Download Experimental Ocular Irradiation with Accelerated Protons

Experimental ocular irradiation with
accelerated protons*
Ian J. Constable and Andreas M. Koehler
High-energy proton beams of 7 mm. diameter or less were used to irradiate monkey eyes.
When the Bragg peak was positioned immediately in front of the retina, it was possible to
apply an acute radiation burn to a discrete area of the retina and choroid while delivering
much smaller doses to other ocular and orbital tissues. The minimal scatter, finite penetration,
and advantageous dose-distribution curve for soft tissues make this mode of radiotherapy very
attractive for the treatment of ocular and orbital tumors.
Key words: irradiation, retina, protons, Bragg peak, dosimetry, stereotaxis, cyclotron.
x-ray machines produce less scattered radiation than orthovoltage equipment, but still
do not allow very large doses to be
delivered to small intraocular targets. In
order to avoid the problem of affecting
tissues beyond the target, electron beams
have been used, but excessive scatter
limits their usefulness for targets as small
as the eye.R> 7 Another limitation inherent
in both photon and electron ocular radiotherapy at present is the lack of precise
aiming techniques for small targets.
The development of cyclotrons, which
can produce beams of high-energy, heavy,
charged particles, has provided another
possible approach to localized irradiation.s>!) Such beams consist of high-energy
protons, deuterons, or alpha particles and
are not subject to significant scatter. Thus,
they can be collimated into narrow beams
which retain their shape while penetrating
to a target. They have a well-defined range
in tissues, and no radiation is delivered
beyond their stopping point. Furthermore,
the density of ionization along the particle's
path through tissue is almost inversely
Ixternal beam irradiation utilizing photons has been successfully employed in the
treatment of retinoblastoma,1'2 since many
of these tumors respond well to relatively
small doses of radiation. Even at these
doses, however, a variety of ocular and
orbital complications have been reported.3"5
Because the dosage delivered falls off only
exponentially with penetration, external
photon beams deliver excessive doses to
normal tissues beyond the ocular target.
Photon beams from modern supervoltage
From the Department of Retina Research, Retina
Foundation, Boston, and the Department of
Physics, Harvard University, Cambridge, Mass.
Supported by Grant CA-12180 from the National
Cancer Institute, National Institutes of Health,
and by Grant GI-32991-X from the National
Science Foundation.
Submitted for publication Dec. 28, 1973.
Reprint requests: Editorial Services Unit, Retina
Foundation, 20 Staniford St., Boston, Mass.
02114.
"Presented in part at the meeting of the Association for Research in Vision and Ophthalmology,
Birmingham, Ala., Nov. 1, 1973.
280
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Number 4
proportional to the energy of the particle,
resulting in a characteristic maximum dose
near the end of the path, called the Bragg
peak.s Tissue effects are thus much more
pronounced in the last few millimeters of
the path of the beam. Finally, the concentration of energy transfer to tissues located
at the Bragg peak may result in greater
relative biologic effectiveness than X- or
gamma-rays of comparable dose.10 These
characteristics make heavy particle irradiation especially suitable for focusing large
doses on small targets.
During the past decade, the Bragg peak
effect has been utilized to apply necrotizing
doses to the pituitary gland.11"13 This method has proved to be an acceptable form of
therapy in acromegaly11 and Cushing's disease.
This paper describes the technique we
are developing for irradiating discrete areas
of the posterior segment of the eye, utilizing high-energy protons generated by the
160 MeV Harvard cyclotron.
Materials and methods
Proton beam generation and colHmation. Hydrogen atoms are bombarded in the cyclotron with
electrons, converting them to hydrogen ions
(protons). The protons are then accelerated by
electric fields while being guided in stable orbits
by a magnetic field.1 r> The high-energy particles
are channelled off at a tangent, using subsidiary
magnetic forces.
The proton beam is directed along an evacuated
pipe by magnetic lenses, and out of the cyclotron
chamber into a treatment area. Here the beam
passes through a large cylindrical collimator (Fig.
1). Within the collimator, the protons pass through
polystyrene slabs (P), which reduce their capacity
to penetrate and scatter them so that a uniform
beam passes through aperture A. The beam then
passes through an ionization chamber (I), which
monitors the dose during treatment. The diameter
and angular divergence of the final beam emitted
is determined by the aperture (D) in the extension column.
Preliminary beam alignment and dosimetry.
Prior to irradiation of an animal, the axial alignment of the beam is checked by irradiating
photographic film which is placed in the position
of the ocular target,
A small silicone diode1" is then placed on the
end of the extension column to map the dosedistribution of the beam in a water-filled phantom.
Experimental ocular irradiation 281
i
k A i4
Pi
IS
Fig. 1. Schematic view of the path of the proton
beam through the collimator. The beam emerges
from the wall outlet, O, passes through polystyrene
slabs, P, and through apertures A, B, C, and D
in brass plates. I, ionization chamber to monitor
dose; X, telescoping water-filled extension. The
beam stops at a predetermined point, S.
Fig. 2. View of the treatment area with monkey
in position prior to radiographic alignment. 0,
beam outlet from cyclotron; C, collimator; H,
head-holder suspended from overhead circular
plate; X, x-ray apparatus.
This diode is calibrated against the ionization
chamber (I) used to monitor dosage during treatment. Absolute calibration of the diode is made
against a Faraday cup which measures the proton
beam in a standardized geometry.
Once the dose-distribution of the beam in
water has been located in space, the collimator is
adjusted so that the plane of the Bragg peak will
coincide with the vertical axis of rotation of the
stereotactic apparatus.
Preparation of animals. Young owl monkeys
(350 to 600 grams) have been selected for these
experiments. The animals are anesthetized with
pentobarbital sodium (30 mg. per kilogram). The
pupils are dilated with phenylephrine 10 per cent
and scopolamine 0.3 per cent.
Alignment of the ocular target. The monkey's
head is fixed in a metal frame (Fig. 2, H) which
is suspended from an overhead circular metal plate
around which the frame can be accurately rotated
to a tenth of a degree. The design of the headholder incorporates screw-motion slide assemblies
and Vernier scales to allow accurate adjustment
of the head in the horizontal, vertical, and anteroposterior directions. After approximate visual align-
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Investigative Ophthalmology
April 1974
282 Constable and Koehler
Fig. 3. Posteroanterior radiograph with markers
(M) on head-holder aligned with right orbit of
monkey.
Fig. 4. Lateral radiograph with circular test beam
superimposed on orbits. The center of the beam
spot measured 5.5 mm. anterior to the posterior
orbital wall, and 5.5 mm. superior to the junction
of the posterior wall with the orbital floor and
base of the skull.
ment of the target, accurate alignment is achieved
by stereotactic radiography. The radiographic
equipment is precisely aligned with the path of
the beam from the collimator, being mounted
behind the animal to the same overhead apparatus
(Fig. 2, X). An x-ray picture is first taken from
the posteroanterior direction to verify symmetry of
the head position, and to check the alignment
of two markers mounted on the head-holder (Fig.
3). The head-holder is then adjusted horizontally
until the markers are the desired distance from the
midline. This distance is varied depending on
what area of the retina is to be treated. The
head-holder and animal are then rotated exactly
90°. A lateral x-ray is taken, and a test-beam
spot of protons is superimposed on the film to
confirm the alignment (Fig. 4).
The animal may now be moved forward or
backward so that the center of the test spot
Fig. 5. Anesthetized monkey in position ready for
treatment. A latex diaphragm on the end of the
water-filled extension column (X) is in direct
contact with the eye.
(and hence the Bragg peak) will fall an arbitrary
distance in front of the posterior orbital wall
(Fig. 4). This distance is selected on the basis of
previous combined A and B scan ultrasonography.17 In converting x-ray measurements
to actual distances in space, a magnification factor
of 1.23 must be taken into account. Vertical positioning of the target is measured from the center
of the test spot on the lateral x-ray to the junction
of the posterior wall of the orbit with the base
of the skull (Fig. 4). Once the ocular target is
positioned on the center of rotation of the headholder, it is possible to treat from any direction,
and the Bragg peak will always fall on this same
target.
Treatment procedure. The telescoping extension
is placed on the end of the collimator and the
animal is rotated into position for the treatment
(Fig. 5). The beam is either directed through
the center of the lens, or around the lens, in
which case the eye is held in a position of duction
by a traction suture at the limbus. Using this
technique, it is possible to treat peripheral areas
of the retina without passing the beam through
bone. The thin rubber diaphragm on the end of
the water-filled extension tube is brought into
direct contact with the eye. Care is taken to
avoid excessive pressure on the eye, while maintaining even contact. The operators then retire
from the treatment area to monitor the dose, which
under these conditions is delivered at the rate
of about 300 to 400 rads per minute. A closedcircuit television screen is used to watch the
animal.
Forty-six monkey eyes have been irradiated with
single doses ranging from 800 to 20,000 rads. Most
beams have been 7 mm. in diameter, directed
either around the lens or through its center. The
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Experimental ocular irradiation 283
diameter
SOOOr
36
Distance in mm (from Bragg Peak)
Fig, 6. Top, dose-distribution curves of 7 mm. diameter proton beam with Bragg peak doses
of 7,500 rads, 5,000 rads, and 3,500 rads. Below, sagittal section of the eye and orbit drawn
on the same scale as above, and aligned so that the Bragg peaks fall 5 mm. anterior to the
retina. The cornea and lens receive low doses on the plateau portion of the curves, while tissues
beyond the eye receive minimal irradiation due to the steep fall-off.
Bragg peak has been focused at various positions
ranging from the center of the lens to 5 mm.
behind the posterior orbital wall in the frontal lobe
of the brain.
Results
Dose distribution to tissues. The dose
distribution of the 7 mm. collimated beam
measured with the water phantom prior
to treatment of an eye is depicted in the
graphs in Fig. 6. The curves have been
plotted after calculation for peak doses of
7,500, 5,000, and 3,500 rads, respectively.
Below the curves is a diagrammatic section
of the eye and orbit drawn to the same
scale as the graphs. It can be seen that
if the Bragg peak is focused 1 or 2 mm.
in front of the retina, very small doses are
delivered to the orbit and brain surface.
Table I shows the approximate dosage to
each tissue from the cornea to the brain
surface when the eye is treated from the
direct anteroposterior portal, and a peak
dose of 5,000 rads is located 4.5 mm. and
5.5 mm. anterior to the posterior orbital
wall, respectively. If the Bragg peak is
placed 4.5 mm. in front of this point, the
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284
Investigative Ophthalmology
April 1974
Constable and Koehler
Fig. 7. Composite fundus photograph of a sharply demarcated circular lesion, 36 hours after
a Bragg peak dose of 7,500 rads was applied 4.5 mm, anterior to the posterior orbital wall with
a 7 mm. diameter beam. The irradiated area of the retina is edematous and detached.
cornea receives about 50 per cent of the
peak dose. The brain surface receives about
27 per cent, assuming it is located 1 mm.
posterior to the orbital wall. If the Bragg
peak is placed 5.5 mm. anterior to the
x-ray landmark, then the cornea receives
52 per cent and the brain surface about
14 per cent of the peak dose.
Effect of varying single dose. No early
changes were seen in any eyes given less
than 3,500 rads at the retina. Clinical observations over the first eight months have
shown no delayed changes in the lens,
retina, or optic disc in this dose range,
whether treating through the center of the
lens or around it.
With retinal doses of 3,600 to 4,000 rads,
three out of five eyes treated with a 7 mm.
beam developed a localized patch of acute
retinal edema within one to two days. The
patch was smaller in diameter than the
beam. It settled gradually over two weeks,
leaving a barely discernible stippling of
the retinal pigment epithelium.
Retinal doses of 4,500 to 12,000 rads
caused a sharply demarcated circular lesion
in the fundus, which appeared one day
after treatment and corresponded in
diameter to that of the beam (Fig. 7). The
retina was locally detached with underlying
serous fluid. Multiple folds were present
in the deep retinal layers. Several small
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Experimental ocular irradiation 285
Fig. 8. The same eye as shown in Fig. 7 after four months. The lesion is diffusely pigmented,
with sharp edges due to atrophy and thinning of the irradiated retinal area.
Table I. Dose distribution to tissues with Bragg peak dose of 5,000 rads
Tissue
Cornea
Lens
Retina
Sclera
Orbital tissues
Bone
Brain surface
Bragg peak 4.5 mm, anterior to
posterior wall of orbit
Distance from
Bragg peak (mm.)
Dose (rads)
18.5
2,500
2,800
11.5
1.0
4,800
2.0
4,350
3.5
3,350
5.0
2,350
6.5
l : 300
intraretinal hemorrhages were sometimes
found with larger doses. Beyond the sharp
edges of the lesion, the retina and choroid
appeared normal. Over the first two weeks,
each lesion flattened, losing all signs of
edema. A slight flare in the aqueous and
vitreous also resolved within two weeks.
In this intermediate dose range, the lesion
Bragg peak 5.5 mm. anterior to
posterior wall of orbit
Distance from
Bragg peak (mm.)
Dose (rads)
2,600
17.5
10.5
2,900
2.0
4,350
3.0
3,700
2,650
4.5
6.0
1,700
700
7.5
evolved into a discrete circular area of
thinned retina with mottled pigmentation
(Fig. 8). By six to eight months, the surrounding retina, the vitreous, and lens all
appeared normal. There were no signs of
extraocular side effects within this period
of observation.
When retinal doses of 15,000 to 20,000
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Investigative Ophthalmology
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286 Constable and Koehler
Table II. Effect of moving plane of Bragg
peak relative to posterior orbital wall
Bragg peak
position
Retinal dose
in rods
Acute retinal
lesion
2,000
+10 mm.
No
Yes
5,100
+7 mm.
+4 mm.
Yes
7,400
+1 mm.
Yes
6,750
Yes
-2 mm.
5,400
Yes
-5 mm.
4,750
+ Anterior, -posterior to posterior orbital wall. Peak dose
of 7,509 rads.
Retina is assumed to be 3.5 mm. anterior to the posterior
orbital wall.
rads were applied, the same localized
disciform exudative retinal detachment occurred within one day, but large numbers
of intraretinal hemorrhages also developed
within the irradiated area. The retinal
detachment settled, but the retina itself
developed a ragged appearance over the
first month. All small retinal and choroidal
vessels within the treated area became
obliterated, and the retinal pigment epithelium did not proliferate. After six weeks, a
sharply demarcated necrotic white lesion
remained with little clinical evidence of
reparative processes in the retina or
choroid. The large retinal vessels were irregular in caliber and showed sheathing.
As in the intermediate dose range, no
corneal, lenticular, or extraocular side effects developed within six months. If the
optic disc was included in the treated area,
it became atrophic, and all the major vessels were partially obliterated. Six to eight
weeks later, secondary edema and hard
exudates appeared in the entire peripheral
retina outside the treated area.
Effect of varying the position of the
Bragg peak. In a group of six eyes, a 7,500
rad peak was delivered to each eye through
the center of the lens. When the Bragg
peak was placed 10 mm. anterior to the
retina, the retina received 2,000 rads. No
retinal, lenticular, or corneal lesion developed. As expected from the estimated
retinal doses in Table II, a discrete, acute
retinal lesion developed when the Bragg
peak was placed 7 mm., 4 mm., and 1 mm.
in front of the posterior wall of the orbit.
A visible retinal lesion also developed
when the Bragg peak was placed at 2 mm.
and 5 mm. behind the posterior orbital
wall.
Discussion
The dose-distribution curves (Fig. 6)
illustrate the theoretical advantages of
heavy particle irradiation for a small target
within the orbit. If the Bragg peak is
focused in front of the retina, the steep
fall-off in penetration insures that acceptably small doses will be delivered to tissues
beyond the eye. At the same time, the
plateau on the curve before the Bragg
peak falls on the cornea and lens (or the
sclera, if treating around the lens). The
result is that doses of only 40 to 60 per
cent of the peak dose are delivered to
these tissues. The negligible scatter of the
protons allows a sharply circumscribed lesion to be placed on the retina. It is hoped
that this lack of scatter will also avoid
complications in the lens or optic nerve.
Electrons of appropriate energy (about
5 million volts) also have a sufficient
range of penetration in tissue and give a
steep fall-off in dose beyond the lesion.0'7
However, being small particles, they scatter more than protons. In addition, it is
not possible to deliver a smaller dose to
the cornea and lens or to the sclera, there
being essentially no plateau and Bragg
peak effect.
It will require long-term observations
to prove whether it is possible to treat
through the center of the lens with proton
beams. Even with orthovoltage x-rays,
however, there is good evidence that the
axial portion of the lens is less sensitive
than the equatorial region, where the epithelial cells undergo mitosis throughout
life.18
Our present indirect stereotactic aiming
method allows precise positioning of the
Bragg peak in the eye. However, the aiming procedure is only accurate to 2 or 3
mm. in the vertical and horizontal meridians, particularly if the target is located
in the peripheral fundus, and if the posi-
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tion of gaze varies. We are, therefore,
developing an ophthalmoscopic aiming system to supplement stereotactic radiography.
It seems likely that the improved dose
distribution of proton irradiation as compared to that of photons or electrons will
be better tolerated by the eye. It should
then be possible to apply larger doses of
therapeutic irradiation to ocular tumors
with this method and obtain decreased
side-effects.
The authors wish to thank Robert Schmidt
and Michael Andreottola for their skilled assistance in this project.
Experimental ocular irradiation 287
7.
8.
9.
10.
11.
12.
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