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<article xmlns:xlink="http://www.w3.org/1999/xlink">
  <front>
    <journal-meta />
    <article-meta>
      <title-group>
        <article-title>AUTOMATIC SEGMENTATION OF ORGANS AT RISK IN THORACIC CT SCANS BY COMBINING 2D AND 3D CONVOLUTIONAL NEURAL NETWORKS</article-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <string-name>Louis D. van Harten</string-name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Julia M. H. Noothout</string-name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Joost J. C. Verhoeff</string-name>
          <xref ref-type="aff" rid="aff0">0</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Jelmer M. Wolterink</string-name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <string-name>Ivana Isˇgum</string-name>
          <xref ref-type="aff" rid="aff1">1</xref>
        </contrib>
        <aff id="aff0">
          <label>0</label>
          <institution>Department of Radiotherapy, University Medical Center Utrecht</institution>
          ,
          <addr-line>Utrecht</addr-line>
          ,
          <country country="NL">The Netherlands</country>
        </aff>
        <aff id="aff1">
          <label>1</label>
          <institution>Image Sciences Institute, University Medical Center Utrecht</institution>
          ,
          <addr-line>Utrecht</addr-line>
          ,
          <country country="NL">The Netherlands</country>
        </aff>
      </contrib-group>
      <issue>4</issue>
      <abstract>
        <p>Segmentation of organs at risk (OARs) in medical images is an important step in treatment planning for patients undergoing radiotherapy (RT). Manual segmentation of OARs is often time-consuming and tedious. Therefore, we propose a method for automatic segmentation of OARs in thoracic RT treatment planning CT scans of patients diagnosed with lung, breast or esophageal cancer. The method consists of a combination of a 2D and a 3D convolutional neural network (CNN), where both networks have substantially different architectures. We analyse the performance for these networks individually and show that a combination of both networks produces the best results. With this combination, we achieve average Dice coefficients of 0.84 0.05, 0.94 0.02, 0.91 0.02, and 0.93 0.01 for the esophagus, heart, trachea, and aorta, respectively. These results demonstrate potential for automating segmentation of organs at risk in routine radiotherapy treatment planning.</p>
      </abstract>
    </article-meta>
  </front>
  <body>
    <sec id="sec-1">
      <title>-</title>
      <p>Index Terms— Organs at risk segmentation, dilated
convolutional neural network, residual connections, CT, deep
learning</p>
    </sec>
    <sec id="sec-2">
      <title>1. INTRODUCTION</title>
      <p>
        Cancer is a global leading cause of death, with an increasing
prevalence due to growth and aging of the population [
        <xref ref-type="bibr" rid="ref1">1</xref>
        ]. One
treatment available for cancer is radiation therapy (RT),
during which high doses of radiation are delivered to kill cancer
cells [
        <xref ref-type="bibr" rid="ref2">2</xref>
        ]. RT treatment planning often starts with
segmentation of the target volume and healthy organs surrounding the
tumor, i.e. organs at risk (OARs), in CT scans [
        <xref ref-type="bibr" rid="ref3">3</xref>
        ]. Manual
segmentation is often time-consuming and error prone due to
large anatomical variation between patients, poor soft-tissue
contrast, and high levels of image noise in scans. Therefore,
methods have been proposed to automatically segment OARs
in CT scans.
      </p>
      <p>
        Previously published methods for OAR segmentation
have used techniques such as thresholding and Hough
transforms [
        <xref ref-type="bibr" rid="ref4">4</xref>
        ] or multi-atlas registration and level sets [
        <xref ref-type="bibr" rid="ref5">5</xref>
        ].
Recently, convolutional neural networks (CNNs) have been used
for OAR segmentation. Trullo et al. [
        <xref ref-type="bibr" rid="ref6">6</xref>
        ] used a CNN in
combination with a conditional random field, implemented as a
recurrent neural network architecture, to segment OARs in
thoracic CT scans. Men et al. [
        <xref ref-type="bibr" rid="ref7">7</xref>
        ] used a CNN containing
dilated convolutions at the front- and back-end of a VGG-16
inspired network architecture to segment OARs in treatment
planning CT scans for rectal cancer.
      </p>
      <p>
        In this work, we propose to use an ensemble of CNNs for
segmentation of the esophagus, heart, trachea, and aorta in
RT treatment planning CT scans for patients suffering from
lung, breast or esophageal cancer. It has been shown that the
combination of multiple segmentation CNNs in an ensemble
can lead to improved segmentation results [
        <xref ref-type="bibr" rid="ref8">8</xref>
        ]. However, a
drawback of ensemble methods is that training and
combining multiple CNNs leads to an increase in computation time
during both training and testing. Therefore, we propose an
ensemble containing only two CNNs with substantially
different architectures. We hypothesize that these architectures
lead to different errors, which will be evened out when
combining segmentation results of both networks. The first CNN
exploits a 3D network architecture, inspired by [
        <xref ref-type="bibr" rid="ref9">9</xref>
        ], and
contains strided convolutional down- and upsampling layers and
residual blocks. The second CNN exploits a 2D network
architecture containing dilated convolutions [
        <xref ref-type="bibr" rid="ref10 ref11">10, 11</xref>
        ]. This
network independently predicts voxel labels in axial, coronal and
sagittal image slices, and obtains individual voxel predictions
by averaging the three predictions. We compare the individual
performance of each network and show improvement when
both networks are combined into one ensemble.
We used data provided in the ISBI 2019 Segmentation of
THoracic Organs at Risk in CT images (SegTHOR)
challenge1. This data set contains 60 thoracic CT scans of
patients diagnosed with non small cell lung cancer and referred
for curative-intent radiotherapy. CT scans were acquired with
or without intravenous contrast. Scans have an in-plane
res1https://competitions.codalab.org/competitions/
21012
3x33x3x33xxx333
32332,2,,//22/2
      </p>
      <p>3x33xx33
3x33x33x3xxx3
643,x/323
64,/2/2
64664,4,,//22
Downsampling
x16</p>
      <p>Upsampling
(a)
(b)
olution varying between 0.90 mm and 1.37 mm, and a
slicethickness between 2 mm and 3.7 mm.</p>
      <p>
        For each scan, manual reference delineations of the
esophagus, heart, trachea, and aorta were available. The
esophagus was delineated from the 4th cervical vertebra (C4)
to the esophago-gastric junction. The heart was delineated as
recommended by the Radiation Therapy Oncology Group 2.
The trachea was delineated from the lower limit of the larynx
to 2 cm below the carina, excluding the lobar bronchi. The
aorta was delineated from its origin above the heart down to
below the diaphragm pillars [
        <xref ref-type="bibr" rid="ref6">6</xref>
        ].
      </p>
    </sec>
    <sec id="sec-3">
      <title>3. METHOD</title>
      <p>
        We train two CNNs with substantially different architectures:
one 3D network that contains a deep segment of residual
blocks [
        <xref ref-type="bibr" rid="ref9">9</xref>
        ], and one 2D network containing dilated
convolutions [
        <xref ref-type="bibr" rid="ref10 ref11">10, 11</xref>
        ]. The 3D network performs multi-label
segmentation using sigmoids in the output layer, meaning the
network can predict high probabilities for multiple classes in
one voxel. The 2D network performs multi-class
segmentation using a softmax in the output layer. This distinction is
implemented to promote additional diversity in the networks.
      </p>
      <p>
        The 3D network is a fully convolutional network using
residual blocks, inspired by the 2D network used in [
        <xref ref-type="bibr" rid="ref9">9</xref>
        ]. The
network analyses patches of 64 64 64 voxel and produces
an equally sized output. The deep segment of residual blocks
allows the network to focus on highly detailed local
geometry. The network contains two strided convolutional
downsampling layers, followed by 16 fully pre-activated residual
blocks [
        <xref ref-type="bibr" rid="ref12">12</xref>
        ], and two transposed convolutional upsampling
layers. Rectified linear unit (ReLU) activation functions
and batch normalization [
        <xref ref-type="bibr" rid="ref13">13</xref>
        ] are used in all layers, along
with dropout [
        <xref ref-type="bibr" rid="ref14">14</xref>
        ] (p=0.5) in all of the residual blocks. An
overview of the architecture is shown in Fig. 1a.The output
layer contains four sigmoid functions that each identify
presence of a single foreground class (esophagus, heart, trachea or
aorta). To obtain one prediction per voxel, the class with the
highest probability is chosen; background is selected when
none of the class predictions exceed a probability of 0.5.
      </p>
      <p>
        The second network is a 2D fully convolutional network
containing dilated convolutions (Fig. 1b) [
        <xref ref-type="bibr" rid="ref10 ref11">10, 11</xref>
        ].
Segmentation of large anatomical structures with homogeneous
textures as in CT can benefit from long-range context
information [
        <xref ref-type="bibr" rid="ref15">15</xref>
        ]. Dilated convolutions allow large receptive fields
while exploiting the input resolution of the image throughout
the network. The network contains ten convolutional layers
with increasing levels of dilation, leading to a receptive field
of 131 131 voxels. The ReLU activation functions is used in
all layers, along with dropout [
        <xref ref-type="bibr" rid="ref14">14</xref>
        ] (p=0.5) and batch
normalization [
        <xref ref-type="bibr" rid="ref13">13</xref>
        ] on the fully connected layers.
      </p>
      <p>During training, batches containing sub-images from the
axial, coronal and sagittal plane are used. Sub-images have
a size of 256 256 voxels (green square in Fig. 1b) of which
the center 125 125 voxels (dashed green square in Fig. 1b)
are classified by the network. During inference, the network
is evaluated using all slices in the axial, coronal and sagittal
direction, resulting in three 3D multi-class probability maps
that are averaged to obtain a probability distribution per voxel.
Each voxel is assigned the class with the highest resulting
Method
3D CNN (Fig 1a)
2D CNN (Fig 1b)
2D + 3D
probability.</p>
      <p>Given that voxel classification may result in isolated
(clusters of) voxels disconnected from the target structure,
connected components smaller than 0.2 times the largest
component in the class were removed using largest component
selection.</p>
    </sec>
    <sec id="sec-4">
      <title>4. EXPERIMENTS AND RESULTS</title>
      <p>The dataset was split into a set of 40 scans and a test set of 20
scans by the challenge organisers. Delineations for the test set
were not available during method development. The
remaining set was randomly split into a training set (35 scans) and a
validation set (5 scans) for the development of this work.</p>
    </sec>
    <sec id="sec-5">
      <title>4.1. Training</title>
      <p>Both networks were trained using Adam (learning rate=0.001).
The 3D network was trained using a cross-entropy loss for
200,000 mini-batch iterations. Each mini-batch contained 15
pseudo-randomly sampled 64 64 64 voxel sub-images,
balanced such that each foreground class appears in at least one
fourth of all training patches. The 2D network was trained
using a Dice loss for 50,000 mini-batch iterations. Each
minibatch contained 40 256 256 pixel sub-images. These were
randomly sampled along the axial, sagittal, or coronal axis.
Random rotation augmentations of up to 10 degrees were
applied to each slice.</p>
    </sec>
    <sec id="sec-6">
      <title>4.2. Results</title>
      <p>Table 1 lists performance on the validation set and the test set.
For evaluation on the validation set, we trained and evaluated
the 3D and 2D networks separately. In addition, we combined
the probabilistic outputs provided by both networks prior to
thresholding and largest component selection.</p>
      <p>We investigated the effect of weighting the contribution
of each network in the ensemble on the performance on the
validation set. Fig. 2 shows the Dice score for each class
resulting from different linear combinations of the probability
maps from both networks. While the left-middle section of
this figure shows an improvement in performance, the
performance gain is numerically inconsequential compared to the
3D network results. However, qualitatively, some properties
of the resulting segmentation visibly improve. An example is
shown in Fig. 3, where the 3D network has difficulties
detecting locally arbitrary borders of organ segmentations as appear
in the bottom of aorta, the top of the esophagus and on both
sides of the trachea. In this case, the information from the
larger receptive field in the 2D network improves the
combined network performance.</p>
      <p>Fig. 2 suggests that the best performance is achieved when
using a combination of both networks where the probability
maps from the 3D network are weighted slightly stronger than
those from the 2D network. Several combinations were
submitted and scored in the challenge interface and a
combination of 63.5% 3D and 37.5% 2D performed best on the test
set by a small margin. The results listed as 2D+3D in Table 1
correspond to this combination.</p>
    </sec>
    <sec id="sec-7">
      <title>5. DISCUSSION AND CONCLUSION</title>
      <p>
        Even though both networks individually are able to accurately
segment the organs at risk, we have shown that combining the
predictions of both networks further improves segmentation
performance. Considering prior work has shown that
ensembles generally outperform individual networks [
        <xref ref-type="bibr" rid="ref8">8</xref>
        ], these
results are as expected. The historical success of large
ensembles implies that segmentation accuracy of this method could
be further improved by adding additional networks. Notable
here is the size of the presented networks: the 3D and 2D
architectures contain only 3.7 million and 73 thousand
parameters respectively. The small computational footprints mean
both architectures can be attractive additions to a larger
segmentation ensemble, even in computationally limited
situations.
      </p>
      <p>We have presented a method for automatic segmentation
of organs at risk in thoracic radiotherapy treatment planning
CT scans. The segmentation was performed using a
combination of 2D and 3D convolutional neural networks. The results
show the method achieves accurate segmentations,
demonstrating potential for automating segmentation of organs at
risk in routine radiotherapy treatment planning.</p>
    </sec>
    <sec id="sec-8">
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