tomographic x-ray images  20  of the patient and a drawing of an outline around the particular volumes of interest. This process establishes x-y boundaries for each tomographic x-ray image  20  and multiple x-y boundaries over different images along the z-axis established by the remaining dimension of the VOI. The marking of the volumes of interests will typically be with respect to the volumetric CT image set  30  but may be informed by the data of the volumetric emitted-radiation image set  28  as well or may use the volumetric emitted-radiation image set  28  alone. 
         [0044]    Upon completion of the definition of the volumes of interest, as indicated by process block  56 , the program may proceed to process block  57  where time activity curves are calculated for each of the volumes so identified. Time activity curves provide instantaneous radiation dose-rates as a function of time and the integral or area under the time activity curves provides total radiation dose. 
         [0045]    This calculation process first segregates data elements of the volumetric emitted-radiation image set  28  to one of the volumes of interest  50  and  52  for each time period associated with the acquisition of the volumetric emitted-radiation image set  28 . The emitted-radiation in each data element of a given volume of interest  50  and  52  for a particular time is then convolved with a radiation dose point kernel to define the dose-rate for that time period. Together, the dose-rates for the different time periods provide time activity curve  58  (tumor TAC) associated with tumor VOI  50  and healthy-tissue time activity curve  60  (healthy-tissue TAC) associated with healthy-tissue VOI  52 . The radiation dose point kernel may be density corrected (using tissue density derived from the CT scan or the like). Other methods for determining dose rate may also be used including but not limited to a Monte Carlo dose calculation and similar techniques. 
         [0046]    As depicted in  FIG. 3 , the healthy-tissue TAC  60  associated with tissue that is not targeted by the radiopharmaceutical  26  will generally exhibit lower uptake (indicated by the lower peak of the healthy-tissue TAC  60 ) and a shorter activity time (indicated by the shorter duration of the peak of healthy-tissue TAC  60 ). In contrast, the targeting effect of the radiopharmaceutical  26  with respect to the tumor cells in the tumor VOI  50  results in a higher peak for tumor TAC  58  and a far longer duration as the radiopharmaceutical  26  is held in the tissues. 
         [0047]    Referring now momentarily to  FIG. 5 , as shown by process block  65 , at the time of computation of the tumor TAC  58  and the healthy-tissue TAC  60 , a radiation dose map  62  of tumor VOI  50  may be developed providing multiple iso-radiation dose lines  63  indicating the radiation dose received within the tumor VOI  50 . This dose map  62  may be a single map obtained by integrating the total radiation dose of the tumor VOI  50  for each volume element of the data set  33  within the tumor VOI  50  for the entire time of the tumor TAC  58 , or may be a set of dose maps associated with each volumetric emitted-radiation image set  28 . The use of this dose map  62  will be described below. 
         [0048]    Referring now again to  FIG. 1 , during the second treatment phase  12  of the present invention, the patient  24  will be injected with a treatment-radiopharmaceutical  64 . In this example, the treatment-radiopharmaceutical  64  is an NM404 with the radionuclide I131 or I125 substituted for I124. As will be understood, the present invention is not limited to this particular treatment-radiopharmaceutical  64  or this particular radionuclide nor is it necessary that the radiopharmaceutical  64  be suitable for imaging. 
         [0049]    Generally, the radionuclide used in the treatment-radiopharmaceutical  64  will have a longer half-life than that used with the imaging-radiopharmaceutical  26  however; the same tracer component may be used to provide comparable uptake mechanisms. The treatment-radiopharmaceutical  64  will be administered to the patient  24  in a treatment schedule providing for delivery amounts and delivery times of the treatment-radiopharmaceutical  64  as computed by the present invention per process block  66  of  FIG. 2 . 
         [0050]    Referring now to  FIG. 4 , the treatment schedule may be automatically calculated using a few setting parameters input by a clinician. The first parameter is a toxicity limit  70  for tissue in one or more healthy-tissue VOIs  52 . The toxicity limit  70  may be, for example, automatically provided from a stored library of toxicity limits associated with particular organs and the clinician may simply assign an organ name to each of the healthy-tissue VOIs  52 . When multiple healthy-tissue VOIs  52  have been identified with toxicity limit  70 , a treatment schedule will be calculated to keep the radiation dose-rate below the toxicity limit  70  of all of the healthy-tissue VOIs  52 . Alternatively, the absorbed dose, being the integral of the TAC  58 , may be kept below the toxicity limit  70  expressed as an absorbed dose. 
         [0051]    The clinician may also enter a desired radiation dose-rate  72  for the tumor VOI  50 . This desired radiation dose-rate is set to provide a given minimum dose rate necessary to kill the tumor cells. Additionally, the clinician may enter a dose duration time indicating the desired length of treatment. 
         [0052]    The time activity curves, shown in  FIG. 3 , are now adjusted to account for the different radionuclide used in the imaging-radiopharmaceutical  26  versus the treatment-radiopharmaceutical  64  to provide a healthy-tissue model curve  74  and a tumor model curve  76 , conforming generally in shape to the healthy-tissue TAC  60  and the tumor TAC  58  adjusted in scale and possibly duration. The healthy-tissue model curve  74  and a tumor model curve  76  will be associated with a normalized treatment amount of the treatment-radiopharmaceutical  64  and can be simply scaled to accommodate different treatment quantities. 
         [0053]    Using this principle, the healthy-tissue model curve  74   a  may be used to determine an administered quantity of the treatment-radiopharmaceutical  64  at a first radiopharmaceutical application  78   a  so that the peak of the healthy-tissue model curve  74   a  stays below the toxicity limit  70  for that tissue. 
         [0054]    A second radiopharmaceutical application  78   b  may then be timed so that the sum (linear superposition) of the healthy-tissue model curve  74   b  for the second radiopharmaceutical application  78   b  and the healthy-tissue model curve  74   a , being healthy-tissue rate total  80 , stay below the toxicity limit  70 . 
         [0055]    Using these administered quantities, a corresponding tumor tissue rate total  81  can be determined by summing tumor model curves  76   a  and  76   b  associated with the radiopharmaceutical applications  78   a  and  78   b  in a manner similar to that used to produce healthy-tissue rate total  80 . As a result of the longer retention time of the treatment-radiopharmaceutical  64  in the tumor tissue of tumor VOI  50 , the tumor tissue rate total  81  continues to climb during this time to exceed the desired radiation dose-rate  72  while the healthy-tissue rate total  80  is constrained below the toxicity limit  70 . In this way, either manually or automatically, an optimized schedule of the times of radiopharmaceutical applications  78  and quantities of the treatment-radiopharmaceutical  64  administered at those times can be determined. This schedule pattern may be repeated to provide the necessary duration of treatment time defined by the time during which the tumor tissue rate total  81  exceeds desired radiation dose-rate  72 . 
         [0056]    Referring still to  FIG. 4 , in some cases the desired radiation dose-rate  72 ′ may exceed a peak level of the tumor tissue rate total  81  obtainable in the tumor VOI  50  while observing the toxicity limit  70  in the healthy-tissue VOI  52 . Accordingly, the present invention may calculate an augmenting dose that may be output to the external-beam radiation therapy machine  40  to provide an augmenting radiation dose to the tumor VOI  50  to correct for a shortfall  82  in the dose-rate in the tumor VOI  50 . The modeling system of the present invention allows precision in definition of the dose rate in particular volumes of interest  50  and  52  consistent with performing this type of augmentation by external-beam radiation therapy machines  40 . Normally external-beam radiotherapy and targeted radionuclide therapy have quite different dose rates and accordingly their doses are added by conversion of both to a common “biologically effective dose” (BED). BED effectively normalizes both of these processes into infinitesimally small fractions. As shown in  FIG. 4 , this fractionation of the external radiation beam may be implemented by applying a radiation beam at multiple fractionation times  84  using the external-beam radiation therapy machine  40 . 
         [0057]    Referring again to  FIG. 2 , the computation of an augmenting radiation therapy plan shown generally by process block  86  may also be used to address a lack of uniformity in the radiation dose to the tumor VOI  50  by the treatment-radiopharmaceutical  64 . Referring again to  FIG. 5 , the user may enter a desired radiation dose  90  to be received by the tumor VOI  50  here shown as a constant value in a cross section  92  through the tumor VOI  50 . As computed at process block  65 , lack of vascularization of the tumor tissue in the tumor VOI  50  (tumor hypoxia) may cause a lower radiation dose in a central region  94  of the tumor shown in a representative cross-section  92 ′. 
         [0058]    The process of providing information to the external-beam radiation therapy machine  40  for this augmenting treatment made employ a subtraction of the actual radiation dose of the tumor VOI  50  defined by iso-radiation dose lines  63  (adjusted to accommodate the change of radiopharmaceutical  64  from radiopharmaceutical  26 ) from the desired radiation dose  90  to produce a difference dose  96  which can provide a desired radiation dose pattern for conventional treatment planning software for the external-beam radiation therapy machine  40 . 
         [0059]    Referring again to  FIG. 2 , this process of augmentation of the action of the radiopharmaceuticals with an external radiation beam may be performed iteratively with the actual radiation dose produced by the external-beam radiation therapy machine  40  being modeled and added to the radiation dose described by the iso-radiation dose lines  63  computed at process block  65 . A new difference dose  96  may then be computed and used to adjust either the treatment schedule for the radiopharmaceutical  64  or the dose provided by the external-beam radiotherapy machine  40  as indicated by iteration arrows  100 . 
         [0060]    At process block  102 , an output is provided consisting of a set of delivery amounts and delivery times for the radiopharmaceutical  64  and scheduled times and dose patterns for external-beam radiation. It will be understood that other of treatment planning outputs may also be provided including an indication of total dose and other graphic elements depicting the treatment planning process of the present invention including for example an estimated total dose or time activity curves for the treatment radiopharmaceutical  62  in each region of interest. 
         [0061]    It will be appreciated that the present invention permits implementation of radiobiological monitoring, for example, using the Linear Quadratic Model and the determination of biological effective doses (BED). By incorporating the Lea-Catcheside factor into the biological effective dose equation, it is possible to set the desired radiation dose-rate  72  to include the radiobiological effects of radiation dose-rate and sub-lethal repair of both early and late responding tissues. 
         [0062]    It is specifically intended that the present invention not be limited to the embodiments and illustrations contained herein, but include modified forms of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the following claims.