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Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?
Radiotherapy and Oncology xxx (2016) xxx–xxx
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Original article
Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition? Maximilian P. Schmid a,⇑, Nicole Nesvacil a, Richard Pötter a,b, Gernot Kronreif c, Christian Kirisits a,b a Department of Radiation Oncology, Comprehensive Cancer Center; b Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna; and c Austrian Center for Medical Innovation and Technology – ACMIT, Wiener Neustadt, Austria
a r t i c l e
i n f o
Article history: Received 11 September 2015 Received in revised form 27 December 2015 Accepted 9 January 2016 Available online xxxx Keywords: Cervix cancer Radiotherapy Image-guided adaptive brachytherapy MRI Transrectal ultrasound
a b s t r a c t Purpose: To compare the maximum high risk clinical target volume (CTVHR) dimensions and image quality between magnetic resonance imaging (MRI), transrectal ultrasound (TRUS) and computed tomography (CT) in image guided adaptive brachytherapy (IGABT) of locally advanced cervical cancer. Material and methods: All patients with locally advanced cervical cancer treated with radiochemotherapy and IGABT between 09/2012-05/2013 were included in this study. T2-weighted MRI (1.5 tesla), TRUS and CT were performed before (MRIpreBT, TRUSpreBT) and/or after (MRIBT, TRUSBT and CTBT) insertion of the applicator. 3D TRUS image acquisition was done with a customized US stepper device and software. The HR CTV was defined on 3D image sequences acquired with different imaging modalities by one blinded observer, in accordance to the GEC-ESTRO recommendations for MRI-based target volume delineation, as the complete cervical mass including the tumour, any suspicious areas of parametrial involvement and the normal cervical stroma. Maximum HR CTV width and thickness were measured on transversal planes. Image quality was classified using the following scoring system: Grade 0: not depicted, Grade 1: inability to discriminate, margin not recognizable, Grade 2: fair discrimination, margin indistinct, Grade 3: excellent discrimination, margin distinct. Descriptive statistics, mean differences between the groups, with MRIBT as reference, and a paired t-test were calculated. Results: Images from 19 patients (FIGO IB: 3, IIB: 9, IIIB: 5, IVB: 2) were available for analysis. The mean difference in maximum HR CTV width of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT was 0.0 mm ± 4.7 (n.s.), 1.1 mm ± 5.6 (n.s.), 0.7 mm ± 6.4 (n.s.) and 13.8 mm ± 6.7 (p < 0.001). The mean difference in maximum HR CTV thickness of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT was -3.4 mm ± 5.9 (p = 0.037), 3.4 mm ± 4.2 (p < 0.001), 2.0 mm ± 6.1 (n.s.) and 13.9 mm ± 6.3 (p < 0.001). Mean scores of image quality of the target volume was 2.9 for TRUSpreBT, 2.3 for TRUSBT, 2.9 for MRIpreBT, 2.7 for MRIBT and 2.1 for CTBT. Conclusion: For the assessment of the HR CTV in IGABT of cervical cancer, TRUS is within the intraobserver variability of MRI. TRUS is superior to CT as it yields systematically smaller deviations from MRI, with good to excellent image quality. Small differences of TRUS HR CTV thickness are likely related to differences in image slice orientation and compression of the cervix by the TRUS probe before insertion of the brachytherapy applicator. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx
Image-guided adaptive brachytherapy (IGABT) is an evolving method, which is being increasingly applied for locally advanced cervical cancer in the frame of primary radiochemotherapy. Recommendations for various steps of this effective and sophisticated treatment procedure have been published so far and first clinical results using MRI as imaging modality indicate an improved therapeutic ratio in comparison to traditional (X-ray/point A based) brachytherapy [1–6]. The main advantage of IGABT is the possibil⇑ Corresponding author at: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected] (M.P. Schmid).
ity of shaping the radiation delivery according to the individual tumour spread and response and surrounding organs at risk. Precise assessment and definition of the adaptive target volume is therefore a main cornerstone within this treatment procedure. T2-weighted MRI is currently considered as the imaging modality of choice for IGABT in cervix cancer [7], but its limited availability, additional costs and challenging logistics (if not directly integrated in the brachytherapy/radiotherapy department) hamper the worldwide application of MRI based IGABT [8]. Computed tomography (CT) is more frequently performed for IGABT, however CT appears to overestimate the target volume in comparison to MRI [9,17,21]. Transrectal ultrasound (TRUS) – an imaging modality
http://dx.doi.org/10.1016/j.radonc.2016.01.021 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
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Transrectal ultrasound for IGABT
with good soft tissue contrast, which had been widely used in gynaecologic oncology before MRI and which is extensively and successfully used for prostate cancer brachytherapy – could eventually serve as a sophisticated but more easy available alternative to MRI for IGABT [10]. In a first unblinded study comparing TRUS and MRI, the basic feasibility of TRUS for target volume assessment in cervix cancer brachytherapy could be shown in a limited number of selected patients [11]. The aim of the present study is a blinded quantitative and qualitative comparison of the target volume and organs at risk between TRUS, MRI and CT in consecutive cervix cancer patients undergoing primary radiochemotherapy and IGABT. Material and methods Patients and treatment All patients with cervix cancer FIGO Ib to IVb (paraaortic lymph node metastases) treated with definitive radiochemotherapy between September 2012 and May 2013 at the Department of Radiation Oncology of the Medical University of Vienna were included in this study. Treatment consisted of whole pelvis EBRT (45–50.4 Gy with 1.8 Gy per fraction) with or without concomitant chemotherapy and IGABT. IGABT was performed in the end or after EBRT in two applications with two fractions each delivering in total (EBRT + IGABT) > 85 Gy EQD2 (biologically equieffective dose; reference dose per fraction = 2 Gy, linear quadratic model, a/b = 10 Gy) to the D90 of the high risk clinical target volume (HRCTV). Inclusion criterion for the study was the performance of complete 3D TRUS, CT and MRI datasets at the time of brachytherapy after insertion of the applicator. MRI MRI was performed before brachytherapy without applicator (MRIpreBT) and at the time of brachytherapy with applicator (MRIBT) according to the Gyn GEC ESTRO recommendations for imaging in IGABT with a 1.5 tesla system (Avanto, Siemens, Erlangen, Germany) [12]. T2-weighted axial, para-axial, sagittal and coronal images were obtained from the level above the uterine fundus to the inferior border of the symphysis pubis below any vaginal tumour extension. Slice thickness was 5 mm. CT The CT images were acquired at the time of brachytherapy with applicator (CTBT) with a Somatom Plus S scanner (Siemens, Erlangen, Germany) in 2-mm slice intervals from the iliac crest to the ischial tuberosities. TRUS TRUS was performed before (TRUSpreBT) and after insertion of the applicator (TRUSBT) with a 5–10 MHz transducer (BIOPSEE, Medcom, Darmstadt, Germany). Patients were examined under anaesthesia in lithotomy position using a defined imaging protocol. Bowel preparation and bladder filling was routinely performed as part of the brachytherapy procedure. The TRUS probe was inserted and fixated transrectally with a customized ultrasound stepper unit. 3D image acquisition was performed by a dedicated registration software during a manual pull-back of the TRUS probe in the stepper unit from the fundus uteri – if accessible – to the upper third of the vagina (or below any vaginal tumour extension). Image analysis Image analysis was focused on the quantitative and qualitative assessment of the high risk clinical target volume (HR CTV) and
organs at risk. The HR CTV was defined according to the GYN GEC-ESTRO Recommendations on T2 weighted MRI as the macroscopic residual tumour extension at the time of brachytherapy visualized as high signal intensity mass, potential surrounding ‘‘grey zones” with intermediate signal intensity in the area of the initial tumour infiltration and the remaining low signal intensity cervical stroma [13]. Based on this definition, the HR CTV was defined on TRUS as the complete hypoechogenic (cervical ± parametrial) mass depicted by grey-scale imaging. The HR CTV on CT was defined in accordance to the consensus guidelines for CT-based brachytherapy as the complete (cervical ± parametrial) mass with intermediate density (‘‘grey/white”) [14]. The quantitative analysis included the comparison of the maximum HR CTV width (measured as the maximum latero–lateral diameter on transversal images) and the maximum HR CTV thickness (maximum anterior–posterior diameter) for all image data sets (MRIpreBT, TRUSpreBT, MRIBT, TRUSBT and CTBT) and HRCTV width and thickness at the level of point A for MRIBT, TRUSBT and CTBT. The analysis of image quality was assessed by evaluating the ability to discriminate HR CTV, parametria, uterine corpus, uterine fundus, rectum, urinary bladder, sigmoid colon and bowel using a scoring system based on the previous work from Dimopoulos et al. [15]: Grade 0: not depicted, Grade 1: inability to discriminate, margin not recognizable, Grade 2: fair discrimination, margin indistinct, Grade 3: excellent discrimination, margin distinct. Additionally HR CTV, parametria, rectum and urinary bladder were evaluated anteriorly, posteriorly and laterally separately. All TRUS, MRI and CT data sets were evaluated blinded by one observer (to avoid interobserver variability). To reduce a potential bias, first all TRUS data sets of all patients were analysed, followed then by all CT and then all MRI data sets. Descriptive statistics, mean differences between the groups, with MRIBT as reference, and a paired t-test were calculated. All statistics were performed with Excel 2010 software (Microsoft, Redmond, Washington) and SPSS 21.0 software (SPSS, Chicago, Illinois). A p-value < 0.05 was considered as statistically significant. Results Patients Twenty-three patients with locally advanced cervical cancer were treated with MRI based IGABT from September 2012 to May 2013 at the Department of Radiation Oncology of the Medical University of Vienna. Nineteen patients fulfilled the inclusion criterion. Four patients had to be excluded because of non-availability of the TRUS system during brachytherapy (n = 2) or because of TRUS related technical reasons (n = 2, only screenshots available, no 3D volume recorded). In these 19 patients in total 30 TRUS (16 TRUSBT, 14 TRUSpreBT), 32 MRI (19 MRIBT, 13 MRIpreBT) and 19 CTBT were available. In three patients the acquisition of TRUSBT was not possible due to poor image quality, artefacts and/or difficulties in TRUS probe insertion. In five patients TRUSpreBT was missing due to logistic difficulties. In six patients MRIpreBT was missing because of limited availability. The patient cohort comprised the following FIGO stages: IB: 3, IIB: 9, IIIB: 5, IVB: 2 (paraaortic lymph node metastasis). Quantitative image analysis The median maximum HR CTV width at brachytherapy was 46 mm (range: 27–80 mm) on TRUSBT, 45 mm (range: 34– 80 mm) on TRUSpreBT, 46 mm (range: 34–85 mm) on MRIBT, 47 mm (range: 33–82 mm) on MRIpreBT and 58 mm (range: 45– 96 mm) on CTBT. The median maximum HR CTV thickness at
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
M.P. Schmid et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx
brachytherapy was 33 mm (range: 23–56 mm) on TRUSBT, 29 mm (range: 21–55 mm) on TRUSpreBT, 36 mm (range: 26–60 mm) on MRIBT, 36 mm (range: 26–60 mm) on MRIpreBT and 51 mm (range: 38–85 mm) on CTBT. The mean differences in maximum HR CTV width and thickness of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT and mean differences of HR CTV width and thickness at the level of point A are presented in Table 1 and Fig. 1. A comparison of TRUSpreBT and TRUSBT was available in 11 patients and showed a mean difference in maximum HR CTV width and thickness of 0,3 mm ± 3.7 mm (p = 0.752) and 5.5 ± 3.5 (p = 0.001), respectively.
Qualitative image analysis The results from the qualitative image analysis for the HR CTV and organs at risk are presented in Table S1+2 (Supplementary material). Overall, the mean scores for the HR CTV were 2.9 for TRUSpreBT, 2.3 for TRUSBT, 2.9 for MRIpreBT, 2.7 for MRIBT and 2.1 for CTBT. The mean scores for the most relevant areas of the organs at risk (anterior rectal wall, posterior bladder wall, sigmoid colon and bowel (if in direct proximity to the target volume/applicator)) showed comparable results between TRUSpreBT, TRUSBT, MRIpreBT, MRIBT and CTBT, except for the posterior bladder wall in TRUSBT, which was inferior to the others. Examples of the different imaging modalities for the various FIGO stages are presented in Fig. 2. An atlas for different TRUS findings is provided in the Supplementary material. Discussion In this study we investigated the value of TRUS for HRCTV assessment in cervical cancer brachytherapy. For this purpose the HRCTV dimensions were measured and compared to MRI and CT. MRIBT is currently considered the gold standard in IGABT and Table 1 Quantitative analysis of TRUSBT, TRUSpreBT, MRIpreBT and CTBT in comparison to MRIBT. Mean Difference to MRI with applicator in mm Maximum target width TRUS with 0.0 applicator TRUS without 1.1 applicator MRI without 0.7 applicator CT with 13.8 applicator Maximum Target thickness TRUS with 3.4 applicator TRUS without 3.4 applicator MRI without 2.0 applicator CT with 13.9 applicator Target width at level of Point A TRUS with 0.8 applicator CT with 15.7 applicator Target thickness at level of Point A TRUS with 3.0 applicator CT with 14.5 applicator Bold values highlight the statistically significant findings.
Standard deviation
pValue
4.7
0.988
5.6
0.468
6.4
0.673
6.7
<0.001
5.9
0.037
4.2
<0.001
6.1
0.263
6.3
<0.001
7.8
0.677
9.8
<0.001
5.5
0.061
6.6
<0.001
3
was therefore used as the reference measurement [15,16], whereas CT and TRUS were the primarily investigated imaging modalities. MRIpreBT can be seen as an internal validation indicating the intraobserver variation – if TRUS is within the range of MRIpreBT it could be considered as equivalent. HRCTV width and thickness were measured at different levels (maximum extension and at the level of point A) to represent relevant components of the HRCTV. Due to the limited visibility of the HRCTV height on TRUS and CT, a comparison of HRCTV height as well as a volumetric analysis were not performed [17]. The HRCTV/tumour width is a simple but major prognostic parameter for cervical cancer essential for appropriate dose coverage and probably the most important indicator for the insertion of interstitial needles in cervical cancer brachytherapy [18,19]. It can be assumed that the increase in local tumour control by MRI based IGABT is mainly related to the improved dose distribution in patients with significant residual parametrial disease after EBRT and chemotherapy (and therefore with a high HRCTV width) [20]. The results of our study showed that there were no significant differences between TRUS and MRI for the assessment of the HRCTV width and that the mean differences and standard deviations were in a comparable range. CT, in contrast, yielded significantly higher deviations and was – as shown already by others – systematically overestimating the HRCTV width in all patients and both levels [9,21]. The comparison of HRCTV thickness is generally challenging as the position of the uterus and subsequently the image orientation of MRI, CT and especially of the TRUS probe slightly varies leading to small methodological differences in the measurements. Further, insertion of the TRUS probe may compress the uterus and may cause underestimation of the HRCTV by TRUS. Indeed our previous unblinded study, in which the image orientation between TRUS and MRI could be directly matched, showed a high agreement between TRUS and MRI but with a slight systematical difference [11]. The current study confirms this observation by showing a small but significant difference in terms of an underestimation in HRCTV thickness for both TRUSpreBT and TRUSBT in comparison to MRIBT (mean difference: 3.4 mm). The slightly inferior image quality of the anterior border of the HRCTV (Table S1+2) may also contribute to this finding. On the contrary, with CT a significant overestimation of the HRCTV thickness (mean difference: 14 mm) was observed for all measurements. The results from the quantitative analysis of our study are in line with recent reports from the literature: A prospective multicentre trial with 182 consecutive patients with early-stage cervical cancer undergoing surgery compared preoperative transrectal or transvaginal ultrasound, preoperative MRI and pathological findings and showed that there was high agreement in the maximum tumour dimensions between the three different modalities and that ultrasound was even superior to MRI in assessing parametrial invasion [22]. Pinkakova et al. showed that TRUS and MRI allow for similar assessment of tumour regression during neoadjuvant chemotherapy and that the maximum TRUS based tumour dimensions after neoadjuvant chemotherapy highly correlate with the pathological findings [23]. The ACRIN 6651/GOG 183 Intergroup Study demonstrated in 208 patients that for early cervical cancer tumour size measurements on MRI were superior to CT in comparison to pathological findings and underlined MRI as the gold standard for assessment of local tumour spread [24]. In accordance different authors already observed that in cervical cancer brachytherapy CT is statistically significantly overestimating the MRI based HRCTV leading to significant differences in the reported HRCTV dose parameters [9,17,21]. The qualitative analysis revealed excellent image quality for HRCTV contouring for MRIBT, MRIpreBT and TRUSpreBT. The higher image resolution of TRUS in comparison to MRI should in principle allow for even a higher image quality of TRUS. TRUSBT and CTBT had
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
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Fig. 1. Quantitative analysis of TRUSBT (green triangle), TRUSpreBT (grey cross), MRIpreBT (red square), MRIBT (blue diamond)and CTBT (light blue star) (all y-axis) in comparison to MRIBT (x-axis) for maximum HRCTV width. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
a reasonable but slightly inferior image quality. The decrease in image quality from TRUSpreBT to TRUSBT is likely caused by applicator-related-artefacts typically seen ‘‘behind the applicator” in the periphery of the field of view. The major difference between TRUS and MRI or CT was observed – as expected – in the limited field-of-view of the 3D-TRUS volume. This was reflected in the low rate of visualization of ‘‘complete” pelvic organs such as complete uterus, urinary bladder, rectum and especially colon sigmoideum and small bowel. However, the sub-volumes within these organs relevant for brachytherapy treatment planning were well visualized: The HRCTV was depicted in all patients on TRUSpreBT and TRUSBT. The anterior rectal wall and the posterior bladder wall were depicted in all patients except for two on TRUSBT. If in direct proximity to the HRCTV (and in consequence in the relevant potential high dose area), small bowel loops or the recto-sigmoidal flexure could be also be clearly visualized. Overall scores of TRUS image quality were good to excellent with minor restrictions for the anterior HRCTV border, posterior urinary bladder wall and uterine corpus on TRUSBT. Nevertheless, in three patients TRUSBT could not be performed due to difficulties in positioning the TRUS probe with the stepper unit (mainly to pass the ring applicator and/or the recto-sigmoid curvature), which remains currently a limitation of this method. Therefore adaptations in the TRUS setup initially developed and configurated for the needs in prostate brachytherapy (e.g. more flexible ‘‘stepper” unit with higher degree of freedom, modifications of the TRUS probe, use of longitudinal array for recording the 3D volume) and applicator and needle material meeting the specific needs for cervix cancer brachytherapy are warranted to further improve image quality and reduce the number of patients not accessible for TRUSBT at present. The good to excellent image quality and the good agreement of the HRCTV measurements between TRUS and MRI indicate the potential application of TRUS in cervical cancer brachytherapy, but how could TRUS be implemented in clinical practice? The easy
handling of TRUSpreBT, the possibility for dynamic imaging and the excellent results for TRUSpreBT strongly suggest the pre- and intraoperative use for (1) HRCTV assessment before applicator insertion (for example to support CT-based contouring as described by Pötter et al. for MRIpreBT [21]), (2) preplanning purposes (decision on the appropriate applicator system with or without interstitial needles based on HRCTV dimensions, configuration, and the precise measurement of distances between the border of the HRCTV and the cervical canal, and OAR) [25] and (3) TRUS-guided tandem and interstitial needle insertion (not subject of the current study but already described by other authors [26–28]). TRUSBT can ultimately be used as final check for the position of the applicator and the interstitial needles before submitting the patient to CT or MRI for definitive treatment planning. Further, a transfer of TRUSBT via applicator based image fusion on CT (as described by Nesvacil et al. for MRI-CT image fusion [29]) to improve HRCTV delineation could be an attractive way of combining the advantages of these two imaging modalities. However, the potential deformation of the uterus by the TRUS probe and the subsequent impact on the HRCTV (see above: differences in thickness) needs still to be investigated. Whether TRUSBT allows also for TRUS-only treatment planning requires also further research. To outweigh limitations of TRUSBT in depicting the upper third of the uterus and/or certain OARs a combination with transabdominal ultrasound based treatment planning (as described by van Dyk et al. [30]) or even with standard X-ray based ICRU dose points might be conceivable. To further analyse the potential of TRUSBT for HRCTV delineation an interobserver analysis is being planned.
Conclusion For the assessment of the HR CTV in IGABT of cervical cancer, TRUS is within the intraobserver variability of MRI. TRUS is superior to CT as it yields systematically smaller deviations from MRI,
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
M.P. Schmid et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx
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Fig. 2. Examples of MRI, TRUS and CT findings for different FIGO stages with and without applicator. Corresponding image orientation and levels for all imaging modalities. First column: MRI overview, second column: MRI enlarged, third column: TRUS, fourth column: CT enlarged and fifth column: CT overview.
with good to excellent image quality. Small differences of TRUS HR CTV thickness is likely related to differences in image slice orientation and compression of the cervix by the TRUS probe before insertion of the brachytherapy applicator.
Conflict of interest notification The Department of Radiotherapy at the Medical University of Vienna receives/received financial and/or equipment support for research and educational purposes from Nucletron an Elekta company., Varian Medical Systems, Inc., and Isodose Control B.V.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.01. 021.
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Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
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Original article
Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition? Maximilian P. Schmid a,⇑, Nicole Nesvacil a, Richard Pötter a,b, Gernot Kronreif c, Christian Kirisits a,b a Department of Radiation Oncology, Comprehensive Cancer Center; b Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna; and c Austrian Center for Medical Innovation and Technology – ACMIT, Wiener Neustadt, Austria
a r t i c l e
i n f o
Article history: Received 11 September 2015 Received in revised form 27 December 2015 Accepted 9 January 2016 Available online xxxx Keywords: Cervix cancer Radiotherapy Image-guided adaptive brachytherapy MRI Transrectal ultrasound
a b s t r a c t Purpose: To compare the maximum high risk clinical target volume (CTVHR) dimensions and image quality between magnetic resonance imaging (MRI), transrectal ultrasound (TRUS) and computed tomography (CT) in image guided adaptive brachytherapy (IGABT) of locally advanced cervical cancer. Material and methods: All patients with locally advanced cervical cancer treated with radiochemotherapy and IGABT between 09/2012-05/2013 were included in this study. T2-weighted MRI (1.5 tesla), TRUS and CT were performed before (MRIpreBT, TRUSpreBT) and/or after (MRIBT, TRUSBT and CTBT) insertion of the applicator. 3D TRUS image acquisition was done with a customized US stepper device and software. The HR CTV was defined on 3D image sequences acquired with different imaging modalities by one blinded observer, in accordance to the GEC-ESTRO recommendations for MRI-based target volume delineation, as the complete cervical mass including the tumour, any suspicious areas of parametrial involvement and the normal cervical stroma. Maximum HR CTV width and thickness were measured on transversal planes. Image quality was classified using the following scoring system: Grade 0: not depicted, Grade 1: inability to discriminate, margin not recognizable, Grade 2: fair discrimination, margin indistinct, Grade 3: excellent discrimination, margin distinct. Descriptive statistics, mean differences between the groups, with MRIBT as reference, and a paired t-test were calculated. Results: Images from 19 patients (FIGO IB: 3, IIB: 9, IIIB: 5, IVB: 2) were available for analysis. The mean difference in maximum HR CTV width of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT was 0.0 mm ± 4.7 (n.s.), 1.1 mm ± 5.6 (n.s.), 0.7 mm ± 6.4 (n.s.) and 13.8 mm ± 6.7 (p < 0.001). The mean difference in maximum HR CTV thickness of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT was -3.4 mm ± 5.9 (p = 0.037), 3.4 mm ± 4.2 (p < 0.001), 2.0 mm ± 6.1 (n.s.) and 13.9 mm ± 6.3 (p < 0.001). Mean scores of image quality of the target volume was 2.9 for TRUSpreBT, 2.3 for TRUSBT, 2.9 for MRIpreBT, 2.7 for MRIBT and 2.1 for CTBT. Conclusion: For the assessment of the HR CTV in IGABT of cervical cancer, TRUS is within the intraobserver variability of MRI. TRUS is superior to CT as it yields systematically smaller deviations from MRI, with good to excellent image quality. Small differences of TRUS HR CTV thickness are likely related to differences in image slice orientation and compression of the cervix by the TRUS probe before insertion of the brachytherapy applicator. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx
Image-guided adaptive brachytherapy (IGABT) is an evolving method, which is being increasingly applied for locally advanced cervical cancer in the frame of primary radiochemotherapy. Recommendations for various steps of this effective and sophisticated treatment procedure have been published so far and first clinical results using MRI as imaging modality indicate an improved therapeutic ratio in comparison to traditional (X-ray/point A based) brachytherapy [1–6]. The main advantage of IGABT is the possibil⇑ Corresponding author at: Department of Radiation Oncology, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected] (M.P. Schmid).
ity of shaping the radiation delivery according to the individual tumour spread and response and surrounding organs at risk. Precise assessment and definition of the adaptive target volume is therefore a main cornerstone within this treatment procedure. T2-weighted MRI is currently considered as the imaging modality of choice for IGABT in cervix cancer [7], but its limited availability, additional costs and challenging logistics (if not directly integrated in the brachytherapy/radiotherapy department) hamper the worldwide application of MRI based IGABT [8]. Computed tomography (CT) is more frequently performed for IGABT, however CT appears to overestimate the target volume in comparison to MRI [9,17,21]. Transrectal ultrasound (TRUS) – an imaging modality
http://dx.doi.org/10.1016/j.radonc.2016.01.021 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
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Transrectal ultrasound for IGABT
with good soft tissue contrast, which had been widely used in gynaecologic oncology before MRI and which is extensively and successfully used for prostate cancer brachytherapy – could eventually serve as a sophisticated but more easy available alternative to MRI for IGABT [10]. In a first unblinded study comparing TRUS and MRI, the basic feasibility of TRUS for target volume assessment in cervix cancer brachytherapy could be shown in a limited number of selected patients [11]. The aim of the present study is a blinded quantitative and qualitative comparison of the target volume and organs at risk between TRUS, MRI and CT in consecutive cervix cancer patients undergoing primary radiochemotherapy and IGABT. Material and methods Patients and treatment All patients with cervix cancer FIGO Ib to IVb (paraaortic lymph node metastases) treated with definitive radiochemotherapy between September 2012 and May 2013 at the Department of Radiation Oncology of the Medical University of Vienna were included in this study. Treatment consisted of whole pelvis EBRT (45–50.4 Gy with 1.8 Gy per fraction) with or without concomitant chemotherapy and IGABT. IGABT was performed in the end or after EBRT in two applications with two fractions each delivering in total (EBRT + IGABT) > 85 Gy EQD2 (biologically equieffective dose; reference dose per fraction = 2 Gy, linear quadratic model, a/b = 10 Gy) to the D90 of the high risk clinical target volume (HRCTV). Inclusion criterion for the study was the performance of complete 3D TRUS, CT and MRI datasets at the time of brachytherapy after insertion of the applicator. MRI MRI was performed before brachytherapy without applicator (MRIpreBT) and at the time of brachytherapy with applicator (MRIBT) according to the Gyn GEC ESTRO recommendations for imaging in IGABT with a 1.5 tesla system (Avanto, Siemens, Erlangen, Germany) [12]. T2-weighted axial, para-axial, sagittal and coronal images were obtained from the level above the uterine fundus to the inferior border of the symphysis pubis below any vaginal tumour extension. Slice thickness was 5 mm. CT The CT images were acquired at the time of brachytherapy with applicator (CTBT) with a Somatom Plus S scanner (Siemens, Erlangen, Germany) in 2-mm slice intervals from the iliac crest to the ischial tuberosities. TRUS TRUS was performed before (TRUSpreBT) and after insertion of the applicator (TRUSBT) with a 5–10 MHz transducer (BIOPSEE, Medcom, Darmstadt, Germany). Patients were examined under anaesthesia in lithotomy position using a defined imaging protocol. Bowel preparation and bladder filling was routinely performed as part of the brachytherapy procedure. The TRUS probe was inserted and fixated transrectally with a customized ultrasound stepper unit. 3D image acquisition was performed by a dedicated registration software during a manual pull-back of the TRUS probe in the stepper unit from the fundus uteri – if accessible – to the upper third of the vagina (or below any vaginal tumour extension). Image analysis Image analysis was focused on the quantitative and qualitative assessment of the high risk clinical target volume (HR CTV) and
organs at risk. The HR CTV was defined according to the GYN GEC-ESTRO Recommendations on T2 weighted MRI as the macroscopic residual tumour extension at the time of brachytherapy visualized as high signal intensity mass, potential surrounding ‘‘grey zones” with intermediate signal intensity in the area of the initial tumour infiltration and the remaining low signal intensity cervical stroma [13]. Based on this definition, the HR CTV was defined on TRUS as the complete hypoechogenic (cervical ± parametrial) mass depicted by grey-scale imaging. The HR CTV on CT was defined in accordance to the consensus guidelines for CT-based brachytherapy as the complete (cervical ± parametrial) mass with intermediate density (‘‘grey/white”) [14]. The quantitative analysis included the comparison of the maximum HR CTV width (measured as the maximum latero–lateral diameter on transversal images) and the maximum HR CTV thickness (maximum anterior–posterior diameter) for all image data sets (MRIpreBT, TRUSpreBT, MRIBT, TRUSBT and CTBT) and HRCTV width and thickness at the level of point A for MRIBT, TRUSBT and CTBT. The analysis of image quality was assessed by evaluating the ability to discriminate HR CTV, parametria, uterine corpus, uterine fundus, rectum, urinary bladder, sigmoid colon and bowel using a scoring system based on the previous work from Dimopoulos et al. [15]: Grade 0: not depicted, Grade 1: inability to discriminate, margin not recognizable, Grade 2: fair discrimination, margin indistinct, Grade 3: excellent discrimination, margin distinct. Additionally HR CTV, parametria, rectum and urinary bladder were evaluated anteriorly, posteriorly and laterally separately. All TRUS, MRI and CT data sets were evaluated blinded by one observer (to avoid interobserver variability). To reduce a potential bias, first all TRUS data sets of all patients were analysed, followed then by all CT and then all MRI data sets. Descriptive statistics, mean differences between the groups, with MRIBT as reference, and a paired t-test were calculated. All statistics were performed with Excel 2010 software (Microsoft, Redmond, Washington) and SPSS 21.0 software (SPSS, Chicago, Illinois). A p-value < 0.05 was considered as statistically significant. Results Patients Twenty-three patients with locally advanced cervical cancer were treated with MRI based IGABT from September 2012 to May 2013 at the Department of Radiation Oncology of the Medical University of Vienna. Nineteen patients fulfilled the inclusion criterion. Four patients had to be excluded because of non-availability of the TRUS system during brachytherapy (n = 2) or because of TRUS related technical reasons (n = 2, only screenshots available, no 3D volume recorded). In these 19 patients in total 30 TRUS (16 TRUSBT, 14 TRUSpreBT), 32 MRI (19 MRIBT, 13 MRIpreBT) and 19 CTBT were available. In three patients the acquisition of TRUSBT was not possible due to poor image quality, artefacts and/or difficulties in TRUS probe insertion. In five patients TRUSpreBT was missing due to logistic difficulties. In six patients MRIpreBT was missing because of limited availability. The patient cohort comprised the following FIGO stages: IB: 3, IIB: 9, IIIB: 5, IVB: 2 (paraaortic lymph node metastasis). Quantitative image analysis The median maximum HR CTV width at brachytherapy was 46 mm (range: 27–80 mm) on TRUSBT, 45 mm (range: 34– 80 mm) on TRUSpreBT, 46 mm (range: 34–85 mm) on MRIBT, 47 mm (range: 33–82 mm) on MRIpreBT and 58 mm (range: 45– 96 mm) on CTBT. The median maximum HR CTV thickness at
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
M.P. Schmid et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx
brachytherapy was 33 mm (range: 23–56 mm) on TRUSBT, 29 mm (range: 21–55 mm) on TRUSpreBT, 36 mm (range: 26–60 mm) on MRIBT, 36 mm (range: 26–60 mm) on MRIpreBT and 51 mm (range: 38–85 mm) on CTBT. The mean differences in maximum HR CTV width and thickness of TRUSBT, TRUSpreBT, MRIpreBT, CTBT to MRIBT and mean differences of HR CTV width and thickness at the level of point A are presented in Table 1 and Fig. 1. A comparison of TRUSpreBT and TRUSBT was available in 11 patients and showed a mean difference in maximum HR CTV width and thickness of 0,3 mm ± 3.7 mm (p = 0.752) and 5.5 ± 3.5 (p = 0.001), respectively.
Qualitative image analysis The results from the qualitative image analysis for the HR CTV and organs at risk are presented in Table S1+2 (Supplementary material). Overall, the mean scores for the HR CTV were 2.9 for TRUSpreBT, 2.3 for TRUSBT, 2.9 for MRIpreBT, 2.7 for MRIBT and 2.1 for CTBT. The mean scores for the most relevant areas of the organs at risk (anterior rectal wall, posterior bladder wall, sigmoid colon and bowel (if in direct proximity to the target volume/applicator)) showed comparable results between TRUSpreBT, TRUSBT, MRIpreBT, MRIBT and CTBT, except for the posterior bladder wall in TRUSBT, which was inferior to the others. Examples of the different imaging modalities for the various FIGO stages are presented in Fig. 2. An atlas for different TRUS findings is provided in the Supplementary material. Discussion In this study we investigated the value of TRUS for HRCTV assessment in cervical cancer brachytherapy. For this purpose the HRCTV dimensions were measured and compared to MRI and CT. MRIBT is currently considered the gold standard in IGABT and Table 1 Quantitative analysis of TRUSBT, TRUSpreBT, MRIpreBT and CTBT in comparison to MRIBT. Mean Difference to MRI with applicator in mm Maximum target width TRUS with 0.0 applicator TRUS without 1.1 applicator MRI without 0.7 applicator CT with 13.8 applicator Maximum Target thickness TRUS with 3.4 applicator TRUS without 3.4 applicator MRI without 2.0 applicator CT with 13.9 applicator Target width at level of Point A TRUS with 0.8 applicator CT with 15.7 applicator Target thickness at level of Point A TRUS with 3.0 applicator CT with 14.5 applicator Bold values highlight the statistically significant findings.
Standard deviation
pValue
4.7
0.988
5.6
0.468
6.4
0.673
6.7
<0.001
5.9
0.037
4.2
<0.001
6.1
0.263
6.3
<0.001
7.8
0.677
9.8
<0.001
5.5
0.061
6.6
<0.001
3
was therefore used as the reference measurement [15,16], whereas CT and TRUS were the primarily investigated imaging modalities. MRIpreBT can be seen as an internal validation indicating the intraobserver variation – if TRUS is within the range of MRIpreBT it could be considered as equivalent. HRCTV width and thickness were measured at different levels (maximum extension and at the level of point A) to represent relevant components of the HRCTV. Due to the limited visibility of the HRCTV height on TRUS and CT, a comparison of HRCTV height as well as a volumetric analysis were not performed [17]. The HRCTV/tumour width is a simple but major prognostic parameter for cervical cancer essential for appropriate dose coverage and probably the most important indicator for the insertion of interstitial needles in cervical cancer brachytherapy [18,19]. It can be assumed that the increase in local tumour control by MRI based IGABT is mainly related to the improved dose distribution in patients with significant residual parametrial disease after EBRT and chemotherapy (and therefore with a high HRCTV width) [20]. The results of our study showed that there were no significant differences between TRUS and MRI for the assessment of the HRCTV width and that the mean differences and standard deviations were in a comparable range. CT, in contrast, yielded significantly higher deviations and was – as shown already by others – systematically overestimating the HRCTV width in all patients and both levels [9,21]. The comparison of HRCTV thickness is generally challenging as the position of the uterus and subsequently the image orientation of MRI, CT and especially of the TRUS probe slightly varies leading to small methodological differences in the measurements. Further, insertion of the TRUS probe may compress the uterus and may cause underestimation of the HRCTV by TRUS. Indeed our previous unblinded study, in which the image orientation between TRUS and MRI could be directly matched, showed a high agreement between TRUS and MRI but with a slight systematical difference [11]. The current study confirms this observation by showing a small but significant difference in terms of an underestimation in HRCTV thickness for both TRUSpreBT and TRUSBT in comparison to MRIBT (mean difference: 3.4 mm). The slightly inferior image quality of the anterior border of the HRCTV (Table S1+2) may also contribute to this finding. On the contrary, with CT a significant overestimation of the HRCTV thickness (mean difference: 14 mm) was observed for all measurements. The results from the quantitative analysis of our study are in line with recent reports from the literature: A prospective multicentre trial with 182 consecutive patients with early-stage cervical cancer undergoing surgery compared preoperative transrectal or transvaginal ultrasound, preoperative MRI and pathological findings and showed that there was high agreement in the maximum tumour dimensions between the three different modalities and that ultrasound was even superior to MRI in assessing parametrial invasion [22]. Pinkakova et al. showed that TRUS and MRI allow for similar assessment of tumour regression during neoadjuvant chemotherapy and that the maximum TRUS based tumour dimensions after neoadjuvant chemotherapy highly correlate with the pathological findings [23]. The ACRIN 6651/GOG 183 Intergroup Study demonstrated in 208 patients that for early cervical cancer tumour size measurements on MRI were superior to CT in comparison to pathological findings and underlined MRI as the gold standard for assessment of local tumour spread [24]. In accordance different authors already observed that in cervical cancer brachytherapy CT is statistically significantly overestimating the MRI based HRCTV leading to significant differences in the reported HRCTV dose parameters [9,17,21]. The qualitative analysis revealed excellent image quality for HRCTV contouring for MRIBT, MRIpreBT and TRUSpreBT. The higher image resolution of TRUS in comparison to MRI should in principle allow for even a higher image quality of TRUS. TRUSBT and CTBT had
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
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Fig. 1. Quantitative analysis of TRUSBT (green triangle), TRUSpreBT (grey cross), MRIpreBT (red square), MRIBT (blue diamond)and CTBT (light blue star) (all y-axis) in comparison to MRIBT (x-axis) for maximum HRCTV width. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
a reasonable but slightly inferior image quality. The decrease in image quality from TRUSpreBT to TRUSBT is likely caused by applicator-related-artefacts typically seen ‘‘behind the applicator” in the periphery of the field of view. The major difference between TRUS and MRI or CT was observed – as expected – in the limited field-of-view of the 3D-TRUS volume. This was reflected in the low rate of visualization of ‘‘complete” pelvic organs such as complete uterus, urinary bladder, rectum and especially colon sigmoideum and small bowel. However, the sub-volumes within these organs relevant for brachytherapy treatment planning were well visualized: The HRCTV was depicted in all patients on TRUSpreBT and TRUSBT. The anterior rectal wall and the posterior bladder wall were depicted in all patients except for two on TRUSBT. If in direct proximity to the HRCTV (and in consequence in the relevant potential high dose area), small bowel loops or the recto-sigmoidal flexure could be also be clearly visualized. Overall scores of TRUS image quality were good to excellent with minor restrictions for the anterior HRCTV border, posterior urinary bladder wall and uterine corpus on TRUSBT. Nevertheless, in three patients TRUSBT could not be performed due to difficulties in positioning the TRUS probe with the stepper unit (mainly to pass the ring applicator and/or the recto-sigmoid curvature), which remains currently a limitation of this method. Therefore adaptations in the TRUS setup initially developed and configurated for the needs in prostate brachytherapy (e.g. more flexible ‘‘stepper” unit with higher degree of freedom, modifications of the TRUS probe, use of longitudinal array for recording the 3D volume) and applicator and needle material meeting the specific needs for cervix cancer brachytherapy are warranted to further improve image quality and reduce the number of patients not accessible for TRUSBT at present. The good to excellent image quality and the good agreement of the HRCTV measurements between TRUS and MRI indicate the potential application of TRUS in cervical cancer brachytherapy, but how could TRUS be implemented in clinical practice? The easy
handling of TRUSpreBT, the possibility for dynamic imaging and the excellent results for TRUSpreBT strongly suggest the pre- and intraoperative use for (1) HRCTV assessment before applicator insertion (for example to support CT-based contouring as described by Pötter et al. for MRIpreBT [21]), (2) preplanning purposes (decision on the appropriate applicator system with or without interstitial needles based on HRCTV dimensions, configuration, and the precise measurement of distances between the border of the HRCTV and the cervical canal, and OAR) [25] and (3) TRUS-guided tandem and interstitial needle insertion (not subject of the current study but already described by other authors [26–28]). TRUSBT can ultimately be used as final check for the position of the applicator and the interstitial needles before submitting the patient to CT or MRI for definitive treatment planning. Further, a transfer of TRUSBT via applicator based image fusion on CT (as described by Nesvacil et al. for MRI-CT image fusion [29]) to improve HRCTV delineation could be an attractive way of combining the advantages of these two imaging modalities. However, the potential deformation of the uterus by the TRUS probe and the subsequent impact on the HRCTV (see above: differences in thickness) needs still to be investigated. Whether TRUSBT allows also for TRUS-only treatment planning requires also further research. To outweigh limitations of TRUSBT in depicting the upper third of the uterus and/or certain OARs a combination with transabdominal ultrasound based treatment planning (as described by van Dyk et al. [30]) or even with standard X-ray based ICRU dose points might be conceivable. To further analyse the potential of TRUSBT for HRCTV delineation an interobserver analysis is being planned.
Conclusion For the assessment of the HR CTV in IGABT of cervical cancer, TRUS is within the intraobserver variability of MRI. TRUS is superior to CT as it yields systematically smaller deviations from MRI,
Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021
M.P. Schmid et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx
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Fig. 2. Examples of MRI, TRUS and CT findings for different FIGO stages with and without applicator. Corresponding image orientation and levels for all imaging modalities. First column: MRI overview, second column: MRI enlarged, third column: TRUS, fourth column: CT enlarged and fifth column: CT overview.
with good to excellent image quality. Small differences of TRUS HR CTV thickness is likely related to differences in image slice orientation and compression of the cervix by the TRUS probe before insertion of the brachytherapy applicator.
Conflict of interest notification The Department of Radiotherapy at the Medical University of Vienna receives/received financial and/or equipment support for research and educational purposes from Nucletron an Elekta company., Varian Medical Systems, Inc., and Isodose Control B.V.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2016.01. 021.
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Please cite this article in press as: Schmid MP et al. Transrectal ultrasound for image-guided adaptive brachytherapy in cervix cancer – An alternative to MRI for target definition?. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.01.021