Rev Esp Med Nucl Imagen Mol.

2016;35(6):373378

Original Article

A comparative study of target volume denition in radiotherapy with

Slow CT Scan vs. 4D PET/CT Scan in early stages of non-small cell
lung cancer
M. Molla a, , N. Anducas b , M. Sim c , A. Seoane b , M. Ramos a , G. Cuberas-Borros c , M. Beltran b ,
J. Castell c , J. Giralt a
a
Departamento de Oncologa Radioterpica, Hospital Universitario Vall dHebron, Barcelona, Spain
b
Departamento de Fsica Mdica, Hospital Universitario Vall dHebron, Barcelona, Spain
c
Departamento de Medicina Nuclear, Hospital Universitario Vall dHebron, Barcelona, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To evaluate the use of 4D PET/CT to quantify tumor respiratory motion compared to the
Received 2 December 2015 Slow-CT (CTs) in the radiotherapy planning process.
Accepted 2 February 2016 Material and methods: A total of 25 patients with inoperable early stage non small cell lung cancer (NSCLC)
were included in the study. Each patient was imaged with a CTs (4 s/slice) and 4D PET/CT.
Keywords: The adequacy of each technique for respiratory motion capture was evaluated using the volume denition
4D-PET/CT for each of the following: Internal target volume (ITV) 4D and ITVslow in relation with the volume dened
Lung cancer
by the encompassing volume of 4D PET/CT and CTs (ITVtotal).
Radiotherapy
Treatment planning
The maximum distance between the edges of the volume dened by each technique to that of the total
volume was measured in orthogonal beams eye view.
Results: The ITV4D showed less differences in relation with the ITVtotal in both the cranio-caudal and the
antero-posterior axis compared to the ITVslow. The maximum differences were 0.36 mm in 4D PET/CTand
0.57 mm in CTs in the antero-posterior axis.
4D PET/CT resulted in the denition of more accurate (ITV4D/ITVtotal 0.78 vs. ITVs/ITVtotal 0.63), and
larger ITVs (19.9 cc vs. 16.3 cc) than those obtained with CTs.
Conclusion: Planning with 4D PET/CT in comparison with CTs, allows incorporating tumor respiratory
motion and improving planning radiotherapy of patients in early stages of lung cancer.
2016 Elsevier Espana, S.L.U. and SEMNIM. All rights reserved.

Estudio comparativo en la denicin del volumen de tratamiento en

radioterapia con Slow TC Scan vs. 4D PET/TC Scan en estadios iniciales de
cncer de pulmn de clula no pequena

r e s u m e n

Palabras clave: Objetivos: Evaluar el uso de la 4D PET/TC para capturar el movimiento respiratorio en comparacin con
4D-PET/TC la slow-TC (TCs), en el procedimiento de planicacin de radioterapia.
Cncer de pulmn Material y mtodos: Se ha incluido a 25 pacientes diagnosticados de estadio inicial de cncer de pulmn
Radioterapia
de clula no pequena (NSCLC) mdicamente inoperable. A cada paciente se le realiz una TCs (4 s/corte)
Planicacin del tratamiento
y una 4D PET/TC.
La idoneidad de cada tcnica en la captura del movimiento respiratorio fue evaluada comparando el
volumen denido por cada una de ellas: internal target volumen (ITV) 4D y el ITVslow, con relacin a la
suma de los volmenes de la 4D PET/TC y la TCs (ITVsuma).
La mxima diferencia entre el volumen denido por cada tcnica respecto al volumen suma fue eva-
luada en una proyeccin antero-posterior y otra lateral.
Resultados: Los volmenes generados con 4D PET/TC consiguen una denicin ms precisa del ITV que los
volmenes obtenidos con TCs (ITV4D/ITVsuma 78% vs. ITVslow/ITVsuma 63%). En general, los volmenes
de la 4D PET/TC son de mayor tamano (19,9 vs. 16,3 cc).

Please cite this article as: Molla M, Anducas N, Sim M, Seoane A, Ramos M, Cuberas-Borros G, et al. Estudio comparativo en la denicin del volumen de tratamiento en
radioterapia con Slow TC Scan vs. 4D PET/TC Scan en estadios iniciales de cncer de pulmn de clula no pequena. Rev Esp Med Nucl Imagen Mol. 2016;35:373378.
Corresponding author.
E-mail address: meritxellmolla@gmail.com (M. Molla).

2253-8089/ 2016 Elsevier Espana, S.L.U. and SEMNIM. All rights reserved.
374 M. Molla et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(6):373378
El ITV4D muestra menor diferencia con el ITVsuma en los ejes crneo-caudal y antero-posterior respecto
al ITVslow y capta el movimiento de forma ms exacta. La mxima diferencia observada es de 0,36 mm
en la 4D PET/TC y de 0,57 mm en la TCs en el eje antero-posterior.
Conclusiones: La planicacin con 4D PET/TC en comparacin con TCs permite cuanticar el movimiento
respiratorio del tumor y mejorar la planicacin de radioterapia en estadios iniciales de NSCLC.
Introduction
The objective of treatment with radiotherapy (RT) is to admin-
ister the most accurate radiation dose to a tumoral zone, while
avoiding irradiation to surrounding healthy tissue.
The standard for including movement in external RT treatment
is based on the addition of a wide margin including the gross tumor
volume l (GTV) to ensure adequate coverage of the lesion.
Local relapse after radical RT in lung cancer has been reported
to be of up to 49%.1 The main cause of local relapse is non inclusion
of the tumor during irradiation due to inadequate imaging tools
or tumor movement during breathing.2 The size of the margins is a
crucial point in RT planning. Unnecessarily wide margins may cause
severe adverse effects and may not even allow the administration of
high doses of radiation whereas tight margins may leave part of the
tumor outside the eld of irradiation. In both cases, the possibility
of cure is reduced.
Computerized tomography (CT) images classically acquired for
RT planning are from an X-ray tube and a detector which turns at a
speed of one second/revolution. The mean duration of the respira-
tory cycle is of 26 s. Consequently, rapid CT acquisition might not
show all the area of the tumor along all the respiratory phases. One
solution to this problem is to increase the study time per slice. The
incorporation of slow-CT (sCT) to the acquisition of images at 4 s
per revolution allows the information of movement to be included
in the planning of lung tumors and reduce the GTV margins to the
planning volume.3,4
Later, the development of CT synchronically acquired with
breathing (4 dimension CT [4DCT]) allowed volumetric images to
be acquired in the different respiratory phases and thus, movement
can be characterized for planning.5,6 However, this technology is
not currently available in all radiation oncology departments.
The importance of internal organ movement in the denition
of target treatment volume led the International Commission on
Radiation Units and Mesurements to redene the planning volume
and introduce the concept of internal target volume (ITV).7
The incorporation of positron emission tomography to CT
(PET/CT) in treatment planning for lung cancer has played an
important role in improving RT treatment. On one hand, this
technique selects patients who are true candidates to curative
treatment or radical intention to treat by ruling out the presence
of unsuspected metastatic lesions in other territories. On the other
hand, PET/CT contributes to better denition of the tumor and less
inter-observer variability.8 Bradley et al.9 showed how PET/CT is
able to modify initial planning in up to 50% of the cases.
However, the images obtained by PET have limitations with
respect to their low spatial resolution, uncertainty regarding the
limits of the tumor and the lack of anatomical information.10
The aim of the present study was to evaluate the use of 4D PET/CT
to capture respiratory movement compared to sCT in RT treatment
planning.
Material and methods
The study included 25 patients diagnosed with T1-2N0 non
small-cell lung cancer (NSCLC) according to the classication of
the American Joint Committee on Cancer (AJCC). A committee
2016 Elsevier Espana, S.L.U. y SEMNIM. Todos los derechos reservados.
of experts had previously dened these patients as medically
inoperable. The standard criteria to dene these patients as such
include: basal forced expiratory volume in one second (FEV-1)
<40%, FEV-1 postoperatively predicted <30%, carbon monoxide
diffusion capacity <40%, basal hypoxemia or hypercapnia, severe
pulmonary hypertension, diabetes mellitus with severe organ dam-
age, and severe cardiovascular or cerebral disease.
The initial staging included a thoracoabdominal CT, cerebral CT,
PET/CT and brobronchoscopy.
For treatment positioning a conventional buttery chest immo-
bilizer was used.
Each patient underwent a planning CT, a sCT (4 s/slice) and a 4D
PET/CT with slices of 2.5 mm.
PET/CT study: acquisition of 4D PET/CT
The protocol of the PET/CT study required fasting of at least
6 h prior to intravenous administration of 3.7 MBq/kg of 18 F-FDG
(222370 MBq). Glucose levels were determined before admin-
istration of the radiotracer, being less than 150 mg/dL in all the
patients. None of the patients received either intravenous or oral
radiological contrast. Image acquisition was performed with a
Siemens Biograph mCT, which combines a 64-slice helicoidal CT
with a whole body PET scan. Data from the CT study were used for
attenuation correction of the PET images. The images were gener-
ated and interpreted in a Leonardo Siemens station equipped with
TrueD fusion software.
The images were qualitatively and quantitatively evaluated
according to the standard uptake value (SUV) obtained by 2 nuclear
medicine specialists and one radiologist. Lesions were considered
malignant based on their physiological activity and greater than
normal radiotracer uptake.
Breathing synchronized PET (4D PET) was then performed using
the Anzai system which uses a belt with a sensor placed on the chest
of the patient (supradiaphragmatic) to track breathing movement.
4D image acquisition included all of the thorax (12 beds according
to the patient) at 10 min/bed. The breathing cycles was divided into
8 phases. The nal results of the 4D PET study was therefore of 8
PET images, one from each phase of the breathing cycle.
All patients underwent a whole body PET and 4D PET study. In
one patient the 4D PET was repeated twice in the same session due
to irregularities in the registry of breathing movements.
Acquisition of slow CT (sCT)
Prior to the sCT a planning CT was performed. This was necessary
to calculate the distribution of the RT treatment dose and was done
using a helicoidal CT with the standard chest CT protocol of the
Radiology Department of 120 kV, 2.5 mm slices, pitch of 0.75 and
2 s of scan.
Axial sCT was performed in order to acquire the maximum vision
of the tumor in each patient with a chest CT protocol of 120 kV,
2.5 mm slices and 4 s of study (mean length of breathing cycle).
Both CT scans were done in a LightSpeed RT 4S model CT from
General Electric Medical Systems (GE), and both studies were auto-
matically fused in an Eclipse v.11 planner from Varian Medical
Systems.
 M. Molla et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(6):373378
ITV
GTV
b
Distance 0.25 cm
Distance 0.14 cm
Fig. 1. (a) Scheme of the distances measured between the volumes for each view. (b) Example of the measures for one patient, in pink and cyan. Yellow shows the volumes
of slowITV, 4D ITV and 4D ITV and ITVsum, respectively.
Volume delineation
To delineate the tumor contour in the 4D PET study we used
the Syngo TrueD software installed in a MultiModality WorkPlace
(Siemens) station. The GTV was initially delimited in the 8 phases
of the breathing cycle using 20% of the SUV max of the tumor as the
threshold for each phase. This threshold was the most reproducible
for the tumor size we evaluated. The internal target volume (4D ITV)
was constructed as the addition of the 8 GTVs of the breathing cycle.
The ITV was analogously delimited in the sCT in the pulmonary
window (slowITV).
The 4D PET/CT and sCT images were registered with the planning
CT. After having delimited the 4D ITV and slowITV in the plan-
ning CT, the sum of the volumes was calculated using the Boolean
algebra tool of the planning and calculation RT Eclipse v.11 sys-
tem of Varian Medical Systems. The ITVsum was then obtained to
dene the treatment target tumor volume including the breathing
movements tailored to each patient.
Finally, the planning volume was obtained with uniform expan-
sion of 1 cm from the ITV.
The patients were treated with 46 coplanar photon beams of
nominal energy of 6 MV. The dose prescribed was 6066 Gy admin-
istered in 2022 fractions.
Comparative study
In order to evaluate the suitability of each technique (sCT and 4D
PET/CT) when capturing tumor movement, the ITVs of each method
were compared with the ITVsum dened as the addition of the pre-
vious two. The volumes were calculated in cubic centimeters (cm3 )
using the tools of the Eclipse system.
375
Distance 0.08 cm
Distance 0.19 cm
To determine the proportion to which the volumes of each
method are adjusted to the sum volume, the quotient between the
ITV of each technique and the ITV sum was evaluated.
In order to check the coincidence of the edges of the volumes
in the 3 main axes, the maximum difference (dmax ) between the
borders of each ITV was obtained with the ITVsum in one ante-
riorposterior and another lateral direction (Fig. 1). This distance
provides an idea of the margin to be amplied by the ITV of each
method to cover all the movement described with the ITVsum.
All the results are expressed as mean standard deviation (SD),
except when indicated otherwise.
Statistical signicance was veried by calculating the p value
which rules out the null hypothesis (H0 ) that conrms the absence
of an association between 2 variables studied and accepts the alter-
native hypothesis (H1 ) that indicates a possible relationship or
association between the 2 variables. The p value was obtained using
the bilateral Students t test for samples with different variance
with a condence interval of 95% (CI 95%). Thus, a p value < 0.05
was considered to be statistically signicant.
Results
We analyzed 25 patients (3 females and 22 males) from February
2013 to August 2014. The mean age of the patients included was
73 years (5586). Table 1 shows the characteristics of the patients
and the tumors.
Comparison of volume quotients
Table 2 shows the ITV volumes of each technique and the ITV-
sum of each patient. The average of the volumes obtained with the
376 M. Molla et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(6):373378

Table 1 ITV/ITVsum
Characteristics of the patients and the tumors. 1.0
4D ITV/ITVsum
Characteristics Value Slow mean

Volums quotients
0.8
Age (years) 4D mean
Mean 73 0.6
Range 5586
0.4
Sex, N (%)
Male 22 (88)
0.2
Female 3 (12)

Tumor volume (mm) 0.0

0 5 10 15 20 25
Mean 25
Range (1050) patients

Disease, N (%) Fig. 2. Graph of the slow ITV/ITVsum quotients. 4D ITV/ITVsum and the measures
Adenocarcinoma 8 (32) of the ratio for the 25 patients studied.
Squamous carcinoma 12 (48)
Others 2 (8)
Not veried 3 (12) 4D PET/CT was 19.9 cc3 , being 16.3 cc3 for the sCT. There were no
Stage, N (%) signicant differences between the ITV volumes of the two tech-
T1N0 13 (52) niques (p = 0.506). However, the volume determined by 4D PET/CT
T2N0 12 (48) showed a trend to being higher. In addition it was of note that the
Tumor lLocalization, N (%) difference between the volumes determined by the two techniques
Central 4 (16) was very marked in several patients.
Peripheral 21 (84) On the other hand, the ITV/4D/ITVsum value was 0.78 0.18
Localization by lobes, N (%) while the result of slowITV/ITVsum was 0.63 0.24. This indicates
Upper right lobe 8 (32) that the volumes generated with 4D PET/CT were mainly higher
Lower right lobe 4 (16)
than those delineated in the sCT, and thus, tumor movement was
Upper left lobe 3 (12)
Lower left lobe 10 (40) better detected with 4D PET/CT images. The SD was also lower for
4D PET/CT than for sCT similar to what is usually observed in the
most consistent techniques (Fig. 2).

Maximum difference between the borders of the ITV and the

Table 2 ITVsum
Volume of the ITV in cubic centimeters (cc3 ) delineated with the slow CT technique
(ITVslow), with 4D PET/CT (4D ITV) and the sum volume of the previous 2 (ITVsum)
of the 25 patients studied.
Table 3 shows the maximum distance between the borders of
each ITV (4D ITV and slowITV) and the ITVsum for each axis.
Patient Volume (cc3 ) The separation between the borders of the ITV in the
ITVslow 4D ITV ITVsum sCT technique was 0.54 0.61 cm in the cranialcaudal axis,
1 2.40 3.60 4.04
0.22 0.24 cm in the leftright axis and 0.57 0.49 cm in the
2 38.50 43.00 49.50 anteriorposterior axis, with these values being 0.26 .33;
3 19.80 45.50 49.67 0.35 0.43 and 0.36 0.42 cm, respectively with 4D PET/CT.
4 5.20 27.10 27.46 The ITV of the 4D PET/CT shows a lower difference with the
5 8.40 12.30 13.95
ITVsum in the cranialcaudal (p = 0.046) and anteriorposterior
6 5.20 4.10 6.03
7 5.80 2.00 6.07 axes (p = 0.113) than the slowITV, contrary to the leftright axis
8 20.60 11.30 23.10 (p = 0.171). Only the difference of the cranialcaudal axis was sig-
9 5.50 5.30 7.47 nicant with a p < 0.05. These results show that 4D ITV captures
10 26.40 33.60 40.04 movement more accurately in the cranialcaudal axis, particularly
11 16.80 18.40 23.01
with regard to tumor movement in lung cancer.
12 19.50 15.00 25.27
13 2.00 2.10 3.13
14 45.20 84.60 87.35 Discussion
15 73.50 56.20 86.80
16 40.40 24.90 41.68
17 2.10 2.10 3.18 One of the causes of local recurrence post-radical radiotherapy
18 1.10 3.90 4.16 in patients with medically inoperable NSCLC is due to incom-
19 5.90 6.60 10.29 plete irradiation to the whole tumor volume because of breathing
20 11.60 29.10 30.35
movement.11 One of the methods to minimize this error is to
21 2.00 1.50 2.35
22 0.30 2.30 2.40 include sCT in the RT planning.3,12
23 14.60 20.40 20.83 The present study evaluated the utility of 4D PET/CT in
24 3.70 14.30 14.30 improving complete description of tumor mobility in RT planning
25 30.90 29.30 37.80 compared to the sCT method used up to now in our usual clinical
practice.
Mean (cc3 ) SD (cc3 )
The main observations of the study were: rstly, overall tumor
16.30 17.86 19.94 20.50 24.81 24.13 volume is greater with 4D PET/CT vs. sCT. The differences in volume
were not statistically signicant, with a p value greater than 0.05.
p
This may be because the magnitude of difference was not suf-
ITVslow vs. ITV4D 0.506 ciently large or due to the small number of patients included in the
study. In 9 cases the tumor volume of the sCT was greater than that
with 4D PET/CT, although the difference was greater than 1.5 cc3 in
 M. Molla et al. / Rev Esp Med Nucl Imagen Mol. 2016;35(6):373378 377

Table 3
Maximum difference and mean between the borders of sum volume (ITVsum) and ITVslow and ITV4D in the 25 patients studied.

Patient dmax (cm)

ITVsum ITVslow ITVsum ITV4D

Cranialcaudal Leftright Anteriorposterior Cranialcaudal Leftright Anteriorposterior

1 0.24 0.14 0.32 0.20 0.10 0.08

2 0.70 0.6 0.43 0.00 0.41 0.00
3 1.24 0.65 1.83 0.00 0.00 0.00
4 2.55 0.95 0.99 0.00 0.18 0.00
5 0.00 0.37 0.80 0.24 0.49 0.13
6 0.52 0.35 0.36 0.24 0.29 0.00
7 0.00 0.00 0.19 0.99 0.40 0.65
8 1.46 0.00 0.00 0.25 1.38 0.58
9 0.00 0.24 0.48 0.03 0.38 0.45
10 0.00 0.30 1.31 0.07 0.12 0.64
11 0.24 0.34 0.15 0.24 0.00 0.34
12 0.00 0.00 0.18 0.53 0.69 0.55
13 0.00 0.18 0.57 0.23 0.12 0.50
14 1.27 0.54 0.82 0.00 0.00 0.24
15 1.18 0.00 0.00 0.00 1.68 1.64
16 0.23 0.00 0.00 1.00 0.94 0.40
17 0.46 0.10 0.34 0.50 0.23 0.18
18 0.29 0.27 0.96 0.00 0.00 0.00
19 0.75 0.00 0.59 0.80 0.51 1.43
20 0.71 0.22 1.33 0.00 0.34 0.00
21 0.00 0.16 0.00 0.28 0.07 0.27
22 0.54 0.40 0.76 0.00 0.07 0.05
23 0.23 0.00 0.19 0.00 0.08 0.30
24 0.70 0.12 1.23 0.00 0.00 0.00
25 0.25 0.00 0.30 0.78 0.33 0.47

Mean SD (cm) Mean SD (cm)

0.54 0.62 0.22 0.24 0.57 0.49 0.26 0.33 0.35 0.43 0.36 0.42

Cranialcaudal 0.046 Left 0.171 Antpost 0.113

only 6 cases. One explanation for this may be the possible variabil-
ity in the coregistry of the planning CT with the CT of the 4D PET/CT
which was carried out manually in the RT planner. Another cause
may be the denition of metabolic tumor volume by 4D PET/CT in
small sized lesions since in 4 of the 6 cases the volume was less
than 2 cc3 .
Secondly, the denition of ITV by 4D PET/CT was more con-
sistent with 78% vs. 63% of the volume being captured with the
sCT. The differences were smaller and statistically signicant in the
cranialcaudal axis for the 4D ITV and ITVsum, thereby demonstrat-
ing that tumor movements are better characterized by 4D PET/CT,
and the possibility of excluding tumor volume in the treatment bed
can be reduced with RT.
Finally, this technique allowed more accurate inclusion of
tumor movement in the treatment volume with margins less than
0.36 mm in all the axes vs. 0.57 mm with sCT.
The procedure is well tolerated and could be implemented with-
out additional equipment. At present, RT planning is currently
performed directly in the 4D PET/CT without the need for an addi-
tional sCT.
Other authors have studied the role of 4D PET in RT planning.
Aristophanous et al.13 analyzed 22 lung tumors for planning with
3D vs. 4D PET and found better denition of the extension of move-
ment with 4D, reduced blurriness of the image during breathing,
and also obtained additional information of lymph node status.
Lamb et al.14 proposed the generation of the PET maximum
intensity projection (MIP) as a technique to quantify and include
breathing correlated with the information of the PET for RT plan-
ning. The information obtained from the MIP-PET provided more
accurate delimitation of the treatment volume, especially in tumors
close to very mobile structures such as the heart, diaphragm and rib
wall. Likewise, MIP-PET allows the tumor zone to be distinguished
from lung collapse in central tumors causing obstructive atelectasis.
Several studies have compared the denition of lung tumor
treatment volume of 3D vs. 4D PET/CT and have reported that 4D
PET/CT reduces the risk of not including the whole tumor volume
during irradiation due to movement.15
This individualized method of volume delineation based on the
breathing motion of each patient would reduce unnecessary mar-
gins to include the whole tumor volume during irradiation, taking
into account the imaging verication tools of each center.16,17
New treatments with hypofractionated RT and stereotactic body
RT (SBRT) with elevated doses of radiation within a short period of
time allow excellent local disease control of 97.6% at 3 years.18 For
implementation these techniques require an accurate method of
movement inclusion or control of the treatment volume to ensure
correct treatment.19 It is essential to incorporate the best technique
available in each hospital in order to generate a correct ITV and
ensure the success of RT treatment.
In conclusion, compared with sCT planning, planning with
4D PET/CT better denes tumor movement during breathing and
improves RT planning in patients with early stages of NSCLC.
Conict of interests
All the authors have approved the manuscript and declare no
conict of interests.
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