Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 1, pp.

253–259, 2009
Copyright Ó 2009 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2009.03.029

PHYSICS CONTRIBUTION

WHOLE-BRAIN RADIOTHERAPY WITH SIMULTANEOUS INTEGRATED BOOST TO

MULTIPLE BRAIN METASTASES USING VOLUMETRIC MODULATED ARC THERAPY

FRANK J. LAGERWAARD, M.D., PH.D., ELLES A. P. VAN DER HOORN, WILKO F. A. R. VERBAKEL, PH.D.,
CORNELIS J. A. HAASBEEK, M.D., BEN J. SLOTMAN, M.D., PH.D., AND SURESH SENAN, M.R.C.P., F.R.C.R., PH.D.
Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands

Purpose: Volumetric modulated arc therapy (RapidArc [RA]; Varian Medical Systems, Palo Alto, CA) allows for
the generation of intensity-modulated dose distributions by use of a single gantry rotation. We used RA to plan and
deliver whole-brain radiotherapy (WBRT) with a simultaneous integrated boost in patients with multiple brain
metastases.
Methods and Materials: Composite RA plans were generated for 8 patients, consisting of WBRT (20 Gy in 5 frac-
tions) with an integrated boost, also 20 Gy in 5 fractions, to the brain metastases, and clinically delivered in 3
patients. Summated gross tumor volumes were 1.0 to 37.5 cm3. RA plans were measured in a solid water phantom
by use of Gafchromic films (International Specialty Products, Wayne, NJ).
Results: Composite RA plans could be generated within 1 hour. Two arcs were needed to deliver the mean of 1,600
monitor units with a mean ‘‘beam-on’’ time of 180 seconds. RA plans showed excellent coverage of planning target
volume for WBRT and planning target volume for the boost, with mean volumes receiving at least 95% of the pre-
scribed dose of 100% and 99.8%, respectively. The mean conformity index was 1.36. Composite plans showed
much steeper dose gradients outside the brain metastases than plans with a conventional summation of WBRT
and radiosurgery. Comparison of calculated and measured doses showed a mean gamma for double-arc plans
of 0.30, and the area with a gamma larger than 1 was 2%. In-room times for clinical RA sessions were approxi-
mately 20 minutes for each patient.
Conclusions: RA treatment planning and delivery of integrated plans of WBRT and boosts to multiple brain me-
tastases is a rapid and accurate technique that has a higher conformity index than conventional summation of
WBRT and radiosurgery boost. Ó 2009 Elsevier Inc.

Brain metastases, Volumetric modulated arc therapy, Radiosurgery.

INTRODUCTION radiosurgery techniques, it remains a time-consuming treat-

The combination of whole-brain radiotherapy (WBRT) and
a radiosurgery boost has been shown to improve treatment re-
sults compared with WBRT alone in selected patients with
brain metastases (1, 2). The prospective randomized Radia-
tion Therapy Oncology Group study 9508 reported a survival
benefit for the combined WBRT and radiosurgery approach
for patients with a single brain metastasis but also a significant
improvement in intracranial disease control, performance
status, and steroid use for patients with multiple brain metas-
tases (1). At our center, patients with multiple brain metasta-
ses have been treated with a combination of WBRT and
linear accelerator–based frameless radiosurgery, performed
as separate procedures with a 1- to 2-week interval between
them. Although the delivery of frameless radiosurgery is
more patient friendly and faster than traditional frame-based
ment for both patients and departments.
RapidArc (RA) (Varian Medical Systems, Palo Alto, CA)
is a volumetric modulated arc technique that allows for
highly conformal intensity-modulated three-dimensional
dose distributions to be delivered with a single 358 rotation
of the gantry of the linear accelerator. The planning algorithm
uses progressive sampling optimization by simultaneously
changing the shape of the treatment aperture, dose rate, and
rotation speed of the gantry (3). The combination of accurate
patient setup by use of kilovoltage cone beam computed to-
mography (CT) and RA treatment planning and delivery
constitutes an alternative to conventional stereotactic radio-
therapy. It also allows for the generation and delivery of com-
plex radiotherapy plans such as integrated delivery of WBRT
with a fractionated ‘‘stereotactic’’ boost.

Reprint requests to: Frank J. Lagerwaard, M.D., Ph.D., Depart-
ment of Radiation Oncology, VU University Medical Center, de
Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel:
(+31) 20 4440414; Fax: (+31) 20 4440410; E-mail:
fj.lagerwaard@vumc.nl
253
Conflict of interest: The VU University Medical Center has a
research collaboration with Varian Medical Systems (Palo Alto, CA).
Received Sept 4, 2008, and in revised form March 15, 2009.
Accepted for publication March 19, 2009.
254 I. J. Radiation Oncology d Biology d Physics
In this study we investigated whether RA plans consisting
of integrated WBRT and boost doses to multiple brain metas-
tases would be an appropriate alternative to our traditional
technique. Plans were compared and evaluated with respect
to dosimetry and treatment delivery time. The actual clinical
treatments, including quality assurance (QA) measurements
for this an integrated approach with RA delivery, are
described.
METHODS AND MATERIALS
For 8 patients with brain metastases, two treatment plans were
generated: (1) an integrated RA plan consisting of WBRT and a con-
comitant boost to the brain metastases and (2) a conventional
approach of sequential WBRT followed by a stereotactic boost by
use of multiple non-coplanar conformal arcs, which was customary
at our center. After the evaluation of RA treatment plans and dosi-
metric verification in the first 5 patients, the integrated RA plans
were actually delivered in the last 3 patients (patients F–H). Patient
H had undergone neurosurgical resection for the largest of two brain
metastases and was treated with postoperative WBRT and a simulta-
neous integrated stereotactic boost on the remaining brain metasta-
sis. None of the other patients underwent surgical resection.
Target definition and treatment planning
Patients were positioned supine in a custom-made mask (CIVCO
Medical Solutions [formerly SINMED], Reeuwijk, The Nether-
lands), and planning CT scans without intravenous contrast were
obtained with a 2.5-mm slice thickness. Contrast-enhanced T1 se-
quences of a coregistered diagnostic magnetic resonance imaging
scan (slice thickness, 2 mm; enhanced with gadolinium with
a three-dimensional distortion-correction protocol) were used for
target contouring. The summated gross tumor volumes (GTVs)
(i.e., the summated volume of all GTVs per patient) ranged from
1.0 to 37.5 cm3 (Table 1). The planning target volume (PTV) for
the boost (PTVboost) was derived by adding a 2-mm margin to the
GTVs to correct for possible residual positional inaccuracies by
use of an online cone beam CT setup protocol. The PTV for
WBRT (PTVWBRT) was derived from autosegmentation of the brain
plus the addition of a 2-mm symmetric margin.
For all patients, a composite RA treatment plan (version 8.2.22)
was generated, consisting of WBRT (20 Gy in 5 fractions) with a si-
multaneous integrated stereotactic boost, also 20 Gy in 5 fractions,
to the PTVboost. The cumulative dose received by the center of the
brain metastases was consequently 40 Gy in 5 fractions. Both
WBRT and boost doses were prescribed at 100%, according to In-
ternational Commission on Radiation Units & Measurements crite-
ria. Treatment plans were generated with 6-MV photons, by use of
multileaf collimation with a leaf width of 5 mm (Varian 120 MLC;
Varian Medical Systems) and a collimator rotation of 45 . All final
dose calculations were performed with the Eclipse system, version
8.6.3 (Varian Medical Systems, Palo Alto, CA), by use of the aniso-
tropic analytical algorithm calculation model, with a calculation grid
of 2.5 mm, and with tissue heterogeneity correction. The maximum
dose rate for treatment delivery was 600 monitor units (MU) per
minute, and only a maximum of 999 MU can be delivered in a single
arc with the present version of RA (version 8.2.22).
The minimal accepted doses to the PTVWBRT and the PTVboost
were 95% of the prescribed fraction dose of 4 Gy and 8 Gy, re-
spectively. In the conventional stereotactic radiation treatment
used at our center, a dose of 21 Gy is prescribed to the 80%
Volume 75, Number 1, 2009
Table 1. Patient characteristics.
Patient No. of metastases Summated GTVboost (cm3)
A 4 3.1
B 2 37.5
C 3 9.8
D 2 8.0
E 5 1.0
F* 3 3.3
G* 3 25.8
H* 1 1.5
Abbreviation: GTVboost = summated gross tumor volume for
boost.
* Patients in whom RapidArc treatment was clinically delivered.
PTV encompassing isodose, corresponding to a biologically effec-
tive dose of 65 Gy10, calculated using an alpha/beta ratio of 10 for
tumor tissue. The minimum dose of 95% of 8 Gy per fraction to
the PTVboost volume with RA corresponds to a biologically effec-
tive dose of 67 Gy10. There was no maximum dose limit for the
brain metastasis, although typically, this was confined to 110%
of the prescribed dose. Because of the steep dose gradients gener-
ated around the PTVboost, a maximum dose for the PTVWBRT is
difficult to define. Conformity indices, which were calculated
from the ratio between the total volume receiving more than
95% of the prescribed boost dose and the volume of the PTVboost,
were compared for both techniques. Doses to critical organs, such
as the lens, were evaluated by use of dose–volume histograms.
QA of RA plans
All calculated RA plans were delivered on a Varian Trilogy linear
accelerator (Varian Medical Systems) and measured in a 23-cm cube
solid water phantom in three coronal or sagittal planes with 2 cm of
separation by use of Gafchromic EBT films (International Specialty
Products, Wayne, NJ) (Fig. 1). In each plane double films were used
to reduce the statistical uncertainty per film, which is about 1.8% for
double films (4). All film measurements were compared with calcu-
lated dose distributions of the respective RA plans on the solid water
phantom. Comparisons were performed by means of a gamma eval-
uation (5, 6) with dose and distance criteria of 3% of the WBRT dose
and 2 mm, respectively. Areas that do not meet these criteria will
have a gamma larger than 1.
Patient setup procedure
To ensure the accuracy of delivery of the integrated treatment
plans, daily online setup by use of a combination of a lateral kilo-
voltage image and cone beam CT scans was performed for the
3 patients treated with RA. The lateral kilovoltage image was
used for detecting a pitch larger than 0.8 . Each part of the
PTVWBRT and PTVboost is within 10 cm of the isocenter. A max-
imum pitch or roll of 0.8 leads to a maximum positioning error of
1.4 mm; a combination of the two rotations would lead to a maxi-
mum error of 2 mm (i.e., the clinical target volume–PTV margin
used). All rotations exceeding 0.8 were corrected for by reapply-
ing the mask and repeating the cone beam CT to ensure that the
correct position was obtained. All detected shifts in patient position
were corrected.
RESULTS
In this study we performed a dosimetric comparison of inte-
grated RA plans and a conventional summation of WBRT and
 RA for WBRT and boost to multiple metastases d F. J. LAGERWAARD et al. 255

Fig. 1. Quality assurance measurements of RapidArc plans reconstructed in a cube solid water phantom in coronal or sag-
ittal planes using Gafchromic EBT films in patient G.

stereotactic boosts in 8 patients with brain metastases. After in Fig. 3. Dosimetric analysis of the composite RA plans
completion of the planning study and QA measurements, we showed excellent coverage of both PTVWBRT and PTVboost,
performed clinical delivery of the integrated plans in 3 patients. with mean volumes receiving at least 95% of the prescribed
Dosimetric results are provided in Tables 2 and 3. dose of 100% and 99.8%, respectively (Table 2). The maxi-
More than 999 MU is needed to deliver the fraction doses mum point dose, which was in all cases located within the
of 4 Gy (PTVWBRT) and 8 Gy (PTVboost), and consequently, PTVboost, had a mean value of 108.9% (range, 106.2–
two arcs are needed to deliver the dose. Although it would 110.4%).
have been possible to deliver two identical arcs, we have
opted for the solution of a second arc that uses the results
of the first arc as a starting point for further optimization.
For this second (compensatory) arc, the collimator is rotated Table 2. Dosimetric results in patients A through H obtained
with RA planning
from 45 (first arc) to 40 (second arc), to ensure that pos-
sible tongue and groove underdosage did not add up along V95
the same lines. The use of this two-arc approach also has the
advantage of noninterrupted irradiation without rotation of WBRT (%) Boost (%) Dmax (%)
the gantry back to its starting point. The principle of the Patient
compensatory second arc is illustrated in Fig. 2. The relative A 99.9 99.9 107.3
cold spots and hotspots that can be seen in the dose distri- B 100 99.8 110.4
bution of the baseline plan for the first arc (left panel) are C 99.9 99.9 109.0
D 99.9 99.9 106.2
compensated for in the second arc (middle panel), and the E 99.9 100 109.3
resulting composite plan of both arcs shows improved F 100 99.7 108.2
homogeneity (right panel). All evaluated RA plans were de- G 100 99.3 110.4
rived from the summation of the first arc and the compensa- H 100 99.8 110.4
tory second arc. Mean  SD 100  0.1 99.8  0.2 108.9  1.6
An example of an integrated RA plan for WBRT with si- Abbreviations: RA = RapidArc; V95 = volume receiving at least
multaneous integrated boost to multiple metastases is shown 95% of prescribed dose; Dmax = maximum dose.
256 I. J. Radiation Oncology d Biology d Physics Volume 75, Number 1, 2009

Table 3. Dosimetric comparison between integrated RA plans and a conventional summation of WBRT and stereotactic boosts

Conventional summation RA

V25 (%) V30 (%) V35 (%) Conformity index V25 (%) V30 (%) V35 (%) Conformity index

Patient
A 12.9 4.1 2.1 2.4 4.3 2.1 1.1 1.3
B 21.5 8.5 5.2 1.5 9.3 5.9 4.0 1.2
C 7.1 2.7 1.5 1.6 3.5 2 1.2 1.2
D 8.2 2.8 1.6 2.0 3.3 1.9 1.1 1.2
E 3.7 1.0 0.4 3.4 1.9 0.8 0.3 2.0
F 3.4 1.3 0.7 2.2 2 0.9 0.5 1.2
G 18 7.9 4.9 2.3 6.6 4.2 2.7 1.1
H 0.9 0.4 0.3 1.8 0.6 0.3 0.2 1.1
Mean  SD 9.5  7.4 3.5  3.1 2.1  1.9 2.1  0.6 3.9  2.8 2.3  1.9 1.4  1.3 1.3  0.3

Abbreviations: RA = RapidArc; WBRT = whole-brain radiotherapy; V25 = percent of normal brain receiving total dose of 25 Gy; V30 =
percent of normal brain receiving total dose of 30 Gy; V35 = percent of normal brain receiving total dose of 35 Gy.

One of the most striking, though obvious, advantages of
generating integrated WBRT and boost plans is illustrated
in Fig. 4. The right panel shows a summation of a conven-
tional WBRT plan with a standard radiosurgery boost derived
from five non-coplanar arcs with dynamic conformal arcs. In
the left panel the comparative RA plan shows much steeper
dose gradients outside the PTVboost, resulting from the mod-
ulation of the WBRT dose within the area of the boost dose
gradient. This is reflected by a significantly better conformity
index for RA plans of 1.3  0.3, which contrasted to a confor-
mity index of 2.1  0.6 for the conventional summation (p <
0.001, t test) (Table 3). The volume of normal brain receiving
doses of between 25 and 35 Gy was also smaller with RA
planning. A maximum dose (Dmax) constraint of 5 Gy for
both lenses was routinely used in RA planning, which re-
sulted in a mean Dmax of 9.5 Gy with RA. With the conven-
tional summation of WBRT plus radiosurgery, the Dmax was
5 Gy.
The mean number of monitor units and the mean ‘‘beam-
on’’ time needed to deliver both arcs were 1,600 MU (range,
1,404–1,790 MU) and 180 seconds (range, 160–210 sec-
onds), respectively. In the 3 patients actually treated by use
of the daily setup with cone beam CT scans and RA delivery,
the total time needed for patients to enter and leave the treat-
ment room after delivery has been limited to approximately
20 minutes with growing experience with online patient
setup.
QA measurements
The measured dose distributions generally agreed well
with the calculated distributions. QA film measurements of
single-arc plans showed maximum differences between cal-
culated and measured doses of up to 7.5%. However, the
use of summated plans with two separate arcs averaged out
these differences. The mean gamma, averaged for all mea-
sured planes for the 8 patients, for the single arc and double
arc were 0.50 and 0.30, respectively. The area with a gamma
larger than 1 (3% of WBRT dose, 2 mm), also averaged for
all measurements, was 6% for the single arc comparisons
and only 2% for the double-arc comparisons. Figure 5 shows
a typical example of a comparison in the sagittal plane of
a composite plan consisting of two arcs.
DISCUSSION
Despite the increased speed with the use of noninvasive
immobilization devices, conventional radiosurgery remains
a time-consuming technique. Treatment delivery times on

Fig. 2. RapidArc dose distributions showing baseline plan (left) and a compensatory second plan (middle), leading to
improved homogeneity with an absence of hotspots and cold spots in the summated two-arc plan (right).
 RA for WBRT and boost to multiple metastases d F. J. LAGERWAARD et al. 257

Fig. 3. Composite RapidArc plan with whole-brain radiotherapy and integrated boost to multiple metastases for patient C.

our Novalis linear accelerator (BrainLAB, Feldkirchen, Ger-
many), by use of the frameless method, varies from approx-
imately 30 minutes for a single metastasis to well over 1 hour
for three metastases. Our planning analysis and early clinical
data indicate that integrated WBRT and fractionated stereo-
tactic boost are feasible in a very short mean beam-on time
of 180 seconds by use of RA. Although the use of two arcs
is inevitable as a result of the maximum of 1,000 MU per
arc, this does not prolong the treatment delivery time, be-
cause the gantry does not need to be rotated back to its start-
ing point. The total ‘‘in-room’’ time span, which includes
patient setup by cone beam CT scans and treatment delivery,
has been approximately 20 minutes in patients who have
actually been treated with the RA plans.
The high delivery speed may not only increase patient tol-
erance of radiosurgery procedures and the efficiency of radi-
ation oncology departments but can also decrease the risk of
intrafractional positional shifts of the patient within the fix-
ation device. Although intrafractional three-dimensional
positional shifts were generally small, with a mean SD of
0.3 mm, extremes of up to 1.5 mm were observed in our
population treated with the frameless mask system (7).
As a result of modulation of the WBRT dose in the area
of the dose gradient of the boost doses, integrated plans have
much steeper dose gradients than comparable plans with
conventionally summated WBRT and radiosurgery. This
leads to a large increase in conformity of the high-dose re-
gion, which has been correlated to reduced normal tissue

Fig. 4. Comparison between RapidArc (RA) composite plan (left) and standard summation of whole-brain radiotherapy
(WBRT) and radiosurgery boost (right) for patient B. The dose color wash shows only doses above 23 Gy (115% of WBRT
dose) to demonstrate the steeper dose gradient with RA plans. The dose–volume histograms of the brain in both cases are
shown (middle). The steepest dose–volume histogram (yellow) is for the RA plan.
258 I. J. Radiation Oncology d Biology d Physics
Fig. 5. Results of quality assurance film measurements in patient F, showing excellent agreement between calculated dose
(red line) and measured dose (green line). Gamma analysis showed only very limited areas with a gamma greater than 1
(3% of whole-brain radiotherapy dose, 2 mm).
complication probability values (8). The advantages of
steeper dose gradients appear to be increased with the num-
ber of metastases and the size of metastases treated. Inte-
grated plans of WBRT and simultaneous boosts for brain
metastases have previously been described in planning stud-
ies for helical TomoTherapy (9, 10). RA treatment differs
from TomoTherapy by the simultaneous irradiation of the
entire target volume in contrast to the slice-by-slice delivery
of the latter. This is reflected in the difference in the beam-
on time, which was reported to be on the order of 8 minutes
for TomoTherapy (TomoTherapy Inc, Madison, WI) for this
indication (9).
QA film measurements of single RA plans in a solid water
phantom were performed for all plans. Despite maximum dif-
ferences between calculated and measured doses of up to
7.5% being observed in single-arc plans, the results were im-
proved for plans using two summated arcs. The mean gamma
values for the single- and double-arc plans were 0.50 and
0.30, respectively. Further improvements in the RA planning
algorithm may help to decrease the inaccuracies observed
with a single arc.
RA treatment has now replaced successive WBRT with ra-
diosurgery boost for patients with multiple brain metastases
at our center. Verification of calculated RA plans by use of
Volume 75, Number 1, 2009
phantom measurements is performed before treatment in all
cases, and dedicated online patient setup by use of kilovolt-
age cone beam CT is performed before each fraction. In the
first 3 patients RA treatment was well tolerated under cortico-
steroid protection, although it is too early to assess the effi-
cacy with respect to intracranial disease control.
Future improvements in RA delivery can be expected
shortly, when our Novalis Tx unit is commissioned by use
of micro-multileaf collimation with very low leaf transmis-
sion (<1.2% compared with 1.6% for the Millennium 120
MLC), as well as the ability to correct patient rotations by
use of a Robotics treatment couch (BrainLAB). A newer ver-
sion of RA software will allow for non-coplanar arcs or se-
lected arc ranges to be used, which may be desirable in
some cases (e.g., for avoiding beam directions where radia-
tion is transmitted through immobilization devices).
In conclusion, RA treatment planning of integrated WBRT
and simultaneous fractioned boost to multiple brain metasta-
ses results in highly conformal dose distributions. QA mea-
surements showed high agreement with calculated dose
distributions. Treatment delivery is feasible in a short
beam-on time on the order of 3 minutes. The clinical benefit
of this approach with respect to intracranial disease control
will be investigated in a Phase II study.
 RA for WBRT and boost to multiple metastases d F. J. LAGERWAARD et al.
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