U.S. patent application number 14/413033 was filed with the patent office on 2015-07-16 for multi-spectral fluorescence for in-vivo determination of proton energy and range in proton therapy.
The applicant listed for this patent is H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.. Invention is credited to Brian P. Tonner.
Application Number | 20150196779 14/413033 |
Document ID | / |
Family ID | 49997895 |
Filed Date | 2015-07-16 |
United States Patent
Application |
20150196779 |
Kind Code |
A1 |
Tonner; Brian P. |
July 16, 2015 |
MULTI-SPECTRAL FLUORESCENCE FOR IN-VIVO DETERMINATION OF PROTON
ENERGY AND RANGE IN PROTON THERAPY
Abstract
The accuracy charged-particle beam trajectories used for
radiation therapy in patients is improved by providing feedback on
the beam location within a patient's body or a quality assurance
phantom. Particle beams impinge on a patient or phantom in an
arrangement designed to deliver radiation dose to a tumor, while
avoiding as much normal tissue as can be achieved. By placing
fiducial markers in the tumor or phantom that contain specific
atomic constituents, a detection signal consisting of atomic
fluorescence is produced by the particle beam. An algorithm can
combine the detected fluorescence signal with the known location of
the fiducial markers to determine the location of the particle beam
in the patient or phantom.
Inventors: |
Tonner; Brian P.; (Winter
Springs, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. |
Tampa |
FL |
US |
|
|
Family ID: |
49997895 |
Appl. No.: |
14/413033 |
Filed: |
July 29, 2013 |
PCT Filed: |
July 29, 2013 |
PCT NO: |
PCT/US2013/052563 |
371 Date: |
January 6, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61676673 |
Jul 27, 2012 |
|
|
|
Current U.S.
Class: |
600/1 |
Current CPC
Class: |
A61B 6/583 20130101;
A61N 5/1071 20130101; A61N 5/1049 20130101; A61N 5/1048 20130101;
A61N 2005/1087 20130101; A61N 2005/1059 20130101; A61N 2005/1051
20130101; A61B 6/508 20130101; A61N 5/1064 20130101 |
International
Class: |
A61N 5/10 20060101
A61N005/10 |
Claims
1. A method for improving the trajectory of charged-particle beams
used in cancer therapy in a subject comprising: (a) placing in a
subject one or more fiducial markers that produce fluorescent
x-rays of one or more distinct energies when struck by a
charged-particle beam; (b) determining the locations of the one or
more fiducial markers; (c) changing as a function of time the
energy of a charged-particle beam which impinges on the subject;
(d) recording as a function of time fluorescent x-ray emissions
from the fiducial markers when the subject is struck by the
charged-particles; (e) applying an algorithm to the recorded
information to determine the location of the particle beam in the
target relative to the known locations of the fiducial markers; (f)
processing the results of the algorithm in a form suitable for
display; and (g) displaying location of the particle beam position
relative to the fiducial markers.
2. The method of claim 1, further comprising changing the
trajectory of the charged-particle beam based on the measurement of
particle beam induced fluorescence.
3. The method of claim 1, wherein the one or more fiducial markers
have a composition which produces a first fluorescent x-ray in the
energy range from 20 keV to 150 keV.
4. The method of claim 1, wherein the one or more fiducial markers
have a composition which produces a second fluorescent x-ray in the
energy range from 20 keV to 150 keV that is distinct from the first
fluorescent x-ray.
5. The method of claim 4, further comprising using the ratio of the
intensity of the first fluorescent x-ray and the second fluorescent
x-ray to determine the attenuation thickness of the patient that
the beams have traversed.
6. The method of claim 4, wherein the one or more fiducial markers
have a substantial component of the element gold (Au).
7. The method of claim 1, wherein the fluorescent x-ray emissions
are recorded using one or more scintillation detectors.
8. The method of claim 7, wherein the one or more scintillation
detectors have collimation suitable to exclude substantial response
to radiation not originating from the fiducial markers.
9. A method of treating a tumor in a subject, comprising (a)
implanting one or more fiducial markers in or near the tumor; (b)
identifying an optimize trajectory for a charged-particle beam
using the method of any one of claims 1 to 8; and (c) using the
optimized charged-particle beam to irradiate the cancer.
10. The method of claim 9, wherein the tumor is a lung cancer,
prostate cancer, breast cancer, skull base tumor, or uveal
melanoma.
11. The method of claim 9, wherein the one or more fiducial markers
are placed at one or more of the tumor margins, at one or more
locations inside the tumor, or a combination thereof.
12. A system for improving the accuracy of a charged-particle beam
used in cancer therapy comprising: (a) a source of
charged-particles of suitable energy for therapeutic effect which
can be varied in energy as a function of time; (b) one or more
fiducial markers that produce fluorescent x-rays of one or more
distinct energies when struck by a charged-particle beam; (c) one
or more fluorescent energy detectors suitable for measuring
fluorescent x-rays emitted by the fiducial markers; (d) a recorder
suitable to record the energy of the charged-particle beam and the
fluorescent x-ray emissions as a function of time; (e) a processor
and memory to calculate penetration of the charged-particle beam in
the target based on the recorded information; and (f) a display by
which the information on penetration is presented in suitable
form.
13. The system of claim 12 wherein the fiducial markers have a
composition which produces a fluorescent x-ray in the energy range
from 20 keV to 150 keV.
14. The system of claim 12 wherein the fiducial markers have a
composition which produces a second fluorescent x-ray in the energy
range from 20 keV to 150 keV that is distinct from the first
fluorescent x-ray.
15. The system of claim 14, wherein the fiducial markers have a
substantial component of the element gold (Au).
16. The system of any one of claims 12, wherein the one or more
fluorescence energy detectors are scintillation detectors.
17. The method of claim 16, wherein the one or more fluorescence
energy detectors have collimation suitable to exclude substantial
response to radiation not originating from the fiducial markers.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application No. 61/676,673, filed Jul. 27, 2012, which is hereby
incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The disclosure relates to a method and apparatus for
improving the accuracy of delivery of charged-particle beams for
the treatment of cancer. The disclosure also includes an improved
method for performing quality-assurance measurements on
charged-particle beams used in therapy.
BACKGROUND
[0003] Charged-particle beams are among the most advanced methods
currently available for the treatment of cancer tumors by
radiotherapy. The more common charged-particle beam therapy centers
use protons as the particle of choice, while a few centers have
begun using heavy ion particles such as carbon ion beams.
[0004] The specific advantage of charged-particle beam therapy in
treating tumors is the physical effect known as the "Bragg peak."
The Bragg peak is a sharp increase in delivered dose, which occurs
near the end of a particle trajectory in the patient. The physical
characteristics of the Bragg peak make it possible, in principle,
to more carefully conform the particle-beam to the shape of the
tumor. In addition, since there is very little beam intensity
beyond the range of the Bragg peak, there can be significant
reduction in overall radiation dose to normal tissue, as compared
to photon external beam radiotherapy.
[0005] In order to make use of narrow tumor margins that are
possible in principle with charged particle beams, it is necessary
to have an accurate knowledge of the beam penetration in the
patient. The current practice is to infer the penetration of
charged particles, based on information gathered from x-ray
imagery, particularly computed tomography (CT). However, there are
well-known problems with making the extrapolation from CT imagery
to the expected penetration of charged particle beams, which leads
to an uncertainty in the knowledge of the beam penetration in the
actual patient. In addition, the patient anatomy can change over
time, leading to changes in the actual penetration of the charged
particle beam from one treatment to the next, further leading to
uncertainty in the knowledge of the actual delivered dose to tumor
and to normal tissue.
SUMMARY
[0006] The disclosed systems, methods, and devices address the
uncertainty in beam location by providing a means to determine
particle beam penetration in a patient during the time frame of a
daily treatment. The disclosed systems, methods, and devices may
also be used to determine the charged particle beam penetration in
phantoms constructed from materials chosen to mimic the behavior of
human tissue when exposed to radiation, often called
"water-equivalent" materials. The disclosed systems, methods, and
devices improve the accuracy of determination of charged particle
beam penetration in patients. The disclosed apparatus and methods
also apply to the calibration of charged particle beams for
therapeutic use. This disclosure applies to all charged-particle
beam therapies for treating cancer.
[0007] Disclosed are a system, method, and apparatus that provide
information about the trajectory of a charged particle beam as it
traverses a patient undergoing external beam therapy. Although the
present embodiment primarily addresses proton beam therapy, it is
also applicable to other charged particle beams, and specifically
to carbon atom beams.
[0008] A method is disclosed for determining charged-particle beam
trajectories through the use of a variation of the charged-particle
beam energy as a function of time, and measurement of the yield of
fluorescent radiation from fiducial markers as a function of time,
and application of an algorithm to extract information on the beam
trajectory. A "fiducial marker" as used herein includes any
material with a known composition that is placed at a known
location. In particular, the fiducial marker can contain a material
with x-ray fluorescence.
[0009] Also disclosed is a method to use a charged-particle beam in
a way that is compatible with its use for patient therapy. The
charged-particle beam excites atomic electrons in all of the
materials along the charged-particle beam path. These excited
electrons leave behind an atom in an excited energy state, which is
de-excited through a number of processes. One of the processes is
the production of fluorescent x-rays.
[0010] The method detects these fluorescent x-rays, and uses the
intensity of the fluorescence, along with other information, to
determine the trajectory of the charged-particle beam in the
patient. The energy of the fluorescent x-ray can be selected such
that the x-ray can readily pass through the patient's tissue and
reach the detector. For example, the energy of the fluorescent
x-ray can be at least 20 keV (e.g., at least 30 keV, at least 40
keV, at least 50 keV, at least 60 keV, at least 70 keV, at least 80
keV, at least 90 keV, at least 100 keV, at least 110 keV, at least
120 keV, at least 130 keV, or at least 140 keV). In some
embodiments, the energy of the fluorescent x-ray can be 150 keV or
less (e.g., 140 keV or less, 130 keV or less, 120 keV or less, 110
keV or less, 100 keV or less, 90 keV or less, 80 keV or less, 70
keV or less, 60 keV or less, 50 keV or less, 40 keV or less, or 30
keV or less). The energy of the fluorescent x-ray can range from
any of the minimum energies described above to any of the maximum
energies described above. For example, the energy of the
fluorescent x-ray can range from 20 keV to 150 keV (e.g., from
20-40 keV, from 40-50 keV, from 50-60 keV, from 60-80 keV, or from
60-90 keV).
[0011] By using fluorescent x-rays, the method takes advantage of
the narrow line-width and high detection efficiency of x-rays of
atomic origin. The line-width of the fluorescent x-ray can be
sufficiently narrow, such that the fluorescent x-ray can be readily
detected without interference from a wide range of x-rays from
other processes that do not provide beam position information.
Suitable line-widths for the fluorescent x-ray line-width can be
selected in view of the detector or detectors configured to measure
the fluorescent x-ray. For example, the line-width of fluorescence
x-rays can be approximately 100 eV for high-resolution solid-state
detectors, or a few hundred eV for proportional counters. In
certain embodiments, the line-width of the fluorescent x-ray is 1
keV or less (e.g., 900 eV or less, 800 eV or less, 700 eV or less,
600 eV or less, 500 eV or less, 400 eV or less, 300 eV or less, 300
eV or less, or 100 eV or less). The line-width of the fluorescent
x-ray can be sufficiently narrow to permit the separation of lines
from different elements and/or different inner-shell atomic energy
levels, such as the K and L shell of the element gold (Au).
[0012] A number of materials can be selected to create fiducial
markers that will produce fluorescent x-rays that will pass through
the body with low attenuation but have a high detection efficiency.
The fluorescent x-ray is produced by atomic de-excitation. The
chemical element used as a fiducial marker can be selected to be
compatible with human use and with radiotherapy. In some
embodiments, the method uses gold (Au) fiducial markers, which
produce K-shell fluorescent x-rays of an energy and line-width of
60-80 keV, which is suitable for detection during clinical
procedures. Other atomic elements can also produce suitable x-rays,
and the use of these other elements is included in the scope of the
invention. Suitable materials for producing these fluorescent
x-rays include materials used commonly in medicine and as contrast
agents, including gold (Au), gadolinium (Gd, with K shell
transition radiation in the range of 42-50 keV), iridium (Ir, with
K shell transition radiation in the range of 63-76 keV), iodine (I,
with K shell transition radiation in the range of 28-33 keV), xenon
(Xe, with K shell transition radiation in the range of 29-33 keV),
barium (Ba, with K shell transition radiation in the range of 32-36
keV), lanthanum (La, with K shell transition radiation in the range
of 33-38 keV), samarium (Sm, with K shell transition radiation in
the range of 40-45 keV), europium (Eu, with K shell transition
radiation in the range of 41-47 keV), terbium (Tb, with K shell
transition radiation in the range of 44-50 keV), erbium (Er, with K
shell transition radiation in the range of 48-56 keV), thulium (Tm,
with K shell transition radiation in the range of 50-58 keV),
lutetium (Lu, with K shell transition radiation in the range of
53-61 keV), tungsten (W, with K shell transition radiation in the
range of 58-67 keV), rhenium (Re, with K shell transition radiation
in the range of 58-69 keV), osmium (Os, with K shell transition
radiation in the range of 61-71 keV), and Platinum (Pt, with K
shell transition radiation in the range of 65-76 keV).
[0013] The method uses a known position of fiducial markers to
identify the emission location of fluorescent x-rays. Implanted
fiducial markers are common in radiotherapy, and specific examples
are for prostate therapy and lung therapy. However, implanted
fiducials can be used in many other areas of the body for other
types of cancer treatment, and these uses are included herein.
[0014] Fiducial markers are typically located by performing a
computed-tomography (CT) scan of the patient, which can also be
used with the disclosed methods. However, other means to locate
fiducial markers that can be used in the disclosed methods include
high resolution sonography, radiography, and RF emission from
markers with transmitters.
[0015] Fiducial markers can take different physical forms,
including metallic wires, helical coils, and surgical clips. For
example, fiducial markers commonly used in medical practice for
marking tumor locations, such as the Visicoil.TM. product and
surgical clips made from gold can be used. In addition to these
common fiducial markers, the method incorporates the use of other
suitable classes of fiducial markers which contain x-ray
fluorescent atoms, such as nanoparticles, metal-conjugated
proteins, and imaging contrast agents. For example, fiducial
markers may also take the form of injected liquids containing atoms
that fluoresce in the energy ranges described above (e.g., emit a
fluorescent x-ray having an energy of from 20-150 keV). Examples of
such injectable fiducial markers includes nanoparticles formed from
a suitable x-ray fluorescing material (e.g., gold nanoparticles,
gadolinium nanoparticles, gold-gadolinium nanoparticles, core-shell
nanoparticles containing a suitable x-ray fluorescing material in
the core and a shell formed from a passivating material such as a
polymer), microcontainers encapsulating a solution of a suitable
x-ray fluorescing material (e.g., polymer tubes or capsules filled
with, for example, a gadolinium solution), and radium containing
radiopharmaceuticals.
[0016] The method uses a particular protocol for delivering the
particle beam at any time prior to, during, or after treatment of a
patient, in order to determine the trajectory of the beam within
the patient. The particle beam is delivered with a known beam
energy, which is varied, while measuring fluorescence emission from
implanted fiducial marker(s) in synchrony with the variation of the
beam energy. The variation of the beam energy produces a change in
the depth of penetration of the charged particle beam, which is
reflected in a variation of the detected fluorescence emission.
[0017] In some embodiments, the method involves the detection of an
x-ray of a single energy. Attenuation of the emitted fluorescent
beam can in some embodiments be affected by variations in the
patient's body thickness and composition, which may not be
independently determinable. Therefore, in other embodiments, the
method uses the simultaneous detection of x-rays of two or more
different energies. These x-rays originate at the same location in
the patient. Since the x-rays have two different energies, they
will travel through the patient's body with different levels of
attenuation. The two (or more) x-ray energies will be detected by
an energy selective x-ray detector. A suitable method for this
detection is a pulse-height analysis system, such as a silicon or
germanium detector, or in some cases, a scintillation counter
system. Other methods of detecting the number of x-rays emitted
within each energy channel are known, and may be used in the
disclosed systems, methods, and devices.
[0018] By simultaneously detecting x-rays of more than one energy,
it is possible to determine the ratio of the intensity of these
beams that are detected. The method will work with two or more
beams. In some embodiments, the K-.alpha. (near 80 keV, also called
KN radiation) and K-.beta. shell fluorescence (near 68 keV, also
called KL radiation) from Au (gold) fiducials is used. However,
other materials are suitable for this purpose, including in certain
cases materials that occur naturally in the human body. Materials
commonly used in medicine such as gadolinium, iodine, iridium, and
radium have suitable energy levels that are separated by several
keV and can be distinguished by suitable detectors, including
solid-state detectors.
[0019] Both of the x-ray beams, e.g., K-.alpha. and K-.beta., pass
through the same regions of the patient. Each individually
experiences intensity attenuation that is a function of the energy
of the x-ray beam. The energy of the beam is measured. The energy
of the x-ray beam identifies the type of the beam, e.g., that it is
a K-.alpha. or an K-.beta. shell beam. With the knowledge of the
type of beam, e.g., K-.alpha. or K-.beta. shell, the ratio of the
intensity of these beams can then be used to determine the
attenuation thickness of the patient that the beams have traversed.
This is accomplished by using a formula for x-ray attenuation based
on an exponential function, in which the effective thickness of the
material traversed is multiplied by the attenuation coefficient for
the specific beam, e.g., the K-.alpha. or K-.beta. shell. The
attenuation coefficients can either be taken from widely known
tabulated information, or determined more specifically by
measurements on so-called "phantom" materials selected to mimic
human tissue. The relative intensity of the beams is used with the
knowledge of the exponential attenuation law to correct the
information of x-ray intensity that is used to determine the proton
energy and range.
[0020] The disclosed method can incorporate an algorithm for
determining particle beam trajectory based on the synchronous
variation of incident particle beam energy and fluorescence
emission intensity. The disclosed method may also be used to adapt
a therapeutic particle-beam therapy based on information revealed
by application of the disclosed method, so as to improve the
conformality of the particle-beam and the tumor being treated.
[0021] Energy detectors (e.g., multi-energy detectors) may be
arranged at various locations around the patient to increase the
number of beams that are measured, thereby reducing the time needed
to complete a measurement, and to increase the accuracy of the
measurement. Fluorescence x-rays may also be measured over a
substantial part of the spherical solid-angle surrounding the
fiducial markers using wide-angle detectors, so as to increase
signal detection efficiency and reduce patient dose. As a
beneficial alternative, the method allows for the use of collimated
detectors in an angular arrangement, so as to determine the
location of emission of fluorescence x-rays without the need for
other determination of their position.
[0022] An apparatus and system are disclosed that comprise a source
of charged-particles with an energy that can be varied as a
function of time, fiducial markers with a constituent material that
produces a fluorescence signal suitable for detection at a distance
removed from the treatment field, an arrangement of detectors to
measure the fluorescence signal as a function of time, and suitable
computer control and electronic equipment to implement the method
and apply the disclosed algorithm to extract and display
information on the charged-particle beam trajectory.
[0023] The apparatus and system can incorporate a therapeutic
charged-particle beam with an energy that is varied. Typically this
is accomplished with a "modulation wheel", also called a
"propeller". Implanted fiducial markers containing a high density
of atoms of the desired element to produce fluorescence x-rays may
be placed in or near the tumor treatment location. Fluorescence
detectors may be arranged outside the patient so as to be outside
the path of the incident particle beam, but are otherwise located
close to the patient's skin surface to enhance signal
detection.
[0024] Fluorescence signals may be measured from the detectors, and
selected according to their energy using pulse-height
discrimination techniques. The energy of fluorescence can be
determined by the element used in the fiducial implant. This energy
may be high enough so that large numbers of x-rays are transmitted
outside the patient. By using fiducial markers of the heavy element
gold (Au), the marker is compatible with clinical use, and the
fluorescence x-ray is well-separated from other sources of
background radiation.
[0025] A computer system can be used to record the intensity of
emitted x-rays while monitoring the energy of the incident particle
beam. An algorithm, e.g., derived from Monte-Carlo simulations, can
be used to extract beam trajectory from the measured emission
intensity patterns.
[0026] An imaging detection system may be used to create a spatial
map of the location of the emitted fluorescent x-rays, so as to
more accurately determine the location of protons that create the
fluorescence. This spatial imaging detection system may be capable
of sorting fluorescent x-rays according to their energy, and to use
this information for attenuation correction as described above.
[0027] Also disclosed are method of treating cancer in a subject
that involve implanting fiducial markers in or near the cancer,
determining charged-particle beam trajectories through the use of a
variation of the charged-particle beam energy as a function of
time, measurement of the yield of fluorescent radiation from the
fiducial markers as a function of time, using an algorithm to
optimize beam trajectory, and using the optimized charged-particle
beam to irradiate the cancer. Any cancer, e.g., solid tumor, that
can be treated by charged-particle beam radiotherapy can be treated
by this optimized method. For example, the cancer can be lung,
prostate, breast, skull base tumors, or uveal melanomas.
[0028] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
DESCRIPTION OF DRAWINGS
[0029] FIG. 1 is a schematic view of an apparatus according to an
embodiment of the invention.
[0030] FIG. 2 is a table illustrating steps of a method in
accordance with an embodiment of the current invention.
[0031] FIG. 3 contains a top graph of model variations of the
charged particle beam as a function of time and a bottom graph of
the fluorescence yield as a function of time, showing the response
of the fiducial marker in accordance with an embodiment of the
invention.
[0032] FIG. 4 is a schematic of an experimental design to determine
whether proton-induced x-ray fluorescence can be utilized to
determine clinically important dosimetric parameters during a
proton therapy treatment.
[0033] FIG. 5 is a graph showing pulse height analysis of proton
induced Au fiducial x-ray emission (counts as a function of energy,
keV).
[0034] FIG. 6 is a graph showing analytical model of the experiment
using Bragg curve approximations with stopping power parameters for
Au adapted from NIST data tables (fluorescence as a function of
path length, cm).
DETAILED DESCRIPTION
[0035] In the following description, reference is made to the
accompanying drawings, which form a part hereof, and which show, by
way of illustration, specific examples or processes in which the
invention may be practiced. Where possible, the same reference
numbers are used throughout the drawings to refer to the same or
like components. In some instances, numerous specific details are
set forth in order to provide a thorough understanding of the
invention. The invention, however, may be practiced without the
specific details or with certain alternative equivalent devices
and/or components and methods to those described herein. In other
instances, well-known methods and devices and/or components have
not been described in detail so as not to unnecessarily obscure
aspects of the invention. For the sake of clarity, the various
elements represented in the figures are not necessarily to
scale.
[0036] FIG. 1 is a schematic of one embodiment of the disclosed
apparatus. A source of high energy charged particles 103 produces a
beam of particles 106, which is directed at a target 101. In a
preferred embodiment, the charged particles are protons with energy
ranging from 50 MeV to 250 MeV, but other charged particles and
energy ranges may be used. For example, the method is suited to be
used with helium and carbon atom particle beams, both of which are
used in practice for medical treatment.
[0037] The target 101 contains one or more, e.g., plurality, of
fiducial markers 102 which are placed at fixed locations within the
target. In the embodiment in which the target is a patient, these
fiducial markers may preferably be clinically approved seeds
manufactured from gold, with dimensions of approximately 1 mm
diameter, as commonly used for prostate implant radiotherapy. One
example type of suitable gold fiducial marker is the Visicoil.TM.,
which can range in diameter from 0.35 mm to 1.10 mm and length from
0.5 cm to 3 cm. Other suitable markers include gold markers used to
define tumor locations with the Cyberknife.TM. radiosurgery system
(wherein the gold markers are 0.8 mm.times.5 mm in size), and
surgical clips used to mark tumor boundaries.
[0038] In the embodiment in which the target is a phantom, the
fiducial markers may also be composed of gold wire, with preferable
dimensions of 1 mm diameter by 5 mm length.
[0039] The incident charged particle beam may be directed towards
the target and the fiducial markers, with an energy that changes as
a function of time in a known way. The control of particle beam
energy is a requirement of particle radiotherapy, and the means to
accomplish this are well known to practitioners of the art.
[0040] When the energy of the particle beam 106 is sufficiently
high enough, the Bragg peak will approach the location of the
fiducial markers 102, which will begin to produce fluorescence
radiation 104.
[0041] The fluorescent radiation emitted by the fiducial markers
contains one or more identifiable core-level x-ray emission peak
characteristic of the atomic composition of the fiducial. In some
embodiments, a major elemental component of the fiducial marker is
gold (Au), which emits K shell fluorescent x-rays in the range of
approximately 68-80 keV, which are sufficient to travel through the
target to reach the detectors 105 without excessive attenuation. In
some embodiments, both K and L shell fluorescence from Au (gold)
fiducials is used.
[0042] The fluorescent radiation 104 is not directed into any
specific direction. To efficiently collect the radiation, a
plurality of x-ray detectors 105 (e.g., multi-energy detectors) can
be arranged around the target. In FIG. 1 three such detectors are
shown, but more or fewer detectors can be used.
[0043] In some embodiments the detector 105 is a scintillation
detector, but other detectors of x-ray radiation are known to
practitioners skilled in the art and can be used herein. These
include solid state energy dispersive detectors, commonly called
silicon (Si) and germanium (Ge) detectors, proportional counters,
gas-electron multiplier detectors, energy-dispersive detectors, and
wavelength dispersive detectors.
[0044] The detector 105 produces one or more electrical signals
whose amplitude is proportional to the energy of the x-ray 104 that
reaches the detector. To enhance the signal-to-noise ratio,
pulse-height analysis may be used on the detector signal to isolate
the signal from the x-rays originating from the fiducial markers.
The fiducial markers produce characteristic x-rays which are
sufficiently far from the x-rays produced by other materials in the
patient or the phantom, that there is little interference to the
desired fiducial signal from other materials.
[0045] FIG. 2 is a diagram illustrating steps of one embodiment of
the disclosed methods. The method can begin with the implantation
of fiducial markers in the target, 201. In some embodiments, the
target is either a patient, or a phantom selected for
quality-assurance of the charged-particle treatment beam 103-106.
In the embodiment in which the target is a patient, the fiducial
markers may be similar to those already in clinical use for
treatment of prostate cancer or lung cancer.
[0046] The location of the fiducial markers is identified in the
next step of the method, 202. In the case in which the target is a
phantom, the location of the markers may be accomplished by the
construction of the phantom, or by optical means, or other means
well-known to those practiced in the art. In the case in which the
target is a patient, the fiducial markers by be localized using an
x-ray computed-tomography (CT) scan. Other methods of localizing
the fiducial markers, such as radiography, radio-frequency emitters
coupled to fiducials, magnetic resonance imaging, or ultrasound,
may also be used.
[0047] The particle beam 106 may be prepared at a specific energy,
and directed at the target, step 203. The yield of fiducial marker
fluorescence x-rays can be measured 204 and recorded. Optionally,
two or more fluorescent energies are detected to correct for
attenuation as described above. The energy of the beam 106 can be
incremented, resulting in a stepwise variation of the beam energy
with time, with the precise relationship of time and beam energy
being known. The beam energy can be compared to the desired
endpoint, 205, and the cycle of measurement of x-rays and
incrementing beam energy (203, 204, 205) can be repeated until the
entire range of particle energies is scanned.
[0048] An algorithm 206 can be applied to the measured fluorescence
data as a function of time, to determine the precise time at which
the particle beam reached the known location of the fiducial
markers. This time in turn can be converted into a beam energy,
which was recorded in steps 203-205.
[0049] In some embodiments, the algorithm used to process the
fluorescence data is based on accurate measurements made with
proton beams and fiducial markers in a water-equivalent phantom.
From this measurement, a profile can be determined that represents
the intensity distribution of fluorescence from the fiducial as the
Bragg peak sweeps across the fiducial marker. The specific point in
the profile that represents the location of the fiducial can thus
be accurately determined. This information can be used by the
algorithm to extract the location of the particle beam Bragg peak
in the target from the measured intensity of fluorescence x-rays as
a function of time.
[0050] As an illustration of the process of the algorithm, FIG. 3
(301) shows a model graph (top) of the variation of the charged
particle-beam energy as a function of time, exhibiting a
monotonically increasing behavior. The energy of the beam is known
at any time. The emitted fluorescence yield from a single fiducial
marker is illustrated in the bottom graph of FIG. 3 (302). An
edge-like structure occurs at the location of the time t* (303),
highlighted by the vertical dashed line. The shape of the edge
structure is analyzed to determine the precise time, t*, which
corresponds to the particle beam Bragg peak maximum encountering
the fiducial marker. Since time also determines beam energy (301),
it is then known at which beam energy the particle beam strikes the
fiducials.
[0051] The results of the algorithm are presented in a suitable
form in the final step of the method 207. Specific parts, shapes,
materials, functions and modules have been set forth, herein.
However, a skilled practitioner will realize that there are many
ways to fabricate the disclosed system, and that there are many
parts, components, modules or functions that may be substituted for
those listed above.
[0052] Also disclosed are method of treating a tumor in a subject
that involve implanting fiducial markers in or near the cancer,
determining charged-particle beam trajectories through the use of a
variation of the charged-particle beam energy as a function of
time, measurement of the yield of fluorescent radiation from the
fiducial markers as a function of time, using an algorithm to
optimize beam trajectory, and using the optimized charged-particle
beam to irradiate the cancer. Any tumor, e.g., cancer, that can be
treated by charged-particle beam radiotherapy can be treated by
this optimized method. For example, the cancer can be lung,
prostate, breast, skull base tumors, or uveal melanomas. In some
embodiments, the fiducial markers are placed at around the tumor
margins, at one or more locations inside the tumor, or a
combination thereof.
[0053] The term "subject" refers to any individual who is the
target of administration or treatment. The subject can be a
vertebrate, for example, a mammal. Thus, the subject can be a human
or veterinary patient. The term "patient" refers to a subject under
the treatment of a clinician, e.g., physician.
[0054] The term "treatment" refers to the medical management of a
patient with the intent to cure, ameliorate, stabilize, or prevent
a disease, pathological condition, or disorder. This term includes
active treatment, that is, treatment directed specifically toward
the improvement of a disease, pathological condition, or disorder,
and also includes causal treatment, that is, treatment directed
toward removal of the cause of the associated disease, pathological
condition, or disorder. In addition, this term includes palliative
treatment, that is, treatment designed for the relief of symptoms
rather than the curing of the disease, pathological condition, or
disorder; preventative treatment, that is, treatment directed to
minimizing or partially or completely inhibiting the development of
the associated disease, pathological condition, or disorder; and
supportive treatment, that is, treatment employed to supplement
another specific therapy directed toward the improvement of the
associated disease, pathological condition, or disorder.
[0055] The term "tumor" or "neoplasm" refers to an abnormal mass of
tissue containing neoplastic cells. Neoplasms and tumors may be
benign, premalignant, or malignant. The term "cancer" refers to a
cell that displays uncontrolled growth, invasion upon adjacent
tissues, and often metastasis to other locations of the body.
[0056] While the above detailed description has shown, described,
and pointed out the fundamental novel features of the invention as
applied to various embodiments, it will be understood that various
omissions and substitutions and changes in the form and details of
the components illustrated may be made by those skilled in the art,
without departing from the spirit or essential characteristics of
the invention.
EXAMPLES
Example 1
Proton Induced X-Ray Fluorescence for In-Vivo Determination of
Proton Range and Energy
[0057] FIG. 4 illustrates the experimental design used to determine
whether proton-induced x-ray fluorescence can be utilized to
determine clinically important dosimetric parameters during a
proton therapy treatment.
[0058] Measurements. Therapeutic beams from the UF Proton Therapy
Institute were used to excite proton induced x-ray fluorescence
emission (PIXE) from cylindrical pure gold fiducial markers. The
markers were embedded in a homogeneous water phantom and PIXE was
measured using NaI scintillators with energy dispersive spectral
analysis. The geometry of the phantom and marker placement was
chosen to model parallel-opposed beam treatment of prostate cancer
by proton therapy.
[0059] Modelling. An analytical model of fluroescence yield in
realistic therapy conditions was developed using semi-empirical Au
K and L shell cross-sections for proton induced emission, and
attenuation data for both xray channels. The fluorescence yield
from these markers was further modeled using the GEANT4 Monte-Carlo
package with low-energy corrections.
[0060] Measurements were made with proton beam maximum energy
ranging from 80 MeV to 200 MeV. The pure gold fiducial was placed
at a fixed depth in a water tank. The gold K and L shell x-rays
passed through 13.5 cm of water and the wall of the acrylic tank
before reaching a 2 cm diameter NaI scintillator where they were
detected and energy scaled using pulse height analysis (FIG.
5).
[0061] Backgrounds were taken with no beam and no gold sample, and
with a proton beam but no gold sample. The pulse-height analysis
spectrum was accumulated in a multichannel analyzer, and calibrated
using a Cs-137 source.
[0062] An analytical model of the experiment was developed using
the Bragg curve approximations of Bortfeld [Med. Phys. 24 (1997)
2024-2033] with stopping power parameters for Au adapted from NIST
data tables (FIG. 6). The model incorporates range straggling and
energy spread, and fluence reduction due to inelastic nuclear
events, using a parameterization to fit data of Janni [At. Data
Nucl. Data Tables 27 (1982) 147-339].
[0063] PIXE from gold fiducial markers was readily detected above
background using conventional NaI-T1 scintillation detectors, in a
clinical therapy proton beam. This work shows the feasibility of
using PIXE for in-vivo dosimetry with proton therapy.
[0064] A number of embodiments of the invention have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *