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Department of Radiation Oncology (MAASTRO), GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, The NetherlandsProton Therapy Department South-East Netherlands (ZON-PTC), Maastricht, The Netherlands
Department of Radiation Oncology (MAASTRO), GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, The NetherlandsThe-D Lab: Decision Support for Precision Medicine, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre+, The Netherlands
Department of Radiation Oncology (MAASTRO), GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre, The NetherlandsDepartment of Radiotherapy-Oncology, Leuven Kanker Instituut, UZ Gasthuisberg, Belgium
Clinic for Particle Therapy, University Hospital Essen, West German Cancer Center (WTZ), GermanyWest German Proton Therapy Center Essen (WPE), GermanyGerman Cancer Consortium (DKTK), partnersite Essen, Essen, Germany
The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, United KingdomThe Children’s Brain Tumour Research Network, University of Manchester, Royal Manchester Children’s Hospital, United Kingdom
Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, GermanyInstitute of Radiooncology – OncoRay, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, GermanyOncoRay – National Center for Radiation Research in Oncology, Dresden, GermanyGerman Cancer Consortium (DKTK), partnersite Dresden, Dresden, and German Cancer Research Center (DKFZ), Heidelberg, GermanyNational Center for Tumor Diseases (NCT), partnersite Dresden, Dresden, Germany
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.
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.
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).
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.
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 [
]. 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. [
]. 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 [
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 [
]. 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.
To facilitate future comparison of the structures, the proposed nomenclature is in accordance with work by Santanam et al. [
]. 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. [
]. 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 [
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 [
]. 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 [
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 [
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 [
]. 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 [
]. 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. [
] 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 [
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 [
]. 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) [
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 [
]. 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 [
]. 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 [
]. 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”)”).
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 [
]. 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.
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 [
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. [
]. 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 [
]. 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 [
]. 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 [
]. 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 [
]. 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. [
] 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 [
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 [
]. 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 [
]. 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 [
] 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. [
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 [
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.
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.
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.
Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial.