Value of Magnetic Resonance Imaging Without or With Applicator in Place for Target Definition in Cervix Cancer Brachytherapy

CME

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation

Value of Magnetic Resonance Imaging Without or With Applicator in Place for Target Definition in Cervix Cancer Brachytherapy Richard Po¨tter, MD,*,y Mario Federico, MD, PhD,*,z Alina Sturdza, MD,* Irina Fotina, PhD,*,x Neamat Hegazy, MD, PhD,*,k Maximilian Schmid, MD,*,y Christian Kirisits, DSc,*,y and Nicole Nesvacil, DSc*,y *Department of Radiotherapy, Comprehensive Cancer Center, and yChristian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Vienna, Austria; z Department of Radiation Oncology, Gran Canaria University Hospital, Las Palmas de Gran Canaria, Spain; xInstitute of Physics and Technology, Tomsk Polytechnic University, Tomsk Oblast, Russia; and k Department of Clinical Oncology, Medical University of Alexandria, Alexandria, Egypt Received Mar 30, 2015, and in revised form Sep 9, 2015. Accepted for publication Sep 14, 2015.

Summary Pretreatment magnetic resonance imaging shows a substantial impact on computed tomography-based contouring for cervix cancer brachytherapy, especially in cases with limited parametrial disease.

Purpose: To define, in the setting of cervical cancer, to what extent information from additional pretreatment magnetic resonance imaging (MRI) without the brachytherapy applicator improves conformity of CT-based high-risk clinical target volume (CTVHR) contours, compared with the MRI for various tumor stages (International Federation of Gynecology and Obstetrics [FIGO] stages I-IVA). Methods and Materials: The CTVHR was contoured in 39 patients with cervical cancer (FIGO stages I-IVA) (1) on CT images based on clinical information (CTVHRCTClinical) alone; and (2) using an additional MRI before brachytherapy, without the applicator (CTVHR-CTpre-BT MRI). The CT contours were compared with reference contours on MRI with the applicator in place (CTVHR-MRIref). Width, height, thickness, volumes, and topography were analyzed. Results: The CT-MRIref differences hardly varied in stage I tumors (nZ8). In limitedvolume stage IIB and IIIB tumors (nZ19), CTVHR-CTpre-BT MRIeMRIref volume differences (2.6 cm3 [IIB], 7.3 cm3 [IIIB]) were superior to CTVHR-CTClinicaleMRIref (11.8 cm3 [IIB], 22.9 cm3 [IIIB]), owing to significant improvement of height and width (P<.05). In advanced disease (nZ12), improved agreement with MR volume,

Reprint requests to: Nicole Nesvacil, DSc, Department of Radiotherapy, Medical University Vienna, AKH Vienna Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. Tel: (þ43) 1-40400-2692; E-mail: nicole [email protected] NotedAn online CME test for this article can be taken at http:// astro.org/MOC. This work was supported by the Austrian Science Fund FWF, project L562. Int J Radiation Oncol Biol Phys, Vol. 94, No. 3, pp. 588e597, 2016 0360-3016/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.09.023

Conflict of interest: The Department of Radiotherapy at the Medical University of Vienna receives financial and/or equipment support for research and educational purposes from Elekta AB and Varian Medical Systems Inc. C.K. is a consultant to Elekta AB. Supplementary material for this article can be found at www.redjournal.org.

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width, and height was achieved for CTVHR-CTpre-BT MRI. In 5 of 12 cases, MRIref contours were partly missed on CT. Conclusions: Pre-BT MRI helps to define CTVHR before BT implantation appropriately, if only CT images with the applicator in place are available for BT planning. Significant improvement is achievable in limited-volume stage IIB and IIIB tumors. In more advanced disease (extensive IIB to IVA), improvement of conformity is possible but may be associated with geographic misses. Limited impact on precision of CTVHR-CT is expected in stage IB tumors. Ó 2016 Elsevier Inc. All rights reserved.

Introduction Magnetic resonance imaging (MRI) is the gold standard imaging modality in 3-dimensional (3D) image guided adaptive brachytherapy (BT) of cervical cancer (1-3), owing to its excellent soft-tissue contrast. The Groupe Europe´en de Curiethe´rapieeEuropean Society for Radiotherapy and Oncology (GEC-ESTRO) recommendations for MR-based target volume delineation provide a solid framework for contouring (4, 5), which results in remarkable improvement of tumor control and toxicity (6, 7). Mono- (7, 8) and multi-institutional reports on doseresponse relationships for high-risk clinical target volume (CTVHR) D90, based on large clinical datasets (eg, EMBRACE [http://www.embracestudy.dk] and RetroEMBRACE), will drive the future development of dose prescription and reporting (9). Clinical outcome data have been reported also for computed tomography (CT)-based treatment planning (10-12). However, large systematic and random discrepancies between MRI- and CT-based contouring may result in large discrepancies of reported dose-volume histogram (DVH) data. Despite its recognized superiority, availability of MRI for BT planning is limited (13, 14). At present there is no standardized target contouring on CT images. Viswanathan et al (15) proposed CT-based CTVHR definition based on clinical assessment of the parametrial infiltration. Hegazy et al (16) combined systematic 3D documentation of gynecologic examination and standardized target heights. All previous approaches allowed adequate target coverage, albeit accompanied by a significant target volume increase. It was speculated (15, 17) that a diagnostic MRI scan taken before BT might be a relatively easy option to assess the definitive pre-BT target volume and topography. This retrospective study investigated the value of systematic inclusion of a pre-BT MRI into a CT-based CTVHR contouring protocol, for improving conformity of CT- and MR-based contours. It contains 3D parametric, volumetric, and topographic analyses of 2 CT-based contour sets (based on clinical information only, and using additional pre-BT MRI) in respect to the MRI CTVHR with applicator in place. To identify which patients would benefit most from improved contouring protocols, 4 scenarios were analyzed: tumors limited to the cervix, limited parametrial involvement after external beam radiation therapy (EBRT), extensive residual

parametrial disease after EBRT, and large tumors with infiltration of adjacent organs.

Methods and Materials Patient characteristics Thirty-nine patients with histologically proven cervical cancer, treated between 2006 and 2010, were evaluated. These patients had a curative treatment consisting of pelvic EBRT and 3D MR-based image guided adaptive BT (7, 18). In addition to the routine MRI with applicator in place, an MRI directly before BT and a CT with the applicator in place were acquired. The median age was 55 years (range, 33-85 years). International Federation of Gynecology and Obstetrics (FIGO) stage distribution was IB1 (nZ5), IIB (nZ20), IIIA (nZ1), IIIB (nZ6), and IVA (due to bladder infiltration; nZ4). Patients with FIGO IIB tumors were classified according to volumetric regression during EBRT and tumor width at the time of first BT. Tumors with a reduction >50% and width <5 cm (suggestive of mid- or proximal residual parametrial infiltration) were considered as limited volume IIBs (nZ15). Tumors with a reduction of 50% and tumor width 5 cm (suggestive of distal parametrial infiltration) were regarded as large IIBs (nZ5). Stage IIIB tumors were divided into 2 groups, due to hydronephrosis (nZ4) or pelvic wall infiltration (nZ2).

Imaging and delineation An 0.2 T Magnetom Open Viva (Siemens, Erlangen, Germany) MR scanner was used with the institutional image acquisition protocol (2), and according to GEC-ESTRO imaging recommendations (1). Computed tomography scans from iliac crest to ischial tuberosities were acquired with a Somatom Plus S (Siemens). Slice thickness was 5 mm for MRI and 4 mm for CT. The 2 scans were acquired within 1 hour, with the applicator fixed to the target by vaginal packing and the use of bladder filling and rectum preparation protocols to avoid systematic intrafraction variations (19, 20). T2-weighted fast spin-echo MR scans with applicator in place were contoured according to GEC-ESTRO recommendations (4, 5) by 1 experienced observer. Computed tomographyebased contours were delineated

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by another experienced radiation oncologist and verified by an expert clinician. All observers were blinded to other contours at the time of delineation. On axial CT images with the applicator in situ, a first CTVHR volume (CTVHRCTClinical) was contoured according to preliminary CT contouring guidelines based on clinical tumor extension (15). At our institution the clinical extension of gynecologic malignancies (at diagnosis and at BT) is routinely recorded by the examining radiation oncologist on clinical diagrams (Fig. 1) (16). As previously proposed (16), the definition of CTVHR-CTClinical height was set as half of the uterine length (from ring surface to outer contour of uterine fundus measured on the sagittal plane) for stage IB1, or two-thirds of the uterine length for IB2 or more advanced stages. A second CTVHR (CTVHR-CTpre-BT MRI) was contoured integrating all previous clinical information with the full set of MRI taken at the time of diagnosis and after EBRT completion, at the time of the first BT (without applicator in place) (Fig. 1). Tumor topography and dimensions (width, height, thickness, and distance from cervical canal to the border of tumor infiltration in right and left parametrium) were systematically assessed on pre-BT MR image sets, side by side on a second monitor. The MRI and CT slices were correlated according to the uterine axis and estimated position of the

International Journal of Radiation Oncology  Biology  Physics

ring. Because CT and MR scans had different orientations (axial and paraxial, respectively), CTVHR delineation on CT incorporated the information provided by CT reconstruction in the sagittal plane. The CTVHR-CTClinical and CTVHR-CTpre-BT MRI were compared with CTVHR-MRI reference contours, and differences between CT- and MRI-based values were reported (Fig. 2).

Contouring analysis Magnetic resonance and CT images with corresponding structure sets were transferred to an iPlan RT Image workstation (v4.1; Brainlab, Feldkirchen, Germany) for rigid image registration based on the applicator. The random MRI/CT registration uncertainty was estimated to be half the MRI slice thickness in the cranio-caudal direction, and 2 mm in anteroposterioreposteroanterior and lateral directions. The CTVHR-MRIref were transferred to the CT image sets and evaluated with ARTiView (v2.2.4; Aquilab, Loos, France). Maximum width, length, and thickness were measured for each structure. For spatial agreement analysis, images were resampled to 1-mm3 grid size. The following parameters were

Fig. 1. Upper panels: Axial clinical diagrams at diagnosis (a) and at brachytherapy (b) and corresponding CT images based on clinical information (CTVHR-CTClinical) (c). Lower panels: Magnetic resonance scans of the tumor at diagnosis (d) and after external beam radiation therapy treatment, just before brachytherapy, without applicator (e). (f) The CTVHR-CTpre-BT MRI using clinical and magnetic resonance imaging information (solid line) compared with CTVHR-CTClinical (dotted line). CTVHR Z high-risk clinical target volume; CTClinical Z computed tomographic images based on clinical information; CTpreBT MRI Z magnetic resonance imaging before brachytherapy without the applicator.

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Fig. 2. Three-dimensional parametric comparison of the 2 computed tomography (CT)-based contouring methods. (A-D) CTVHR height, width, thickness and volume. X axes: difference CTVHR-CTclinicalMRIref values; y axes: difference CTVHRCTpreBT MRIMRIref. Dashed line: ideal correlation between the two CT-based contouring methods. CTVHR Z high-risk clinical target volume; CTClinical Z computed tomographic images based on clinical information; CTpre-BT MRI Z magnetic resonance imaging before brachytherapy without the applicator; MRIref Z magnetic resonance imaging reference contours.

calculated for both CT-based contours (clinical and preBT MRI) versus CTVHR-MRref (Fig. 3A). Volume overlap represents the common volume between MRI- and CT-based contours; CT additional volume (VCTadd) stands for the part of the CTVHR volume delineated on CT images that is not present in the CTVHR-MRref, thus representing tissue unnecessarily included in the CTVHRCT. The MRI additional volume (VMRadd) is the volume that was contoured only on MRI but not encompassed in the CTVHR-CT contour and represents the volume of tissue potentially harboring residual disease that has been missed in CT-based delineation. The conformity index (CI) was calculated for each pair of structures for each patient case as a parameter describing the concordance between CT- and MR-based delineations over the volume and slice by slice,

V HRCTVCT XV HRCTVMRI AHRCTVCT XAHRCTVMRI CIvol Z CIslice Z V HRCTVCT WV HRCTVMRI AHRCTVCT WAHRCTVMRI

where A is the area occupied by the respective structure on each CT slice. The volumetric analysis alone yields no information about the spatial distribution of potential areas of disagreement. Therefore a topographic analysis of concordance of CTVHR-CTpre-BT MRI and CTVHR-MRIref was performed via slice-by-slice measurements of the maximum distances between MR and CT contours. Within a tolerance of 3 mm (corresponding to interobserver variability [21] and registration accuracy), all areas of CTVHRMRIref neglected in the respective CTVHR-CTpre-BT MRI contours at the level of parametria were counted and reported in a topographic map.

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Fig. 3. Topographic analysis of the CT contouring methods. (A) Illustration of volumetric parameters. (B) Volume overlap between CT and MRIref contour. (C) Additional volume delineated on CT but not included in MRIref. (D) Volume delineated on MRIref but not included in the CT-based contour. Axes and symbols correspond to Fig. 2. CT Z computed tomography; MRIref Z magnetic resonance imaging reference contours.

Statistical analysis A paired 2-tailed Student t test was performed to test statistical significance of the differences between the 2 CT-based contouring methods (P.05).

Results Analysis of 3D parameters Three-dimensional parameters were analyzed for each tumor group separately, for the whole cohort, and for 2 subgroups of patients with and without residual parametrial disease at time of BT. Mean values for the MRI reference contours are presented in Table 1. Differences between each of the 2 CT-based CTVHR contour sets and the MRI reference contours are given in Tables 2 and 3. Mean values different from 0 indicate systematic differences between CT- and MRI-based contours. Large standard deviations

indicate a large random variation of the differences between individual patients. Mean target volumes delineated on CT ranged from 28.6  10.2 cm3 (IB1) to 90.5  21.6 cm3 (IVA) for CTVHR-CTClinical and 27.9  9.2 cm3 to 82.4  24.2 cm3 for CTVHR-CTpre-BT MRI. For the overall cohort, width, height, and volume were most affected by the CT contouring technique. For the total cohort differences between contouring methods were statistically significant for all parameters, but not for each tumor group separately (Table 2). Generally, a significant decrease of the difference between CT-based and MRI reference contours was observed when pre-BT MRI was included in the protocol. Overall, no large systematic or large random differences (>10%) for individual patients between CTVHR-CTClinical and CTVHR-CTpre-BT MRI were found for stage IB1 to IB2 tumors, in regard to all considered metrics (Tables 2 and 3, Table EA1; available online at www.redjournal.org). In all other groups, systematic differences 18% and random

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Table 1 Three-dimensional parameters of the MRI-based reference contours, CTVHR-MRIref, which were used for comparison analysis of the 2 different CT delineation techniques Volume (cm3), CTVHR-MRIref

Width (cm), CTVHR-MRIref

Thickness (cm), CTVHR-MRIref

Height (cm), CTVHR-MRIref

Tumor stage

No. of patients

Mean

SD

Mean

SD

Mean

SD

Mean

SD

IB1-IB2 IIB proximal IIIB HN IIIA IIB distal IIIB pelvic wall IVA

8 15 4 1 5 2 4

26.4 30.1 23.1 30.6 86.7 49.5 72.4

9.0 11.8 12.4

4.0 4.4 4.0 3.8 5.8 5.3 5.5

0.9 0.6 1.0

3.2 3.0 2.5 3.3 3.9 3.6 4.2

0.3 0.5 0.4

3.9 3.7 3.0 3.4 5.2 4.3 5.0

1.1 1.2 0.5

73.1 21.9 31.2

1.1 0.4 1.3

1.4 0.2 0.6

No. with RPI at BT 0 7 3 1 5 2 4

1.5 1.0 1.5

Abbreviations: BT Z brachytherapy; CT Z computed tomography; CTVHR Z high-risk clinical target volume; HN Z hydronephrosis; MRIref Z magnetic resonance imaging reference contours; RPI Z residual parametrial infiltration. Mean and standard deviation are reported for each tumor stage group separately, as well as the number of patients with RPI assessed on MRI at time of BT.

variations of standard deviation 19% were found for at least 1 of the 3D parameters in each stage group. For individual patients (Table EA2; available online at www.redjournal.org), width reduction from CTVHRCTClinical to CTVHR-CTpre-BT MRI was largest for limited IIBs and IIIBs (mean 3.3  4.5 mm and 9.0  6.1 mm, respectively). For IB and large IIB and IIIB tumors the mean width differences were 0.8  4.3 mm, 1.3  0.8 mm, and 1.3  0.9 mm, which was not significantly larger than the contouring precision on any imaging modality. For stage IVA tumors the mean CTVHR width reduction was 5.3  2.0 mm. Analogue results were found in respect to CTVHR thickness. For limited volume IIBs and IIIBs, mean thickness reduction was 1.7  3.1 mm and 2.2  2.7 mm. For large IIBs, IIIBs with pelvic wall infiltration, and IVA

tumors it was 1.5  1.9 mm, 3.1  2.2 mm (nZ2), and 1.2  1.8 mm, respectively. Figure 2 shows the difference between CT and MRIref height, width, thickness, and volume for the different CT contour sets, for each patient. CTVHR-CTpre-BT MRI values <0 indicate smaller CT-based measurements than those for the MRIref contour. For some patients, mostly the reference target height, but also width was underestimated by the CTVHR-CTpre-BT MRI.

Topographic analysis Results of the slice-by-slice topographic analysis are given in Table 3. Patient-by-patient variations of volume overlap,

Table 2 Three-dimensional comparison between CTVHR-MRIref and the 2 different sets of CT-based CTVHR: width, height, thickness, and volume differences (ie, CTVHR-CTClinical/preBT MRICTVHR-MRIref) CT-MRref volume (cm3) CTVHRCTclin

CTVHRCTpreBT MRI Mean

SD

CT-MRref width (mm)

CT-MRref thickness (mm)

CT-MRref height (mm)

CTVHRCTclin

CTVHRCTclin

CTVHRCTclin

Parameter

n

Mean

SD

IB1-IB2 IIB proximal IIIB HN IIIA IIB distal IIIB pelvic wall IVA No RPI RPI Total

8 15 4 1 5 2 4 17 22 39

2.2 11.8* 22.9 14.6 20.1 30.9 18.1 7.2* 18.8* 13.8*

6.0 1.5 5.0 2.4 9.8 2.6* 5.0 7.5* 13.9 7.3 5.8 12.8 10.6 5.8 22.6 5.6 8.3 8.3* 33.1 4.8 3.8 12.9 19.6 9.5 21.1 9.9 10.4 2.6* 5.8 4.4 16.6 5.6* 9.5 10.0* 15.4 4.3* 8.2 7.6*

CTVHRCTpreBT MRI

Mean SD Mean

SD

6.8 1.5 5.4 6.8 4.2* 4.4 6.5 3.8 3.5 5.0 5.8 7.0 6.6 7.2 13.2 13.9 3.1 4.7 4.0 6.6 2.3 4.5 5.8 6.2* 5.8 6.8 4.5* 5.6

CTVHRCTpreBT MRI

CTVHRCTpreBT MRI

Mean SD Mean

SD

Mean

SD

Mean

SD

2.2 4.5 8.1 3.6 2.9 4.5 2.3 3.1 4.6* 3.9*

3.2 3.8 2.3 6.6 3.6 1.6 3.1 4.3 3.9

2.0* 8.9* 14.8 10 9.4* 11.9 5.3 6.5* 9.1* 7.9*

4.4 11.8 9.6 10.1 3.3 13.6 8.1 11.5 10.2

1.7* 0.7* 4.2 0.1 0.0* 1.3 3.8 0.0* 0.9* 0.5*

3.8 6.0 4.7 5.7 5.2 6.7 4.6 6.1 5.5

4.3 4.5 4.4 6.5 5.8 2.7 3.8 5.2 4.7

1.6 2.8 5.9 3.6 1.4 1.5 1.0 2.1 2.7* 2.5*

Abbreviations: BT Z brachytherapy; CT Z computed tomography; CTVHR Z high-risk clinical target volume; HN Z hydronephrosis; MRIref Z magnetic resonance imaging reference contours; RPI Z residual parametrial infiltration. Mean values and standard deviations are reported for each tumor stage group separately (IB1-IB2, IIB proximal, IIIB HN, IIIA, IIB distal, IIIB pelvic wall, and IVA), for all patients without or with RPI at time of BT, and for the overall patient cohort. A mean value >0 indicates that the CT-based values were on average larger than the MRIref values. * The difference between the 2 CT-based contouring methods was statistically significant for the given parameter and group. Statistical analysis for individual tumor groups was only performed if n5 patients.

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Table 3 Three-dimensional comparison between CTVHR-MRIref and the 2 different sets of CT-based CTVHR: results of the topographical analysis: volume overlap, additional volume on CT (VCTadd), additional volume on MRI (VMRadd), and conformity index (CI) CT-MRref volume overlap (%) CTVHRCTclin

CT-MRref VCTadd (cm3)

CTVHRCTpreBT MRI

CTVHRCTclin

CT-MRref VMRadd (cm3)

CTVHRCTpreBT MRI

CTVHRCTclin

CT-MRref CI

CTVHRCTpreBT MRI

CTVHRCTclin

CTVHRCTpreBT MRI

Parameter

n

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

IB1-IB2 IIB proximal IIIB HN IIIA IIB distal IIIB pelvic wall IVA No RPI RPI Total

8 15 4 1 5 2 4 18 21 39

72.4 70.5 88.4 78.0 80.3 88.5 81.2 72.3 79.2 76.2

10.3 8.4 7.0 6.0 2.5 5.4 9.1 9.8 10.0

73.5 68.7 84.6 79.9 77.8 83.3 78.8 72.1 76.4 74.3

11.8 8.8 8.8 5.5 3.7 5.3 10.3 9.4 9.9

9.2 20.5* 25.9 21.4 35.3 36.9 32.0 12.3* 30.7* 22.7*

4.7 11.6 13.6 30.8 29.3 15.0 6.2 18.5 17.0

8.3 3.7 11.6* 4.1 11.4 5.6 16.8 22.3 18.1 12.6 2.0 25.2 16.0 9.0* 3.1 17.6* 11.7 13.9* 9.9

7.0 8.7 3.0 6.7 15.0 6.0 14.5 7.1 10.5 9.0

2.3 4.3 3.1 9.6 3.8 10.4 3.0 7.9 6.4

6.7 9.0 4.2 6.1 16.7 7.9 16.3 7.2 11.5 9.6

2.7 3.5 4.6 10.2 1.8 10.5 3.4 7.9 6.6

0.53 0.43 0.43 0.46 0.57 0.51 0.56 0.49* 0.48* 0.49*

0.10 0.13 0.10 0.04 0.25 0.10 0.11 0.14 0.12

0.56 0.49 0.56 0.52 0.62 0.65 0.58 0.53* 0.56* 0.54*

0.11 0.10 0.04 0.05 0.11 0.09 0.11 0.10 0.10

Abbreviations: BT Z brachytherapy; CT Z computed tomography; CTVHR Z high-risk clinical target volume; HN Z hydronephrosis; MRIref Z magnetic resonance imaging reference contours; RPI Z residual parametrial infiltration; VCTadd Z additional volume on CT; VMRadd Z additional volume on MRI. Mean values and standard deviations are reported for each tumor stage group separately (IB1-IB2, IIB proximal, IIIB HN, IIIA, IIB distal, IIIB pelvic wall, and IVA), for all patients without or with RPI at time of BT, and for the overall patient cohort. * The difference between the 2 CT-based contouring methods was statistically significant for the given parameter and group. Statistical analysis for individual tumor groups was only performed if n5 patients.

additional volume on CT (VCTadd), and additional volume on MRI (VMRadd) are shown in Figure 3. By inclusion of pre-BT MRI, the volume overlap (Fig. 3B) between CT and MRI contours did not improve with statistical significance for any tumor group. Mean VCTadd was substantially reduced in all stage IIB and IIIB tumors when MRI information at the time of BT was introduced in the CTVHR delineation process. The reduction of VCTadd occurred without systematically increasing VMRadd. A systematic volume and VCTadd reduction was observed in all patients with residual parametrial disease at the time of BT. In some of these patients the reduction of the VCTadd was accompanied by a slight increase of the VMRadd (Fig. 3C, D). Large VCTadd and VMRadd volumes were observed for IVA tumors, but no substantial reduction by inclusion of pre-BT MRI was achieved. Overall, CTVHR-CTpre-BT MRI showed a slightly improved conformity to the reference CTVHR-MRIref contour. To clarify whether areas of disagreement were equally distributed throughout the delineated volumes, the CIslice was analyzed and found to be lower in the most caudal and cranial parts of the CTVHR volume (range, 0.25-0.50). Conversely, the central part of the CTVHR-CTpre-BT MRI corresponding to the parametria showed good agreement to the reference contour set and a stable CIslice of 0.65 to 0.72 for all FIGO stages. Consistent with CIslice analysis and previous reports (22), topographic analysis showed that most disagreements occurred between the contour sets in caudal and cranial regions of CTVHR MRI, corresponding to the level of

vaginal fornices and uterine corpus. Seven patients showed parametrial disagreement between CTVHR-CTpre-BT MRI and reference CTVHR-MRI contours (Fig. 4, Table EA3; available online at www.redjournal.org). The mean discrepancies were 4.7  0.2 mm (limited volume IIB), 9.6  5.0 mm (large IIB), and 6.4  1.9 mm (IVA). Parametrial misses larger than the 3-mm threshold were larger and more frequent in patients with large tumors or more advanced stages.

Discussion Magnetic resonance imagingebased BT for cervical cancer is increasingly recognized as the gold standard BT treatment modality (23, 24). Nevertheless, centers unable to obtain postimplant MRI with the applicator in place for BT planning may consider using CT imaging. A first attempt to systematically define reproducible guidelines for CTVHR contouring on CT images (15) consisted of a standardized approach based on the clinically determined tumor extension. In a limited series of patients it was possible to achieve sufficient target coverage compared with MRI-based contours, although at the price of a significant target volume overestimation (CT- vs MRIbased CTVHR was 5.5  1.3 cm vs 4.5  1.0 cm for width and 3.8  1.3 cm vs 3.6  0.6 cm for thickness, respectively). The dosimetric impact of contouring variability for cervix cancer has been analyzed recently (25). A systematic

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Fig. 4. Spatial distribution of discrepancies between CTVHR-MRIref and CTVHR-CTpreBT MRI. Distances (mm) between tandem (circle’s center) and the location of maximum parametrial disagreement between contours on 1 image slice are indicated for different patients (different colors) and target groups: IIB proximal (circles, nZ2), IIB distal (triangles, nZ3), IVA (stars, nZ2). CTVHR Z highrisk clinical target volume; MRIref Z magnetic resonance imaging reference contours. overestimation of target volumes drawn on CT images corresponds to the introduction of a “margin” around the “optimal” CTVHR. Although this additional shell may compensate for contouring uncertainties due to poor tumor visualization, it should be avoided because of the huge dosimetric impact on tumor and organs at risk dose (approximately 8% dose escalation per mm of margin applied) (26). This is the first study that directly compares 3D parameters and topography of overlaps and geometric misses for a patient cohort stratified into different tumor groups. It seems to be essential to aim for compatibility of CT-based and MRI-based target contouring, to define consistent planning aims in terms of dosedacross different imaging methods applied. Especially in large tumors with parametrial involvement, DVH parameters D90 and D98 are very sensitive to the actual tumor contour. Our results show that, with the exception of stage I tumors, integration of an MR scan taken at the time of BT without the applicator in place in the contouring process, and a thorough clinical examination (16), improves the MR conformity of CT-based CTVHR contours, reducing target overestimation. We distinguished 4 case scenarios at BT to investigate the specific impact of MRI findings on CT-CTVHR. For FIGO stage I (nZ8), where the CTVHR is represented by the cervix only, direct CTVHR contouring on CT

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seems to be sufficient compared with the CTVHR-MRIref. No major improvement seems to be achievable by an extra pre-BT MRI. Magnetic resonance imaging information had a major, statistically significant impact for tumors with good response to EBRT and limited residual parametrial disease (ie, limited IIB or limited size IIIB) (due to hydronephrosis). In these cases CTVHR-CTpre-BT MRI achieved a significant width reduction compared with CTVHRCTClinical and ultimately a significant reduction of the CTVHR volume unnecessarily contoured (VCTadd), without increasing the VMRadd. Considering all FIGO stage IIB to IIIB tumors with limited parametrial involvement, only in 2 of 19 cases the CTVHR-CTpre-BT MRI neglected some limited areas of the CTVHR-MRref at the level of the parametria. Therefore, experienced observers can be expected to delineate CT target contours with comparable precision to MRI with applicator in place, if parametrial invasion is limited, based on the proposed technique. In the more advanced cases (IIB with distal parametrial involvement and limited response to EBRT; IIIB with pelvic wall infiltration and IVA) the reduction of CTVHR overestimation (VCTadd) was sometimes accompanied by a trend to underestimate CTVHR-MRIref (increasing VMRadd). The topographic analysis revealed 5 of 12 cases in which CTVHR-CTpre-BT MRI resulted in a geographic miss at the level of parametria when compared with CTVHR-MRI (with applicator in place). These findings confirm reports on increased CT contouring uncertainties when parametrial involvement is present (15, 16). In a recent interobserver study (27) CT- and MRI-based target contouring was compared for 23 experts in gynecologic radiation oncology and 3 cases: a large IIB with near complete response (case 1), a large IIB with partial response (case 2), and a IB2 with complete response (case 3). The study concluded that “MRI at the time of BT may be of greatest benefit in patients with large tumours with parametrial extension that have a partial or complete response to external beam.” The result of our study with 39 patients and a wide range of different tumor sizes and topographies allows a more detailed view regarding the value of MRI before BT or MRI with applicator in place for the precision of CTbased contouring. Overall, it suggests that MRI without applicator in place, taken before the BT applicator insertion, is helpful to determine the exact tumor load and level of parametrial infiltration after EBRT for CT-based contouring. In stage I tumors no major improvement beyond the intra-/interobserver contouring uncertainty reported for MRI (21, 28) was seen when MRI information was added (analogue case 3 [27]). In case of limited volume IIB and IIIB (with relatively simple CTVHR shapes consisting of the entire cervix plus some limited parametrial extension), MRI before BT helps to safely improve the CT-based CTVHR conformity (analogue case 1 [27]). In the case of large cervical cancer with extensive

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parametrial tumor load after EBRT (analogue case 2 [27]), resulting in larger CTVHRs with complex shapes, MRI with applicator in place seems to be essential. When using pre-BT MRI only, the visual translation of the complex volumes depicted in the pre-BT MR into a CT-based CTVHR contour may have inaccuracies that may cause clinically relevant target volume underestimation. The findings of this study are in concordance with those of Viswanathan et al (24) for stage I tumors, but not for large III-IVA tumors with extensive residual disease and large IIB tumors with partial response. Whereas 1 case per stage category was the basis for the interobserver study (24), the basis was 5, 20, and 11 cases per category in our systematic study whichdin addition to variations in methodologydmay partly explain differences in findings, interpretations, and conclusions. For cases in which MRIref target dimensions were underestimated by CT contours, despite the inclusion of preBT MRI, the use of other 3D imaging tools (eg, transrectal ultrasound [29] or use of a combined workflow of MRI- and CT-guided BT [30]) may be beneficial.

Conclusion Pre-BT MRI helps to define the amount of tumor shrinkage and topography after EBRT. Precise definition of tumor topography before BT implantation supports CTVHR delineation on CT and reduces CTVHR overestimation. Such gain is evident in limited volume IIB to IIIB tumors with limited residual parametrial disease. In large tumors with extensive parametrial involvement or adjacent organ invasion at BT, pre-BT MRI may lead to reduction of CTVHR volumes but may miss at the same time important parts of the CTVHR. Therefore, MRI with applicator in place remains essential. In IB the impact of MRI with applicator in place on CTVHR determination is not evident. Limited impact can be expected for stage IB disease.

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Volume 94  Number 3  2016 21. Petric P, Dimopoulos J, Kirisits C, et al. Inter- and intraobserver variation in HR-CTV contouring: Intercomparison of transverse and paratransverse image orientation in 3D-MRI assisted cervix cancer brachytherapy. Radiother Oncol 2008;89:164-171. 22. Dimopoulos J, De Vos V, Berger D, et al. Inter-observer comparison of target delineation for MRI-assisted cervical cancer brachytherapy: Application of the GYN GEC-ESTRO recommendations. Radiother Oncol 2009;91:166-172. 23. International Commission on Radiation Units and Measurements. Prescribing, recording, and reporting brachytherapy for cancer of the cervix. ICRU report 88. J ICRU 2015. In press. 24. Tan LT. Implementation of image-guided brachytherapy for cervix cancer in the UK: Progress update. Clin Oncol (R Coll Radiol) 2011; 23:681-684. 25. Hellebust TP, Tanderup K, Lervag C, et al. Dosimetric impact of interobserver variability in MRI-based delineation for cervical cancer brachytherapy. Radiother Oncol 2013;107:13-19.

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26. Tanderup K, Po¨tter R, Lindegaard JC, et al. PTV margins should not be used to compensate for uncertainties in 3D image guided intracavitary brachytherapy. Radiother Oncol 2010;97:495-500. 27. Viswanathan AN, Erickson B, Gaffney DK, et al. Comparison and consensus guidelines for delineation of clinical target volume for CT- and MR-based brachytherapy in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2014;90:320-328. 28. Petric P, Hudej R, Rogelj P, et al. Uncertainties of target volume delineation in MRI guided adaptive brachytherapy of cervix cancer: A multi-institutional study. Radiother Oncol 2013;107:6-12. 29. Schmid MP, Po¨tter R, Brader P, et al. Feasibility of transrectal ultrasonography for assessment of cervical cancer. Strahlenther Onkol 2013;189:123-128. 30. Nesvacil N, Po¨tter R, Sturdza A, et al. Adaptive image guided brachytherapy for cervical cancer: A combined MRI-/CT-planning technique with MRI only at first fraction. Radiother Oncol 2013;107: 75-81.