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The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology

Open AccessPublished:March 13, 2018DOI:https://doi.org/10.1016/j.radonc.2017.12.013

      Abstract

      Purpose

      To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging.

      Methods

      CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast 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 were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed 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.

      Keywords

      In order to evaluate the added value of new radiotherapy (RT) modalities and techniques, such as particle therapy and adaptive highly conformal photon RT, it is essential to be able to accurately predict the individual patient’s benefit in term of radiation-induced side effects [
      • Eekers D.B.
      • Roelofs E.
      • Jelen U.
      • Kirk M.
      • Granzier M.
      • Ammazzalorso F.
      • et al.
      Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial.
      ,
      • Roelofs E.
      • Engelsman M.
      • Rasch C.
      • Persoon L.
      • Qamhiyeh S.
      • de Ruysscher D.
      • Verhaegen F.
      • Pijls-Johannesma M.
      • Lambin P.
      ROCOCO Consortium. Results of a multicentric in silico clinical trial (ROCOCO): comparing radiotherapy with photons and protons for non-small cell lung cancer.
      ,
      • van der Laan H.P.
      • van de Water T.A.
      • van Herpt H.E.
      • Christianen M.E.
      • Bijl H.P.
      • Korevaar E.W.
      • Rasch C.R.
      • van 't Veld A.A.
      • van der Schaaf A.
      • Schilstra C.
      • Langendijk J.A.
      • Rococo cooperative group
      The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study.
      ]. The maturation and validation of normal tissue complication probability (NTCP) models are strongly dependent on uniform delineation of the relevant organs at risk (OARs), and reducing the inter- and intra-observer and trial protocol variability between clinicians and radiotherapy departments is an important objective. In this context, Brouwer et al. [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ] and Kong et al. [
      • Kong F.M.
      • Ritter T.
      • Quint D.J.
      • Senan S.
      • Gaspar L.E.
      • Komaki R.U.
      • et al.
      Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
      ] published atlases for OARs relevant for head and neck and lung tumors, respectively.
      During the last decade, several papers have been published on the delineation of OARs relevant to neuro-oncology both for adults and children [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ,
      • Gondi V.
      • Tolakanahalli R.
      • Mehta M.P.
      • Tewatia D.
      • Rowley H.
      • Kuo J.S.
      • et al.
      Hippocampal-sparing whole-brain radiotherapy: A “howto” technique, utilizing helical tomotherapy and LINAC-based intensity modulated radiotherapy.
      ]. These atlases may differ in minor details, but also some major discrepancies might occur, for instance, variations in the upper limit of the brainstem. Discrepancies in a critical OAR may influence the dose distribution and thus compromise the coverage of the target volume [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ].
      Within the Dutch Platform for Neuro-Oncology and the ESTRO taskforce “European Particle Therapy Network (EPTN)” there was a need to generate an atlas, which identifies the relevant OARs for neuro-oncology and can be used both for daily practice as well as research purposes [
      • Weber D.C.
      • Abrunhosa-Branquinho A.
      • Bolsi A.
      • Kacperek A.
      • Dendale R.
      • Geismar D.
      • et al.
      Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire.
      ]. With the ever-growing insight into the influence of radiotherapy on neurological functions, it is essential that this atlas can be easily updated when indicated.

      Selection of OARs

      In order to avoid overlap with existing head and neck atlases, typical head and neck OARs, which were previously published, were excluded from this consensus atlas [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ]. All OARs at present known to be relevant for radiation-induced toxicity in neuro-oncology were included, namely: brain, brainstem, cochlea, vestibulum & semicircular canals, cornea, lens, retina, lacrimal gland, optic nerve, chiasm, pituitary, hippocampus and skin. In case of paired organs, each organ separately (left and right), and the unity of the two were contoured.
      For future development of NTCP models, three distinct parts for the brainstem were defined, and regarding cognition, the posterior cerebellum, a new OAR possibly involved was included, as was the 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 far been published for these separate parts of the brainstem, hippocampus and cerebellum.

      Uniform nomenclature

      To facilitate future comparison of the structures, the proposed nomenclature is in accordance with work by Santanam et al. [
      • Santanam L.
      • Hurkmans C.
      • Mutic S.
      • van Vliet-Vroegindeweij C.
      • Brame S.
      • Straube W.
      • et al.
      Standardizing naming conventions in radiation oncology.
      ] on standardizing naming convention in radiation oncology, illustrated with quotes between brackets behind every structure name, for example: retina (“Retina_R”, “Retina_L” and “Retinas”).

      Delineation

      The fifteen OARs introduced in several previous publications were delineated by the first author (DE) [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ,
      • Gondi V.
      • Tolakanahalli R.
      • Mehta M.P.
      • Tewatia D.
      • Rowley H.
      • Kuo J.S.
      • et al.
      Hippocampal-sparing whole-brain radiotherapy: A “howto” technique, utilizing helical tomotherapy and LINAC-based intensity modulated radiotherapy.
      ]. The anterior and posterior cerebellums were delineated by three authors (DE, LV, IC) using the high-resolution segment of the radiation treatment planning software (Eclipse™ v11.0 software, Varian, Palo Alto, CA). During a multi-disciplinary session, the senior radiation oncologist (DE), neuro-radiologist (AP), and two residents in radiation oncology (LV, IC) discussed the delineation of the OARs and came to consensus on a first draft atlas. This draft was then critically reviewed by Dutch and international experts in neuro-oncology and consensus on the final version of this atlas was reached.

      Acquisition of CT and MR

      CT images were acquired with intravenous contrast (Ultravist®, 150 ml of 300 mg Iodine per mL, 2 mL per sec, 5 min delay, slice thickness 1 mm, 50 cm field of view, 120 kV, 685 mAs) using window-width/window-level settings (WW/WL) of 120/40 and 120/1500 (SOMATOM Sensation 10, Siemens Healthcare, Erlangen, Germany) of the head of an adult male low grade glioma patient after first resection. Moreover, a three-dimensional spoiled gradient (3D-SPGR) axial 3T MR scan (1 mm slice thickness) of the same patient in standard axial, sagittal and coronal reconstruction, and an axial T2- and a gadolinium (Gadovist® 1.0 mmol/ml 0.1 mL/kg bodyweight) contrast-enhanced axial T1-weighted sequence were acquired, with sagittal and coronal reconstruction. Both CT and MR were obtained in the supine position with the head in a neutral position; immobilization devices routinely used in radiation therapy were used for CT acquisition. Rigid MR-CT co-registration and delineation were performed using the Eclipse™ treatment planning system with the high-resolution segment.
      For illustration purposes, 7T MR images of a healthy volunteer were acquired (Siemens Magnetom 7T) with a slice thickness of 0.7 mm using a 32-channel head coil (Nova Medical Inc., Wilmington, CA; Fig. 1). The magnetization-prepared rapid gradient-echo (MP2RAGE) was selected for OAR delineation due to its superior soft tissue contrast (Fig. 2). Scan parameters have previously been published by Compter et al. [
      • Compter I.
      • Peerlings J.
      • Eekers D.B.
      • Postma A.A.
      • Ivanov D.
      • Wiggins C.J.
      • et al.
      Technical feasibility of integrating 7 T anatomical MRI in image-guided radiotherapy of glioblastoma: a preparatory study.
      ]. Vendor-based 3D distortion correction methods were applied.
      Figure thumbnail gr1
      Fig. 1Sagittal (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.
      Figure thumbnail gr2
      Fig. 2Sagittal (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.

      Three-dimensional description of the OARs

      Cornea (“Cornea_R”, “Cornea_L” and “Corneas”)

      The cornea is located at the anterior segment of the eyeball consisting of the structures ventral to the vitreous humor, the iris, ciliary body, and lens [
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ]. Using a brush of 2–3 mm the cornea can easily be delineated on MR as well as CT.

      Retina (“Retina_R”, “Retina_L” and “Retinas”)

      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 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 covering the posterior 5/6 of the globe, extending nearly as far as the ciliary body. The anterior border of the retina is between the insertion of the medial rectus muscle and the lateral rectus muscle, posterior to the ciliary body. The optic nerve is excluded from this contour [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ].

      Lacrimal gland (“LacrimalGland L”, “LacrimalGland_R” and “LacrimalGlands”)

      The lacrimal gland is an almond shaped gland (18 mm craniocaudally, 15 mm axial length and 5 mm axial width) located in the orbit superior-lateral to the eye, superior to the lateral rectus muscle and lateral to the superior rectus muscle. It can be delineated on CT using soft brain 120/40 or soft tissue 350/50 WW/WL settings [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ,
      • Bulbul E.
      • Yazici A.
      • Yanik B.
      • Yazici H.
      • Demirpolat G.
      Evaluation of lacrimal gland dimensions and volume in turkish population with computed tomography.
      ].

      Lens of the Eye (“Lens_R”, “Lens_L” and “Lenses”)

      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 [
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ]. It should be taken into account that without instructing the patient, the position of the lens is not fixed and can vary during treatment.

      Optic nerve (“OpticNerve_R”, “OpticNerve_L” and “OpticNerves”)

      The optic nerve (2–5 mm thick) is delineated from the posterior edge of the eyeball, through the bony optic canal, where it narrows slightly, to the optic chiasm. Close to the optic chiasm, an MR scan (T1 weighted) is recommended for better delineation of the optic nerve. Contouring the optic nerve in continuity with the chiasm is crucial for dose reporting purposes, as dose gradients can be very steep with modern photon and proton techniques [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Celesia G.G.
      • DeMarco Jr., P.J.
      Anatomy and physiology of the visual system.
      ].

      Optic chiasm (“Chiasm”)

      The optic chiasm (14 mm transverse, 8 mm antero-posterior 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 internal carotid artery. The chiasm is superiorly located in the antero-inferior part of the third ventricle, below the supra-optic recess and above the infundibular recess of the third ventricle, with the optic nerves in front and the divergence of the optic tracts behind. The anterior cerebral arteries and the anterior communicating artery are located ventral to the chiasm. A T1 weighted MR (axial, sagittal and coronal) is recommended for delineation of the optic chiasm [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ].

      Pituitary gland (“Pituitary”)

      The pituitary gland cannot be easily identified on axial CT, although the bony margins of the fossa are well shown. It is oval-shaped (craniocaudally up to 12 mm) and lies in the sella turcica. Laterally, the pituitary gland is bordered by the cavernous sinuses, which are well visible with intravenous contrast agent, it is just inferior to the brain, and is connected to the hypothalamus by its pituitary stalk. The borders of the pituitary gland can be defined best in the sagittal view [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Kong F.M.
      • Ritter T.
      • Quint D.J.
      • Senan S.
      • Gaspar L.E.
      • Komaki R.U.
      • et al.
      Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
      ]. Alternatively, the inner part of the sella turcica can be used as a surrogate anatomical bony structure best identified using bone 1500/950 or soft tissue 350/50 WL/WW on CT.

      Hypothalamus (“Hypothalamus_R, “Hypothalamus_L” and “Hypothalami”)

      The hypothalamus (2–4 cm3) is a polygonal structure consisting of two separate volumes on each side of the third ventricle, delineated using MR-based anatomic landmarks representing surrogate boundaries for the hypothalamus itself. The superior boundaries are the axial slices containing the anterior and the posterior commissure. Inferiorly, the boundary consists of the base of the third ventricle or the visible edge of the cerebrospinal fluid (CSF) space within the suprasellar cistern, while posteriorly the contour reaches to the level of the interpeduncular fossa. The mammillary bodies should be included in the contour. The medial border consists of the third ventricle or the visible CSF space. Since the lateral border is not clearly visible, the contour was bounded laterally 3 mm from the third ventricle. Delineation on a T1 weighted MR is strongly recommended [
      • Merchant T.E.
      • Goloubeva O.
      • Pritchard D.L.
      • Gaber M.W.
      • Xiong X.
      • Danish R.K.
      • et al.
      Radiation dose-volume effects on growth hormone secretion.
      ,
      • Elson A.
      • Bovi J.
      • Kaur K.
      • Maas D.
      • Sinson G.
      • Schultz C.
      Effect of treatment modality on the hypothalamic-pituitary function of patients treated with radiation therapy for pituitary adenomas: hypothalamic dose and endocrine outcomes.
      ,
      • Rappaport R.
      • Brauner R.
      Growth and endocrine disorders secondary to cranial irradiation.
      ,
      • Baroncini M.
      • Jissendi P.
      • Balland E.
      • Besson P.
      • Pruvo J.P.
      • Francke J.P.
      • et al.
      MRI atlas of the human hypothalamus.
      ].

      Hippocampus (“Hippocampus_P_R”, “Hippocampus_P_L”, “Hippocampus_A_R”, “Hippocampus_A_L”, and “Hippocampi”)

      The literature describes considerable age- and disease-specific variability in hippocampal size (range 2.8–4.0 cm3) and location [
      • Gondi V.
      • Tolakanahalli R.
      • Mehta M.P.
      • Tewatia D.
      • Rowley H.
      • Kuo J.S.
      • et al.
      Hippocampal-sparing whole-brain radiotherapy: A “howto” technique, utilizing helical tomotherapy and LINAC-based intensity modulated radiotherapy.
      ,
      • Chera B.S.
      • Amdur R.J.
      • Patel P.
      • Mendenhall W.M.
      A radiation oncologist's guide to contouring the hippocampus.
      ,
      • Konrad C.
      • Ukas T.
      • Nebel C.
      • Arolt V.
      • Toga A.W.
      • Narr K.L.
      Defining the human hippocampus in cerebral magnetic resonance images. An overview of current segmentation protocols.
      ,
      • Bender E.T.
      • Mehta M.P.
      • Tomé W.A.
      On the estimation of the location of the hippocampus in the context of hippocampal avoidance whole brain radiotherapy treatment planning.
      ]. The hippocampus (HC) is delineated as the gray matter medial to the medial boundary of the temporal horn of the lateral ventricle, bordered medially by the quadrigeminal cistern as described by Gondi et al. [
      • Gondi V.
      • Tolakanahalli R.
      • Mehta M.P.
      • Tewatia D.
      • Rowley H.
      • Kuo J.S.
      • et al.
      Hippocampal-sparing whole-brain radiotherapy: A “howto” technique, utilizing helical tomotherapy and LINAC-based intensity modulated radiotherapy.
      ]. Blum et al. [
      • Blum S.
      • Habeck C.
      • Steffener J.
      • Razlighi Q.
      • Stern Y.
      Functional connectivity of the posterior hippocampus is more dominant as we age.
      ] suggest a separation of the HC into a posterior (corpus) and anterior (head) part using the lateral ventricle as dorsal border for the anterior hippocampus. In sagittal view, the head of the HC is separated from the body at the narrowing of the HC, with the uncus located dorsally [
      • Blum S.
      • Habeck C.
      • Steffener J.
      • Razlighi Q.
      • Stern Y.
      Functional connectivity of the posterior hippocampus is more dominant as we age.
      ,
      • Sivakumar P.T.
      • Kalmady S.V.
      • Venkatasubramanian G.
      • Bharath S.
      • Reddy N.N.
      • Rao N.P.
      • et al.
      Volumetric analysis of hippocampal sub-regions in late onset depression: a 3 tesla magnetic resonance imaging study.
      ]. Delineation on MR (T1 weighted) is essential.

      Cochlea (“Cochlea_R”, “Cochlea_L” and “Cochleas”)

      The cochlea is a spiral structure (up to 0.6 cm3) located in a bony cavity in the petrous portion of the temporal bone, caudal to the semicircular canals, lateral to the internal auditory canal. Using a WW/WL setting of 120/1500 on CT images, its volume can be defined as a small cavity. The structures of the inner ear are well visible on MR (T2 weighted) images [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ]. The semicircular canals should not be included.

      Vestibular and semicircular canal (“VSCC_R”, “VSCC_L”, “VSCCs”)

      As the semicircular canals are a part of the bony labyrinth with the superior, posterior and lateral canals aligned in three planes, delineation is advised using the bone setting on CT images (WW/WL 120/1500). The semicircular canal is located laterally and cranially of the cochlea. The canals are also visible as small cavities on MR (T2 weighted) [
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ].

      Brain Stem (“BrainStem”, “Brainstem_surface”, “Brainstem_interior” or “Midbrain”, “Pons” and “Medulla Oblongata”)

      The brainstem is to be contoured on MR images and can be divided into three parts, from cranial to caudal, the midbrain, pons and medulla oblongata. The midbrain is defined from the nigral substance at the cerebral peduncle to the upper border of the pons. The pons is an oval shaped structure on sagittal views, which is easy to discriminate (see Fig. 1C). The caudal limit of the medulla oblongata is the tip of the dens of C2 (i.e., the odontoid peg), which is also the cranial border of the spinal cord; the cranial limit is the ponto-medullary junction [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ,
      • Kocak-Uzel E.
      • Gunn G.B.
      • Colen R.R.
      • et al.
      Beam path toxicity in candidate organs-at-risk: Assessment of radiation emetogenesis for patients receiving head and neck intensity modulated radiotherapy.
      ]. For practical reason the cerebral aqueduct is included until it becomes the 4th ventricle. The brainstem interior is the brainstem surface contour cropped by 2 mm (inner border). The brainstem surface is the brainstem excluding the brainstem interior [
      • Noël G.
      • Habrand J.L.
      • Mammar H.
      • Haie-Meder C.
      • Pontvert D.
      • Dederke S.
      • et al.
      Highly conformal therapy using proton component in the management of meningiomas. Preliminary experience of the Centre de Protonthérapie d'Orsay.
      ,
      • Feuvret L.
      • Bracci S.
      • Calugaru V.
      • Bolle S.
      • Mammar H.
      • De Marzi L.
      • et al.
      Efficacy and safety of adjuvant proton therapy combined with surgery for chondrosarcoma of the skull base: a retrospective, population-based study.
      ]. These structures are contoured automatically (and checked thereafter) using a built-in delineation tool commonly found in treatment planning systems.

      Brain (“Brain” and “Brain_Supratentorial”)

      The delineation of the brain includes the cerebellum, CSF and small brain vessels, and excludes the brainstem and large cerebellar vessels, such as the sigmoid sinus, transverse sinus and superior sagittal sinus (Fig. 3C). For delineation purposes, CT in brain soft tissue 350/40 WW/WL-settings is recommended. Alternatively, the brain can be contoured automatically (and checked thereafter) using a built-in delineation tool commonly found in the majority of treatment planning systems [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ,
      • Sun Y.
      • Yu X.-L.
      • Luo W.
      • et al.
      Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy.
      ]. In the middle cranial fossa the carotid canal and cavernous sinuses, most easily seen on contrast-enhanced T1 MRI, should not be included. The supratentorial brain equals the “Brain” excluding the cerebellum (see Section “Cerebellum (“Cerebellum_P”, “Cerebellum_A’ and “Cerebellum”)”).
      Figure thumbnail gr3
      Fig. 33D 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.

      Cerebellum (“Cerebellum_P”, “Cerebellum_A’ and “Cerebellum”)

      The separation of the cerebellum into an anterior and posterior part is best seen on the sagittal T1 weighted MR (see Fig. 1). The anterior cerebellum consists of the cranial part of the cerebellum including half of the medullary corpus. The posterior cerebellum consists of the caudal and posterior part of the cerebellum with a cranial border including the lower half of the medullary corpus. This part includes the flocculonodular lobe. The primary fissure, which is best seen on 7-Tesla MR (see Fig. 2), divides the anterior part from the posterior part of the cerebellum [
      • Schmahmann J.D.
      • Doyon J.
      • McDonald D.
      • Holmes C.
      • Lavoie K.
      • Hurwitz A.S.
      • et al.
      Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space.
      ]. The lateral borders for both parts are the large vessels (the sigmoid sinus, transverse sinus and superior sagittal sinus) and CSF, which are both excluded.

      Skin (“Skin”)

      The skin is the volume defined by the body contour (outer border) and the body contour cropped by 5 mm (inner border), both created on the CT. This structure is contoured automatically (and checked thereafter) using a built-in delineation tool commonly found in treatment planning systems [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ,
      • Sun Y.
      • Yu X.-L.
      • Luo W.
      • et al.
      Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy.
      ].
      All mentioned OARs are delineated on CT and MR (see Fig. 3) in an easily accessible delineation atlas at www.cancerdata.org [
      • Eekers D.B.P.
      • in ‘t Ven L.
      • Roelofs E.
      • Postma A.
      • Troost E.G.C.
      EPTN International Neurological Contouring Atlas.
      ].

      Discussion

      The presented atlas for contouring OARs involved in neuro-oncology aims at reducing the inter- and intra-observer delineation variability and thus enabling more consistent plan comparison. This is especially relevant when comparing different radiation treatment techniques and modalities, and for establishing detailed dose–response relationships and NTCP models for different OARs.
      Toxicity to the optical system is a feared complication especially when it results in partial or total loss of vision or pain to the eye. Despite their small volume, a separate delineation of the different optical structures is crucial in order to derive dose–volume histograms and predict post-radiation toxicity. The optic chiasm is an anatomically cross-shaped structure, as is depicted by Scoccianti et al. [
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ] and not round as presented in the atlas by Brouwer et al. [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ]. Moreover, the chiasm should be contoured in continuity with both optic nerves in order to prevent high-dose deposits in un-delineated voxels. The retina is to be delineated separately from the vitreous body, since radiation induced retinopathy can be treated if observed in an early state. Consequently, correct dose calculation is of utmost relevance in order to refer a patient suffering from this radiation induced side-effect [
      • Jeganathan V.S.
      • Wirth A.
      • MacManus M.P.
      Ocular risks from orbital and periorbital radiation therapy: a critical review.
      ]. Separate delineation of the cornea is proposed since toxicity and tolerance dose differ from that of the retina [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Jeganathan V.S.
      • Wirth A.
      • MacManus M.P.
      Ocular risks from orbital and periorbital radiation therapy: a critical review.
      ,
      • Barabino S.
      • Raghavan A.
      • Loeffler J.
      • Dana R.
      Radiotherapy-induced ocular surface disease.
      ]. Damage to the cornea, radiation keratitis, is painful and deteriorates sight. The mean radiation dose to the lacrimal gland is related to the development of a dry eye, which can be painful and render the eye susceptible to infections [
      • Jeganathan V.S.
      • Wirth A.
      • MacManus M.P.
      Ocular risks from orbital and periorbital radiation therapy: a critical review.
      ]. A cataract can develop at a rather low dose to the lens. This side-effect can be alleviated by surgical implantation of an artificial lens [
      • Jeganathan V.S.
      • Wirth A.
      • MacManus M.P.
      Ocular risks from orbital and periorbital radiation therapy: a critical review.
      ]. A normal lens is well seen because of its high protein content, whereas an artificial lens is difficult to see on CT or MR, but since it tolerates radiation dose, delineation is not required.
      Hypo-pituitarism may take a long time to be diagnosed since its symptoms can be vague. Depending on the mean dose to the pituitary gland, an early referral to an endocrinologist can facilitate early initiation of treatment and thus prevent impaired quality of life [
      • De Marzi L.
      • Feuvret L.
      • Boulé T.
      • Habrand J.L.
      • Martin F.
      • Calugaru V.
      • et al.
      Use of gEUD for predicting ear and pituitary gland damage following proton and photon radiation therapy.
      ,
      • Darzy K.H.
      • Shalet S.M.
      Hypopituitarism following Radiotherapy Revisited.
      ]. In general, it is advised to delineate the entire sella content to be sure the whole pituitary is included rather than the central part only, excluding the suprasellar part of the infundibulum [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ]. Even though there are no established dose constraints for the hypothalamus available yet, we believe that these data need to be collected in a prospective manner, in order to correlate levels of hormone production and regulation of metabolic processes with delivered radiation dose.
      Hearing preservation after radiotherapy is known to be related to dose to the cochlea [
      • Bhandare N.
      • Jackson A.
      • Eisbruch A.
      • Pan C.C.
      • Flickinger J.C.
      • Antonelli P.
      • et al.
      Radiation therapy and hearing loss.
      ,
      • Mujica-Mota M.
      • Waissbluth S.
      • Daniel S.J.
      Characteristics of radiation-induced sensorineural hearing loss in head and neck cancer: a systematic review.
      ,
      • Gondi V.
      • Hermann B.P.
      • Mehta M.P.
      • Tomé W.A.
      Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.
      ]. There is agreement in the literature on its delineation, most optimally done on a CT scan with thin slices using a bone WW/WL-setting considering its location in the mastoid bone [
      • Brouwer C.L.
      • Steenbakkers R.J.
      • Bourhis J.
      • Budach W.
      • Grau C.
      • Grégoire V.
      • et al.
      CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
      ,
      • Scoccianti S.
      • Detti B.
      • Gadda D.
      • Greto D.
      • Furfaro I.
      • Meacci F.
      • et al.
      Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
      ]. Since dizziness is a side-effect occasionally reported after radiotherapy it was decided to delineate the semicircular canals as well, using the same WW/WL-settings as for the cochlea, although future data are needed to establish a validated dose constraint.
      Recent literature has shown some dose–response relationship between the hippocampus and cognition as described by Gondi et al. [
      • Gondi V.
      • Hermann B.P.
      • Mehta M.P.
      • Tomé W.A.
      Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.
      ] using the absolute radiation dose to 40% of both hippocampi (D40%). We firmly encourage delineating the hippocampi separately and into anterior and posterior parts, since the left hippocampus is known to be dominant in most patients (including left-handed patients) for verbal memory, and the right hippocampus for non-verbal memory also known as visual memory. Moreover, the posterior parts of the hippocampi are more related to memory than the anterior parts [
      • Greene-Schloesser D.
      • Moore E.
      • Robbins M.E.
      Molecular pathways: radiation-induced cognitive impairment.
      ,
      • Tsai P.F.
      • Yang C.C.
      • Chuang C.C.
      • Huang T.Y.
      • Wu Y.M.
      • Pai P.C.
      • et al.
      Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study.
      ,
      • Blum S.
      • Habeck C.
      • Steffener J.
      • Razlighi Q.
      • Stern Y.
      Functional connectivity of the posterior hippocampus is more dominant as we age.
      ,
      • Poppenk J.
      • Moscovitch M.
      A hippocampal marker of recollection memory ability among healthy young adults: contributions of posterior and anterior segments.
      ,
      • Lee A.W.
      • Foo W.
      • Chappell R.
      • Fowler J.F.
      • Sze W.M.
      • Poon Y.F.
      • et al.
      Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma.
      ].
      The brain is often automatically delineated and for practical reasons the included small vessels are left in the contour since editing the contour would be too time consuming. There are dose constraints for brain tissue, especially on high doses related to temporal lobe radionecrosis in head and neck cancer patients [
      • Armstrong G.T.
      • Jain N.
      • Liu W.
      • Merchant T.E.
      • Stovall M.
      • Srivastava D.K.
      • et al.
      Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies.
      ,
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • Ten Haken R.K.
      • Constine L.S.
      • Eisbruch A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ,
      • Su S.F.
      • Huang S.M.
      • Han F.
      • Huang Y.
      • Chen C.Y.
      • Xiao W.W.
      • et al.
      Analysis of dosimetric factors associated with temporal lobe necrosis (TLN) in patients with nasopharyngeal carcinoma (NPC) after intensity modulated radiotherapy.
      ,
      • Hsu Y.C.
      • Wang L.F.
      • Lee K.W.
      • Ho K.Y.
      • Huang C.J.
      • Kuo W.R.
      Cerebral radionecrosis in patients with nasopharyngeal carcinoma.
      ,
      • Zeng L.
      • Huang S.M.
      • Tian Y.M.
      • Sun X.M.
      • Han F.
      • Lu T.X.
      • et al.
      Normal tissue complication probability model for radiation-induced temporal lobe injury after intensity-modulated radiation therapy for nasopharyngeal carcinoma.
      ,
      • Mulhern R.K.
      • Fairclough D.
      • Ochs J.
      A prospective comparison of neuropsychologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation.
      ]. Regarding neuro-cognition, some publications on pediatric patients have shown a correlation between low dose radiation to the supra-tentorial brain and cognitive decline [
      • Mulhern R.K.
      • Kepner J.L.
      • Thomas P.R.
      • Armstrong F.D.
      • Friedman H.S.
      • Kun L.E.
      Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study.
      ,
      • Armstrong G.T.
      • Jain N.
      • Liu W.
      • Merchant T.E.
      • Stovall M.
      • Srivastava D.K.
      • et al.
      Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies.
      ]. Further data are needed to transfer this knowledge to adult patients. Data on whole brain radiotherapy and prophylactic cranial irradiation have hinted at the negative effect of low dose on cognition [
      • Peiffer A.M.
      • Leyrer C.M.
      • Greene-Schloesser D.M.
      • Shing E.
      • Kearns W.T.
      • Hinson W.H.
      • et al.
      Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline.
      ,
      • Ravn S.
      • Holmberg M.
      • Sørensen P.
      • Frøkjær J.B.
      • Carl J.
      Differences in supratentorial white matter diffusion after radiotherapy–new biomarker of normal brain tissue damage?.
      ,
      • Gregor A.
      • Cull A.
      • Traynor E.
      • Stewart M.
      • Lander F.
      • Love S.
      Neuropsychometric evaluation of long-term survivors of adult brain tumours: relationship with tumour and treatment parameters.
      ,
      • Tallet A.V.
      • Azria D.
      • Barlesi F.
      • Spano J.P.
      • Carpentier A.F.
      • Gonçalves A.
      • et al.
      Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment.
      ,
      • Gan H.K.
      • Bernstein L.J.
      • Brown J.
      • Ringash J.
      • Vakilha M.
      • Wang L.
      • et al.
      Cognitive functioning after radiotherapy or chemoradiotherapy for head-and-neck cancer.
      ,
      • Makale M.T.
      • McDonald C.R.
      • Hattangadi-Gluth J.A.
      • Kesari S.
      Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours.
      ,
      • Edelstein K.
      • Richard N.M.
      • Bernstein L.J.
      Neurocognitive impact of cranial radiation in adults with cancer: an update of recent findings.
      ,
      • Shih H.A.
      • Sherman J.C.
      • Nachtigall L.B.
      • Colvin M.K.
      • Fullerton B.C.
      • Daartz J.
      • et al.
      Proton therapy for low-grade gliomas: Results from a prospective trial.
      ]. However, there still is a strong need for an adult NTCP model on brain tissue and cognition.
      Symptomatic brainstem necrosis is a feared, but rare complication following radiotherapy to the brain [
      • Mayo C.
      • Yorke E.
      • Merchant T.E.
      Radiation associated brainstem injury.
      ,
      • DeSalvo M.N.
      Radiation necrosis of the pons after radiotherapy for nasopharyngeal carcinoma: diagnosis and treatment.
      ]. It was decided to contour the brainstem in three anatomically distinct parts, because some hypothesize that specific volumes within the brainstem are more sensitive to radiation than others. In particle beam therapy, the anterior surface and center of the brainstem are delineated separately since a higher tolerance at the surface of the brainstem has been observed [
      • Noël G.
      • Habrand J.L.
      • Mammar H.
      • Haie-Meder C.
      • Pontvert D.
      • Dederke S.
      • et al.
      Highly conformal therapy using proton component in the management of meningiomas. Preliminary experience of the Centre de Protonthérapie d'Orsay.
      ,
      • Feuvret L.
      • Bracci S.
      • Calugaru V.
      • Bolle S.
      • Mammar H.
      • De Marzi L.
      • et al.
      Efficacy and safety of adjuvant proton therapy combined with surgery for chondrosarcoma of the skull base: a retrospective, population-based study.
      ]. This should be subject to further research for both photon and particle radiotherapy.
      The delineation of the cerebellum is also added as a possible new OAR for research purposes, since there are data suggesting a relationship between the posterior cerebellum and cognition [
      • Eekers D.B.P.
      • ’t Ven L.
      • Deprez S.
      • Jacobi L.
      • Roelofs E.
      • Hoeben A.
      • Lambin P.
      • de Ruysscher D.
      • Troost E.G.C.
      The posterior cerebellum, a new organ at risk?.
      ]. Cantelmi et al. [
      • Cantelmi D.
      • Schweizer T.A.
      • Cusimano M.D.
      Role of the cerebellum in the neurocognitive sequelae of treatment of tumours of the posterior fossa: an update.
      ] state that recognition of the important 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 dose, which is only possible when agreement is reached in the delineation, as proposed based on Schmahmann et al. [
      • Schmahmann J.D.
      • Doyon J.
      • McDonald D.
      • Holmes C.
      • Lavoie K.
      • Hurwitz A.S.
      • et al.
      Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space.
      ,
      • Mayo C.
      • Yorke E.
      • Merchant T.E.
      Radiation associated brainstem injury.
      ,
      • Cantelmi D.
      • Schweizer T.A.
      • Cusimano M.D.
      Role of the cerebellum in the neurocognitive sequelae of treatment of tumours of the posterior fossa: an update.
      ].
      For radiation treatment planning purposes, the skin is added as an OAR since alopecia and erythema are disturbing side-effects. Using the skin structure enables lowering the dose during treatment planning, which is of particular importance in proton therapy with its relatively high entry dose [
      • Whaley J.T.
      • Kirk M.
      • Cengel K.
      • McDonough J.
      • Bekelman J.
      • Christodouleas J.P.
      Protective effect of transparent film dressing on proton therapy induced skin reactions.
      ].
      A limitation of the atlas is the fact that the three dimensional angulation possibilities in a radiation treatment planning systems are often limited and patients are mostly not aligned perfectly in the midline. This is why the atlas was based on a random CT/MR-dataset of an imperfectly aligned patient, resembling routine clinical practice. The atlas includes transversal, coronal and sagittal views to assist the delineation process. A second potential limitation of this atlas is that we had to limit the number of OARs proposed for otherwise the atlas would have been impracticable and thus not used in routine clinical practice. Future research should unravel the role of additional OARs and the NTCP value for: Eustachian tube, circle of Willis, optic tract, frontal & temporal lobe, anterior eye chambers, macula, mammillary bodies, spinal canal and cerebrospinal space. Thirdly, this atlas does not summarize the available literature on dose constraints for the contoured organs at risk; this enormous effort will be a separate project of the EPTN. Finally, even though this atlas was contoured on a 3T MR scan, it can be easily transferred to 1.5T MR images.
      Uniform contouring of structures in the central nervous system, both in photon and particle therapy, is considered important for: (1) the generalization of normal tissue dose constraints, (2) establishment or update of NTCP models taking into account new radiation treatment techniques, and (3) for comparative multicenter clinical studies on radiotherapy in patients with primary brain tumors. Besides uniform contouring, consensus on OAR dose constraints is also required for implementing and improving NTCP models. A separate article on dose constraints for the given OARs, again consented by the EPTN, is currently being prepared.

      Conclusion

      In order to decrease variability in delineating OARs involved in neuro-oncology and to allow the generation of consistent dosimetric data, we propose an atlas for neuro-oncology including some new OARs in order to give an anatomical basis for the development of international acknowledged constraints and volumes. This will enable the community to amplify existing and new NTCP models such that more accurate prediction, and possibly prevention, of long-term radiation toxicity comes within reach. The atlas is available online on www.cancerdata.org and will be updated whenever required.

      Acknowledgement

      The authors sincerely thank all the members of the Dutch Platform for Radiation in Neuro-Oncology for their input and consensus, and they thank Marlies Granzier, radiation technologist at MAASTRO clinic for her expertise and support with data transfer and image fusion. NGB is supported by the National Institute for Health Research Cambridge Biomedical Research Centre .

      Disclosure of conflicts of interest

      This research was partially supported by the Brains Unlimited Pioneer Fund of the Limburg University Fund /SWOL (S.2013.1.011).

      Ethical publication statement

      We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

      References

        • Eekers D.B.
        • Roelofs E.
        • Jelen U.
        • Kirk M.
        • Granzier M.
        • Ammazzalorso F.
        • et al.
        Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial.
        Radiother Oncol. 2016; 121: 387-394
        • Roelofs E.
        • Engelsman M.
        • Rasch C.
        • Persoon L.
        • Qamhiyeh S.
        • de Ruysscher D.
        • Verhaegen F.
        • Pijls-Johannesma M.
        • Lambin P.
        ROCOCO Consortium. Results of a multicentric in silico clinical trial (ROCOCO): comparing radiotherapy with photons and protons for non-small cell lung cancer.
        J Thorac Oncol. 2012; 7: 165-176
        • van der Laan H.P.
        • van de Water T.A.
        • van Herpt H.E.
        • Christianen M.E.
        • Bijl H.P.
        • Korevaar E.W.
        • Rasch C.R.
        • van 't Veld A.A.
        • van der Schaaf A.
        • Schilstra C.
        • Langendijk J.A.
        • Rococo cooperative group
        The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study.
        Acta Oncol. 2013; 52: 561-569
        • Brouwer C.L.
        • Steenbakkers R.J.
        • Bourhis J.
        • Budach W.
        • Grau C.
        • Grégoire V.
        • et al.
        CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines.
        Radiother Oncol. 2015; 117: 83-90
        • Kong F.M.
        • Ritter T.
        • Quint D.J.
        • Senan S.
        • Gaspar L.E.
        • Komaki R.U.
        • et al.
        Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
        Int J Radiat Oncol Biol Phys. 2011; 81: 1442-1457
        • Scoccianti S.
        • Detti B.
        • Gadda D.
        • Greto D.
        • Furfaro I.
        • Meacci F.
        • et al.
        Organs at risk in the brain and their dose-constraints in adults and in children: a radiation oncologist's guide for delineation in everyday practice.
        Radiother Oncol. 2015; 114: 230-238
        • Gondi V.
        • Tolakanahalli R.
        • Mehta M.P.
        • Tewatia D.
        • Rowley H.
        • Kuo J.S.
        • et al.
        Hippocampal-sparing whole-brain radiotherapy: A “howto” technique, utilizing helical tomotherapy and LINAC-based intensity modulated radiotherapy.
        Int J Radiat Oncol Biol Phys. 2010; 78: 1244-1252
        • Weber D.C.
        • Abrunhosa-Branquinho A.
        • Bolsi A.
        • Kacperek A.
        • Dendale R.
        • Geismar D.
        • et al.
        Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire.
        Radiother Oncol. 2017; 124: 185-189
        • Santanam L.
        • Hurkmans C.
        • Mutic S.
        • van Vliet-Vroegindeweij C.
        • Brame S.
        • Straube W.
        • et al.
        Standardizing naming conventions in radiation oncology.
        Int J Radiat Oncol Biol Phys. 2012; 83: 1344-1349
        • Compter I.
        • Peerlings J.
        • Eekers D.B.
        • Postma A.A.
        • Ivanov D.
        • Wiggins C.J.
        • et al.
        Technical feasibility of integrating 7 T anatomical MRI in image-guided radiotherapy of glioblastoma: a preparatory study.
        MAGMA. 2016; 29: 591-603
        • Bulbul E.
        • Yazici A.
        • Yanik B.
        • Yazici H.
        • Demirpolat G.
        Evaluation of lacrimal gland dimensions and volume in turkish population with computed tomography.
        J Clin Diagn Res. 2016; 10: TC06-8
        • Celesia G.G.
        • DeMarco Jr., P.J.
        Anatomy and physiology of the visual system.
        J Clin Neurophysiol. 1994; 11 ([Review]): 482-492
        • Merchant T.E.
        • Goloubeva O.
        • Pritchard D.L.
        • Gaber M.W.
        • Xiong X.
        • Danish R.K.
        • et al.
        Radiation dose-volume effects on growth hormone secretion.
        Int J Radiat Oncol Biol Phys. 2002; 52: 1264-1270
        • Elson A.
        • Bovi J.
        • Kaur K.
        • Maas D.
        • Sinson G.
        • Schultz C.
        Effect of treatment modality on the hypothalamic-pituitary function of patients treated with radiation therapy for pituitary adenomas: hypothalamic dose and endocrine outcomes.
        Front Oncol. 2014; 9: 73
        • Rappaport R.
        • Brauner R.
        Growth and endocrine disorders secondary to cranial irradiation.
        Pediatr Res. 1989; 25 ([Review]): 561-567
        • Baroncini M.
        • Jissendi P.
        • Balland E.
        • Besson P.
        • Pruvo J.P.
        • Francke J.P.
        • et al.
        MRI atlas of the human hypothalamus.
        Neuroimage. 2012; 59: 168-180
        • Chera B.S.
        • Amdur R.J.
        • Patel P.
        • Mendenhall W.M.
        A radiation oncologist's guide to contouring the hippocampus.
        Am J Clin Oncol. 2009; 32: 20-22
        • Konrad C.
        • Ukas T.
        • Nebel C.
        • Arolt V.
        • Toga A.W.
        • Narr K.L.
        Defining the human hippocampus in cerebral magnetic resonance images. An overview of current segmentation protocols.
        Neuroimage. 2009; 47: 1185-1195
        • Bender E.T.
        • Mehta M.P.
        • Tomé W.A.
        On the estimation of the location of the hippocampus in the context of hippocampal avoidance whole brain radiotherapy treatment planning.
        Technol Cancer Res Treat. 2009; 8: 425-432
        • Blum S.
        • Habeck C.
        • Steffener J.
        • Razlighi Q.
        • Stern Y.
        Functional connectivity of the posterior hippocampus is more dominant as we age.
        Cogn Neurosci. 2014; 5: 150-159
        • Sivakumar P.T.
        • Kalmady S.V.
        • Venkatasubramanian G.
        • Bharath S.
        • Reddy N.N.
        • Rao N.P.
        • et al.
        Volumetric analysis of hippocampal sub-regions in late onset depression: a 3 tesla magnetic resonance imaging study.
        Asian J Psychiatr. 2015; 13: 38-43
        • Kocak-Uzel E.
        • Gunn G.B.
        • Colen R.R.
        • et al.
        Beam path toxicity in candidate organs-at-risk: Assessment of radiation emetogenesis for patients receiving head and neck intensity modulated radiotherapy.
        Radiother Oncol. 2014; 111: 281-288
        • Noël G.
        • Habrand J.L.
        • Mammar H.
        • Haie-Meder C.
        • Pontvert D.
        • Dederke S.
        • et al.
        Highly conformal therapy using proton component in the management of meningiomas. Preliminary experience of the Centre de Protonthérapie d'Orsay.
        Strahlenther Onkol. 2002; 178: 480-485
        • Feuvret L.
        • Bracci S.
        • Calugaru V.
        • Bolle S.
        • Mammar H.
        • De Marzi L.
        • et al.
        Efficacy and safety of adjuvant proton therapy combined with surgery for chondrosarcoma of the skull base: a retrospective, population-based study.
        Int J Radiat Oncol Biol Phys. 2016; 95: 312-321
        • Sun Y.
        • Yu X.-L.
        • Luo W.
        • et al.
        Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy.
        Radiother Oncol. 2014; 110: 390-397
        • Schmahmann J.D.
        • Doyon J.
        • McDonald D.
        • Holmes C.
        • Lavoie K.
        • Hurwitz A.S.
        • et al.
        Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space.
        Neuroimage. 1999; 10: 233-260
        • Eekers D.B.P.
        • in ‘t Ven L.
        • Roelofs E.
        • Postma A.
        • Troost E.G.C.
        EPTN International Neurological Contouring Atlas.
        CancerData. 2017; https://doi.org/10.17195/candat.2017.08.1
        • Jeganathan V.S.
        • Wirth A.
        • MacManus M.P.
        Ocular risks from orbital and periorbital radiation therapy: a critical review.
        Int J Radiat Oncol Biol Phys. 2011; 79: 650-659
        • Barabino S.
        • Raghavan A.
        • Loeffler J.
        • Dana R.
        Radiotherapy-induced ocular surface disease.
        Cornea. 2005; 24 ([Review]): 909-914
        • De Marzi L.
        • Feuvret L.
        • Boulé T.
        • Habrand J.L.
        • Martin F.
        • Calugaru V.
        • et al.
        Use of gEUD for predicting ear and pituitary gland damage following proton and photon radiation therapy.
        Br J Radiol. 2015; 88: 20140413
        • Darzy K.H.
        • Shalet S.M.
        Hypopituitarism following Radiotherapy Revisited.
        Endocr Dev. 2009; 15: 1-24
        • Bhandare N.
        • Jackson A.
        • Eisbruch A.
        • Pan C.C.
        • Flickinger J.C.
        • Antonelli P.
        • et al.
        Radiation therapy and hearing loss.
        Int J Radiat Oncol Biol Phys. 2010; 76: S50-S57
        • Mujica-Mota M.
        • Waissbluth S.
        • Daniel S.J.
        Characteristics of radiation-induced sensorineural hearing loss in head and neck cancer: a systematic review.
        Head Neck. 2013; 35: 1662-1668
        • Gondi V.
        • Hermann B.P.
        • Mehta M.P.
        • Tomé W.A.
        Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.
        Int J Radiat Oncol Biol Phys. 2012; 83: e487-e493
        • Greene-Schloesser D.
        • Moore E.
        • Robbins M.E.
        Molecular pathways: radiation-induced cognitive impairment.
        Clin Cancer Res. 2013; 19: 2294-2300
        • Tsai P.F.
        • Yang C.C.
        • Chuang C.C.
        • Huang T.Y.
        • Wu Y.M.
        • Pai P.C.
        • et al.
        Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study.
        Radiat Oncol. 2015; 10: 253
        • Blum S.
        • Habeck C.
        • Steffener J.
        • Razlighi Q.
        • Stern Y.
        Functional connectivity of the posterior hippocampus is more dominant as we age.
        Cogn Neurosci. 2014; 5: 150-159
        • Poppenk J.
        • Moscovitch M.
        A hippocampal marker of recollection memory ability among healthy young adults: contributions of posterior and anterior segments.
        Neuron. 2011; 72: 931-937
        • Lee A.W.
        • Foo W.
        • Chappell R.
        • Fowler J.F.
        • Sze W.M.
        • Poon Y.F.
        • et al.
        Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma.
        Int J Radiat Oncol Biol Phys. 1998; 40: 35-42
        • Armstrong G.T.
        • Jain N.
        • Liu W.
        • Merchant T.E.
        • Stovall M.
        • Srivastava D.K.
        • et al.
        Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies.
        Neuro Oncol. 2010; 12: 1173-1186
        • Marks L.B.
        • Yorke E.D.
        • Jackson A.
        • Ten Haken R.K.
        • Constine L.S.
        • Eisbruch A.
        • et al.
        Use of normal tissue complication probability models in the clinic.
        Int J Radiat Oncol Biol Phys. 2010; 76: S10-S19
        • Su S.F.
        • Huang S.M.
        • Han F.
        • Huang Y.
        • Chen C.Y.
        • Xiao W.W.
        • et al.
        Analysis of dosimetric factors associated with temporal lobe necrosis (TLN) in patients with nasopharyngeal carcinoma (NPC) after intensity modulated radiotherapy.
        Radiat Oncol. 2013; 22: 17
        • Hsu Y.C.
        • Wang L.F.
        • Lee K.W.
        • Ho K.Y.
        • Huang C.J.
        • Kuo W.R.
        Cerebral radionecrosis in patients with nasopharyngeal carcinoma.
        Kaohsiung J Med Sci. 2005; 21: 452-459
        • Zeng L.
        • Huang S.M.
        • Tian Y.M.
        • Sun X.M.
        • Han F.
        • Lu T.X.
        • et al.
        Normal tissue complication probability model for radiation-induced temporal lobe injury after intensity-modulated radiation therapy for nasopharyngeal carcinoma.
        Radiology. 2015; 276: 243-249
        • Mulhern R.K.
        • Fairclough D.
        • Ochs J.
        A prospective comparison of neuropsychologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation.
        J Clin Oncol. 1991; 9 ([Erratum in: J Clin Oncol 1991 Oct;9(10):1922]): 1348-1356
        • Mulhern R.K.
        • Kepner J.L.
        • Thomas P.R.
        • Armstrong F.D.
        • Friedman H.S.
        • Kun L.E.
        Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study.
        J Clin Oncol. 1998; 16: 1723-1728
        • Peiffer A.M.
        • Leyrer C.M.
        • Greene-Schloesser D.M.
        • Shing E.
        • Kearns W.T.
        • Hinson W.H.
        • et al.
        Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline.
        Neurology. 2013; 80: 747-753
        • Ravn S.
        • Holmberg M.
        • Sørensen P.
        • Frøkjær J.B.
        • Carl J.
        Differences in supratentorial white matter diffusion after radiotherapy–new biomarker of normal brain tissue damage?.
        Acta Oncol. 2013; 52: 1314-1319
        • Gregor A.
        • Cull A.
        • Traynor E.
        • Stewart M.
        • Lander F.
        • Love S.
        Neuropsychometric evaluation of long-term survivors of adult brain tumours: relationship with tumour and treatment parameters.
        Radiother Oncol. 1996; 41: 55-59
        • Tallet A.V.
        • Azria D.
        • Barlesi F.
        • Spano J.P.
        • Carpentier A.F.
        • Gonçalves A.
        • et al.
        Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment.
        Radiat Oncol. 2012; 28: 77
        • Gan H.K.
        • Bernstein L.J.
        • Brown J.
        • Ringash J.
        • Vakilha M.
        • Wang L.
        • et al.
        Cognitive functioning after radiotherapy or chemoradiotherapy for head-and-neck cancer.
        Int J Radiat Oncol Biol Phys. 2011; 81: 126-134
        • Makale M.T.
        • McDonald C.R.
        • Hattangadi-Gluth J.A.
        • Kesari S.
        Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours.
        Nat Rev Neurol. 2017; 13: 52-64
        • Edelstein K.
        • Richard N.M.
        • Bernstein L.J.
        Neurocognitive impact of cranial radiation in adults with cancer: an update of recent findings.
        Curr Opin Support Palliat Care. 2017; 11: 32-37
        • Shih H.A.
        • Sherman J.C.
        • Nachtigall L.B.
        • Colvin M.K.
        • Fullerton B.C.
        • Daartz J.
        • et al.
        Proton therapy for low-grade gliomas: Results from a prospective trial.
        Cancer. 2015; 121: 1712-1719
        • Mayo C.
        • Yorke E.
        • Merchant T.E.
        Radiation associated brainstem injury.
        Int J Radiat Oncol Biol Phys. 2010; 76: S36-S41
        • DeSalvo M.N.
        Radiation necrosis of the pons after radiotherapy for nasopharyngeal carcinoma: diagnosis and treatment.
        J Radiol Case Rep. 2012; 6: 9-16
        • Eekers D.B.P.
        • ’t Ven L.
        • Deprez S.
        • Jacobi L.
        • Roelofs E.
        • Hoeben A.
        • Lambin P.
        • de Ruysscher D.
        • Troost E.G.C.
        The posterior cerebellum, a new organ at risk?.
        Clin TranslRadiat Oncol. 2018; 8: 22-26
        • Cantelmi D.
        • Schweizer T.A.
        • Cusimano M.D.
        Role of the cerebellum in the neurocognitive sequelae of treatment of tumours of the posterior fossa: an update.
        Lancet Oncol. 2008; 9: 569-576
        • Whaley J.T.
        • Kirk M.
        • Cengel K.
        • McDonough J.
        • Bekelman J.
        • Christodouleas J.P.
        Protective effect of transparent film dressing on proton therapy induced skin reactions.
        Radiat Oncol. 2013; 24: 19