European Journal of Surgical Oncology xxx (2018) 1e6

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European Journal of Surgical Oncology

journal homepage: www.ejso.com

What a difference a clip makes! Analysis of boost volume definition in

radiation therapy for conservative breast surgery
Thiago Brasileiro de Freitas a, Kennya Medeiros Lopes de Barros Lima a,
Heloísa de Andrade Carvalho b, c, Patricia de Azevedo Marques d,
Fabio Teixeira Belfort Mattos d, Alexandre Siqueira Franco Fonseca d,
Alexandre Mendonça Munhoz d, e, Jose
Roberto Filassi f, Silvia R. Stuart b,
g , c, *
Gustavo Nader Marta
a
Department of Radiology and Oncology, Division of Radiation Oncology, Faculdade de Medicina da Universidade de Sa ~o Paulo, Sao Paulo, Brazil
b
Department of Radiology and Oncology, Division of Radiation Oncology, Instituto de Radiologia (INRAD), Faculdade de Medicina da Universidade de Sa ~o
Paulo, Sa~o Paulo, Brazil
c
Department of Radiation Oncology, Hospital Sírio-Liban^ es, Sao Paulo, Brazil
d ~o Paulo, Faculdade de Medicina da Universidade de Sa
Department of Plastic Surgery, Division of Breast Reconstruction, Cancer Institute of Sa ~o Paulo, Sa
~o
Paulo, Brazil
e
Division of Plastic Surgery, Hospital Sírio-Liban^ ~o Paulo, Brazil
es, Sa
f
Department of Obstetrics and Gynecology, Faculdade de Medicina da Universidade de Sa ~o Paulo, Sa
~o Paulo, Brazil
g
Department of Radiology and Oncology, Division of Radiation Oncology, Instituto do Ca ^ncer do Estado de Sa
~o Paulo (ICESP), Faculdade de Medicina da
Universidade de Sa ~o Paulo, Sao Paulo, Brazil

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

Article history: Purpose/objective(s): To evaluate the role of surgical clips placement in the definition of boost treatment
Accepted 11 June 2018 volume.
Available online xxx Materials/methods: Clinical Target Volumes (CTV) were defined as: CTV Breast, CTV Quadrant (based on
physical exam and pre-surgical images), CTV Boost, defined by clip plus margin (1 cm for 2 or more clips
Keywords: and 2 cm for 1 clip only) plus radiological changes, CTV NT (normal tissue), defined by CTV Quadrant
Breast cancer
minus CTV Boost and CTV MISS (CTV that would be outside the treatment volume), defined by CTV Boost
Radiation therapy
minus CTV Quadrant.
Boost
Surgical clips
Results: A total of 247 patients were included. Upper lateral quadrant was the most common clinical
Breast conserving surgery location (47.3%). The median number of clips used was three. The mean volumes were: CTV
Breast:982.52 cc, CTV Boost:36.59 cc, CTV Quadrant:285.07 cc, CTV NT:210.1 cc and CTV MISS:13.57 cc.
Only 50.6% (125) of the patients presented the CTV Boost completely inside the CTV Quadrant and in
47.3% (117), partially inside. Among patients with any CTV MISS, 80.3% (98) had 10% or more of CTV Boost
outside the treatment volume. Regarding CTV MISS, there were no statistically significant differences
between the groups with 1 clip versus 2 or more clips, nor between patients with or without recon-
structive surgery. In average, the CTV Boost was 87% smaller than the CTV Quadrant. The whole quadrant
irradiation would lead to unnecessary irradiation of 26% of normal breast tissue.
Conclusion: Surgical bed clipping is up most important in the definition of the boost volume irradiation
to ensure precision minimizing geographical miss and optimizing surrounding normal tissue sparing.
© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical
Oncology. All rights reserved.

Andrade Carvalho), marques.patricia307@gmail.com (P. de Azevedo Marques),

* Corresponding author. Department of Radiology and Oncology, Division of Ra-
fabio.belfort@hotmail.com (F.T. Belfort Mattos), dr.alexandre@vivermelhor.com.br
diation Oncology, Instituto do C^
ancer do Estado de S~ ao Paulo (ICESP), Faculdade de
~o Paulo. Av. Dr. Arnaldo, 251 e Cerqueira Ce
sar, Sa
~o (A.S. Franco Fonseca), alexandremunhoz@hotmail.com (A.M. Munhoz), ffilassi@
Medicina da Universidade de Sa
terra.com.br (J.R. Filassi), silviastuart@me.com (S.R. Stuart), gustavo.marta@hc.fm.
Paulo, SP, 01246-000, Brazil.
usp.br (G.N. Marta).
E-mail addresses: vjbrasileir@gmail.com (T.B. de Freitas), kennyamedeirosl@
gmail.com (K.M. Lopes de Barros Lima), heloisa.carvalho@hc.fm.usp.br (H. de

https://doi.org/10.1016/j.ejso.2018.06.010
0748-7983/© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Please cite this article in press as: de Freitas TB, et al., What a difference a clip makes! Analysis of boost volume definition in radiation therapy for
conservative breast surgery, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.06.010
2 T.B. de Freitas et al. / European Journal of Surgical Oncology xxx (2018) 1e6
Introduction
Breast cancer is the most frequent malignancy in women, dis-
regarding non-melanoma skin cancer, corresponding to about 25%
of newly diagnosed cancer cases annually worldwide [1].
The impact of breast conserving surgery in early breast cancer
started to be studied in the 70's. Since then, the oncological safety
of the association of breast conserving surgery followed by whole
breast irradiation has been proved, with similar results in terms of
overall survival compared to radical mastectomy. This approach
became a consensus during the 90's in the medical community [2].
At that time, several studies evaluated the radiation dose
enhancement (boost) in the tumor bed, since most relapses
occurred in that area. Romestaing et al. randomized 1024 patients,
with early breast cancer (less than 3 cm) who had undergone breast
conserving surgery and whole breast irradiation (50 Gy), to receive
10 Gy electron boost dose in tumor bed versus observation. After 5
years, less local recurrences were observed among patients in the
boost group (4.5% versus 3.6%; p ¼ 0.044) [3].
Similarly, the EORTC group confirmed the local control benefit.
They randomized 5318 patients in two groups after whole breast
irradiation: additional 16 Gy boost dose versus observation [4].
After 10 years of follow-up, the boost group presented lower local
recurrence when compared to the observation arm (6.2% versus
10.2%; p < 0.0001). In a subgroup analysis, local control was higher
in patients with 40 years or less [5].
In general, the boost volume delineation is based on pre-surgical
(clinical examination, mammography, ultrasonography and mag-
netic resonance) and post-surgical (seroma/hematoma palpation,
scars, surgical clips and tumor bed changes in images) information.
The most common challenge is surgical bed definition especially in
patients underwent to oncoplastic surgery.
Landis et al. showed that in situations where the surgical bed
definition was not clear, there was agreement in only 57% of the
planning target volume (PTV) boost volumes delineated by
different physicians, regarding the same planning tomography (CT)
[6]. Other authors showed the importance of the surgical clips in
the boost volume delineation [7,8], improvement of tumor bed
coverage and reduction of normal tissue irradiation [9,10].
However, the surgical bed clipping in breast conserving surgery is
not a worldwide systematic practice, leading to a major difficulty in
the definition of the boost volume. In practice, when the surgical bed
is not marked, to compensate for uncertainties, the boost dose is given
to the whole quadrant (tumor pre-surgical clinical location) [8].
In the last years, after a continuous and persistent discussion
about the importance of marking the tumor bed with the breast
and plastic surgeons at our hospital, patients submitted to con-
servative surgery due to breast cancer have their surgical bed
marked with clips. This strategy raised a few questions regarding
the period where clips were not routinely used for this purpose and
that may reflect a situation, still present nowadays in many de-
partments, where no markers are placed: are we missing the boost
target? If so, how much? Is irradiation of the whole quadrant
adequate when surgical clips are absent? How much normal tissue
are we unnecessary irradiating? Breast reconstruction can impact
in the surgical bed coverage? Thus, the purpose of this study was to
try to answer these questions.
Materials and methods
This was a retrospective study of all patients with breast cancer
treated between 2015 and 2016 at our institution, who underwent
breast conserving surgery with clipping of the tumor bed. Radiation
therapy simulation CT images of each patient were reviewed and
the boost volumes were contoured by two radiation oncologists (TF
Please cite this article in press as: de Freitas TB, et al., What a difference a clip makes! Analysis of boost volume definition in radiation therapy for
conservative breast surgery, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.06.010
and KL). Five clinical target volumes (CTV) were defined, using two
contouring softwares available in our institution (Eclipse™ Treat-
ment Planning System e Varian Medical Systems and Monaco®
Treatment Planning System e Elekta Medical Systems).
1) CTV breast: following RTOG consensus [11]:
- cranial border: clinical reference plus second rib insertion
- caudal: clinical reference plus loss of CT apparent breast
- lateral: clinical reference plus mid axillary line typically
- medial: sternal-rib junction
2) CTV quadrant: defined by clinical tumor location (physical
exam/palpation, mammography/ultrasonography image data).
The nipple was used as a central reference point to delineate the
quadrants, as seen in Fig. 1. In the absence of the nipple, the
central reference point was the intersection of the craniocaudal
and transversal diameters in the center of CTV Breast. Each
radius was divided in two equal segments by a perpendicular
line, so each quadrant was divided in four numbered areas. This
allowed the definition of CTV Quadrant when the tumor was
located at the border of the quadrants (i.e.: junction of upper
quadrants represented in Fig. 1 by numbers 2, 3, 6 and 7).
3) CTV boost: the clips were contoured and 1 cm (in patients with
2 or more clips) or 2 cm (in patients with only one clip) sym-
metrical margins were added to define the CTV Boost volume.
Seromas, hematomas, or other imaging related alterations were
included in the volume.
4) CTV normal tissue (CTV NT): defined as the result of the sub-
traction of CTV Boost from CTV Quadrant (CTV Quadrant e CTV
Boost). This volume measured the normal tissue that would be
unnecessary irradiated, if the whole quadrant was included in
the boost volume.
5) CTV MISS: this volume represented the potential geographical
miss of the surgical bed when only the affected quadrant was
delineated. It was calculated by the subtraction of the inter-
section volume between CTV Boost and CTV Quadrant from CTV
Boost as described by the formula:
CTV MISS ¼ CTV Boost e (CTV Boost ∩ CTV quadrant)
All contours were cropped from the skin surface, muscles and
chest wall.
Examples of contouring CTV Boost and CTV Quadrant are pre-
sented in Fig. 2.
To avoid the possible differences in the positioning of the clips in
the tumor bed between different surgeons all surgeons followed
the same protocol to placement of surgical clips: the clips were
allocated into the surgical cavity after tumor resection and were
subsequently sutured to the mammary parenchyma to avoid clips
migration.
The potential geographical miss according to the number of
surgical clips and the performance or not of a reconstruction sur-
gery was evaluated by comparing CTV MISS volumes between pa-
tient groups: 1 clip versus 2 or more clips, and with or without
oncoplastic surgery. The Mann-Whitney Rank-Test was used to
compare the groups volumes and respective means. Statistical
analysis was performed with the software SigmaPlot v.11.0® with
the significance level set as 5% (p value < 0.05).
Results
In the studied period, 247 patients were selected. The median
age was 58 years (range 32e87), 81.0% presented invasive carci-
noma (not otherwise specified), 81.8% positive estrogen receptor,
76.1% positive progesterone receptor, 89.9% HER-2 negative, 88.2%
Tis, T1 or T2, 92.9% N0-N1. Only 12.1% underwent oncoplastic
 T.B. de Freitas et al. / European Journal of Surgical Oncology xxx (2018) 1e6 3

Fig. 1. Definition of quadrant volumes. LAT: lateral; MED: medial; ULQ: upper lateral quadrant; UMQ: upper medial quadrant; LLQ: lower lateral quadrant; LMQ: lower medial
quadrant; JUQ: junction of upper quadrants; JLQ: junction of lower quadrants; JLLQ: junction of lateral quadrants; JMQ: junction of medial quadrants; CP: central portion.

surgery. The most prevalent clinical location of the breast cancer
was the upper lateral quadrant (47.36%). The median number of
clips that were used was three (Table 1). The mean volumes were:
CTV Breast: 982.52 cm3 (267.20e2357.49), CTV Quadrant:
285.07 cm3 (41.80e892.06), CTV Boost: 36.59 cm3 (7.00e105.12),
CTV MISS: 13.57 cm3 (0.10e44.25), and CTV Normal Tissue:
210.10 cm3 (23.70e865.24). Of the 247 patients, 122 (49.3%) had
some surgical bed volume loss when the whole quadrant was
contoured and in 2%, the CTV Boost was completely outside the CTV
Quadrant. Among the patients with any geographical miss (122
patients), the mean CTV MISS volume was 13.57 cm3. When not
considering the clips, only 19.67% of the patients would have less
than 10% volume loss.
There were no statistically significant differences in CTV MISS
volume when comparing the patient groups with one versus 2 or
more clips (p ¼ 0.283) and the groups with or without oncoplastic
surgery (p ¼ 0.290) (Table 2).
When considering the occurrence or not of any geographic miss,
104 (47.9%) patients without reconstruction surgery presented
some geographical miss, compared to 18 (60.0%) submitted to
breast reconstruction (p ¼ 0.215, Chi-Square test). Still considering
only the 122 patients with any miss, those with breast recon-
struction presented similar volume loss (CTV MISS) as those
without reconstruction, respectively, 13.84 (±11.33) cm3 and 11.98
(±7.99) cm3 (p ¼ 0.826, Mann Whitney Rank Test).
Table 3 shows that there was 86.64% of agreement between tu-
mor pre-surgical location (CTV Quadrant) and boost location (CTV
Boost). To evaluate the level of agreement between the volumes
location, the Kappa test was applied and demonstrated a strong level
of agreement classified as “almost perfect” with 0.826 [12].
Discussion
Although some studies have already assessed the importance of
the surgical clips in the boost volume definition in radiation ther-
apy of breast cancer patients, to the best of our knowledge, our
study is the largest addressing the impact of surgical clips in the
boost area definition [10,13,14].
Benda et al. [10] selected 30 patients that underwent CT simu-
lation for postoperative radiation treatment planning and
compared two techniques of boost volume definition: electron
boost volume (EBV) generated from clinically palpable tumor bed
or surgical scar plus defined margin and PTV generated from sur-
gical clips and radiological changes plus defined margin. Only 51%
of the PTV received 90% or more of the prescribed dose when EBV
was used (p < 0.0001). Moreover, a high amount of normal tissue
received more than 50% of the prescribed dose. Thus, the authors
recommended the use of surgical clips and CT for delineation and
treatment planning.
In the study of Bedwinek [13], 35 patients had surgical clips
placed in the excision cavity at the time of tumor excision. The
boost field locations were determined by encompassing the sur-
gical induration or surgical scar with defined margin. In X-ray
simulation images, in 54% of patients the surgical clips were outside
of the boost fields.
Machtay et al. [14], also concluded that the use of scars is often a
poor indicator of the location of the tumor bed, compared to the
definition from surgical clips.
In addition, the use of three or more clips ensured more accu-
racy in surgical bed volume delineation as observed by Kirova et al.
[15]. The authors compared the intersection volume of pre-surgical
tumor volume and postoperative volume defined by surgical clips.
The superposition volume was significantly larger in patients with
three or more clips versus only two clips (35.45% vs 0.73%,
p ¼ 0.028).
Nevertheless, mainly in middle and underdeveloped countries,
the use of surgical clips in breast conserving surgery is still incip-
ient, making the ideal delineation of the surgical bed difficult.
Moreover, cosmesis is an important issue in some countries and
usually the surgical cavity is either closed or corrected with breast
tissue rotations or flaps, making the boost location even more
difficult to be identified. In most cases, to compensate for the un-
certainties, the whole quadrant, based on pre-surgical information
of tumor location, is irradiated in the boost phase. Therefore, we
decided to develop a study to analyze the efficacy and assurance of
the whole quadrant irradiation. Interestingly, in our study, in only
half (50.6%) of the patients the CTV Boost was totally included in
CTV Quadrant, allowing an appropriate dose coverage. Stratifying
in percentages of boost volume loss, defined by the formula (CTV
MISS/CTV Boost *100), in more than 80% of the patients the loss was

Please cite this article in press as: de Freitas TB, et al., What a difference a clip makes! Analysis of boost volume definition in radiation therapy for
conservative breast surgery, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.06.010
4 T.B. de Freitas et al. / European Journal of Surgical Oncology xxx (2018) 1e6

Fig. 2. Examples of contouring: a) CTV Boost totally inside of the CTV Quadrant; b) CTV Boost partially inside of the CTV Quadrant; c) CTV Boost totally outside of the CTV Quadrant.
Surgical clips: purple; CTV Breast: orange; CTV Quadrant: yellow; CTV Boost: pink; CTV Boost minus CTV Quadrant: cyan (in b).

expressive (10% or more) (Table 2). This shows that in the absence
of surgical clips, the whole quadrant irradiation does not warrant
ideal surgical bed coverage in the boost phase. Furthermore, a large
amount of normal tissue would be unnecessary irradiated in this
case (25.2% of normal tissue in relation to CTV Breast volume).
Not considering the volumes, but only the correlations of CTV
Quadrant and CTV Boost locations, there was a good level of
agreement (Kappa test ¼ 0.826), showing that the pre-surgical
information (clinical and radiological) were efficient in predict
the tumor location, although not the geographical miss.
Goldberg et al. [8] compared the boost volume definition by
surgical clips versus CT-based definition, showing the importance
of integration of CT information in the boost field planning. Addi-
tionally, they observed a larger distance between the geometric
centers in the coronal plane and the tumor bed center in patients
with a single clip when compared to those with multiple clips
(p < 0.025), which means that more uncertainties are expected in
delineation with a single clip.
On the other hand, besides the fact that the mean CTV MISS
volume was larger in the group with only one clip, there were no
significant differences between the patients with only one versus
two or more clips, in relation to CTV MISS (p ¼ 0.283). The greater
margin applied to the one clip group (2 cm margin versus 1 cm)
might have compensated for the uncertainties generated by the

Please cite this article in press as: de Freitas TB, et al., What a difference a clip makes! Analysis of boost volume definition in radiation therapy for
conservative breast surgery, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.06.010
 T.B. de Freitas et al. / European Journal of Surgical Oncology xxx (2018) 1e6 5

Table 1 Table 3
Characteristics of the tumors and reconstruction surgery in the 247 patients. Relation between boost location and tumor pre-surgical location (Correlation Kappa
test ¼ 0.826).
Characteristic Number (%)
Pre-surgical location Total
Histology
Invasive carcinoma 200 (80.97%) ULQ UMQ LLQ LMQ RAR JUQ JLQ JMQ JLLQ
Lobular invasive carcinoma 15 (6.07%)
Boost location
Other 32 (12.95%)
ULQ N 95 0 0 0 0 0 0 0 0 95
Estrogen receptor
% 81.2 0 0 0 0 0 0 0 0 38.5
Positive 202 (81.78%)
UMQ N 4 25 0 0 0 1 0 0 0 30
Negative 45 (18.21%)
% 3.4 96.2 .0 .0 .0 3.8 0 0 0 12.1
Progesterone receptor
LLQ N 0 0 4 0 0 0 1 0 0 5
Positive 188 (76.11%)
% 0 0 66.7 .0 .0 .0 14.3 0 0 2
Negative 59 (23.88%)
LMQ N 0 0 0 19 0 0 0 0 0 19
HER-2 receptor
% 0 0 0 82.6 0 0 0 0 0 7.7
Positive 25 (10.12%)
RAR N 2 0 0 1 15 0 0 0 1 19
Negative 222 (89.87%)
% 1.7 0 0 4.3 100 0 0 0 4.8 7.7
T stage
JUQ N 12 1 0 0 0 25 0 0 0 38
Tis 22 (8.9%)
% 10.3 3.8 0 0 0 96.2 0 0 0 15.4
T1 104 (42.10%)
JLQ N 0 0 0 1 0 0 6 0 0 7
T2 92 (37.24%)
% 0 0 0 4.3 0 0 85.7 0 0 2.8
T3 26 (10.52%)
JMQ N 0 0 0 2 0 0 0 6 1 9
T4 3 (1.21%)
% 0 0 0 8.7 .0 .0 .0 100 4.8 3.6
N stage
JLLQ N 4 0 2 0 0 0 0 0 19 25
N0 175 (70.92%)
% 3.4 .0 33.3 0 0 0 0 0 90.5 10.1
N1 55 (22.02%)
Total N 117 117 26 6 23 15 26 7 6 21
N2 16 (6.60%)
% ,5 100 100 100 100 100 100 100 100 100
N3 1 (0.44%)
Pre-surgical tumor localization ULQ: upper lateral quadrant; UMQ: upper medial quadrant; LLQ: lower lateral
Upper Lateral Quadrant 117 (47.36%) quadrant; LMQ: lower medial quadrant; JUQ: junction of upper quadrants; JLQ:
Upper Medial Quadrant 26 (10.52%) junction of lower quadrants; JLLQ: junction of lateral quadrants; JMQ: junction of
Lower Lateral Quadrant 6 (2.42%) medial quadrants; CP: central portion.
Lower Medial Quadrant 23 (9.31%)
Junction of Upper Quadrants 15 (6.07%) markings and also placing surgical clips at the tumor margins. In
Junction of Lower Quadrants 26 (10.52%) our previous studies [16e19], clips have not interfered with exams
Junction of Lateral Quadrants 7 (2.83%)
and have actually helped recognize areas at risk for recurrence.
Junction of Medial Quadrants 6 (2.42%)
Central Portion 21 (8.50%) Additionally, clips have not been mentioned as interfering with
Breast reconstruction surgery aesthetic results [20]. On the other hand, Poortmans et al. [21]
Yes 30 (12.14%) pointed out that the location of clips can be misleading in cases
No 217 (87.85%)
where volume displacement techniques are utilized, especially
Number of clips
1 59 (23.88%)
where the boost area is not the entire surgical cavity. According to
2 51 (20.64%) other authors, this usually results in larger boost volumes than
3 92 (37.24%) actually necessary, potentially leading to local fibrosis and poorer
4 40 (16.19%) aesthetic outcome [21].
5 5 (2.02%)
In the present study, it is expected that reconstructive surgery
would impact in CTV MISS, once there can be displacement of the
presence of only one clip in the tumor bed. Moreover in both surgical bed by breast tissue rotations and flaps. In our study,
groups the radiological changes like seromas and hematomas were however, possibly due to the low number of patients with breast
included in CTV Boost, minimizing the volume miss. reconstructive surgery (12.14%), there were not significant differ-
Even though there have been major efforts to standardize the ences in CTV MISS volumes between the groups of patients sub-
delineation method in this study and margins definitions, unde- mitted or not to reconstruction (p ¼ 0.290). Studies with a larger
sirable biases related to individual contouring features of each number of patients submitted to breast reconstructive surgery are
physician could not be avoided. necessary to prove the hypothesis that this procedure can impact in
Concerning reconstructive techniques, one might surmise that the correlation of clinical tumor location (quadrant) and the boost
surgical techniques that involve rearrangement of breast tissue location defined by surgical clips. An adequate coverage of tumor
may jeopardize the boost radiation dose delivery [16]. For this bed is essential to warrant the gain in local control with the boost
reason, coordinated planning with the radiation therapy team is after whole breast irradiation.
crucial since some “oncoplastic techniques” could change the In conclusion, this study confirms, in a large patient cohort, the
normal architecture of the quadrants [16e19]. Thus, our plastic importance of surgical clips placement in breast conserving surgery
surgery team advocates orienting the original tumor area by skin to ensure precision and assurance in the dose delivered to the boost
Table 2 volume, while decreasing normal tissue irradiation. Our results
CTV MISS volume according to the number of clips and presence or absence of breast suggest that whole quadrant irradiation may lead to inadequate
reconstruction surgery. coverage in a significant percentage of patients. The results of this
Volume of CTV MISS Mean (range) pa study demonstrate that the present technique is a reliable pro-
cedure and should be considered in cases of conservative breast
Number of clips
1 clip 7.79 cm3 (0e44.25) 0.283
surgery.
2 or more clips 6.73 cm3 (0e42.25)
Breast reconstruction surgery
Yes 7.09 cm3 (0e27.20) 0.290 Funding source
No 13.57 cm3 (0.10e44.25)
a
Mann Whitney Rank-Test. None.

Please cite this article in press as: de Freitas TB, et al., What a difference a clip makes! Analysis of boost volume definition in radiation therapy for
conservative breast surgery, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.06.010
6 T.B. de Freitas et al. / European Journal of Surgical Oncology xxx (2018) 1e6
Conflict of interest
None declared.
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