Biomedical Applications of Particle Accelerators:
Radiotherapy, Radioisotope Production, and Radiation Sterilization
Youngho Seo
UCLA Dark Matter Laboratory and Department of Physics and Astronomy
405 Hilgard Ave, Los Angeles, California 90095-1547; E-mail: [email protected]
The emergence of an unexpectedly large number of new diseases has required
the community of people with biomedical professions to contemplate new methods
to better treat or early diagnose them. New technologies have come in as a key role
to improve the doctor’s proficiency in diagnostics and treatment of patients. Radiotherapy is a great example to better treat cancers. Positron Emission Tomography
(PET) is also an excellent invention for the early detection of malign tumors. Seemingly unrelated, radiotherapy and PET share one common component, which is a
particle accelerator. The radioisotope production for PET and the radiation source
for radiotherapy are obtained by biomedical particle accelerators. In this paper, the
overview of how particle accelerators are used in biomedicine is presented.
With a particular interest, I include a detailed description of the radioisotope
production in nuclear medicine. The most recent developments for heavy ion and
proton therapy are among other highlighted discussions.
I. MOTIVATION
Not until the very recent years there was a far distance between physics and biomedicine. For the
people with biomedical professions, physics is just another subject that they must study to receive
a high score on the standardized exam to enter biomedical professional schools. E. K. Hobbie
noted in his book that he was amazed at the amount of physics in the courses at the University
of Minnesota Medical School and how little of it is taught to pre-med students in general physics
courses typically offered in modern pre-med programs at the US universities [1]. However, the
technology in biomedicine is found everywhere in the world because most human beings regard the
human life as number one priority so that we always want to use modern technologies in saving
the human lives. As all physicists are aware, technology and physics are inseparable subjects to
talk about.
Here comes my motivation to investigate how closely physics and biomedicine are related. I
have studied several areas of medically-applied physics before taking Physics 150 at UCLA. The
biomedical imaging is the field that combines physics, engineering, and biomedicine. Nuclear Magnetic Resonance Imaging (nMRI), Computed Tomography (CT), Positron Emission Tomography
(PET), and now accelerator applications in biomedicine are some of my long list of interests. For
this course, I would like to discuss the particle accelerator applications for biomedicine, especially focusing on the medical radioisotope production which is an essential part of Single Photon
Emission CT (SPECT) and PET. General review of other applications is also presented.
II. INTRODUCTION
For the past 65 years of the charged-particle accelerator developments, the concepts, design,
and applications have extended from the discovery of new elementary particles to hospital-housed
medical accelerators. Even at the very early stage of accelerator development in the 1930s, the
potential use of accelerators in radiation therapy (RT) for cancer treatment was discussed [2]. The
range of charged-particles used for radiation therapy is from conventional high energy photons
and electrons to unconventional heavy ions and protons. Although the initial cost to set up a
hospital-housed accelerator-based radiotherapy facility is rather high, the usefulness and the longterm cost-effectiveness have proved themselves, serving many patients with cancers as primary
treatment options thus far. Industries and the major research laboratories often collaborate to
develop a specifically-designed medical accelerator for this purpose.
Since the invention of PET scanner revolutionized the field of nuclear medicine, the accelerator
that produces positron-emitting radionuclides has been an essential part in a growing number
1
FIG. 1. Clinac manufactured by Varian Associates (USA).
of hospitals that already owned or plan to buy a PET scanner for an alternative non-invasive
biological imaging option, combined with MRI, to diagnose early-stage cancers. It is the same case
for SPECT that needs an accelerator that produces single-photon-emitting radionuclides.
The fact that harmful -sometimes beneficial- microorganisms disappear when irradiated with
X-ray or higher-energy radiation has boosted the ideas of using accelerator-based radiation to
sterilize biohazard disposals from hospitals, such as syringes and needles after medical care. The
technique using accelerator-based radiation has technical edges in sterilization over common hightemperature methods and ethylene oxide (ETO) cold sterilization that is toxic at even very low
concentration. The use of accelerator-based radiation for sterilization of medical products had to
increase dramatically because of the recent regulation by the US government to restrict the use of
ETO.
III. RADIOTHERAPY
The first attempt to use X-ray radiation in the treatment of malign tumors was made only
several months after the discovery of X-ray by W. K. Röntgen. The need of harder -higher energyX-ray brought up naturally the idea of using accelerator-based radiation that could produce a very
high radiation source. Van de Graaff and the betatron accelerators were early machines that were
installed and used for the treatment of fairly a large number of patients before the eras of the
cyclotron developed by E. O. Lawrence at Berkeley, the synchrotron, and the rf linacs (Fig. 1).
The future of conventional radiotherapy using photons (also electrons in a very common case) now
lies along with unconventional radiotherapy using heavy ions or protons, because both have their
advantages over the others.
The new proton synchrotron facility at the Loma Linda Medical Center in 1990 marked a new era
of proton therapy with hospital-based synchrotron. Before that and even now the rf linac (Fig. 1)
is most popular in radiation therapy and used by most medical centers in the departments of
radiation oncology. As well as synchrotron, synchrocyclotron and cyclotron are the other popular
types of accelerator installed in many proton radiotherapy facilities (e.g. Massachusetts General
Hospital (MGH) Boston and Orsay, Uppsala).
A. Conventional radiotherapy
The fundamental principle of radiotherapy is to deliver a proper dose of radiation to eradicate
the malign tumor(s). The area of dose must be limited to the limited area around the tumor(s),
minimizing the expected damage to normal tissues. Strategically the choice of radiation beams
is made upon the target area. Increasing the sensitivity of tumor(s) to specific radiation and
decreasing the sensitivity of normal tissues are obtained by radiation sensitizer. This seemingly
2
straightforward concept faces a complication of operation in in-situ implementations. If one increases the amount of dose to eradicate the malign tumor(s) more, there is a higher risk to affect
normal tissues.
Table I shows the beam preferences chosen by metropolitan area physicians for treatment of each
tumor site, listed in a nice survey book by Karzmark et al. [3]. As indicated, for most of the cancer
cases, low megavoltage X-ray is normally recommended, but about one fourth of the cases needed
a widely-separated high-energy X-ray treatment. The advantage of an electron beam over X-ray is
its limit of penetration into the body (only in centimeters), which makes electron beams an ideal
choice for the treatment of tumors that overlie very radiosensitive normal tissues, for example,
chest wall tumors as well as protecting normal tissues around the lung. Through early accelerator
developments for electron beam treatment, including betatrons that was found to produce too low
electron beam current for modern clinical radiation use, the modern rf linac is the dominant type
of machine in the market of electron beam radiotherapy.
Body area
Lung
Pelvis
Prostate
Cervix
Head and neck
Breast (intact)
Adomen
Pancreas
Brain primary
Chest wall
Tranchea and esophagus
Nodes
Bone mets
Brain CNS mets
Other
Caseload (%)
22
20
7
7
5
4
3
2
3
18
3
6
100
Soft X
35
Physician's beam preference
Hard X
Electrons
43
13
17
4
83
96
70
78
0
0
4
4
57
52
0
74
52
78
87
9
0
61
15
9
57
0
Beam utilization at two multimodality departments
Soft X (%)
71
Hard X (%)
23
Electrons boost (%)
12
Electrons alone(%)
6
TABLE I. The usage of electron beams from Karzmark et al..
Photon beams (hard and soft X-rays) and electron beams are considered conventional choices for
many radiotherapy cases. The requirement of both high-energy and low-energy X-rays for effective
treatment propelled the design of a multi-modal accelerator that is capable of producing multienergy X-rays. One accelerator that can produce multi-energy X-rays and multi-energy electron
beams is hard to develop because the energy switch in X-rays is relatively very difficult, whereas
the same switch in electron beams is quite easy due to the very small currents involved. Two
common ways of changing the output X-ray energy are: (1) varying the rf power, and (2) varying
the beam load current in the accelerating structure. Both of the methods have been implemented in
commercially-available medical accelerators. The disadvantage of varying the beam load is a very
rapid degradation of the beam energy spectrum even though the method can be simply applied
and is very reliable. The method of varying the rf power is utilized in some commercial medical
accelerators (e.g. Philips SL 25 machine, with which one can treat patients with 6 MV - 25 MV
X-rays and 4 MeV - 22 MeV electrons).
3
B. Unconventional radiotherapy
If one is concerned with the effectiveness of treatment for number one priority, regardless of
cost, a heavy-particle beam is the choice, which has an advantage of localization of dose in the
body over traditional light-particle beams, photons and electrons. Fig. 2 displays the treatment
room of the PSI (Villigen, Switzerland) proton therapy facility [4]. The first hospital-based facility
with proton gantries was located at the Loma Linda University Medical Center in 1990, which is
now playing an important role for the design of future medical proton accelerators with more than
ten years of operation experience [5]. The electronics-controlled fast and accurate modification
of beam parameters is one of the projects highly placed on the list of their next agenda in order
to satisfy every-demanding clinical needs. A hospital-based accelerator has required a bettercoordinated management of operation within the organization. Currently about 10 hospital-based
proton or ion therapy facilities are approved to be available already or soon in the United States
and Japan. Heavy ions have an advantage over protons as protons over X-rays and electrons.
as an example the potential use of the
technique for delivering intensitypy with protons (IMPT) (courtesy of T.
6]. With only 4 modulated fields one can
conformal dose to the primary target and
e to the affected lymph nodes (the
) with a maximal sparing of the organs at
m and parotid glands). All this can be
delivered just under computer control
ed of patient specific hardware. With
avoid the "dose bath" outside the target
f photon-IMRT.
ieve at PSI that in order to remain
h the most advanced photon techniques,
by active beam scanning will be a
2. Proton
treatmentroom
roomofatthe
PSI.
Figure 3.FIG.
Picture
of the treatment
PSI gantry.
y future proton therapy facility. This is
Less multiple
scattering and the range straggling in the body put the heavy-ion-beams the most
he fact that the existing
hospital based
for the most sensitive human organ areas. Also the ionization
Linda, Boston andsensitive
Tsukuba)radiation
are nowtherapy choice
6 PROTON ACCELERATORS
2
density,
plement beam scanning
in proportional
addition to to Z , much greater than protons is beneficial to minimize the total dose
of cancers.
Neon, within
one of the
thefield
early
for this use, turned out
competition
of candidates
proton regards
g in the near future. required in the treatmentAnother
to be a wrong choice because
of its
The focus
now turns to carbon ions,
the choice
of unexpected
the type of late-effects.
accelerator used.
The major
and the corresponding rivalry
research
is still going
on (e.g.
an R&D effort
is between
cyclotrons
and synchrotrons
[8].at LBNL [6]). For instance,
PROTON GANTRIES
from 1994 to March 2000,
Ion Medical
Accelerator
ChibaLinda)
(HIMAC) in Chiba, Japan
• Heavy
Synchrotrons
(example:
LLUMC in
at Loma
800advantage
MeV/amu
(10 synchrotron
T-m) synchrotrons
using
of characterisationconducted
of protontreatments
therapy with
Thetwo
main
of the
solution is
the three ion sources, a
PIGgantries.
(Penning Ionization
Gauge)
and two
ECR
(Electron
Resonance)
sources providing
the design of the proton
variable
choice
of the
beam
energy Cyclotron
extracted from
the
up world
to Xe.where
The main
ion source
for the
treatment isis the
carbon
at nature
energies
University is the placeions
in the
machine.
The main
disadvantage
pulsed
of at 290, 350, and 400
Further
thorough
will show
ion (even
proton being still one of
-based facility with MeV/amu.
proton gantries
was and
themore
beam,
which isstudy
not well
suitedwhich
for beam
scanning.
the
best
candidates)
will
be
the
best
choice
for
the
ultra-localized
and
biologically-safe
(to normal
e facility started operation in 1991. The One can however overcome parts of the problem by
tissues)
radiotherapy.
the world is the compact gantry of PSI. providing a stable slow extraction of the beam.
ts started there in 1997. A third gantry
• Cyclotrons (example: MGH Boston)
cently at Kashiwa (Japan) (the start of
TheIV.
advantage
of the cyclotron is the high duty factor
RADIOISOTOPE PRODUCTION
ts was last year). An almost identical
of the beam (DC beam), which is well suited for beam
as been realised and is now ready to go scanning, the high proton current and the inherent
In order
to produce
radionuclides that are medically useful, particle accelerators, mostly cyBoston (U.S.A) this year.
Another
new stability
of the beam (including a possible precise control
clotrons,
are
commonly
Some of non-invasive medical imaging systems implementing
presently being assembled in Tsukuba of adopted.
the beam intensity at the ion source for active beam
tracer method developed by G. de Hevesy (1943 Nobel prize for Chemistry) are the frontier technolscanning).
The PET.
main Both
disadvantage
theeither
fixed photon-emitting
energy,
ogy in nuclear medicine,
SPECT and
of them is
need
or positrondedicated to passive scattering (either of which requires the use of a degrader followed by an
emitting radionuclides, respectively. Radioisotopes used in PET imaging are well summarized in
" type like the gantry of Loma Linda
analysing
line. Thisnecessary
implies afor
higher
of short decay times,
Table II [7]. Since some
of the beam
radioisotopes
the activation
imaging have
of the "barrel" 11
type
13 like at 15 the
the
components
in
the
initial
region
of
the
facility.
C, N, and O, on-site particle accelerators are often needed. Almost every PET facility has a
Hospital in Boston)
are necessarily
Synchrocyclotrons
(examples:
Orsay,
Uppsala)
dedicated
accelerator for •radioisotope
production.
This part
of PET
facility is the most expensive
a very large diameter
of
the
rotating
18machines are used only at old physic facilities.
Such
component of PET scanner. F-labeled tracers that have moderately long half-life times can be
e order of 11-12 transported
m.
This modest
is the distances
They have
been re-proposed
new facilities since
not not
requiring
a dedicatedforaccelerator.
the need of a long throw to spread the
they combine the disadvantages of cyclotron and
ng the beam towards the patient.
synchrotron (fixed beam energy and pulsed beam).
eccentric gantry of PSI (fig. 3) is the only
4
• Linacs (Rome)
antry dedicated to beam scanning. The
A proton Linac with a high pulse repetition rate of 400
ed along orthogonal axes (Cartesian
Hz suitable for beam scanning (with adjustment of the
Isotope
Production reaction
11
14
C
13
11
N(p, α) C
16
N
13
O(p, α) N
Threshold
(MeV)
3.13
5.5
13
C(p, n)13N (1.1% of C)
15
14
O
N(d, n)15O
15
N(p, n)15O (.36% of N)
F
18
Saturation yield
per µA (mCi)
130
8
36
Radiopharmaceutical
11
Diagnostic use
( C)methylspiperone
Dopamine binding
(11C)acetate
Cardiac metabolism
(11C)methionine
Amino acid metabolism
(cancer detection)
Cardiac blood flow
(brain)
13
20
54
( N)ammonia
8
82
(13N)amino acids
Protein synthesis
8
50
(15O)water, (15O)CO2
Brainblood flow (all tissue)
(15O)O2
Oxygen metabolism
3.8
8
47
O(p, pn)15O
16.6
29
30
O(p, n)18F (.2% of O)
2.57
14
216
(18F)2-deoxy-2-fluoro-D-glucose (FDG)
Glucose metabolism
0
14
84
(18F)fluorodopa
Dopamine
8
46
40
40
16
18
2.36
Beam energy
(MeV)
14
20
20
18
Ne(d, α) F
Ne(p, 2pn)18F
26
Synthesis (brain)
*These isotopes are produced by on-site accelerators by one of the nuclear reactions shown and used to synthesize radiopharmaceuticals.
TABLE II. The radioisotopes used in PET imaging.
The production of radioisotopes is made through operating on-site cyclotron as shown in Fig. 3.
A radioisotope delivery system (RDS 111 by CTI, Inc. [8] shown in Fig. 4) is a cyclotron which
accelerates negative hydrogen ions (one proton and two electrons in the left electromagnet in
Fig. 3) to 11 MeV, and then striking the ions through a thin carbon foil that strips the two
electrons leaving only one proton. Bombarded with stable nuclei, this proton with high kinetic
energy creates unstable isotopes that are useful for medical use [9].
A more detailed description of the operation of this medical cyclotron and the production of
radionuclides are the following [10]. Between the “dees” (electromagnets in Fig. 3), there is a
narrow gap where an ion source (typically an electrical arc device in a gas) is placed. By this ion
source, negative hydrogen ions are created in bursts, generating a proton and adding two electrons
that compose a H− . A high-frequency alternating electric field induced in dees enables energy gain
of the negative hydrogen ions. Two external magnets that are located one above and the other
below allow the charged particles (H− in this case) to rotate in circular orbit by a simple Lorenz
→
−
→
−
−
force equation in external magnetic field, F = q →
v × B . Whenever the charged particles pass
through the gap between two dees, radio-frequency (RF) oscillator alternates the polarities on the
dees. With these alternating polarities, the particles are accelerated in a circular orbit spiraling
outward (gaining more velocities makes the radius of orbit bigger). Once H − ions are accelerated
to a desired level, the stream of ions is struck to thin carbon foils that strip two electrons out
of each H− ion, making a proton or H+ ion. The proton beam now has a positive charge but
is still under the magnetic field that deflects the beam out of the orbit (away from the center
of the cyclotron). Extracted proton beam is, then, targeted to a chamber that contains stable
chemical isotopes. Through the bombardment process, the stable isotopes transform into unstable
radioisotopes by nuclear reaction. The radioisotopes created by RDS 111 are positron emitting
radionuclides that will be utilized in PET imaging. The final step of medically-useful radioisotope
production is biosynthesis. Radioisotopes produced by a cyclotron are combined with biological
markers using biosynthesizer to be ready for injection into a human body.
V. RADIATION STERILIZATION
Amongst other applications of particle accelerators biologically and medically, the radiation
sterilization is a field that becomes very important in modern medicine. The rapid development in
this field over three decades is a result from the widespread use of disposable medical supplies and
sterile dressings in clinics [11]. For the cost-effectiveness, most of the disposable medical supplies
are made from plastics, which makes hot-temperature sterilization very difficult. Gas sterilization is
one of the other options, while this type of sterilization has different drawbacks including a difficulty
of handling. If the high-energy radiation is used for this purpose, sterilization can be practiced
5
electromagnets
magnetic field
orbit of negative ions
stripping foil
- ++ proton
target
FIG. 3. Schematic diagram of medical cyclotron.
FIG. 4. RDS 111 from CTI, Inc..
practically cold, and there is no need to worry about handling. Also with the penetrating power
of high-energy beam of electrons or photons, the sterilization is possible even after the supplies
are packed. With these reasons, if one can maintain the cost of operating radiation sterilization
comparable to the other types of sterilization, the method is very desirable for volume treatment.
Choice of kind and energy of radiation depends on the penetrating power of the high-energy beam.
The system that consists of an accelerator or more and the other facilities for radiation sterilization
has been realized in a few countries including one in a former-Soviet facility, in which there are
two independent electron linacs, control system, safety system, conveyer, and irradiation chamber.
The each linac in the facility has the energy range 8 - 10 MeV and a beam power of 8 kW.
VI. CONCLUSION
I have listed the aspects of how the particle accelerators are used in biomedicine in this paper.
The somewhat old technique of particle beams have been used in saving human lives with the form
of radiotherapy (RT), a very important component of diagnostic nuclear medicine (SPECT and
PET), and the sterilization of medical supplies. Practically, the demand for more applications of
the technology from biomedicine encouraged a higher concentration of R&D work in rather small
but more feasible accelerator research programs throughout the world since the current advanced
accelerator concepts for high-energy physics are already too big and too expensive. Even with an
old technology of accelerator and an old type of accelerator design, if one can find its usability like
the applications I listed here, I believe that there is an open road to the excellence of a lifetime
6
achievement potentially contributing to the history of human beings.
Acknowlegment: I personally thank Prof. J. B. Rosenzweig for giving me an opportunity
to write this survey paper for the Physics 150 course offered by the Department of Physics and
Astronomy at UCLA. I also thank G. Andonian for his help as a TA for the course. I have been
benefited from a review paper of PET written by Prof. M. A. Mandelkern at UCI, who kindly gave
me a reprint. My final thanks is to Prof. D. B. Cline who has been supporting me throughout my
graduate program leading to a Physics Ph.D. in Dark Matter Search program.
[1] R. K. Hobbie, Intermediate Physics for Medicine and Biology (Springer-Verlag, New York, NY, 1997).
[2] W. H. Scharf, Biomedical Particle Accelerators (AIP Press, Woodbury, NY, 1994).
[3] C. J. Karzmark, C. S. Nunan, and E. Tanabe, Medical Electron Accelerators (McGraw-Hill, New York,
NY, 1993).
[4] E. Pedroni, in Proceedings of the 7th European Particle Accelerator Conference, Vienna, Austria,
June 26-30, 2000, edited by J. L. Laclare, W. Mitaroff, Ch. Petit-Jean-Genaz, J. Poole, and M.
Regler (http://accelconf.web.cern.ch/accelconf/e00/, 2000).
[5] G. Coutrakon, J. M. Slater, and A. Ghebremedhin, in Proceedings of the 1999 Particle Accelerator
Conference, New York, NY, March 29 - April 2, 1999, edited by A. Luccio and W. MacKay (IEEE,
Piscataway, NJ, 1999).
[6] J. R. Alonso, in Proceedings of the 7th European Particle Accelerator Conference, Vienna, Austria,
June 26-30, 2000, edited by J. L. Laclare, W. Mitaroff, Ch. Petit-Jean-Genaz, J. Poole, and M. Regler
(http://accelconf.web.cern.ch/accelconf/e00/, 2000).
[7] M. A. Mandelkern, Annu. Rev. Nucl. Part. Sci., 45, 205 (1995).
[8] CTI, Inc., RDS 111 cyclotron.
[9] S. R. Cherry and M. E. Phelps, in Diagnostic Nuclear Medicine, edited by M. P. Sandler, J. A. Patton,
R. E. Coleman, A. Gottschalk, F. J. Th. Wackers, and P. B. Hoffer (Williams & Wilkins, Baltimore,
MD, 1996), p. 139.
[10] Crump Institute for Melecular Imaging, in Let’s Play PET
(http://www.crump.ucla.edu/lpp/radioisotopes/radioisoprod.html).
[11] W. H. Scharf, Particle Accelerators and Their Uses (Harwood Academic Publishers, New York, 1986).
7