Radiosurgery: The Photon Radiosurgical System
Rees Cosgrove, M.D., F.R.C.S. ( C ) , Osama S. Abdelaziz, M.B.Ch.B.,
M.Ch., Nicholas T. Zervas, M.D.
Neurosurgical Service, Massachusetts General Hospital,
Harvard Medical School, Boston, Massachusetts
(GRC, NTZ), and Department of Neurosurgery,
Faculty Of Medicine, Alexandria University, Egypt (OSA).
Address for Correspondence:
N. Eskandar, M.D.
Massachusetts General Hospital
15 Parkman St. ACC # 331
Boston, MA 02114
Patient Appointments: 617.724.6590
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Intracerebral metastases are common
and occur in up to 15% of cancer patients (14). The relatively
well-circumscribed, non-invasive nature of brain metastases, as
compared with the diffuse, infiltrating primary brain tumors,
makes them appropriate candidates for focal therapy (12,29). Focal
irradiation has been used successfully for both newly diagnosed
and recurrent brain metastases and can administer a lethal tumor
dose while minimizing exposure to normal brain (2,6,17,20,22,31).
Stereotactic radiosurgery is " the
non-invasive delivery of a high dose single fraction of ionizing
radiation to a limited, stereotactically-defined target volumes"
(20,25). Interstitial brachytherapy provides focal intratumoral
irradiation over a period of hours or days (27). Fractionated
stereotactic radiotherapy combines the conformal three- dimensional
dose distribution with the biologic advantage of fractionation
(33,37). In all these therapeutic modalities, the objective is
to deliver a high dose of radiation to a discrete volume with
minimal exposure to surrounding normal brain structures.
Interstitial radiosurgery implies
the delivery of ionizing radiation interstitially to the tumor
(as in brachytherapy) in a high dose single fraction (as in radiosurgery)
and hence the name. In this chapter, we present our experience
using a battery-powered, miniature x-ray generator that can be
placed stereotactically into intracranial tumors to deliver a
single fraction of high dose interstitial irradiation in less
than an hour. The physical characteristics of the Photon Radiosurgical
(PRS) will be described and the
preliminary clinical experience as well as possible future clinical
applications will be discussed.
Conventional irradiation uses dose
fractionation over time to take advantage of the differences in
radiosensitivity between neoplastic and normal tissues. Dose fractionation
allows repair of sublethal damage in normal tissues, which therefore
receive a lesser radiobiological effect and are relatively spared.
Neoplastic tissues receive a relatively greater radiobiological
effect with fractionation because of reoxygenation, cell cycle
redistribution and repopulation of tumor cells (20,25,33).
Stereotactic radiosurgery employs
accurate target localization and steep dose gradients to deliver
a single fraction of high dose irradiation. Radiosurgery is safe
and efficacious if the target volume is kept as small as possible
and the volume of normal tissue irradiated to high doses is minimized
The major radiobiologic advantage
of interstitial brachytherapy is due to intratumoral placement
of the radioactive isotope. The dose is attenuated in tissue and
a dose decline rate proportional to 1/r2 yields sharp dose fall-off,
thus allowing a high dose to be delivered to the tumor while minimizing
exposure to the surrounding normal brain (7). Additional advantages
of conventional low dose rate interstitial irradiation (0.5-2.0
cGy/min) over days or weeks include tumor cell reoxygenation and
repopulation, a lower oxygen enhancement ratio and cell cycle
redistribution with resultant accumulation of tumor cells in a
sensitive phase of the cell cycle during the course of irradiation
The total irradiation dose required
to produce a given biologic effect in tissue depends on the time
period over which the tissue is irradiated (27). The dose rate
is a major determinant of the biological effect of a given dose
of ionizing radiation. In general, lowering the dose rate (and
increasing the exposure time), reduces the biological effect of
a given dose of radiation (7). Dose rates of approximately 1-2
Gy/min with the PRS, are possible and can reach up to 500 Gy/min
at the tumor center (15). In addition, the irradiation dose rate
varies across the target volume according to the radiation technique
used. The dose rate of conventional radiotherapy varies by about
5% to 10%, whereas that of external beam radiosurgery or the PRS
may vary by 50% across the target volume. In each technique, the
normal tissue away from the target will receive the minimum dose
rate, but a full dose rate will be delivered to any normal tissue
lying within the target volume (27).
The radiobiology of the interstitial
radiosurgery is probably similar to external radiosurgery; that
is, both deliver a high dose in a single fraction over a period
of perhaps 15 minutes to an hour. Interstitial brachytherapy using
standard implanted radionuclides, generally requires days to weeks
for completion of the treatment (27). The PRS combines the short
treatment times of radiosurgery with the dose delivery advantages
of an interstitial source.
The Photon Radiosurgical System
(Photoelectron Corporation, Waltham, MA) is a new, battery-powered
miniature x-ray generator capable of delivering a prescribed therapeutic
radiation dose directly to small brain lesions (15).
The device itself weighs 3.8 pounds
and is designed to be compatible with current stereotactic frames
(Fig. 1). It contains a step-up converter that can amplify the
9.6-V supplied by the battery to 40 KV and an internal electron
gun which creates a 40 (A electron beam (approximately 0.5 mm
wide). The beam is accelerated through a high-voltage field (range
15-40 KV in 5 KV increments) and then passes through a deflection
chamber to control beam position and thus assure beam straightness.
After traveling down the evacuated, magnetically shielded, rigid
probe (3 mm in diameter and 100 mm in length), the electron beam
strikes a thin gold foil target (0.5 ( m) at the probe tip producing
x-ray photons whose effective energies are in the 10-20 KeV range.
The gold foil is thick enough to stop the electrons but thin enough
to allow the x-rays thus generated to pass through. The last 20
mm of the probe tip is constructed from beryllium, which is transparent
to these low energy x-ray photons. The x-rays are emitted from
the tip in a spherical symmetrical pattern resulting in a dose
rate in tissue of up to 120 Gy per hour at a 10 mm radius. Two
scintillation counters monitor radiation and are positioned on
the stereotactic frame to detect the small number of photons that
pass through the skull and compare these to the expected treatment
levels. Although 99.9% of the energy created by the electron collision
with the gold foil is in the form of heat and only 0.1% is generated
as x-rays, hyperthermia has been excluded as a possible tumoricidal
factor by limiting the power of the electron beam to maintain
the temperature at the tumor margin to less than 420C. Operation
of the system is directed from a low-voltage electronic control
box that contains a 9.6-V rechargeable nickel-cadmium battery
as the power source. A cable from the control box provides the
low voltage electrical power to the unit. Battery operation and
packing of all high-voltage components within a grounded housing
result in a compact device with total electrical isolation for
the safety of the patient (5,10,15,16,36).
The Photoelectron Device produces
a radiation field similar to that of a conventional high dose
rate interstitial brachytherapy source (28), but has the advantage
of electronic control. The probe tip delivers point-source emission
of low-energy photons directly into the lesion, with adjustable
intensity and peak energies (15).
The x-ray beam behaves essentially
as a point isotropic source. Ionization chamber measurements,
determined that the dose rate in water for the PRS x-ray beam
with a current of 40 (A and voltage of 40 KV is 15 Gy/min at a
distance of 10 mm. The absolute dose is estimated to be (10% (5,16).
Because the photons produced by
the PRS are low in energy, their absorption characteristics are
different from standard brachytherapy sources. The "soft x-rays"
of the device are attenuated rapidly within tissue and a dose
decline rate of (1/r3) is obtained rather than (1/r2) as seen
for standard higher energy interstitial radioactive sources. The
resultant 30% dose reduction per millimeter of unit tissue creates
an extremely steep dose fall off (Fig. 2). Background exposure
to personnel more than 2 meters away from the probe when inserted
in a patient has been measured at approximately 5-10 mrem/hour
and therefore no special shielding of the patient or health care
personnel is required (5,11,27).
To evaluate the dosimetry provided
by the PRS with other currently available technologies, dose-volume
histograms generated for the PRS, linac radiosurgery, proton beam
radiation therapy were compared (16). All three treatment plans
prescribed a dose to a 2 cm diameter spherical lesion, using a
three-dimensional treatment planing system. The PRS plan used
a single probe at the center of the lesion. The linac radiosurgery
plan utilized a 6 MV linear accelerator with four arcs. The proton
treatment plan used three circular beam portals. The linac and
proton treatment plans were prescribed so that the 80% and 90%
isodose lines, respectively, covered the treatment volume. The
PRS plan prescribed 100% of the dose to the tumor volume, plus
a 2 mm margin of presumed normal tissue beyond the defined tumor
border (16). Comparison of dose-volume histograms from the proton
beam, linac, and PRS treatment plans (Fig. 3) demonstrated relative
normal tissue sparing with the PRS plan beyond that provided with
the proton or linac radiosurgery plans for treatment volumes less
than 50 cc. The high dose region in the PRS dose curve is due
to the point-source nature of the PRS treatment with its dependence
on treatment radius.
The dosimetry provided with the
PRS treatment plan was similar to, and perhaps better, than that
achieved with proton beam or linac three- dimensional treatment
planning for small spherical intracranial lesions. However, one
might not expect the dosimetric advantages of the PRS treatment
plan to disappear, if the treated tumor targets were larger in
size and/or more irregular in shape (16).
The PRS is designed for use with
stereotactic frames, and initial experience has been acquired
using the CRW system (Radionics Inc, Burlington, MA). After fixation
of the frame to the patient, a stereotactic CT scan with contrast
is obtained using 1.5-mm contiguous slices through the tumor.
The antero-posterior, lateral, and vertical dimensions of the
tumor are determined and target coordinates are calculated for
the center of the lesion. If appropriate, a standard stereotactic
biopsy is then performed through a burr hole and specimens from
the target were submitted for pathological analysis.
If intra-operative frozen section
analysis confirms the diagnosis of tumor, then the irradiation
treatment can be instituted at the same sitting. First, the biopsy
needle tract is dilated slightly to accommodate the probe tip
(3-mm diameter) using a graduated series of dilators. The PRS
device is then mounted on the arc of the CRW stereotactic apparatus
and advanced along the biopsy tract to the target coordinates
(Fig. 4). In general, lesions less than 2.0 cm in diameter are
prescribed 18 Gy, and lesions greater than 3.0 cm are prescribed
15 Gy. The exact lesion dimensions obtained from the contrast-enhanced
CT are combined with dose/depth and isodose curves of the PRS
to determine the optimal radiation treatment plan. The probe tip
position, beam voltage, and current are used to calculate the
duration of treatment required to administer the prescribed dose
to the periphery of the tumor with a 2-mm margin. With all components
connected to the control box, the prescribed voltage and current
parameters are selected, and the timer is set to the calculated
treatment time. The device is activated by starting the timer
and automatically terminates after completion of the selected
treatment time. The PRS probe is then removed, and the incision
is closed in standard fashion. The procedure is carried out under
local anesthesia with intravenous sedation to minimize patient
Interstitial radiosurgery using
the PRS has been utilized at the Massachusetts General Hospital
since December 1992. Case selection has been limited to those
patients with either primary or secondary malignant brain tumors
who were not considered suitable for conventional surgical treatment.
Lesions had to be 3 cm or less in greatest dimension and supratentorial
in location. All patients had to be in good general health with
Karnofsky Performance Score (KPS) rating of 70% or greater and
with an expected survival of more than 4 months. Brain stem
or cerebellar lesions and tumors with significant cyst formation,
hemorrhage, or calcification were excluded.
All patients underwent a detailed
clinical evaluation, KPS rating and contrast-enhanced computarized
tomography (CT) scan or magnetic resonance imaging (MRI) prior
to treatment. An immediate post-treatment CT scan was obtained
within 24 hours to exclude peri-operative complications. All
patients were asked to return at regular intervals for follow-up
clinical evaluation and imaging studies to document any changes
in lesion size. Tumor response was graded independently by a
neuroradiologist with direct measurement of the maximal tumor
dimensions as seen on the last post-treatment MRI study and
compared to pre-treatment studies. Reduction or stabilization
of the tumor size was accepted as local control whereas enlargement
of the tumor indicated local failure. Clinical and radiological
outcomes were measured at the last follow-up visit or at the
time of death. If the tumor showed signs of progression at any
time following treatment, alternative methods of treatment were
used as clinically necessary. Patients with metastases who had
not received whole brain radiation therapy (WBRT) prior to interstitial
radiosurgery were given 30 Gy in 10 fractions after treatment.
To date, 27 patients have undergone
interstitial radiosurgery with the PRS. This includes 25 patients
with cerebral metastases ( sixteen men, eleven women; ages 37
- 80 years, mean 56 years ) of whom twelve had solitary lesions
and thirteen who had multiple (from 2 to 7) lesions. The primary
source of the cerebral metastases was lung cancer in 16, malignant
melanoma in 6, renal cell carcinoma in 2, and Merkle cell carcinoma
in one. Lesions ranged in size from 4-30 mm (mean 16.8 mm) in
greatest diameter and were located in various lobes. Treatment
diameter (lesion diameter + 2 mm margin) ranged from 8-34 mm
(mean 21.4 mm). Single doses of radiation between 10 and 20
Gy (mean 15.8 Gy) were administered, with an average treatment
time of 19.5 minutes (range 4-75 minutes). Fourteen patients
with cerebral metastases had received prior WBRT while the remainder
received 30 Gy in 10 fractions within 2 weeks of PRS treatment.
Two patients were felt to have
unresectable primary brain tumors. One patient was diagnosed
with a primary CNS lymphoma while the other was believed to
have a malignant glioma based on clinical presentation, radiological
findings and intraoperative pathological analysis. Subsequent
pathological evaluation suggested that the abnormal glial cells
and necrosis were not due to tumor but were probably reactive
astrocytes adjacent to an area of ischemic necrosis. Only necrotic
tissue was irradiated and the patient has suffered no adverse
effects from treatment.
All patients tolerated the procedure
well and most patients were discharged home the day after treatment.
Follow up has ranged from 10 days to more than 30 months (mean
7 months). Two patients experienced isolated focal motor seizures
within 24-48 hours of surgery and required anti-convulsants.
Two patients developed brain edema that resolved on corticosteroids
and diuretics. One patient developed a subdural hematoma, three
months after treatment but it was on the side opposite the treated
lesion. There were no deaths, infections, or serious neurological
Local control of the lesion (defined
as stabilization or reduction of tumor size) was obtained in
19 (73%) of the 26 patients with tumors. Tumor progression was
observed at 3 months post-PRS treatment in 5 patients, at 6
months in one patient, and at 10 months in one patient. Surgical
resection was performed in two patients with enlarging tumors
at 4 and 10 months post-PRS treatment and pathological analysis
demonstrated central necrosis along with a thin rim of viable
tumor around the periphery of the lesion. Two patients had post-mortem
examination. One patient with malignant melanoma who died twelve
months after treatment, documented absence of tumor cells in
the treated lesion. The second patient with adenocarcinoma of
lung died twenty months after treatment and demonstrated no
tumor cells in the treated frontal lesion, but rare viable tumor
cells were detected in the treated temporal lesion.
At last follow-up, 19 patients
with cerebral metastases have died; 13 from systemic disease
(between 12 days and 31 months after treatment), 5 from distant
central nervous system (CNS) metastases (between 5.5 and 12
months after treatment), and one patient 10 days after percutaneous
gastrostomy for recurrent aspiration pneumonia. Local control
of the treated tumors was documented in all 5 patients who died
from progressive CNS metastases and in 9 patients of those who
died from systemic disease, while local failure was evident
in the others. Six patients with cerebral metastases are alive
and well. Median survival was 13 months.
Future role of interstitial radiosurgery
The goal of any radiosurgical procedure
is to accurately deliver a large single fraction of radiation
to a small target volume while minimizing exposure to surrounding
tissue (23). With external radiosurgical systems, the desired
dose/volume distribution is obtained when the focused beams intersect
and summate at the target point after traversing cranial tissue
from varied angles (11). Conventional interstitial brachytherapy
obtains its desired dose/volume distribution by placing a radiation
source directly in the tumor. Dose rates for conventional implanted
radionuclides, are in the range of 0.5 to 2.0 cGy/min and the
treatment takes many hours to several days (28).The dose rate
during radiosurgery, either with a linear accelerator (linac),
or gamma knife is typically several hundred cGy/min with treatment
times averaging 15 to 60 minutes (27).
The PRS has operational characteristics
that combine the short treatment times of external beam radiosurgery
with the radiobiological advantages of interstitial brachytherapy
(10). The major radiobiological advantage of interstitial brachytherapy
is related to intratumoral placement of the radioactive isotope.
The emitted dose is attenuated in tissue with increasing distance(1/r2)
from the source which results in maximal delivery of radiation
to the tumor with relative sparing of the surrounding normal brain
(7). Of two commonly used isotopes, I125 generates low-energy
photons (28-35 KeV) but has a very low dose rate typically requiring
treatment times of several days. Radioisotopes with very low dose
rates may require permanent implantation (10,11). Ir192 emits
high-energy photons (300-610 KeV) and higher dose rates that can
shorten treatment times but has less sharply-defined dosimetry.
These conventional radioactive isotopes have been effective in
the treatment of certain brain tumors but do decay in activity
during storage and require special facilities and procedures for
their safe handling and disposal. Protective shielding of health
personnel must also be considered. Compared with interstitial
brachytherapy using standard implanted radionuclides, the PRS
treatment has significant advantages because of the adjustable
dose rate and steeper dose gradient it provides and hence less
dose to normal tissue outside the target. Also, PRS treatment
eliminates the need to handle radioactive sources (5).
Unlike external radiosurgical systems,
which require very large and expensive facilities, the portable
PRS provides a unique cost effective opportunity for providing
interstitial radiation therapy immediately following histologic
confirmation of malignancy in patients undergoing biopsy of intracranial
lesions (16). Moreover, the dosimetry provided by the PRS is similar
to, and perhaps better, than that achieved with proton beam or
linac three-dimensional treatment planning for small spherical
intracranial lesions (16).
An obvious difference between interstitial
approaches ( brachytherapy and PRS) and other non-invasive radiosurgical
techniques (gamma knife, linac ,or proton beam therapy) is that
with the former, a catheter(s) or probe tip must be placed into
the tumor. This imparts a small but definite risk of hemorrhage,
injury to the surrounding brain, or infection. Given the need
for tissue diagnosis prior to many forms of radiation treatment,
however, the added risk of the treatment procedure can be minimized
by inserting the probe at the time of the stereotactic biopsy.
The PRS should not impart any more risk than conventional interstitial
procedures and since the procedure is performed over a very short
time period, the risk of infection is less (11,27).
Potential inaccuracies involving
target selection and volume determination exist with any radiosurgical
system, but the extremely sharp dose distribution curves of this
device require targeting accuracy. Opening of the cranial vault
with shift of intracranial structures may induce additional targeting
error. Placement of the probe itself could displace the tumor
volume from its imaged position, and may increase the inaccuracy
related to dose distribution. The same problem of mechanical perturbation
of tissues exist with interstitial brachytherapy using temporary
I125 implants. The ability, however, to check the actual position
of the implanted sources with post-operative radiographs, and
to modify the source positions by placing or adjusting the catheters
positions, may be one potential advantage of the I125 catheter
implant system (10,27).
The spherical and non-infiltrative
nature of cerebral metastases makes them ideal candidates for
interstitial brachytherapy and radiosurgical treatment (20,27).
Whole brain radiation therapy (WBRT) in patients with cerebral
metastases extend median survival time to between 3 and 6 months
depending on the type of primary cancer, extent of systemic disease,
and a variety of other factors, but overall prognosis is poor
(8). Patients with solitary cerebral metastases who undergo surgical
excision plus WBRT experience improved overall survival (10-12
months) and better local control rates as compared to WBRT alone
(32,35,38). Resection of multiple metastases may also lead to
improved survival in those patients with controlled systemic disease,
but resective surgery necessitates hospitalization and operative
risk which could be minimized by less invasive techniques. Palliation
of symptoms and improvement in long-term survival has already
been demonstrated in patients with both new and recurrent solitary
brain metastases using I125 implant (31). If the PRS device is
similarly effective, it could represent an attractive alternative
to conventional surgery in this population of patients (10,11).
Treatment that provides local control
of single, multiple, or recurrent brain metastases imparts clinical
benefit in terms of quality of life and survival (3,24,32). Patchell
et al. demonstrated that the combination of surgery and radiotherapy
for solitary brain metastases improved local control from 48%
to 80% and increased median survival from 15 to 40 weeks (32).
Alexander et al. demonstrated local control rates of 89% and median
survival of 9.4 months in 248 radiosurgically treated patients
with brain metastases (3). The results of radiosurgery are encouraging
and suggest that radiosurgery can be an effective alternative
to surgery in patients with single, multiple, or recurrent cerebral
Interstitial radiosurgery using
the photoelectron device offers a safe alternative for the treatment
of brain metastases. Results of treatment using the PRS technique,
demonstrate a 73% local control rate and median survival of 13
months, which are within the range previously reported by others
and appear to be comparable to those of other radiosurgical modalities.
When tissue diagnosis is required,
the ability to perform stereotactic biopsy and interstitial radiosurgery
at the same procedure could be advantageous and cost-effective.
However, the PRS is unlikely to replace conventional radiosurgery
devices such as gamma knife, linac, or proton beam especially
with regard to treatment of patients with arteriovenous malformations
or acoustic neurinomas (11).
Interstitial radiosurgery imparts
less dose to non-target normal tissue when compared to other forms
of radiosurgery. This reduction in dose at larger volumes may
represent a clinical advantage for selected cases and may allow
for treatment of metastases too large to be treated with external
radiosurgery. It is not yet clear what role the photoelectron
device will have in the treatment of primary brain tumors. Malignant
and even low-grade gliomas are generally larger than 3-4 cm at
the time of diagnosis and tend to infiltrate locally along white
matter tracts. However, the device may be of use in small, deep
gliomas or recurrences, and treatment plans incorporating multiple
isocenters are feasible (10,11).
Perhaps its most useful role will
be for intraoperative irradiation during open neurosurgical procedures
in a fashion similar to that employed by other surgical specialities.
The probe tip can be easily shielded to allow for unidirectional
irradiation of resection cavities, tumor margins, dural attachments,
or skull base lesions. Conversely, sensitive neural structures
could be shielded by thin radio-opaque metals to prevent radiation
injury during treatment. It may have even broader application
in other surgical subspecialities including breast cancer surgery,
urology, gynecology, orthopedics, and otolaryngology (10,11).
The PRS is a new device for the
interstitial radiosurgical treatment of cerebral metastases and
possibly other brain tumors. It offers a convenient and cost efficient
method for providing interstitial radiation therapy in patients
undergoing diagnostic biopsy of intracranial lesions.
When treating small, circumscribed,
nearly spherical intracranial lesions, the PRS treatment appears
to offer superior dosimetric advantages over linac, gamma knife,
or proton beam therapy in sparing the surrounding normal brain
tissue. Given its operational characteristics and dosimetry profile,
it compares favorably to current external radiosurgical devices
and has certain logistical advantages over standard interstitial
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EM, et al: Treatment of single brain metastasis: Radiotherapy
alone or combined with neurosurgery. Ann Neurol 1993;33:583-590.
- Figure 1 - Internal diagram of the
Photon Radiosurgical System.
- Figure 2 - Spherical isodose contours
of the PRS along the probe axis (a) and in the plane of the probe
axis (b). ( From Beatty J et al. (5) ).
- Figure 3 - Dose-volume histograms
from the linac (x-ray), proton beam, and PRS treatment plans,
demonstrate that with the PRS treatment, high doses are delivered
to small volumes with some normal tissue sparing for volumes less
than 50 cc in comparison to the linac or proton beam therapy plans.
( From Douglas RM et al. (16) ).
- Figure 4 - The PRS is mounted on
the arc carrier of the CRW frame that stereotactically places
the probe tip at the target center. After device activation, low-energy
x-ray beam emanates from the probe tip to irradiate the lesion