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Stereotactic Body Radiation Therapy

Stereotactic Body Radiation Therapy

ABSTRACT: Stereotatic body radiation therapy (SBRT) is a rapidly evolving cancer treatment method in which concepts and techniques previously developed for brain tumor radiosurgery are adapted to eradicate tumors elsewhere in the body. The spatial accuracy, conformality, and steep radiation dose gradients of radiosurgery, which have been critical to its success in the treatment of intracranial tumors, are applied in SBRT to treat a variety of extracranial tumors. Early results demonstrate excellent response rates and low toxicity with a variety of hypofractionated dose regimens and localization/immobilization techniques. This article provides an overview of the rationale and results of SBRT for specific indications, descriptions of some methods of treatment delivery, and discussion of potential areas of future investigation.

Stereotactic radiosurgery (SRS)
is a term originally created by
Lars Leksell to describe a new
approach to radiotherapy for brain tumors
using multiple convergent
beams, precise localization via a stereotactic
coordinate system, rigid
patient immobilization, and singlefraction
treatment. The technique contrasts
sharply with conventional
three-dimensional (3D) conformal
external-beam radiotherapy (CRT), in
which the total radiation dose is given
in numerous-often 25 or more-
small daily doses or fractions. The
dose-fractionation allows for repair
in normal tissues between fractions,
but the need to reproduce the patient's
initial positioning on multiple occasions
necessitates the inclusion of an
extra margin of normal tissue around
the tumor in the treatment field to
account for daily set-up variations.

With SRS, a stereotactic immobilization
frame is tightly pinned to the
patient's skull, allowing the spatial
precision for treating with zero to minimal
margin of surrounding tissue. The
resulting reduction in volume of normal
tissue irradiated leads to the ability
to deliver higher doses, thereby
potentially improving tumor control.
Positive clinical experience accumulated
over the past 2 decades has affirmed
the utility of SRS in the treatment
of a variety of intracranial tumors.
For brain metastases, treatment
with SRS lengthens median survival
compared to conventional radiotherapy,[
1] and for other clinical entities
(eg, arteriovenous malformations,
trigeminal neuralgia, acoustic schwannomas),
SRS has offered a valuable
new alternative to surgery.[2]

Recent advances in 3D-CRT include
alterations in the treatment
schedule to shorten the length of treatment
as well as modulation of the
intensity of the radiation beam profile,
either to provide selective boost
doses to gross disease within a larger
field or to minimize the radiation dose
to irregularly shaped normal tissues
adjacent to the area treated. However,these approaches have changed the
daily or fractional dose by a very limited
proportion relative to conventional
doses, and the capability of
delivering higher fractional doses in
the radiosurgical range have not been
previously tested. The anatomic characteristics
of the skull and stability of
cranial contents make SRS feasible
for intracranial tumors, but the lack of
a similar fixed bony reference structure
as well as respiration-induced
movement creates difficulty for application
outside the cranium.

In 1994, Lax et al of the Karolinska
Institute reported a method for
performing what is now called stereotactic
body radiation therapy (SBRT)
for abdominal malignancies, using a
custom body cast with stereotactic
coordinates.[3] Blomgren and Lax
subsequently reported an 80% progression-
free rate in 42 tumors of the
lung, liver, or abdomen treated with
this method to mean doses of 30 Gy
delivered in one to four fractions.[4]
Since this report, there has been increasing
interest in and reports on the
use of a similar approach of spatially
precise, single-dose treatment or very
brief regimens involving typically
three to five individual doses (hypofractionation).

The principles that have generally
been used in the selective application
of SBRT mirror those of SRS. Treatment
is limited to small- to moderatevolume
discrete tumor targets.
Prophylactic coverage of the surrounding
region of potential microscopic
disease is not performed,
thereby maintaining a simple volume
and eliminating dose gradients between
spatially separated target structures.
Targets are within radiosensitive
normal tissue or surrounding structure
with parallel (as opposed to serial)
architecture, where small portions
of normal tissue surrounding the structure
can receive high doses of radiation without clinical consequences due
to functional reserve of unaffected
organ. A dose-response relationship
should be exploited using the capacity
for increased dose delivery offered
by SBRT.

In this paper, we describe the methods
used in treating patients with "extracranial
radiosurgery," "extracranial
radiotherapy," or SBRT, the clinical
scenarios in which it is applicable and
why, and unresolved issues and future
directions for investigation.

Physics and
Technology of SBRT

For single high-dose or hypofractionated
SBRT, it is necessary to maintain
a higher confidence in radiation
dose delivery than with 3D-CRT.
Several methods have been used to
achieve spatial accuracy during SBRT,
and herein are discussed methods that
have been described in published reports
of patients treated with hypofractionated,
high-dose radiation and
multiple beams. The term stereotactic
implies the use of an external frame
of reference indexed to internal volumes
to be targeted. Not all of the
methods necessarily utilize strict stereotactic
localization methods, but the
term stereotactic has been a common
denominator when describing this literature
as a whole.

In general, the sequence of events
for patients undergoing SBRT include
the following: (1) computed tomography
(CT) simulation, (2) immobilization,
(3) planning, (4) repositioning,
(5) relocalization, and (6) treatment
delivery. The CT simulation is used to
assess tumor size, location, and range
of motion and to determine if the patient
can tolerate the planned immobilization.
During the initial CT, the
range of tumor motion observed provides
the necessary data for the required
margin to be added around the
gross target volume to define the planning
target volume-the actual volume
to be targeted in order to be certain
that the gross target volume
receives the full intended dose during
each treatment. Immobilization includes
a custom-fitted device to minimize
motion and breathing effects, and
provide a reproducible setup.

The planning must address the
small-field dosimetry issues common
to cranial stereotactic radiosurgery but
with the additional focus of inhomogeneity
corrections for lung fields, and
volumetric considerations for normal
tissue complications of the critical organ
being treated (ie, lung or liver).
Repositioning addresses the accurate
setup of the patient in the planned
position, whereas relocalization addresses
the specific identification of
the tumor and planned isocenter in the
treatment field. Finally, treatment delivery
is performed using any of a wide
array of high-precision beam delivery
techniques, including mini-multileaf
collimation, gantry mounted linear accelerators
(linacs), and combined imaging
and treatment units.

Patient Immobilization,
Positioning, and Relocalization

All of the reports on SBRT have
included a CT simulation to assess
tumor location, size, range of motion,
and feasibility of treatment within the
established parameters of the particular
institute. Lax's initial report
involved the use of a body cast within
a rigid box frame with radio-opaque
scale markers for acquisition of imaging
data. The scales mounted on the
frame, corresponding to fiducials,
were used to establish a coordinate
system in the 3D space of the treatment
room. Diaphragmatic movement
was limited by using a plate applying
pressure on the abdomen.[3] Blomgren's
mean reproducibility for 75
evaluable tumors was reported as
3.7 mm in the transverse plane and
5.7 mm longitudinal; a margin of
5 mm was added to the gross target
volume in the transverse plane and a
margin of 10 mm was added in the
longitudinal direction to define the
planning target volume.[4]

Since the report of the Karolinska's
treatment method, some institutions
have used the same technique of
a body frame with diaphragmatic pressure
plate and stereotactic coordinates
to treat lung and liver tumors (eg,
Leibinger frame, Elekta frame), while
others have used a variety of immobilization
and repositioning methods in attempts
to achieve similar accuracy.
Overall, the reported accuracy is within
5 mm for the various methods utilized.
A comprehensive evaluation of
these methods is beyond the scope of
this paper, but Table 1 lists some of the
methods used; select methods are described
in more detail below.[3,5-17]

Sato et al described a frameless
stereotactic technique for metastatic
liver cancer in which 14 patients were
instructed to keep shallow respiration
with an oxygen mask and abdominal
belt on the treatment table.[5] Patients
received transcatheter arterial chemoembolization
with lipiodol, which
played a role as a radio-opaque marker
for x-ray simulation and CT monitoring.
Relocalization accuracy was
performed with a multifunctional unit
incorporating CT scanner, x-ray simulator,
and linac sharing one treatment
couch. Patients underwent
imaging and target localization prior
to each daily treatment without getting
off the couch between scan and
treatment. No overall statistics on the
patient immobilization and tumor relocalization
were reported.[5] Nakagawa
et al utilized a similar approach
of immediate pretreatment image verification
with a megavoltage (6-MV)
CT scanner mounted on a linac.[6]
Hara et al employed a method of transferring
the patient to the treatment
unit within a custom bed after a CT
scan was performed to place the isocenter;
treatment was performed with
respiratory gating.[7]

The CyberKnife (Accuray, Sunnyvale,
Calif) consists of a gantrymounted
linac coupled with a realtime
image guidance system. The
treatment site is imaged by two x-ray
fluoroscopes and bony landmarks are
referenced to the components of the
hardware. Once the location of the
bony landmark has been determined
relative to the robot arm, the position of the tumor is accounted for and adjusted
accordingly. The cameras can
frequently update the body position
and accommodate for patient motion
and setup changes, and in that regard,
this device has six degrees of freedom
allowing for volumes with more
complex shapes. Murphy reported a
mean total radial error of 1.6 mm and
found that the accuracy of the system
was equal to or better than that of
frame-based systems currently in
use.[8]

Whereas the Lax system was designed
to treat soft-tissue tumors,
Hamilton et al described a system for
spinal cord irradiation for extracranial
stereotactic radiosurgery using a
screw fixation technique.[9] The
Hamilton system was based on the
principles of rigid skeletal fixation. A
rigid box is used for the patient to lie
prone and a clamp is fixated on the
surgically exposed spinous process
above and below the target areas. Once
the coordinates of the target have been
acquired from the CT images, the box
is transferred to the linac treatment
table and aligned using standard lasers.
The clinical experience with this frame has shown reproducibility on
the order of 2 mm.

Primary Lung Tumors

Several reports have described the
treatment of early-stage primary non-
small-cell lung cancer (NSCLC) with
SBRT. Although surgical resection is
the primary modality of treatment, radiotherapy
has been used in patients
who are not medically fit to undergo
surgery. Survival rates among patients
who received 3D-CRT are generally
inferior to those of surgery, but selection
bias likely plays a role on the
observed difference, since patients referred
for 3D-CRT usually have significant
intercurrent illness. The use
of higher doses has been associated
with improved outcomes.[18,19] Sibley
summarized the results of CRT in
patients with T1/2, N0 tumors, concluding
that elective nodal irradiation
was unwarranted and higher doses
were associated with improved tumor
control and disease-free survival.[20]

Although 3D-CRT doses of 60 to
66 Gy were not associated with radiation
pneumonitis in this review, a
study by Langendijk et al suggests
that 3D-CRT may negatively affect
quality of life.[21] Patient-reported
quality of life was assessed at intervals
starting prior to radiotherapy in
46 patients, and showed worsening
trends in dyspnea, appetite, and fatigue
up to 24 months posttherapy.
Despite the fact that progression of
medical comorbidities is common in
this population, the worsening trend
was seen to begin at 2 weeks into
therapy. Dysphagia was the only
symptom that was statistically different
between patients treated to locoregional
fields vs those receiving
treatment to the lung primary alone.

Reports of SBRT in early-stage
NSCLC describe doses that are biologically
higher than doses used in
3D-CRT. Based on tumor control
probability calculations derived from
a database of patients treated with conventional
techniques, Martel et al predicted
that a dose of 84 Gy (in 2-Gy
fractions) was necessary to achieve
local progression-free survival in 50%
of patients.[22] However, any doseescalation
scheme using convention-al fractionation requires an increase
in overall treatment time, which has
been negatively correlated with tumor
control rates and patient outcomes.[
23] Randomized clinical
evidence supports the use of a shortened
treatment duration (accelerated
fractionation) in NSCLC, albeit at a
cost of increased pneumonitis with
CRT.[24]

Numerous series have documented
the efficacy and safety of SBRT in
the treatment of early-stage NSCLC
(see Table 2).[7,13,14,16,25-27] Although
median follow-up durations are
short, local control rates are high and
compare favorably with those for conventional
treatment. Due to the large
differences in fraction sizes between
SBRT and conventional treatment, direct
comparison of total nominal doses
is not feasible. The linear quadratic
method is generally accepted for drawing
comparisons between different
fractionation schemes.

Table 3 compares the biologic effective
dose of the two types of treatment,
assuming an alpha/beta ratio of
10.[7,13,16,27,28] One can readily
see that the biologic effective doses
for SBRT are higher than the standard
60 to 66 Gy for conventional
therapy. Despite the use of higher
doses than typically given, SBRT has
not been associated with an increased
rate of complications. Table 4 summarizes
the toxicities described in the
literature for SBRT in patients with
lung tumors (both NSCLC and metastatic),
with the reported incidence of
grade 3 toxicities generally less than
5%.[4,6,7,13,14,25-27,29] Fukumoto
performed routine pulmonary function
testing before and after treatment
and found no decline in median forced
expiratory volume in 1 second (FEV1)
or diffusing capacity of the lung for
carbon monoxide (DLCO) values following
therapy.[15]

Given that a dose-response relationship
exists for NSCLC, and SBRT
has been found to have little associated
toxicity, dose-escalation studies are
needed. Timmerman et al have performed
the only dose-finding study
for SBRT thus far.[16] A total of 36
patients with medically inoperable
stage I NSCLC were treated in a
phase I study using a three-fraction regimen, starting at 8 Gy per fraction.
The technique employed was the same
as that of the Karolinska Institute.
Dose was safely escalated to 20 Gy
per fraction (total dose: 60 Gy), with
the maximal tolerated dose not
reached. Toxicity consisted of one
case of grade 3 pneumonitis and one
case of grade 3 hypoxia; pulmonary
function testing revealed no statistically
significant changes following
treatment. Radiographic response was
seen in 87% of patients. At a median
follow-up of 15 months, there were
6 local failures, all occurring in patients
treated with less than 18 Gy per
fraction.[16]

Despite the stated potential advantages
of SBRT, a similar dose-escalation
study using CRT has not been
performed in this patient population.
Thus, one cannot exclude the possibility
of similar results being achievable
with higher doses of CRT.

Lung Metastases

Most series describing SBRT for
lung tumors include patients treated for
metastatic disease. Dose-fractionation
schemes and techniques employed are
similar to those for primary lung tumors,
and control rates range from 66%
to 100% with minimal reported toxicitiy (see Table 5).[4,6,7,13,25-27] Although
radiotherapy has not traditionally
been employed in curative fashion
for these patients due to perceived poor
prognosis, data exist to support aggressive
local therapy for selected patients
with lung metastases.[30]

The International Registry of Lung
Metastases reported the largest series
to date of surgical metastasectomy in
5,206 cases from 18 institutions in
Europe and North America. Primary
histology was epithelial in 2,260 cases,
sarcoma in 2,173, germ cell in 363,
and melanoma in 328. With a median
follow-up of 35 months, actuarial survival
after complete metastasectomy
(achieved in 88% of patients) was 36%
at 5 years and 26% at 10 years. Multivariate
analysis showed better prognosis
for patients with a single
metastasis, disease-free intervals of
36 months or more, and germ cell
tumors, although long-term survivors
were seen in all histologic types.[31]

Some series of surgical metastasectomy
have also found tumor size
and nonmelanoma histology to be of
prognostic significance, although others
report no differences.[30,32] Given
the high rates of local control and
low toxicity demonstrated for SBRT,
similarly selected patients who are
not otherwise eligible for surgery may receive comparable benefit from treatment
with SBRT and should be considered
for treatment.

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