Fitton et al. 1 Impact of coronal and sagittal views on lung gross tumor volume delineation

Isabelle Fitton1, Ph.D., Joop C. Duppen2, M.Sc., Roel J.H.M. Steenbakkers3, M.D., Ph.D., Heidi

Lotz3, Ph.D., Peter J.C.M. Nowak4, M.D., Ph.D., Coen R.N. Rasch5, M.D., Ph.D., Marcel van

Herk6, Ph.D.

1Georges Pompidou European Hospital, Paris, France, 2The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands, 3University Medical Center Groningen,

Groningen, The Netherlands, 4ERASMUS University Medical Center, Rotterdam, The Netherlands,

(current address: Radiotherapeutisch Centrum Suriname, Paramaribo, Surinam), 5Academic

Medical Center, Amsterdam, The Netherlands, 6 University of Manchester, c/o Christie Hospital

NHS Foundation Trust, Manchester, United Kingdom.

.

Corresponding author:

Professor Marcel van Herk, Chair in Radiotherapy Physics Institute of Cancer Sciences, University of Manchester, c/o Christie Hospital NHS Foundation Trust, Radiotherapy Related Research, Dept

58, Floor 2A, Wilmslow Road, Withington, Manchester, M20 4BX, United Kingdom.

Contact number: Sally Cusselleburrows, +44 (0) 0161 918 7029, fax: +44 (0) 0161 446 8111. email: [email protected]

Running title: Impact of coronal and sagittal views on GTV

Number of pages: 14

Number of tables: 3

Number of figures: 3

Keywords:

Coronal view; Sagittal view; Radiotherapy; Lung cancer; Target delineation; Inter-observer variability. Fitton et al. 2

Acknowledgments- The following persons that delineated the target volumes are acknowledged:

Katrien de Jaeger, Jose S.A. Belderbos, Gijsbert W.P. Kramer (†), Johan Bussink, Appollonia L.J.

Uitterhoeve, Caro C.E. Koning, Geert-Jan van Tienhoven, Patrick T.R. Rodrigus, Bing Oei, P. De

Brouwer.

This work was financially supported by The Dutch Cancer Society (NKB Grant NKI 2000-2247).

Conflicts of Interest Notification

There is no conflict of interest in this manuscript. Fitton et al. 3 Abstract

Background and Purpose: To study the impact of coronal and sagittal views (CSV) on the gross tumor volume (GTV) delineation on CT and matched PET/CT scans in non-small cell lung cancer.

Material and Methods: GTV delineations were performed by 11 experienced radiation oncologists on CT and PET/CT in 22 patients. Two tumor groups were defined: Group I: Primary tumors surrounded by lung or visceral pleura, without venous invasion, and without large extensions to the chest wall or the mediastinum. Group II: Tumors invading the hilar region, heart, large vessels, pericardium, and the mediastinum and/or associated with atelectasis. Tumor volumes and inter- observers variations (SD) were calculated and compared according to the use of axial view only

(AW), axial/coronal/sagittal views (ACSW) and ACSW/PET (ACSWP).

Results: CSV were not frequently used (57.4% out of 242 delineations on CT). For group I, ACSW didn’t improve significantly mean GTVs. SDs were small on CT and on PET (SD=0.3cm). For group II, ACSW had 27-46% smaller observer variation (mean SD=0.7cm) than AW (mean

SD=1.1cm). The smaller observer variation of ACSW users was associated with, on average, a 40% smaller delineated volume (p=0.038). Mean GTV of ACSWP was 21% larger than mean GTV of

ACSW on CT.

Conclusions: For smaller lung tumors surrounded by healthy lung tissue the effect of multiple axis delineation is limited. However, application of coronal and sagittal windows is highly beneficial for delineation of more complex tumors, with atelectasis and/or pathological lymph nodes even if PET is used. Fitton et al. 4 1. Introduction

Progress in diagnostic imaging techniques such as PET-CT allows more and more accurate detection and visualization of lung tumors and their extension (1-2). One aspect of these developments is that patient anatomy can be visualized in different complementary views i.e., axial, coronal and sagittal. The combination of these views allows a better definition of the extent of the lesions and improves diagnostic accuracy in many cases (3-4). The benefit of axial, coronal and sagittal imaging planes in Magnetic Resonance Imaging (MRI) in the thorax was previously investigated (5). Axial images are often superior in evaluating the pretracheal space, subcarinal space, and hilum whereas on coronal images, lateral hilar masses are better defined than anterior or posterior hilar masses (5). Webb et al. (6) described that coronal images in MRI are superior to axial images in evaluating the aortopulmonary window and masses at the lung apex or base. Sagittal images (7) in MRI are most helpful in the evaluation of structures lying in the sagittal plane such as the thoracic aorta and for the estimation of the relationship of subcarinal masses to the trachea, left atrium, and pulmonary artery. For X-ray Computed Tomography (CT) imaging, the application of coronal and sagittal windows was discussed for head and neck tumors. Lell et al. (8) defined the optimal image planes for the delineation of the tumor and specific anatomical structures. Choi et al.

(9) showed that interpreting both axial and coronal images improves the diagnostic accuracy for supraclavicular metastasis. Rousset et al. (10) demonstrated that for evaluation of mediastinal nodes in non-small cell lung cancer before thoracotomy, the measurements of short axis and surface area of the largest nodes were more accurate by the combination of axial and coronal planes. The benefits of using coronal and sagittal views for diagnostic and delineation purposes are available to radiation oncologist and radiologists; while some modern Treatment Planning Systems (TPS) also allows direct contouring on non-axial views. However, the impact of using these views on delineation variability has never been studied. Moreover, the rapid development of new treatment protocols involving nuclear medicine physicians, interventional radiologists and oncologists has led to tumour volume delineation on standard image processing workstations (11) that are much less advanced than their counterparts used in the radiotherapy environment. Finally in routine practice, Fitton et al. 5 even though sagittal and coronal reconstructions are available, they are often ignored for target volume delineation.

The aim of this paper is therefore to study the behaviour of physicians while delineating lung cancer gross tumour volume GTV on CT and PET/CT images, focusing specifically on the consultation of coronal and sagittal views to evaluate its impact on inter-observer variation and size of the delineated GTV.

2. Materials and methods

2.1 CT and PET acquisition

CT and PET images were acquired separately in two different hospitals: the Netherlands Cancer

Institute-Antoni van Leeuwenhoek hospital (Amsterdam, The Netherlands) for the CT images and

VU University Medical Center (Amsterdam, The Netherlands) for the PET images. CT and PET image acquisitions were performed within 10 days.

CT scans were obtained using a single slice helical CT scanner (GE Hispeed LX/i), with the following parameters: 120 kVp, 150 mA, 0.8s per CT rotation, slice thickness and slice distance of

5 mm (pitch of 1). The matrix size was 512*512 pixels. No contrast was applied at that time.

PET data were acquired with an ECAT EXACT HR+ PET scanner (CTI/Siemens, Knoxville, TN,

USA) [10]. The slice thickness and spacing were 5 mm and the matrix size was 128*128 pixels.

PET transmission scans were based on three rotating 68Ge rod sources and the rod windowing technique. PET emission scans were retrospectively corrected for attenuation using the registered

CT scans, where the PET transmission scans were used to establish the proper registration (12).

2.2 Patient study

Our study involved twenty-two patients (five females and seventeen males, ranging from 57 to 87 years old), with localized non-small cell lung cancer staging from I to IIIB. CT images were acquired just before RT. The patients were scanned in a supine position on a flat tabletop for CT and on a rounded tabletop for PET scanning. The patients were asked to breathe normally during Fitton et al. 6 CT and PET scan acquisitions. There was no compensation for tumour movement but scans with large respiratory artifacts in the tumor region were excluded from the study. This manuscript is based upon the same patients dataset as used by Steenbakkers et al. (13).

2.3 Patient classification

Patients were classified as follows. Group I included primary tumors of any size which met the following criteria: surrounded by lung or visceral pleura, no venous invasion, and no significant extension to the chest wall or the mediastinum (of more than one quarter of the surface) (14). Group

II included primary tumor of any dimension that invaded any of the following: hilar region, heart, large vessels, pericardium, mediastinum over more than one quarter of its surface and/or that were associated with atelectasis. Patients were also characterized according to the Tumor Node

Metastasis classification (TNM) (15) (Table 1): three patients as clinical stage IA, five as stage IB, one as stage IIA, five as stage IIB, five as stage IIIA and three as stage IIIB.

2.4 Radiation oncologists and delineations

Eleven radiation oncologists from five different institutes in The Netherlands delineated primary tumors and pathological lymph nodes. All radiation oncologists were experienced in lung cancer treatment and tumor delineation. For the first phase of the study, they delineated the primary tumor on the axial slices of the CT scan. They were able to consult, simultaneously on the same screen, coronal and sagittal reconstructions of the CT data which also showed the intersection of the delineated contours with these planes. No instruction was given to observers about the application of these views during delineation: they were free to consult these views for delineation or not. The three views could be linked in 3-D: the mouse cursor in the axial window was then at the same time displayed in the identical anatomical location on coronal and sagittal windows. Physicians had a hard copy of the diagnostic CT scan with contrast enhancement including the report of radiologist, and all clinical findings from bronchoscopy, mediastinoscopy (if applicable) at their disposal for every patient. They were instructed to delineate the GTV only. The delineation protocol was Fitton et al. 7 adapted from a phase I/II 3-D conformal RT dose escalation trial in non-small-cell–lung cancer

(16). Afterwards, two groups of radiation oncologists were constructed based on analysis of detailed log files made during delineation as described in the next section: one group where coronal and sagittal windows were ignored during and after GTV delineation; the other group where at least two of the three views were used even once for GTV delineation (Figure 1).

For the second phase of the study, new delineations were performed one year later using fused CT and PET scans. Physicians had the same information about patients as in the first phase but with the addition of the complementary information from the PET report. A few new recommendations were given to the observers for delineation: for atelectasis patients without a clear distinction between primary tumor and atelectasis on CT scan, the edge of the FDG-uptake had to be followed for delineation of this interface. Physicians were forced to select at least one suitable slice in coronal/sagittal views by a mouse click in the tumor before starting delineation; therefore all radiation oncologists viewed the tumor at least once in the coronal and sagittal views.

2.5 Big brother

To delineate, observers used software developed at the NKI-AVL. All radiation oncologists used identical computers with calibrated 19-inch monitors (17). Every interaction between the radiation oncologist and the software was recorded in log files during delineation using our so called ´Big

Brother´ function (18). From these log files, we were able to detect when and how physicians used the coronal and sagittal views – in particular when the coronal and sagittal slice locations were changed, e.g., to center the view on the GTV. An analysis program was developed that extracted the number and moment of location changes in each of the windows of the delineation software for each physician and patient. The assumption was that users actively inspected sagittal and coronal views when more than three slice changes were recorded for these views per patient, i.e., to center these views on the tumour. We distinguished three periods in the log files: before, during and at the end of GTV delineation. Fitton et al. 8 2.6 Contour analysis

Besides calculating their volume, contours of the observers were evaluated as follows: first, the delineated contours were triangulated for each patient and each physician. Then, a 3D median surface for each patient was created from the delineations of all observers as arbitrary reference surface. The perpendicular distance between each contour point of each observer and the reference surface was measured. Then for each point of the median surface, the mean and standard deviation the observer distance and were calculated. Since the reference surface was only used as a guide for intercomparison, the mean distances were not considered important. Therefore only the local standard deviations for each region and interface were reported. The local standard deviations were next displayed on the reference surface using a color scale. In order to refine the comparison between observers, an approach based on regions and interfaces proposed by Steenbakkers et al. was used (13). The median surface was first separated into top, bottom and remainder regions. Top and bottom were defined as the two involved cranial and caudal slices respectively. Moreover several interfaces between tissues and tumor were defined on the median surface: hilar- mediastinum/tumor, lung/tumor, chest wall/tumor and finally atelectasis/tumor. For each region and interface the local standard deviations between delineations were calculated and averaged.

3. Results

3.1 Role of coronal and sagittal views in the process of delineation

The mean number of slice changes per physician for the total of patients was 2350±1515 (min=473- max=5220) on CT and reduced to 546±213 (min=130-max=1250) on matched PET/CT. When several slice changes in sequence were defined as one “call”, the total number of calls for coronal and sagittal windows for all physicians was 201 for 242 delineated tumors on CT: the largest number of consultations (77%) occurred during and afterwards delineation. On PET/CT, the total number of calls for coronal and sagittal windows was 150 for 242 delineated tumors with 35% of consultations during and after delineation. Fitton et al. 9 In the first phase of the study, the use of coronal and sagittal views depended mainly on the physician. Physicians chose to use the three views for 57.4% of the 242 delineations. Two physicians used coronal and sagittal windows frequently and three very rarely. In the second phase of the study, although the selection of suitable slices in coronal/sagittal views before starting delineation was required (we asked the observers to click the centre of the tumour), the number of coronal and sagittal slice changes was very limited for all radiation oncologists. From this we concluded that adding the PET information reduced the necessity to use the non-axial views to reduce observer variation.

3.2 Consultation of coronal and sagittal windows related to location of primary tumor, lymph nodes and atelectasis

The location of primary tumor and the presence of lymph nodes and atelectasis had a minor influence on the use of coronal and sagittal views. Physicians chose to use the three views for 52% of the 121 delineations of ‘easy’ group I, and for 62% of delineations for the ‘difficult’ group II. In case of patients with pathological lymph nodes, for 61% of the 176 delineations the coronal and sagittal windows were used compared with 47% of 66 delineations for node negative patients. Also for atelectasis patients, the three views were consulted more often. However, none of these findings show statistical significance above p=0.1.

3.3 Influence of the use of coronal and sagittal windows on inter-observer variability

We studied the correlation between the voluntary use of coronal and sagittal windows with the inter-observer variability (Table 1). For patient group I, the average inter-observer variability was fairly small with a global SD of 0.3 cm on CT images: the use of coronal and sagittal views had no impact for this group. On PET/CT images, the average inter-observer variability was 0.3 cm and therefore identical to delineation on CT only. Per anatomical interface, we noticed that the inter- observer variabilities for lung/tumour and chest wall/tumour interfaces were the same on PET/CT as on CT, and strongly reduced (about 2 times) for the mediastinum/tumour interface due to a better Fitton et al. 10 discrimination on PET images than by using coronal and sagittal views on CT only. For patient group II on CT, the results were more difficult to analyze due to a large variability over patients and interfaces. The average inter-observer variability was much larger than for patient group I: 0.9 cm versus 0.3 cm. Local SD values ranging from 0.9 cm to 2.2 cm were found, with the largest variability at the interface between atelectasis and tumour. This variability was, however, likely mostly related to an unclarity in the instruction (should atelectasis be included or not) and was therefore not further analysed. Analysis showed a large impact of use of the coronal and sagittal windows on inter-observer variability for the patients without atelectasis considering all interfaces

(Table 2) (p=0.01, paired Student’s t-test). For all interfaces of this patient group, the reduction of interobserver variability relative to non-ACSW users was similar and on average 39% by using

ACSW on CT only and about 75% when PET/CT was used as well (Figures 2 and 3).

3.4 Influence of the use of coronal and sagittal windows on delineated volume

In the first phase, when the coronal and sagittal views were ‘called’, a smaller delineated volume was found for 18 out of 22 patients (Table 1). For four patients a slightly larger volume was observed, however, these were the patients with the smallest GTVs: less than 23 cm3.

Correspondingly, when the coronal and sagittal views were ‘called’, the average delineated volume was slightly smaller in patient group I (7 cm3). In patient group II, the reduction of the GTV was much larger: in cases where all three views were ‘called’ the average volume was almost a factor of two smaller (61.2±36.2 cm3 vs 102.7±76.3 cm3; p=0.038, paired Student’s t-test). In the second phase of the study for patient group II, we noted an increase of the mean GTV equal to 21% compared to the mean GTV delineated on CT only by ACSW users (Table 3). This result can be explained by the limited use of coronal and sagittal windows when PET images were available resulting in difficulty to define upper and lower borders of the tumor where partial volume effects cause an unclear PET signal boundary. Fitton et al. 11 4. Discussion

The aim of this paper was to study the impact of coronal and sagittal views on lung GTV delineation; indeed despite delineation guidelines advise to use them, their impact had never been specifically studied. The main restriction in this study was that CT and PET equipments couldn't be considered as competitive equipments anymore arguing that integrated respiratory correlated PET and CT imaging is a widely established technique that decreases image degradation due to patient breathing during the image acquisition. However the recommendations of this study are about the way to use coronal and sagittal windows for delineation according to locations of tumors in lung and they must be still valid whatever respiratory phase, blurring, image degradation or type of equipments. Moreover, we can hypothetize that a better image quality should encourage physicians to a minor use of coronal and sagittal windows in CT and PET, and our goal was to remind the importance of these views on GTV delineation.

No instructions were given to physicians about the use of these views; however for delineation on

PET/CT images, the software forced users to select a relevant plane in the coronal/sagittal views prior to starting delineation but there were no further instructions. The impact was analysed by monitoring how the three views were used for delineation from log files of the human-computer- interaction. For this reason, it may be that the results were affected by the level of expertise of the users. Moreover the study exclusively involved radiation oncologists: Doll et al. (19) showed there were a better concordance and agreement in GTV delineation by the interdiscipinary cooperation of radiation oncologists and nuclear medicine physicians. However, all users included in this study were considered experts in lung cancer, and would have had experience delineation on three-views systems before. It is surprising, then, how often the coronal and sagittal views were not ‘touched’, especially in the case of complex tumors or also to avoid false positive points visible on the axial

PET views, due for example to the partial volume effect.

By separating patients into two groups according to anatomical characteristics of the periphery of the primary tumor, a good reproducibility (better than 0.5 cm SD) was found for all observers and interfaces in the first patient group (‘simple tumors’). The presence of pathological lymph nodes Fitton et al. 12 seemed to be a criterion to start using the three views. Observers that used the three views had a good reproducibility at the tumor/mediastinum interface (better than 0.5 cm SD), while the inter- observer variability was much poorer for those that did not use coronal and sagittal windows.

Therefore, we may conclude that using three views is important to achieve reproducibility of the delineation of pathological lymph nodes in the mediastinum and interfaces of ‘difficult tumors’. In addition, the users that chose to use the coronal and sagittal windows had significant smaller target volumes, indicated more confidence in the delineation.

The inter-observer variability for both groups reduced further by using PET images. However, even though we expected the impact of coronal and sagittal views to be less than PET images on delineation (13), we found a significant reduction for those users that used the sagittal and coronal windows, likely due to the low spatial resolution of the PET. Accurate delineation of the tumor boundary remains challenging especially for patient group II. Even with PET, users that consulted coronal and sagittal views for GTV delineation showed a reduced GTV volume. This observation confirms that, excepted for regions with atelectasis, PET is not preferred to define tumour boundaries. The higher resolution of CT in axial, coronal and sagittal views makes it a more suitable modality to define the tumour boundary than PET, especially at the top and bottom of lung tumor and at the lung/tumor interface.

We therefore recommend consultation of CT and PET in three views before and during GTV delineation for all patients, with a particular focus on patients with pathological lymph nodes, atelectasis and also in the case of primary tumor close to the mediastinum, the hilar region, the heart and the diaphragm. All delineations must be done in a radiotherapy treatment planning environment using suitable softwares for GTV delineations in 3D.

5. Conclusion

We demonstrated that for smaller lung tumors surrounded by healthy lung tissue the effect of multiple axis delineation is limited. However, in more complex cases, the use of the coronal and sagittal views allowed a decreased inter-observer variability and tumor volume. CT coronal and Fitton et al. 13 sagittal views are therefore strongly recommended for patients with atelectasis and/or pathological lymph nodes during GTV delineation, even when PET/CT is used. Fitton et al. 14 References

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