Radiotherapy and Oncology: EPTN Consensus
Radiotherapy and Oncology: EPTN Consensus
Radiotherapy and Oncology: EPTN Consensus
EPTN consensus
a r t i c l e i n f o a b s t r a c t
Article history: Purpose: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on
Received 17 September 2017 high-quality computed tomography (CT) and magnetic resonance (MR) imaging.
Received in revised form 1 December 2017 Methods: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were
Accepted 19 December 2017
obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous con-
Available online 13 March 2018
trast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation
oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology
Keywords:
were determined, excluding typical head and neck OARs previously published. The draft atlas was delin-
Atlas for neuro-oncology
Organs at risk
eated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist
Particle therapy incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed
European Particle Therapy Network by European radiation oncologists until consensus was reached.
Results: The online atlas includes one CT-scan at two different window settings and one MR scan (3T)
showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional
descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for
neuro-cognition, the posterior cerebellum (illustrated on 7T MR images).
Conclusion: In order to decrease inter- and intra-observer variability in delineating OARs relevant for
neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon
and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever
required.
Ó 2017 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 128 (2018) 37–43 This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
⇑ Corresponding author at: MAASTRO Clinic, Doctor Tanslaan 12, 6229 ET Maastricht, The Netherlands.
E-mail address: danielle.eekers@maastro.nl (D.BP Eeker.
https://doi.org/10.1016/j.radonc.2017.12.013
0167-8140/Ó 2017 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
38 Neuro-Oncology organs at risk atlas
In order to evaluate the added value of new radiotherapy (RT) to consensus on a first draft atlas. This draft was then critically
modalities and techniques, such as particle therapy and adaptive reviewed by Dutch and international experts in neuro-oncology
highly conformal photon RT, it is essential to be able to accurately and consensus on the final version of this atlas was reached.
predict the individual patient’s benefit in term of radiation-
induced side effects [1–3]. The maturation and validation of nor-
mal tissue complication probability (NTCP) models are strongly Acquisition of CT and MR
dependent on uniform delineation of the relevant organs at risk
(OARs), and reducing the inter- and intra-observer and trial proto- CT images were acquired with intravenous contrast (UltravistÒ,
col variability between clinicians and radiotherapy departments is 150 ml of 300 mg Iodine per mL, 2 mL per sec, 5 min delay, slice
an important objective. In this context, Brouwer et al. [4] and Kong thickness 1 mm, 50 cm field of view, 120 kV, 685 mAs) using
et al. [5] published atlases for OARs relevant for head and neck and window-width/window-level settings (WW/WL) of 120/40 and
lung tumors, respectively. 120/1500 (SOMATOM Sensation 10, Siemens Healthcare, Erlangen,
During the last decade, several papers have been published on Germany) of the head of an adult male low grade glioma patient
the delineation of OARs relevant to neuro-oncology both for adults after first resection. Moreover, a three-dimensional spoiled gradi-
and children [4,6,7]. These atlases may differ in minor details, but ent (3D-SPGR) axial 3T MR scan (1 mm slice thickness) of the same
also some major discrepancies might occur, for instance, variations patient in standard axial, sagittal and coronal reconstruction, and
in the upper limit of the brainstem. Discrepancies in a critical OAR an axial T2- and a gadolinium (GadovistÒ 1.0 mmol/ml 0.1 mL/kg
may influence the dose distribution and thus compromise the cov- bodyweight) contrast-enhanced axial T1-weighted sequence were
erage of the target volume [4,6]. acquired, with sagittal and coronal reconstruction. Both CT and MR
Within the Dutch Platform for Neuro-Oncology and the ESTRO were obtained in the supine position with the head in a neutral
taskforce ‘‘European Particle Therapy Network (EPTN)” there was position; immobilization devices routinely used in radiation ther-
a need to generate an atlas, which identifies the relevant OARs apy were used for CT acquisition. Rigid MR-CT co-registration
for neuro-oncology and can be used both for daily practice as well and delineation were performed using the EclipseTM treatment
as research purposes [8]. With the ever-growing insight into the planning system with the high-resolution segment.
influence of radiotherapy on neurological functions, it is essential For illustration purposes, 7T MR images of a healthy volunteer
that this atlas can be easily updated when indicated. were acquired (Siemens Magnetom 7T) with a slice thickness of
0.7 mm using a 32-channel head coil (Nova Medical Inc., Wilming-
Selection of OARs ton, CA; Fig. 1). The magnetization-prepared rapid gradient-echo
(MP2RAGE) was selected for OAR delineation due to its superior
In order to avoid overlap with existing head and neck atlases, soft tissue contrast (Fig. 2). Scan parameters have previously been
typical head and neck OARs, which were previously published, published by Compter et al. [10]. Vendor-based 3D distortion cor-
were excluded from this consensus atlas [4]. All OARs at present rection methods were applied.
known to be relevant for radiation-induced toxicity in neuro-
oncology were included, namely: brain, brainstem, cochlea,
vestibulum & semicircular canals, cornea, lens, retina, lacrimal Three-dimensional description of the OARs
gland, optic nerve, chiasm, pituitary, hippocampus and skin. In case
of paired organs, each organ separately (left and right), and the Cornea (‘‘Cornea_R”, ‘‘Cornea_L” and ‘‘Corneas”)
unity of the two were contoured. The cornea is located at the anterior segment of the eyeball con-
For future development of NTCP models, three distinct parts for sisting of the structures ventral to the vitreous humor, the iris, cil-
the brainstem were defined, and regarding cognition, the posterior iary body, and lens [6]. Using a brush of 2–3 mm the cornea can
cerebellum, a new OAR possibly involved was included, as was the easily be delineated on MR as well as CT.
separation of the hippocampus into anterior and posterior parts.
For research purposes also the hypothalamus was included. Of
note, no validated dose–response curve relationships have thus
Retina (‘‘Retina_R”, ‘‘Retina_L” and ‘‘Retinas”)
far been published for these separate parts of the brainstem, hip-
pocampus and cerebellum. The retina is a neurosensorial membrane of 2–3 mm thickness,
located at the posterior part of the eyeball, posterior to the cornea
and lens, and is the innermost of the three layers that form the wall
Uniform nomenclature
of the eyeball (sclera, uvea/choroid and retina). Using a 3 mm
brush, it can be delineated on MR as well as CT as a membrane cov-
To facilitate future comparison of the structures, the proposed
ering the posterior 5/6 of the globe, extending nearly as far as the
nomenclature is in accordance with work by Santanam et al. [9]
ciliary body. The anterior border of the retina is between the inser-
on standardizing naming convention in radiation oncology, illus-
tion of the medial rectus muscle and the lateral rectus muscle, pos-
trated with quotes between brackets behind every structure name,
terior to the ciliary body. The optic nerve is excluded from this
for example: retina (‘‘Retina_R”, ‘‘Retina_L” and ‘‘Retinas”).
contour [4,6].
Delineation
Lacrimal gland (‘‘LacrimalGland L”, ‘‘LacrimalGland_R” and
The fifteen OARs introduced in several previous publications
‘‘LacrimalGlands”)
were delineated by the first author (DE) [4,6,7]. The anterior and
posterior cerebellums were delineated by three authors (DE, LV, The lacrimal gland is an almond shaped gland (18 mm cranio-
IC) using the high-resolution segment of the radiation treatment caudally, 15 mm axial length and 5 mm axial width) located in
planning software (EclipseTM v11.0 software, Varian, Palo Alto, the orbit superior-lateral to the eye, superior to the lateral rectus
CA). During a multi-disciplinary session, the senior radiation oncol- muscle and lateral to the superior rectus muscle. It can be delin-
ogist (DE), neuro-radiologist (AP), and two residents in radiation eated on CT using soft brain 120/40 or soft tissue 350/50 WW/
oncology (LV, IC) discussed the delineation of the OARs and came WL settings [4,6,11].
D.BP Eekers et al. / Radiotherapy and Oncology 128 (2018) 37–43 39
Fig. 1. Sagittal (midline) view of the delineation. (A) Sagittal CT image (WL 140/40), (B + C) sagittal 3 Tesla MRI (T1 with gadolinium), (D) sagittal 7 Tesla MRI. Light blue =
cerebellum anterior, dark blue = cerebellum posterior, red = midbrain, magenta = pons, pink = medulla oblongata, orange = spinal cord, light yellow = hypothalamus, green =
chiasm, purple = pituitary, orange = brainstem surface, yellow = brainstem interior.
Fig. 2. Sagittal (midline) view of cerebellum delineation on 7 Tesla MRI. From left to right: 7 Tesla MRI, sagittal, coronal and transversal. Light blue = cerebellum anterior, dark
blue = cerebellum posterior.
Lens of the Eye (‘‘Lens_R”, ‘‘Lens_L” and ‘‘Lenses”) is crucial for dose reporting purposes, as dose gradients can be very
steep with modern photon and proton techniques [4,12].
The lens (diameter up to 10 mm) is a clearly visible biconvex
avascular structure, located between the vitreous humor and the
iris and can easily be delineated on CT [6]. It should be taken into Optic chiasm (‘‘Chiasm”)
account that without instructing the patient, the position of the
The optic chiasm (14 mm transverse, 8 mm antero-posterior
lens is not fixed and can vary during treatment.
and 2–5 mm thick) is located 1 cm superior to the pituitary gland,
which has high signal on T1 MRI, and just anterior to the pituitary
stalk (located above the sella turcica). The lateral border is the
Optic nerve (‘‘OpticNerve_R”, ‘‘OpticNerve_L” and ‘‘OpticNerves”)
internal carotid artery. The chiasm is superiorly located in the
The optic nerve (2–5 mm thick) is delineated from the posterior antero-inferior part of the third ventricle, below the supra-optic
edge of the eyeball, through the bony optic canal, where it narrows recess and above the infundibular recess of the third ventricle, with
slightly, to the optic chiasm. Close to the optic chiasm, an MR scan the optic nerves in front and the divergence of the optic tracts
(T1 weighted) is recommended for better delineation of the optic behind. The anterior cerebral arteries and the anterior communi-
nerve. Contouring the optic nerve in continuity with the chiasm cating artery are located ventral to the chiasm. A T1 weighted
40 Neuro-Oncology organs at risk atlas
MR (axial, sagittal and coronal) is recommended for delineation of nially of the cochlea. The canals are also visible as small cavities
the optic chiasm [4,6]. on MR (T2 weighted) [6].
Fig. 3. 3D view of the OARs delineation on CT. (A) From ventral to dorsal: yellow = cornea, orange = retina, brown = lacrimal gland, green = optic nerve, light green = chiasm,
purple = pituitary, yellow (central) = hypothalamus, red = midbrain, green (central) = hippocampus anterior, dark green = hippocampus posterior, pink = cochlea, magenta =
pons, pink = medulla oblongata, orange = spinal cord, light blue = cerebellum anterior, dark blue = cerebellum posterior. (B) From cranial to caudal: yellow = hypothalamus,
red = midbrain, light green = chiasm, green = hippocampus anterior, dark green = hippocampus posterior, magenta = pons, pink = medulla oblongata, Light blue =
anterior cerebellum, dark blue = posterior cerebellum, orange = spinal cord. (C) Yellow = brain, red = brainstem, orange = spinal cord.
Discussion for the hypothalamus available yet, we believe that these data
need to be collected in a prospective manner, in order to correlate
The presented atlas for contouring OARs involved in neuro- levels of hormone production and regulation of metabolic pro-
oncology aims at reducing the inter- and intra-observer delin- cesses with delivered radiation dose.
eation variability and thus enabling more consistent plan compar- Hearing preservation after radiotherapy is known to be related
ison. This is especially relevant when comparing different radiation to dose to the cochlea [32–34]. There is agreement in the literature
treatment techniques and modalities, and for establishing detailed on its delineation, most optimally done on a CT scan with thin
dose–response relationships and NTCP models for different OARs. slices using a bone WW/WL-setting considering its location in
Toxicity to the optical system is a feared complication especially the mastoid bone [4,6]. Since dizziness is a side-effect occasionally
when it results in partial or total loss of vision or pain to the eye. reported after radiotherapy it was decided to delineate the semicir-
Despite their small volume, a separate delineation of the different cular canals as well, using the same WW/WL-settings as for the
optical structures is crucial in order to derive dose–volume his- cochlea, although future data are needed to establish a validated
tograms and predict post-radiation toxicity. The optic chiasm is dose constraint.
an anatomically cross-shaped structure, as is depicted by Scoc- Recent literature has shown some dose–response relationship
cianti et al. [6] and not round as presented in the atlas by Brouwer between the hippocampus and cognition as described by Gondi
et al. [4]. Moreover, the chiasm should be contoured in continuity et al. [34] using the absolute radiation dose to 40% of both hip-
with both optic nerves in order to prevent high-dose deposits in pocampi (D40%). We firmly encourage delineating the hippocampi
un-delineated voxels. The retina is to be delineated separately from separately and into anterior and posterior parts, since the left hip-
the vitreous body, since radiation induced retinopathy can be trea- pocampus is known to be dominant in most patients (including
ted if observed in an early state. Consequently, correct dose calcu- left-handed patients) for verbal memory, and the right hippocam-
lation is of utmost relevance in order to refer a patient suffering pus for non-verbal memory also known as visual memory. More-
from this radiation induced side-effect [28]. Separate delineation over, the posterior parts of the hippocampi are more related to
of the cornea is proposed since toxicity and tolerance dose differ memory than the anterior parts [35–39].
from that of the retina [4,28,29]. Damage to the cornea, radiation The brain is often automatically delineated and for practical
keratitis, is painful and deteriorates sight. The mean radiation dose reasons the included small vessels are left in the contour since
to the lacrimal gland is related to the development of a dry eye, editing the contour would be too time consuming. There are dose
which can be painful and render the eye susceptible to infections constraints for brain tissue, especially on high doses related to
[28]. A cataract can develop at a rather low dose to the lens. This temporal lobe radionecrosis in head and neck cancer patients
side-effect can be alleviated by surgical implantation of an artificial [40–45]. Regarding neuro-cognition, some publications on pedi-
lens [28]. A normal lens is well seen because of its high protein atric patients have shown a correlation between low dose radiation
content, whereas an artificial lens is difficult to see on CT or MR, to the supra-tentorial brain and cognitive decline [40,46]. Further
but since it tolerates radiation dose, delineation is not required. data are needed to transfer this knowledge to adult patients. Data
Hypo-pituitarism may take a long time to be diagnosed since its on whole brain radiotherapy and prophylactic cranial irradiation
symptoms can be vague. Depending on the mean dose to the pitu- have hinted at the negative effect of low dose on cognition [47–
itary gland, an early referral to an endocrinologist can facilitate 54]. However, there still is a strong need for an adult NTCP model
early initiation of treatment and thus prevent impaired quality of on brain tissue and cognition.
life [30,31]. In general, it is advised to delineate the entire sella Symptomatic brainstem necrosis is a feared, but rare complica-
content to be sure the whole pituitary is included rather than the tion following radiotherapy to the brain [55,56]. It was decided to
central part only, excluding the suprasellar part of the infundibu- contour the brainstem in three anatomically distinct parts, because
lum [4,6]. Even though there are no established dose constraints some hypothesize that specific volumes within the brainstem are
42 Neuro-Oncology organs at risk atlas
more sensitive to radiation than others. In particle beam therapy, sus, and they thank Marlies Granzier, radiation technologist at
the anterior surface and center of the brainstem are delineated MAASTRO clinic for her expertise and support with data transfer
separately since a higher tolerance at the surface of the brainstem and image fusion. NGB is supported by the National Institute for
has been observed [23,24]. This should be subject to further Health Research Cambridge Biomedical Research Centre.
research for both photon and particle radiotherapy.
The delineation of the cerebellum is also added as a possible Disclosure of conflicts of interest
new OAR for research purposes, since there are data suggesting a
relationship between the posterior cerebellum and cognition This research was partially supported by the Brains Unlimited
[57]. Cantelmi et al. [58] state that recognition of the important Pioneer Fund of the Limburg University Fund/SWOL (S.2013.1.011).
cognitive contributions of the cerebellum might lead to improved
cognitive outcome and quality of life. This definitely needs further
research into a possible dose–response relationship and tolerance Ethical publication statement
dose, which is only possible when agreement is reached in the
delineation, as proposed based on Schmahmann et al. [26,55,58]. We confirm that we have read the Journal’s position on issues
For radiation treatment planning purposes, the skin is added as involved in ethical publication and affirm that this report is consis-
an OAR since alopecia and erythema are disturbing side-effects. tent with those guidelines.
Using the skin structure enables lowering the dose during treat-
ment planning, which is of particular importance in proton therapy References
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