Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients
Volumetric modulated arc therapy with flattening filter free beams for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in oligometastatic patients
Filippo Alongi 1
Antonella Fogliata 0
Elena Clerici 1
Pierina Navarria 1
Angelo Tozzi 1
Tiziana Comito 1
Anna Maria Ascolese 1
Alessandro Clivio 0
Francesca Lobefalo 1
Giacomo Reggiori 1
Luca Cozzi 0
Pietro Mancosu 1
Stefano Tomatis 1
Marta Scorsetti 1
0 Oncology Institute of Southern Switzerland, Medical Physics Unit , Bellinzona , Switzerland
1 IRCCS Istituto Clinico Humanitas, Radiation Oncology Dept , Rozzano-Milan , Italy
Background: SBRT is a safe and efficient strategy to locally control multiple metastatic sites. While research in the physics domain for Flattening Filter Free Beams (FFF) beams is increasing, there are few clinical data of FFF beams in clinical practice. Here we reported dosimentric and early clinical data of SBRT and FFF delivery in isolated lymph node oligometastatic patients. Methods: Between October 2010 and March 2012, 34 patients were treated with SBRT for oligometastatic lymph node metastasis on a Varian TrueBeam treatment machine using Volumetric Modulated Arc Therapy (RapidArc). We retrospectively evaluated a total of 25 patients for isolated lymph node metastases in abdomen and/or pelvis treated with SBRT and FFF (28 treatments). Acute toxicity was recorded. Local control evaluation was scored by means of CT scan and/or PET scan. Results: All dosimetric results are in line with what published for the same type of stereotactic abdominal lymph node metastases treatments and fractionation, using RapidArc. All 25 FFF SBRT patients completed the treatment. Acute gastrointestinal toxicity was minimal: one patient showed Grade 1 gastrointestinal toxicity. Three other patients presented Grade 2 toxicity. No Grade 3 or higher was recorded. All toxicities were recovered within one week. The preliminary clinical results at the median follow up of 195 days are: complete response in 12 cases, partial response in 11, stable disease in 5, with an overall response rate of 82%; no local progression was recorded. Conclusions: Data of dosimetrical findings and acute toxicity are excellent for patients treated with SBRT with VMAT using FFF beams. Preliminary clinical results showed a high rate of local control in irradiated lesion. Further data and longer follow up are needed to assess late toxicity and definitive clinical outcomes.
Abdominal/pelvic lymphnodes; VMAT; FFF
The detection of single or limited organ metastases,
defined oligometastases, has been recently increased by
advancements in imaging technology . In this subgroup
of cancer patients, local treatments for oligometastases
have been widely investigated for many cancers with the
objective to impact on disease control and survival . In
selected oligometastatic patients, surgical resection of
limited metastatic burden of disease prolongs survival [1,2].
However, the ideal candidates for local therapy are difficult
In this scenario, radiation treatments can play a role to
achieve local control of oligometastatic focal disease. As
smaller foci of metastases are defined, highly conformal
radiation therapy, such as Stereotactic Body
Radiotherapy (SBRT) or similar techniques, can prove to be less
invasive and more effective than surgery because of
decreasing morbidity, less costs and the potential of
delivering ablative doses on an outpatient basis. Emerging
data show that SBRT, in its various treatment modalities,
is a safe and efficient strategy to locally control multiple
metastatic sites . SBRT does not replace systemic
therapy but rather can augment its effects on focal areas
of gross disease, as well as metastatic lymph nodes.
Previous published experiences in our Institute have
shown how SBRT for abdominal targets resulted to be
feasible with good early local control rate and acute toxicity
profile . In particular, the medium-term clinical outcome
of hypofractionated SBRT seemed to be promising in a
series of patients with either a solitary metastasis or
oligometastases from different tumors to abdominal lymph
Recently, two new technological platforms have been
made available to clinical practice in radiation therapy
departments. Firstly, Volumetric Modulated Arc Therapy
(VMAT) in its RapidArcW format, allowed a significantly
time reduction to deliver complex intensity modulated
plans, permitting to treat with hypofractionated regimes
within few minutes [6-8]). Secondly, there has been
increasing interest into the clinical use of linear
accelerators (LINAC) with photon beams generated without
usage of the flattening filter [9-15]. It seems possible to
predict a reduction of out-of-field dose when flattening
filter free (FFF) beams are used. This is mainly related to
the reduced head scattering and the residual electron
contamination. FFF beams should therefore lead to
reduced peripheral doses and patients can benefit by
decreased exposure of healthy tissue to scattered doses
outside the radiation field. Removal of the flattening filter
implies also the possibility to deliver treatments with
higher dose rates, up to factor 4 at 10 MV, and with a
much higher dose per pulse. This, beside further
improving time efficiency for delivery, might have subsequent
potential radiobiology implications; now still unclear and
deserving dedicated investigations. While research in the
physics domain for FFF beams is increasing, there are
few clinical data where FFF beams are applied in clinical
practice, particularly in SBRT treatments .
Here we reported dosimetric and early clinical data of
SBRT with FFF in isolated lymph node oligometastatic
Between October 2010 and March 2012, a total of 34
patients were treated with SBRT for isolated lymph node
metastases in abdomen and or pelvis on a Varian
Beam treatment machine (Varian Medical Systems, Palo
Alto, CA, USA) using RapidArc technology. Twenty-eight
of those patients were treated with SBRT and FFF beams;
among them 3 were lost to follow-up. The following will
refer to this 25 patient cohort with follow-up, for a total of
28 treatments. Patient data were collected and
retrospectively analyzed. Table 1 summarized inclusion criteria and
Table 2 summarized demographic data of the population
of study. Patients were stratified for metastatic disease site
(abdominal or pelvic).
Dose prescription, simulation procedures and target
Prescription doses were 45 Gy in 6 consecutive fractions
of 7.5 Gy for all 28 treatments. The inclusion criteria
were: age 18years, WHO performance status 2,
histologically-proven of primary cancer disease, M1
stage with primary cancer site radically treated with
complete response/resection or stable, no other site of
disease in progression (a maximum of 3 lymph node sites
of disease to treat), diameter of lymph node Target less
than 5 cm, Abdomen/pelvic site, no previous surgery or
RT in the region to treat, obtained informed consent.
Chemotherapy, when prescribed, was interrupted from
20 days before the simulation to the first evaluation after
the end of SBRT treatment, as scheduled.
Table 1 Inclusion criteria
Histologically-proven of primary cancer disease
M1 stage with primary cancer site radically treated
with complete response/resection or stable.
No other site of disease in progression (a maximum
of 3 lymph node sites of disease to treat)
No previous surgery or RT in the region to treat
Table 2 Demographic patient and treatment data
Patient Gender (Nb of patients)
Tumour Primary (Nb of patients)
Biliary tract / pancreas
Metastasis site (Nb of treatments)
Nb of metastases (Nb of treatments)
CTV volume (cm3)
PTV volume (cm3)
Previous chemotherapy (Nb of patients)
17.421.0 (1.2, 103,8)
56.842.0 (9.6, 185.9)
Patient preparation for planning CT and each
treatment session foresees a 3-hour fast to avoid large
displacement of stomach and bowel during daily treatment
with respect to planning CT anatomy.
CT scans for planning were acquired for all patients in
supine position, with the arms above their head and
immobilized with a thermoplastic body mask including a
styrofoam block for abdominal compression to minimize
internal organ motion. Contrast free and
contrastenhanced CT scans were acquired in free breathing mode
at 3 mm slice thickness in the same patient treatment
position during the same acquisition session. The abdominal
compression was assessed in our clinic to adequately
minimize the internal motion, with 4DCT acquisitions in
some past cases to assess the residual movement being of
< 5mm. Such an immobilization is the standard in our
clinic for all stereotactic (or hypofractionated) abdominal
irradiations, without adding a 4DCT acquisition for ITV
(internal target volume) delineation.
The clinical target volume (CTV) included
macroscopic (for practical reasons, the gross tumor volume
GTV was not explicitely outlined) and microscopic
disease, based on CT as well as on PET imaging when
available. Set-up margin was minimised using the
conebeam CT (CBCT) verification before each treatment
session. The overall CTV to PTV (planning target volume)
margin was of 610 mm in all directions, based on
previous study on 4DCT acquisitions as mentioned above.
Margins were differentiated depending on the lesion
location. Since the residual internal organ motion was
limited due to abdominal compression, no planning organ
at risk volumes (PRV) was defined for any organ at risk
(OAR) nor included in the optimization process.
Prescription dose was defined as the mean dose to the
PTV, aiming to cover the PTV with 95% of the
prescribed dose. If organs at risk tolerance doses did not
allow that coverage, the prescription was then applied to
the mean dose to the CTV, aiming to cover the CTV
with 95% of the prescribed dose, and the PTV with 80%
of the same prescribed dose. Maximum dose was to be
kept below 107% of the prescription.
Main OAR considered were: stomach, duodenum,
small bowel, liver, spinal cord, kidneys. Plans were
required to meet the following physical dose objectives
(which account for the used fractionation):
SBRT planning and delivery procedure
Flattening filter-free (FFF) photon beams of nominal 6
or 10 MV from a Varian TrueBeam were used for all 28
treatments, using the maximum available dose rate of
1400 or 2400 MU/min (for 6 or 10 MV FFF,
respectively). Plans were individually set-up with the VMAT
using the RapidArcW technology. Full arcs were used in
9 cases, while for the other plans partial arcs setting was
chosen. Single arc was planned for only 4 cases, and
multiple arcs (mostly two) were preferred according to
patient anatomy and mutual PTV and OAR location in
order to obtain the best adherence to planning objectives
for each patient. All dose distributions were computed
with the Anisotropic Analytical Algorithm (AAA,
version 8.9) implemented in the Eclipse treatment planning
system (Varian). The jaw tracking option available for
TrueBeam facilities was applied during the optimization
phase. With this tool the main jaws are driven by the
control system to follow the actual minimum MLC
aperture during the arc delivery. For multiple lesions the
attempt was to keep one single isocentre, but the choice of
single or multiple isocentre was driven by the obtained
dose distribution in the two competitor plans. Only one
case of multiple lesions was treated with two isocentres.
Treatment was possibly delivered in 6 consecutive
working days. Treatment delivery was preceded by CBCT
image guidance with, whenever needed, on-line couch
adjustment. Image matching was performed on bony
structures and, when visible, on tumors and/or other soft tissue
structures (e.g. main blood vessels).
Prior to the first session, pre-treatment quality
assurance was performed using the MatriXX (IBA Dosimetry,
Shwarzenbruck, Germany) 2D array of ion chambers
(distance between detectors: 0.76 cm) placed in a PMMA
slab phantom. The dose at the detectors plane was
calculated with the same patient plan in the phantom and
compared with measurement. Evaluation was based on index,
with criteria of 3 mm and 3% as distance to agreement and
dose difference. Acceptability was set to 95% of the points
passing the threshold of <1.
Efficiency of the treatment was evaluated in terms of
beam on time, that is reduced by the usage of FFF
beams, allowing dose rates up to 2400 MU/min.
Evaluation of dosimetric data
The quantitative evaluation of plans was performed by
means of dosevolume histograms (DVH) data. For PTV
and CTV, the values of D99% and D1% (dose received by
99%, and 1% of the volume) were defined as metrics for
minimum and maximum doses; V95% (the volume
receiving at least 95% of the prescribed dose), homogeneity as
Standard Deviation parameter of DVH and D5%-D95%, as
well as the conformity index CI (defined as the ratio
between the patient volume receiving 95% of the prescription
dose and the PTV volume) were also reported.
For OARs, the analysis included the mean dose, the
maximum dose expressed as D1%, and a set of
appropriate VX(Gy) and DY(% or ccm) values.
Average cumulative DVH for PTV, CTV and OARs were
determined from the individual DVHs. These histograms
were obtained by averaging the corresponding volumes
over the whole patient cohort for each dose bin of 0.05 Gy.
Evaluation of clinical data
Patients had clinical evaluations planned before and
during the treatment, at the end of the last fraction. Then,
the first follow-up visit was scheduled, based on site and
general condition, within 45120 days from the end of
the treatment, then every 34 months, Acute toxicity
induced from the radiation treatment were scored and
recorded according to the National Cancer Institutes
Common Terminology Criteria for Adverse Events
(CTCAE version 3.0).
Local control was evaluated on CT images at the first
follow-up for all cases; patients who had a PET scan before
SBRT, the same metabolic examination and response were
also evaluated during the follow-up and scored according
PERCIST criteria. Local control evaluation was scored
according to the WHO criteria as complete remission
(CR), partial remission (PR), stable disease (SD) for each
treatment. Distant progression disease (PD) scored the
clinical results on possible lesions out of the local target.
Although obviously very early, a first assessment of
initial treatment outcome was performed at first and
second follow up visits.
Figure 1 illustrates two examples of dose distributions of
abdominal and pelvic lymph node treatments in axial,
sagittal and coronal views. Figure 2 presents the average
cumulative dose volume histograms for the PTV and the
involved organs at risk. Table 3 shows results from DVH
analysis for the analyzed structures.
We compared the present data using FFF beams with
previous dosimetric data of the same group, for the same
type of stereotactic abdominal lymph node metastases
treatments and fractionation with RapidArcW technology
. All dosimetric results are in line with what we
previously published without FFF, as reported in the last
column of Table 3 for the published data. The differences
between the two dataset are that they are based on a
different group of patients, and that the published data
refer to standard flattened beams, while the present
work reports on FFF results.
In particular a very highly degree of conformality is
available in the present study with FFF, with very high
volume fraction receiving the 95% of the dose
prescription: around 98 and 100% of the PTV and CTV
respectively. The PTV coverage was 90% for non-FFF beams.
For OARs, it was possible to respect the planning
objectives in all the cases, also the V36Gy for stomach,
duodenum and bowels. Dose reduction in the CTV to
PTV margin (requiring minimum dose to PTV higher
than 80% while keeping the 95% coverage for CTV) was
required for organs at risk tolerance dose in three cases.
Delivery accuracy determined by the pre-treatment
quality assurance was recorded, for the patients of this study,
as the percentage of the point passing the gamma criteria
of 3 mm/3%. The average of this value over all the patient
cohort was 99.20.5, with a range of 97.3-99.9. All cases
were carefully analysed, not only fixing the attention on
the number of gamma passing point, in the whole dose
map, and considered acceptable.
Arc delivery with FFF beams was with a maximum
of 2400 MU/min for 10 FFF beam, with an average
beam on time of 1.470.44 min [range: 0.82-2.02 min].
Figure 1 Dose colorwash from 50% dose level for an abdominal lymph node case (left) and a pelvic lymph node case (right).
For a comparison, the plans were delivered also with a
maximum dose rate of 600 MU/min, that is the usual
maximum dose rate available in normal linacs using
standard flattened beams. With this setting, the
average beam on time would have been 3.490.81 min [range:
2.52-5.72 min] and thus, for this dose per fraction, the
maximum dose rate of 2400 MU/min reduced the beam
on time more than 200%.
Clinical results as acute gastrointestinal GI toxicity as
well treatment outcome are summarized in numbers in
All 25 FFF SBRT patients completed the treatment, as
programmed, with no interruptions.
Acute gastrointestinal toxicity was minimal: one patient
showed Grade 1 gastrointestinal toxicity, as gastralgia.
Figure 2 Average DVH of the main structures on the whole patient cohort.
Table 3 Dose distribution statistics
Table 4 Toxicity and response results
Nb of patients (total 25)
At first Follow-up:
Nb of treatments (total 28)
Nb of treatments (total 28)
At median Follow-up of 152 months:
Three other patients presented Grade 2 toxicity, one with
gastric pyrosis, one with epigastralgia and one with nausea/
vomiting. No severe acute toxicity with Grade 3 or more
was recorded. All toxicities were recovered within one week
(G1 without intervention, G2 with symptomatic drugs).
No late toxicity, as per the rather short follow-up time,
The median follow-up was 195 days (range 48589
days). All patients had at least the first follow up at a
median of 92 days (minimum 47 days) from the end of
the radiation treatment.
At the first follow-up, early clinical outcome was
assessable at diagnostic evaluation of last control with PET
and/or CT in 25 patients (28 treatments). At the end of
the first follow-up evaluation, a complete response
(according to World Health Organization criteria) was
found in 11 cases. A partial response was achieved in 13
cases. The overall response rate was of 86% (24/28
treatments). Four patients had stable disease. No local
progression was found.
The results at the median follow up of 195 days (18
patients had a second follow-up) are: complete response
in 12 cases, partial response in 11, stable disease in 5,
with an overall response rate of 82%; no local
progression was recorded.
Of the patient cohort of this study, 6 presented distant
progressive disease (outside the treated region) at the
first follow-up. This number increase to 15 for the 195
median days follow-up.
Discussion and conclusions
Rationale of local therapy for oligomestases is that when
primary cancer is controlled, the solitary or few
metastases can be cured locally to effort systemic therapy [1,2].
Actually, few published data do exist on local control
rates of radiotherapy in the context of isolated or few
lymph node metastases. Although dose and fractionation
schedules are extremely heterogeneous, early data from
some recent series are promising in term of local control
rates . Because small volumes are irradiated for
metastatic lymph nodes, a dose escalation might improve
efficacy without prohibitive toxicity.
Most of reported experiences regarded oligometastatic
lymph node in pelvis or abdomen and are summarized
in Table 5.
The results of the current study with SBRT by RapidArcW
and FFF, at the median follow up of 195 days confirm a
response rate of 82% and no local progression was recorded.
Local control provided by the current initial experience
may be potentially significant for preserving quality of life
and delaying further systemic treatments. Obviously, the
most significant criticism remain: a) the heterogeneity of
the population of study, composed by a miscellaneous of
cases from different primary tumors (see Table 1) b) the
short follow-up (median of 195 days), c) the retrospective
nature of the study in patient data analysis. Nevertheless,
the end point of the study was to define the dosimetric and
early clinical results of SBRT by RapidArcW with FFF, and
this finding was largely confirmed: all plan objectives were
met and no toxicity were recorded in acute setting,
achieving an intial high rate of local control.
Concerning FFF beams, previous our report showed as
the treatment delivery with FFF beams for abdominal
lesion is faster and more efficient, improving patients
comfort and thus reducing intra-fraction motion,
characteristic that becomes particularly important in SBRT
. Some preliminary studies for SBRT using FFF
beams are present in literature [11,22] and in a recent
study performed in our institute it was described our
early experience in the use of FFF beams for SBRT
Table 5 Clinical details of published studies of SBRT for oligometastases lymph nodes
Choi et al. 
Kim et al. [19,20]
Bignardi et al. 
LC= local control; OS= overall survival.
33-45 Gy in 3 fractions
36/51 in 3/fractions
45 in 6 fractions
LC:67.4% at 4 years
OS:43% at 3 years
LC: 77,8% at 1 year
treatments including liver metastases, lung primitive and
metastases, isolated abdominal lymph nodes, adrenal
glands, and pancreas . Also in the present report,
acute toxicity profile was excellent: no severe acute
Grade 3 toxicity or more was recorded and all toxicities
(2 cases of Grade 1 and 3 cases of Grade 2) were
recovered within one week.
From the radiobiological point, some literature starts
to show that FFF beams, relatively to standard flattened
beams, have higher efficacy, possibly in reducing survival
fraction for the same delivered physical dose, due to the
higher dose per pulse of such beams (up to 4 times)
. This fact is today only a suggestion coming from
sparse laboratory studies on cell lines, and not yet
clinically proven in terms of patient studies. In principle the
improvement is present, but the increased cell killing
effect is rather minimal, so difficult to be proven at the
present stage with small clinical studies. To clinically
demonstrate the differences in cell killing effect between
standard beams and beams with high dose per pulse,
clinical trials should be set on a rather large scale. Also
the time factor, not only the dose per pulse, is known to
have a role the on radiation induced damage. This was
subject of different studies where, both on theoretical
bases and in vitro irradiations [24,25] it is demonstrated
that the shorter is the treatment session time, the higher
is the tumor control probability for the same physical
delivered dose. Although not yet clinically proven, all
those studies suggest the possible benefit in using FFF
beams, for which the present study can present a
From the technical viewpoint, a first point to underline
about such beams is the known reduction of peripheral
dose, coming from the absence of the flattening filter
that reduces the scattered dose from the linac head. To
enhance this effect, with the TrueBeam linac it is also
possible to allow the jaws to follow the MLC movement,
minimizing the field area shielded by only the MLC: this
option further reduces the dose in the proximity of the
target, potentially improving the dose fall-off toward the
critical structures and surrounding tissues. Technically
speaking, no specific study has been undertaken up to
now to systematically quantify the peripheral dose
reduction when using the jaw tracking option, as its
application is part of the optimization process, ending in
different MLC sequencing if the option is used or not.
As a second technical point to mention is the use of the
abdominal compressor to minimize the internal organ
motion. This was considered adequate in our institution,
but the possible use of 4DCT acquisition for ITV
delineation, in conjunction to the compressor, could be a
more precise solution to better include the motion
management, an essential point for SBRT in this anatomical
region. The 4DCT is indeed going to be included in our
next clinical studies for thoracic and abdominal
Considering these promising results, a prospective
study of dose escalation in 4 fraction of SBRT with FFF
beams for pelvic/abdominal lymph node oligometastatic
patients (genito-urinary and gynecology primary) was
recently proposed and accepted by internal ethical
committee of our Institute and preliminary results will be
reported in a further study.
L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Head of
Research and Technological Development at the Oncology Institute of
Southern Switzerland, Bellinzona. Other authors report no conflict of interest.
FA, MS and AF coordinated the entire study. Data collection and clinical data
analysis were conducted by FA, EC, PN, AT, TC, AMA, MS. Dosimetric data
collection and analysis were conducted by AF, AC, FL, GR, LC, PM, ST. All
authors read and approved the final manuscript.
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