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Trans-abdominal ultrasound (US) and magnetic resonance imaging (MRI) correlation for conformal intracavitary brachytherapy in carcinoma of the uterine cervix
Radiotherapy and Oncology 102 (2012) 130–134
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Cervix uterine brachytherapy
Trans-abdominal ultrasound (US) and magnetic resonance imaging (MRI) correlation for conformal intracavitary brachytherapy in carcinoma of the uterine cervix Umesh Mahantshetty a,⇑, Nehal Khanna a, Jamema Swamidas a, Reena Engineer a, Meenakshi H. Thakur b, Nikhil H. Merchant b, Deepak D. Deshpande a, Shyamkishore Shrivastava a a
Department of Radiation Oncology and Medical Physics; and b Department of Radiology, Tata Memorial Hospital, Mumbai, India
a r t i c l e
i n f o
Article history: Received 18 September 2009 Received in revised form 4 August 2011 Accepted 5 August 2011 Available online 30 August 2011 Keywords: ICBT Image guided conformal brachytherapy Ultrasonography MR imaging Carcinoma of uterine cervix
a b s t r a c t Purpose: Trans-abdominal ultrasonography (US) is capable of determining size, shape, thickness, and diameter of uterus, cervix and disease at cervix or parametria. To assess the potential value of US for image-guided cervical cancer brachytherapy, we compared US-findings relevant for brachytherapy to the corresponding findings obtained from MR imaging. Materials and methods: Twenty patients with biopsy proven cervical cancer undergoing definitive radiotherapy with/without concomitant Cisplatin chemotherapy and suitable for brachytherapy were invited to participate in this study. US and MR were performed in a similar reproducible patient positioning after intracavitary application. US mid-sagittal and axial image at the level of external cervical os was acquired. Reference points D1 to D9 and distances were identified with respect to central tandem and flange, to delineate cervix, central disease, and external surface of the uterus. Results: Thirty-two applications using CT/MR compatible applicators were evaluable. The D1 and D3 reference distances which represent anterior surface had a strong correlation with R = 0.92 and 0.94 (p < 0.01). The D2 and D4 reference distances in contrast, which represent the posterior surface had a moderate (D2) and a strong (D4) correlation with R = 0.63 and 0.82 (p < 0.01). Of all, D2 reference distance showed the least correlation of MR and US. The D5 reference distance representing the fundal thickness from tandem tip had a correlation of 0.98. The reference distances for D6, D7, D8, and D9 had a correlation of 0.94, 0.82, 0.96, and 0.93, respectively. Conclusions: Our study evaluating the use of US, suggests a reasonably strong correlation with MR in delineating uterus, cervix, and central disease for 3D conformal intracavitary brachytherapy planning. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 130–134
Brachytherapy forms an integral part of radiation therapy and cornerstone for both local control and toxicity in treating cervical cancer patients. The International Commission on Radiation Units and Measurement (ICRU) 38 Recommendations have been attempted using X-rays for treatment planning for uniform reporting of intracavitary brachytherapy (ICBT) [1]. However, there have been many reports critically reviewing and challenging the ICRU 38 Recommendations [2,3]. In the last two decades, the advent of better imaging modalities and technological advances, have paved the way for Image Based Brachytherapy and various imaging modalities like ultrasound, CT, MRI, and PET have been explored [3–6]. CT scans are used at some centers for image guidance during gynecological brachytherapy [7], but CT images have significant limitations. On CT images, it is challenging when visualizing the
⇑ Corresponding author. Address: Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest Borges Marg, Parel, Mumbai 400012, India. E-mail address: [email protected] (U. Mahantshetty). 0167-8140/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2011.08.001
tumor and separating the tumor from the cervix, the uterine corpus, vagina, parametria, and in the absence of contrast also from the surrounding organs (bladder, rectum, sigmoid, and small bowel) [7]. On the other hand, MR imaging is the modality of choice for assessment of local tumor extension and is also becoming increasingly popular for brachytherapy treatment planning [7,8]. GYN GEC ESTRO Working Group has recommended contouring guidelines, concepts and terms in 3D Image Based Treatment Planning in cervical cancer brachytherapy [9,10]. Recent reports confirm the safety, feasibility, definite advantages and clinical outcome of MR Image Based Brachytherapy Planning [11–15]. The inability to use MR and CT scans with the conventional, stainless steel, after loading applicators has discouraged the implementation of MR and CT guidance for gynecologic brachytherapy in routine clinical practice. Moreover, in developing countries including India with limited resources, lack of availability of MR scanning at all the centers and poor socio-economic status of patients make conformal image guided treatment less feasible. However, it does not exclude the use of commonly available low cost technology like ultrasonography.
U. Mahantshetty et al. / Radiotherapy and Oncology 102 (2012) 130–134
Trans-abdominal ultrasonography (US) is capable of determining size, shape, thickness, and diameter of uterus, cervix and disease at cervix and the parametria [16,17]. Trans-abdominal intraoperative US is useful during difficult intracavitary applications and in avoiding inadvertent uterine and organ perforation [18,19]. It has also been used to establish the relative positions of the bladder and rectum during gynecologic brachytherapy applications [17,4]. The rectal and bladder doses determined using ultrasound localization are often greater than those calculated using the conventionally defined dose specification points [4,17,20]. Integration of trans-rectal US for interstitial brachytherapy planning in prostate cancer is a success story today. However, its use in gynecological brachytherapy and planning has been sparingly reported. To assess the potential value of US for image-guided cervical cancer brachytherapy, we undertook this study. We compared US-findings relevant for brachytherapy to the corresponding findings obtained from MR imaging (gold standard). Materials and methods Patients and treatment Between August 2006 and November 2007, 20 patients with biopsy proven cervical cancer undergoing definitive radiotherapy with/without concomitant Cisplatin chemotherapy and suitable for brachytherapy after obtaining the informed consent were invited to participate in this study. There were no strict inclusion or exclusion criteria except phobia for MR imaging. The selection of patients for the study was random and was based on availability of MR appointments. FIGO stage distribution was as follows: stage II = 11 and stage III = 9 patients. The EBRT and HDR ICBT doses were planned according to stage and as per Institutional Management Protocols [21]. The external radiation doses range between 45–50 Gy and 1.8–2.0 Gy per fraction followed by 3–5 fractions of HDR ICBT depending on the FIGO stage. A dose of 7 Gy was prescribed to point A per fraction to a total brachytherapy dose of 21– 35 Gy to point A. Each HDR ICBT application was performed with the Nucletron standard tandem-ovoid CT/MR compatible applicator and a rectal separator under short general anesthesia. The procedure is similar to conventional application except that the radio-opaque gauze used for vaginal packing was soaked with a cocktail of betadine solution and Gadolinium (10:1), to aid the visualization of vaginal mucosal/disease. US and MR imaging protocol After the insertion of the intracavitary applicator, US and pelvic MR were performed in a similar reproducible patient positioning. To stabilize the applicator and maintain a constant and reproducible applicator position, the patients were placed in supine position with legs horizontal and a thermocol block below the applicator between the two thighs. US imaging was performed with a trans-abdominal probe (SDU 450XL 3–5 MHz, Shimadzu). To facilitate visualization of the uterus, the emptied urinary bladder was filled with 200–250 cc isotonic saline solution infused through the Foley’s catheter. Trans-abdominal US was performed in the hypogastric region. After confirming that the central tandem length was adequate and that it was placed in the uterine cavity, the US Images were acquired. Mid-sagittal image with complete depiction of the tandem and transaxial image at the level of external cervical os was acquired (Fig. 1). Various reference points D1 to D9 were identified with respect to central tandem, flange, and external os. With the aid of these points, reference distances were calculated from the central tandem. These reference distances/points were used to
131
delineate the cervix, central disease, and external surface of the uterus as indicated in Fig. 1. The D1 and D3 to tandem reference distance represents the anterior uterine surface while D2 and D4 to tandem reference distance represents the posterior uterine surface at different levels from the cervical os with respect to the central tandem. The reference distance of D5 point from the tip of the tandem represents the fundal surface. Cervical canal and distorted echoes were taken as standard for identifying the cervix and central disease in the axial sections. D6, D7, D8, and D9 reference distances were recorded as shown in Figs. 1 and 2. Fig. 2a represents an example of US Images and various references points/distances. All the images showing the reference points and distances were recorded and stored. US imaging for all patients and applications were performed by the same radiologist (MT) to eliminate interobserver variability. After completion of US, MR (1.5 Tesla, Signa, GE Systems) imaging was performed using a body coil. Fast Spin Echo (FSE) T1 axial for localization and catheter reconstruction in the initial period and FSE T2 axial (true), sagittal and coronal (in the plane of central tandem) sequences were obtained with 3–4 mm thick slices and 0– 1 mm slice gap. To maintain a constant and reproducible bladder filling, 200–250 cc isotonic saline solution were infused again into the emptied urinary bladder through the Foley’s catheter prior to MR imaging. The MR Images were then transferred to ONCENTRA (V 0.9 Nucletron, Veenendal NL) or PLATO Sunrise Planning System (V 14.3.5 Nucletron, Veenendal NL). The D1–D9 point based reference distances measured during US were mapped on the MR Images and correlated as shown in Fig. 2b. Statistical methods All the reference distances for D1 to D9 were recorded and analyzed with the help of SPSS Software Version 14.0. Descriptive statistics for the entire reference distances were evaluated. With the use of one-sample Kolmogorov–Smirnov test each value was tested for normal distribution. Comparison and correlation with corresponding reference distances estimated by US and MR was done using Pearson’s correlation coefficient test. R = 1–0.7 is considered as a strong correlation, R = 0.7–0.5 is considered as a moderate correlation, and R = 0.5–0.3 is a poor correlation. Absolute differences for each corresponding US and MR reference distance were compiled for each patient separately and averaged. The standard mean and the standard error for each reference distance was calculated and recorded. For a particular reference distance estimate of variation was calculated by using the formula: % variation = (MR US)/MR 100. Results Thirty two applications using CT/MR compatible applicators were evaluable. Eighteen brachytherapy applications were on patients with FIGO stage II (11 patients) and 14 on FIGO stage III (9 patients). Out of 11 patients with FIGO stage II, seven patients had imaging data for two applications while four patients had for one application only. Similarly, for FIGO stage III, imaging data for two applications were available for five patients and for one application for the other four patients. US and MR correlation Table 1 shows the correlation of the various US and MR reference distances. The D1 and D3 reference distances which represent anterior surface had a strong correlation with R = 0.92 and 0.94 (p < 0.01). The D2 and D4 reference distances in contrast, which represent the posterior surface had a moderate (D2) and a strong (D4) correlation with R = 0.63 and 0.82 (p < 0.01). Of all, D2
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Abdominal ultrasonography in brachytherapy for carcinoma of the uterine cervix
Fig. 1. Definition of reference points and distances.
D6 D3
D1
D5
D8 D9 D7
D4
D2
(a) : Various reference points and distances on US Images
D5
D4 D1
D6 D2
D3 D2
D8
D9
D1
D7
(b) : Various reference points and distances on MR Images Fig. 2. Shows various reference points and distances on: (a) US Images and (b) MR Images.
reference distance showed the least correlation of MR and US. The D5 reference distance representing the fundal thickness from tandem tip had a strong correlation with R = 0.98. The reference distances for D6, D7, D8, and D9 had a correlation of 0.94, 0.82, 0.96, and 0.93, respectively. For reference distances at cervix, D7 had the least correlation. Nevertheless, all the reference points D1 to D9 of US and MR correlated significantly (p < 0.01). Mean absolute differences of reference distances The mean differences between US and MR for each reference distance separately were for D1: 0.7 mm ± 0.6 (0–2.1), D2: 2.0 mm ± 3.00 (0.1–15.9), D3: 0.7 mm ± 0.7 (0–2.9), D4:
2.3 mm ± 2.9 (0.1–12.4), D5: 0.7 mm ± 0.72 (0–3.2), D6: 0.7 mm ± 0.7 (0–3.5), D7: 1.0 mm ± 1.8 (0–10), D8: 0.7 mm ± 0.9 (0–4.5), and D9: 0.9 mm ± 1.3 (0–6.4). Estimation of variation Table 2 shows applications with an estimated variation of >15% and >10% for various reference distances. For D1 and D3, the number of applications showing more than 15% difference between US and MR were 3/32 (9%) and 2/32 (6%). The same for 10% difference for D1 and D3 was 6/32 (18%) and 7/32 (22%). Similarly, for D2 and D4, the number of applications showing more than 15% difference in between the US and MR values were 5/32 (16%) and 8/32 (25%).
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U. Mahantshetty et al. / Radiotherapy and Oncology 102 (2012) 130–134 Table 1 Mean, standard deviation and mean standard error for correlation of various US and corresponding MR points. Reference dimension
USG (mean) in mm
MRI (mean) in mm
Mean absolute diff. D MRI D USG (range) in mm
D1 D2 D3 D4 D5 D6 D7 D8 D9
11.9 17.7 13.9 20.1 13.4 13.1 16.2 15.4 16.8
12.1 17.7 14.3 19.8 13.4 13.2 16.2 15.3 16.2
0.7 (0–2.1) 2 (0.1–15.9) 0.7 (0–2.9) 2.3 (0–12.4) 0.7 (0–3.2) 0.7 (0–3.5) 1.0 (0–10) 0.7 (0–4.5) 0.9 (0–6.4)
(n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32)
Paired differences S. D. in mm
Std. error mean
0.6 3.0 0.7 2.9 0.7 0.7 1.8 0.9 1.3
0.1 0.5 0.1 0.5 0.1 0.1 0.3 0.2 0.2
Pearson’s correlation ‘‘R’’
Sig. 2-tailed
0.92 0.63 0.94 0.82 0.98 0.94 0.82 0.96 0.93
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01
Table 2 Estimation of variation. Reference dimension
D1 D2 D3 D4 D5 D6 D7 D8 D9
No. of applications with >15% difference
No. of applications with >10% difference
MR > US
US > MR
Total
MR > US
US > MR
Total
3 1 1 3 1 1 2 0 0
0 4 1 5 0 1 1 1 3
3 5 2 8 1 2 3 1 3
5 4 6 4 3 2 4 2 1
1 6 1 7 2 1 1 2 4
6 (19%) 10 (31%) 7 (21%) 11 (34%) 5 (16%) 3 (9%) 5 (16%) 4 (13%) 5 (16%)
For reference distances D6, D7, D8, and D9, the number of applications showing more than 15% difference between the US and MR were 2/32 (6%), 3/32 (9%), 1/32 (3%), and 3/32 (9%), respectively. Discussion To overcome the limitations of conventional X-ray based intracavitary brachytherapy planning, MRI has been considered as the standard imaging modality for tumor and OAR contouring [9– 13]. However, cervical cancer is a disease of developing countries and the use of MRI in routine practice is unrealistic in these countries. In this study, we investigated the potential of US as an alternate imaging modality for guidance of intracavitary brachytherapy in cervical cancer. Ultrasound imaging can reasonably delineate the uterus and cervical contour or central disease. Multiple studies have been done which emphasize that cervical tumor contour and volume can be measured well with US [17,20]. US has been compared with CT scan and MR Images and has shown comparable results in delineating and measuring volume of the uterus, cervix, and central disease [16–18]. However, this has not been validated with applicators in situ in brachytherapy planning. To validate this we compared US findings relevant for brachytherapy to the corresponding findings obtained from MR imaging (gold standard). In published literature so far, US role in brachytherapy has been in image guidance and helps in the selection of appropriate applicator, guides appropriate applicator placement, decreases the need of revision/repeat applications and decreases the overall procedure time but not in assisting brachytherapy planning [19]. In our study, we took reference distances with the help of various points (D1–D9) along the uterine surface with respect to the central tandem and obtain a reasonable outline of the uterus, cervix and central disease. Further, these US points were extrapolated on corresponding MR Images. In our cohort of 20 patients accounting for 32 evaluable HDR ICBT applications, we found that all reference points of US, correlated significantly with the corresponding
(9%) (16%) (6%) (25%) (3%) (6%) (9%) (3%) (9%)
distances obtained from MR imaging (p < 0.01). The anterior reference distances from US had a strong correlation of 0.96 (p < 0.01) with corresponding the MR reference distance. The reference distances for posterior surface, however, had a moderate to strong correlation (p < 0.01) with differences up to 15.9 mm. The mean variation and average correlation was poor with the posterior reference distances which can be attributed to the attenuation of echoes while traversing the uterine wall. The reference distances for cervix/central disease had strong correlation, however, with differences up to 6.4 mm. Estimated variation of >10–15% was seen in only few patients. These findings suggest that US imaging is reasonably comparable to the gold standard MR in delineating the uterus, cervix, and central cervical disease with the help of reference points and distances. Nevertheless, it has to be taken into account that despite the predominantly strong correlation of the reference point distances, differences of >1 cm were observed for the posterior surface of the uterus. This observed limitation should be taken into account if US is used for image guidance and subsequently for treatment planning. Although in this study, we were able to demonstrate a reasonable correlation between US and MRI, there are limitations with the use of US. The general limitations of US observer dependency and subjectivity, presence of uterine pathologies like pyometra, hematometra, fibroids, retroversion, uterus off axis, etc. may influence the image acquisition. The advantages of universal availability of US, its cost effectiveness, advances in 3D and real time US imaging and small learning curve outweigh these limitations especially in developing countries [22]. The specific limitations for brachytherapy planning include on the one hand poor delineation of the posterior surface of uterus due to poor echoes and on the other hand the inability to define rectum, sigmoid and small bowel. However, sculpting the isodoses to the uterine surface may indirectly reduce inadvertent dose delivery to the adjacent structures [18]. Recent advances in US technology in terms of improved US software enabling 3D and 4D reconstructed anatomies may overcome these limitations.
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Abdominal ultrasonography in brachytherapy for carcinoma of the uterine cervix
Recording dynamic events such as catheter insertion and withdrawal may assist further in brachytherapy planning [23–26]. At the moment, measurement of the various points/distances on trans-abdominal US as defined in our study, extrapolation on to ICBT X-rays and prescribing dose to these points may improve conformity of ICBT for cervical cancers especially in patients with complete response or residual central disease confined to cervix in the absence of MR imaging. Recently, Peter Macallum Melbourne Group, has shown that US can identify an effective target volume and it is possible to improve technical accuracy, visualize organ boundaries, and with experience, plan conformal treatments, which means that improvements can be made to current treatments based on standardized 2D X-ray image-based planning [26]. In summary, conventional X-ray based ICBT planning although time tested has several limitations. 3D Image Based Brachytherapy Planning with CT/MR and advances in Planning Software are becoming increasingly popular but cannot be widely applied in the majority of the developing countries. As an initial experience we report here the evaluation and validation of US as an alternate imaging modality to outline uterus, cervix, and central disease. This information could be utilized in 3D conformal brachytherapy planning. Our study, demonstrates a reasonably good correlation of US based reference points/distances with MR imaging. Although, posterior wall delineation showed differences >1 cm, this could be resolved with incorporation of newer US systems. Finally, US based conformal intracavitary brachytherapy planning needs further evaluation. Conflict of interest None of the authors have any conflict of interest whatsoever. Acknowledgements
[4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Dr. Kailash Narayan and van Dyk Sylvia, Peter Macallum Cancer Centre, Melbourne for their technical assistance and training in ‘abdominal ultrasound during intracavitary brachytherapy in cervical cancers’.
[17]
Appendix A. Supplementary data
[20]
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.radonc.2011.08.001.
[21]
References
[23]
[1] ICRU Report No. 38. Dose and volume specification for reporting Intracavitary therapy in Gynecology. Bethesda, MD: International Commission on Radiation Units and Measurements; 1985. [2] Potter R, Limbergen EV, Gerstener N, et al. Survey of the use of the ICRU 38 in recording and reporting cervical cancer brachytherapy. Radiother Oncol 2001;58:11–8. [3] Pelloski CE, Palmer M, Chronowski GM, et al. Comparison between CT-based volumetric calculations and ICRU reference point estimates of radiation doses
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delivered to bladder and rectum during Intracavitary radiotherapy for cervical cancer. Int J Radiat Oncol Biol Phys 2005;62:131–7. Barillot I, Horiot J, Maingon P, et al. Maximum and mean bladder dose defined from ultrasonography: comparison with the ICRU reference in gynaecological brachytherapy. Radiother Oncol 1994;30:231–8. Erickson B. MRI and ultrasound guide gynecologic brachytherapy. Diagn Imaging 2000;22:78–83. Mutic S, Grigsby P, Low D, et al. PET – Guided three-dimensional treatment planning of intracavitary GYN implants. Int J Radiat Oncol Biol Phys 2002;52:1104–11. Viswanathan AN, Dimopoulos J, Kirisits C, et al. Computed tomography versus magnetic resonance imaging based contouring in cervical cancer brachytherapy: results of a prospective trial and preliminary guidelines for standardized contours. Int J Radiat Oncol Biol Phys 2007;68:491–8. Lindegaard JC, Tanderup K, Nielsen SK, et al. MRI-guided 3D optimization significantly improves DVH parameters of pulsed-dose-rate brachytherapy in locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2008;71:756–64. Meder-Haie C, Potter R, Limbergen EV, et al. Recommendations from gynecological (GYN) GEC-ESTRO working group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74:235–45. Potter R, Haie-Meder C, Limbergen EV, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancers brachytherapy 3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67–77. Wachter-Gerstner N, Wachter S, Reinstadler E, et al. The impact of sectional imaging on dose escalation in endocavitary brachytherapy of cervical cancer: results of a prospective comparative trial. Radiother Oncol 2003;68:51–9. Potter R, Dimopoulos J, George P, et al. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol 2007;83:148–55. Potter R, Dimopoulos J, Bachtiary B, et al. 3D Conformal HDR-brachytherapy and external beam therapy plus simultaneous Cisplatin for high-risk cervical cancer: clinical experience with 3 year follow-up. Radiother Oncol 2006;79:80–6. De Brabandere M, Mousa AG, Nulens A, et al. Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma. Radiother Oncol 2008;88:217–26. Chargari C, Magne N, Dumas I, et al. Physics contributions and clinical outcome with 3D-MRI-based pulsed-dose-rate intracavitary brachytherapy in cervical cancer patients. Int J Radiat Oncol Biol Phys 2009;74:133–9. Hricak H, Yu KK. Radiology in invasive cervical cancer. Am J Roentgenol 1996;167:1101–8. Brascho DJ. Diagnostic ultrasound in radiation treatment planning. J Clin Ultrasound 1973;1:320–9. van Dyk S, Bernshaw D. Ultrasound-based conformal planning for gynaecological brachytherapy. J Med Imaging Rad Oncol 2008;52:77–84. Davidson MTM, Yuen J, D’Souza PD, et al. Optimisation of high-dose-rate cervix brachytherapy applicator placement: the benefits of intraoperative ultrasound guidance. Brachytherapy 2008;7:248–53. Erickson B. MRI and ultrasound guide gynecologic brachytherapy. Diagn Imaging 2000;192:78–83. Tongaonkar HB, Evidence based management guidelines, gynecological cancers, vol. III. Tata Memorial Centre. ISBN: 81-7525-583-8; 2004. p. 7–9. Fleischer AC. Gynecologic sonography. Past, present and future. J Ultrasound Med 2003;22:759–63. Yaman C, Fridrik M. 3D Ultrasonography to assess the response to treatment in gynecological malignancies. Gynecol Oncol 2005;97:665–8. Bega G, Lev-Toaff AS, O’Kane P, et al. 3-Dimentional ultrasonography in gynecology. J Ultrasound Med 2003;22:1249–69. Andreotti RF, Fleischer AC, Mason LE, et al. 3-Dimensional sonography of the endometrium and the adjacent myometrium. J Ultrasound Med 2006;25:1313–9. Van Dyk S, Narayan K, Fischer R, Bernshaw D. Conformal brachytherapy planning for cervical cancer using trans-abdominal ultrasound. Int J Radiat Oncol Biol Phys 2009;75:64–70.
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Cervix uterine brachytherapy
Trans-abdominal ultrasound (US) and magnetic resonance imaging (MRI) correlation for conformal intracavitary brachytherapy in carcinoma of the uterine cervix Umesh Mahantshetty a,⇑, Nehal Khanna a, Jamema Swamidas a, Reena Engineer a, Meenakshi H. Thakur b, Nikhil H. Merchant b, Deepak D. Deshpande a, Shyamkishore Shrivastava a a
Department of Radiation Oncology and Medical Physics; and b Department of Radiology, Tata Memorial Hospital, Mumbai, India
a r t i c l e
i n f o
Article history: Received 18 September 2009 Received in revised form 4 August 2011 Accepted 5 August 2011 Available online 30 August 2011 Keywords: ICBT Image guided conformal brachytherapy Ultrasonography MR imaging Carcinoma of uterine cervix
a b s t r a c t Purpose: Trans-abdominal ultrasonography (US) is capable of determining size, shape, thickness, and diameter of uterus, cervix and disease at cervix or parametria. To assess the potential value of US for image-guided cervical cancer brachytherapy, we compared US-findings relevant for brachytherapy to the corresponding findings obtained from MR imaging. Materials and methods: Twenty patients with biopsy proven cervical cancer undergoing definitive radiotherapy with/without concomitant Cisplatin chemotherapy and suitable for brachytherapy were invited to participate in this study. US and MR were performed in a similar reproducible patient positioning after intracavitary application. US mid-sagittal and axial image at the level of external cervical os was acquired. Reference points D1 to D9 and distances were identified with respect to central tandem and flange, to delineate cervix, central disease, and external surface of the uterus. Results: Thirty-two applications using CT/MR compatible applicators were evaluable. The D1 and D3 reference distances which represent anterior surface had a strong correlation with R = 0.92 and 0.94 (p < 0.01). The D2 and D4 reference distances in contrast, which represent the posterior surface had a moderate (D2) and a strong (D4) correlation with R = 0.63 and 0.82 (p < 0.01). Of all, D2 reference distance showed the least correlation of MR and US. The D5 reference distance representing the fundal thickness from tandem tip had a correlation of 0.98. The reference distances for D6, D7, D8, and D9 had a correlation of 0.94, 0.82, 0.96, and 0.93, respectively. Conclusions: Our study evaluating the use of US, suggests a reasonably strong correlation with MR in delineating uterus, cervix, and central disease for 3D conformal intracavitary brachytherapy planning. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 130–134
Brachytherapy forms an integral part of radiation therapy and cornerstone for both local control and toxicity in treating cervical cancer patients. The International Commission on Radiation Units and Measurement (ICRU) 38 Recommendations have been attempted using X-rays for treatment planning for uniform reporting of intracavitary brachytherapy (ICBT) [1]. However, there have been many reports critically reviewing and challenging the ICRU 38 Recommendations [2,3]. In the last two decades, the advent of better imaging modalities and technological advances, have paved the way for Image Based Brachytherapy and various imaging modalities like ultrasound, CT, MRI, and PET have been explored [3–6]. CT scans are used at some centers for image guidance during gynecological brachytherapy [7], but CT images have significant limitations. On CT images, it is challenging when visualizing the
⇑ Corresponding author. Address: Department of Radiation Oncology, Tata Memorial Hospital, Dr. Ernest Borges Marg, Parel, Mumbai 400012, India. E-mail address: [email protected] (U. Mahantshetty). 0167-8140/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2011.08.001
tumor and separating the tumor from the cervix, the uterine corpus, vagina, parametria, and in the absence of contrast also from the surrounding organs (bladder, rectum, sigmoid, and small bowel) [7]. On the other hand, MR imaging is the modality of choice for assessment of local tumor extension and is also becoming increasingly popular for brachytherapy treatment planning [7,8]. GYN GEC ESTRO Working Group has recommended contouring guidelines, concepts and terms in 3D Image Based Treatment Planning in cervical cancer brachytherapy [9,10]. Recent reports confirm the safety, feasibility, definite advantages and clinical outcome of MR Image Based Brachytherapy Planning [11–15]. The inability to use MR and CT scans with the conventional, stainless steel, after loading applicators has discouraged the implementation of MR and CT guidance for gynecologic brachytherapy in routine clinical practice. Moreover, in developing countries including India with limited resources, lack of availability of MR scanning at all the centers and poor socio-economic status of patients make conformal image guided treatment less feasible. However, it does not exclude the use of commonly available low cost technology like ultrasonography.
U. Mahantshetty et al. / Radiotherapy and Oncology 102 (2012) 130–134
Trans-abdominal ultrasonography (US) is capable of determining size, shape, thickness, and diameter of uterus, cervix and disease at cervix and the parametria [16,17]. Trans-abdominal intraoperative US is useful during difficult intracavitary applications and in avoiding inadvertent uterine and organ perforation [18,19]. It has also been used to establish the relative positions of the bladder and rectum during gynecologic brachytherapy applications [17,4]. The rectal and bladder doses determined using ultrasound localization are often greater than those calculated using the conventionally defined dose specification points [4,17,20]. Integration of trans-rectal US for interstitial brachytherapy planning in prostate cancer is a success story today. However, its use in gynecological brachytherapy and planning has been sparingly reported. To assess the potential value of US for image-guided cervical cancer brachytherapy, we undertook this study. We compared US-findings relevant for brachytherapy to the corresponding findings obtained from MR imaging (gold standard). Materials and methods Patients and treatment Between August 2006 and November 2007, 20 patients with biopsy proven cervical cancer undergoing definitive radiotherapy with/without concomitant Cisplatin chemotherapy and suitable for brachytherapy after obtaining the informed consent were invited to participate in this study. There were no strict inclusion or exclusion criteria except phobia for MR imaging. The selection of patients for the study was random and was based on availability of MR appointments. FIGO stage distribution was as follows: stage II = 11 and stage III = 9 patients. The EBRT and HDR ICBT doses were planned according to stage and as per Institutional Management Protocols [21]. The external radiation doses range between 45–50 Gy and 1.8–2.0 Gy per fraction followed by 3–5 fractions of HDR ICBT depending on the FIGO stage. A dose of 7 Gy was prescribed to point A per fraction to a total brachytherapy dose of 21– 35 Gy to point A. Each HDR ICBT application was performed with the Nucletron standard tandem-ovoid CT/MR compatible applicator and a rectal separator under short general anesthesia. The procedure is similar to conventional application except that the radio-opaque gauze used for vaginal packing was soaked with a cocktail of betadine solution and Gadolinium (10:1), to aid the visualization of vaginal mucosal/disease. US and MR imaging protocol After the insertion of the intracavitary applicator, US and pelvic MR were performed in a similar reproducible patient positioning. To stabilize the applicator and maintain a constant and reproducible applicator position, the patients were placed in supine position with legs horizontal and a thermocol block below the applicator between the two thighs. US imaging was performed with a trans-abdominal probe (SDU 450XL 3–5 MHz, Shimadzu). To facilitate visualization of the uterus, the emptied urinary bladder was filled with 200–250 cc isotonic saline solution infused through the Foley’s catheter. Trans-abdominal US was performed in the hypogastric region. After confirming that the central tandem length was adequate and that it was placed in the uterine cavity, the US Images were acquired. Mid-sagittal image with complete depiction of the tandem and transaxial image at the level of external cervical os was acquired (Fig. 1). Various reference points D1 to D9 were identified with respect to central tandem, flange, and external os. With the aid of these points, reference distances were calculated from the central tandem. These reference distances/points were used to
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delineate the cervix, central disease, and external surface of the uterus as indicated in Fig. 1. The D1 and D3 to tandem reference distance represents the anterior uterine surface while D2 and D4 to tandem reference distance represents the posterior uterine surface at different levels from the cervical os with respect to the central tandem. The reference distance of D5 point from the tip of the tandem represents the fundal surface. Cervical canal and distorted echoes were taken as standard for identifying the cervix and central disease in the axial sections. D6, D7, D8, and D9 reference distances were recorded as shown in Figs. 1 and 2. Fig. 2a represents an example of US Images and various references points/distances. All the images showing the reference points and distances were recorded and stored. US imaging for all patients and applications were performed by the same radiologist (MT) to eliminate interobserver variability. After completion of US, MR (1.5 Tesla, Signa, GE Systems) imaging was performed using a body coil. Fast Spin Echo (FSE) T1 axial for localization and catheter reconstruction in the initial period and FSE T2 axial (true), sagittal and coronal (in the plane of central tandem) sequences were obtained with 3–4 mm thick slices and 0– 1 mm slice gap. To maintain a constant and reproducible bladder filling, 200–250 cc isotonic saline solution were infused again into the emptied urinary bladder through the Foley’s catheter prior to MR imaging. The MR Images were then transferred to ONCENTRA (V 0.9 Nucletron, Veenendal NL) or PLATO Sunrise Planning System (V 14.3.5 Nucletron, Veenendal NL). The D1–D9 point based reference distances measured during US were mapped on the MR Images and correlated as shown in Fig. 2b. Statistical methods All the reference distances for D1 to D9 were recorded and analyzed with the help of SPSS Software Version 14.0. Descriptive statistics for the entire reference distances were evaluated. With the use of one-sample Kolmogorov–Smirnov test each value was tested for normal distribution. Comparison and correlation with corresponding reference distances estimated by US and MR was done using Pearson’s correlation coefficient test. R = 1–0.7 is considered as a strong correlation, R = 0.7–0.5 is considered as a moderate correlation, and R = 0.5–0.3 is a poor correlation. Absolute differences for each corresponding US and MR reference distance were compiled for each patient separately and averaged. The standard mean and the standard error for each reference distance was calculated and recorded. For a particular reference distance estimate of variation was calculated by using the formula: % variation = (MR US)/MR 100. Results Thirty two applications using CT/MR compatible applicators were evaluable. Eighteen brachytherapy applications were on patients with FIGO stage II (11 patients) and 14 on FIGO stage III (9 patients). Out of 11 patients with FIGO stage II, seven patients had imaging data for two applications while four patients had for one application only. Similarly, for FIGO stage III, imaging data for two applications were available for five patients and for one application for the other four patients. US and MR correlation Table 1 shows the correlation of the various US and MR reference distances. The D1 and D3 reference distances which represent anterior surface had a strong correlation with R = 0.92 and 0.94 (p < 0.01). The D2 and D4 reference distances in contrast, which represent the posterior surface had a moderate (D2) and a strong (D4) correlation with R = 0.63 and 0.82 (p < 0.01). Of all, D2
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Fig. 1. Definition of reference points and distances.
D6 D3
D1
D5
D8 D9 D7
D4
D2
(a) : Various reference points and distances on US Images
D5
D4 D1
D6 D2
D3 D2
D8
D9
D1
D7
(b) : Various reference points and distances on MR Images Fig. 2. Shows various reference points and distances on: (a) US Images and (b) MR Images.
reference distance showed the least correlation of MR and US. The D5 reference distance representing the fundal thickness from tandem tip had a strong correlation with R = 0.98. The reference distances for D6, D7, D8, and D9 had a correlation of 0.94, 0.82, 0.96, and 0.93, respectively. For reference distances at cervix, D7 had the least correlation. Nevertheless, all the reference points D1 to D9 of US and MR correlated significantly (p < 0.01). Mean absolute differences of reference distances The mean differences between US and MR for each reference distance separately were for D1: 0.7 mm ± 0.6 (0–2.1), D2: 2.0 mm ± 3.00 (0.1–15.9), D3: 0.7 mm ± 0.7 (0–2.9), D4:
2.3 mm ± 2.9 (0.1–12.4), D5: 0.7 mm ± 0.72 (0–3.2), D6: 0.7 mm ± 0.7 (0–3.5), D7: 1.0 mm ± 1.8 (0–10), D8: 0.7 mm ± 0.9 (0–4.5), and D9: 0.9 mm ± 1.3 (0–6.4). Estimation of variation Table 2 shows applications with an estimated variation of >15% and >10% for various reference distances. For D1 and D3, the number of applications showing more than 15% difference between US and MR were 3/32 (9%) and 2/32 (6%). The same for 10% difference for D1 and D3 was 6/32 (18%) and 7/32 (22%). Similarly, for D2 and D4, the number of applications showing more than 15% difference in between the US and MR values were 5/32 (16%) and 8/32 (25%).
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U. Mahantshetty et al. / Radiotherapy and Oncology 102 (2012) 130–134 Table 1 Mean, standard deviation and mean standard error for correlation of various US and corresponding MR points. Reference dimension
USG (mean) in mm
MRI (mean) in mm
Mean absolute diff. D MRI D USG (range) in mm
D1 D2 D3 D4 D5 D6 D7 D8 D9
11.9 17.7 13.9 20.1 13.4 13.1 16.2 15.4 16.8
12.1 17.7 14.3 19.8 13.4 13.2 16.2 15.3 16.2
0.7 (0–2.1) 2 (0.1–15.9) 0.7 (0–2.9) 2.3 (0–12.4) 0.7 (0–3.2) 0.7 (0–3.5) 1.0 (0–10) 0.7 (0–4.5) 0.9 (0–6.4)
(n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32) (n = 32)
Paired differences S. D. in mm
Std. error mean
0.6 3.0 0.7 2.9 0.7 0.7 1.8 0.9 1.3
0.1 0.5 0.1 0.5 0.1 0.1 0.3 0.2 0.2
Pearson’s correlation ‘‘R’’
Sig. 2-tailed
0.92 0.63 0.94 0.82 0.98 0.94 0.82 0.96 0.93
<0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01
Table 2 Estimation of variation. Reference dimension
D1 D2 D3 D4 D5 D6 D7 D8 D9
No. of applications with >15% difference
No. of applications with >10% difference
MR > US
US > MR
Total
MR > US
US > MR
Total
3 1 1 3 1 1 2 0 0
0 4 1 5 0 1 1 1 3
3 5 2 8 1 2 3 1 3
5 4 6 4 3 2 4 2 1
1 6 1 7 2 1 1 2 4
6 (19%) 10 (31%) 7 (21%) 11 (34%) 5 (16%) 3 (9%) 5 (16%) 4 (13%) 5 (16%)
For reference distances D6, D7, D8, and D9, the number of applications showing more than 15% difference between the US and MR were 2/32 (6%), 3/32 (9%), 1/32 (3%), and 3/32 (9%), respectively. Discussion To overcome the limitations of conventional X-ray based intracavitary brachytherapy planning, MRI has been considered as the standard imaging modality for tumor and OAR contouring [9– 13]. However, cervical cancer is a disease of developing countries and the use of MRI in routine practice is unrealistic in these countries. In this study, we investigated the potential of US as an alternate imaging modality for guidance of intracavitary brachytherapy in cervical cancer. Ultrasound imaging can reasonably delineate the uterus and cervical contour or central disease. Multiple studies have been done which emphasize that cervical tumor contour and volume can be measured well with US [17,20]. US has been compared with CT scan and MR Images and has shown comparable results in delineating and measuring volume of the uterus, cervix, and central disease [16–18]. However, this has not been validated with applicators in situ in brachytherapy planning. To validate this we compared US findings relevant for brachytherapy to the corresponding findings obtained from MR imaging (gold standard). In published literature so far, US role in brachytherapy has been in image guidance and helps in the selection of appropriate applicator, guides appropriate applicator placement, decreases the need of revision/repeat applications and decreases the overall procedure time but not in assisting brachytherapy planning [19]. In our study, we took reference distances with the help of various points (D1–D9) along the uterine surface with respect to the central tandem and obtain a reasonable outline of the uterus, cervix and central disease. Further, these US points were extrapolated on corresponding MR Images. In our cohort of 20 patients accounting for 32 evaluable HDR ICBT applications, we found that all reference points of US, correlated significantly with the corresponding
(9%) (16%) (6%) (25%) (3%) (6%) (9%) (3%) (9%)
distances obtained from MR imaging (p < 0.01). The anterior reference distances from US had a strong correlation of 0.96 (p < 0.01) with corresponding the MR reference distance. The reference distances for posterior surface, however, had a moderate to strong correlation (p < 0.01) with differences up to 15.9 mm. The mean variation and average correlation was poor with the posterior reference distances which can be attributed to the attenuation of echoes while traversing the uterine wall. The reference distances for cervix/central disease had strong correlation, however, with differences up to 6.4 mm. Estimated variation of >10–15% was seen in only few patients. These findings suggest that US imaging is reasonably comparable to the gold standard MR in delineating the uterus, cervix, and central cervical disease with the help of reference points and distances. Nevertheless, it has to be taken into account that despite the predominantly strong correlation of the reference point distances, differences of >1 cm were observed for the posterior surface of the uterus. This observed limitation should be taken into account if US is used for image guidance and subsequently for treatment planning. Although in this study, we were able to demonstrate a reasonable correlation between US and MRI, there are limitations with the use of US. The general limitations of US observer dependency and subjectivity, presence of uterine pathologies like pyometra, hematometra, fibroids, retroversion, uterus off axis, etc. may influence the image acquisition. The advantages of universal availability of US, its cost effectiveness, advances in 3D and real time US imaging and small learning curve outweigh these limitations especially in developing countries [22]. The specific limitations for brachytherapy planning include on the one hand poor delineation of the posterior surface of uterus due to poor echoes and on the other hand the inability to define rectum, sigmoid and small bowel. However, sculpting the isodoses to the uterine surface may indirectly reduce inadvertent dose delivery to the adjacent structures [18]. Recent advances in US technology in terms of improved US software enabling 3D and 4D reconstructed anatomies may overcome these limitations.
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Recording dynamic events such as catheter insertion and withdrawal may assist further in brachytherapy planning [23–26]. At the moment, measurement of the various points/distances on trans-abdominal US as defined in our study, extrapolation on to ICBT X-rays and prescribing dose to these points may improve conformity of ICBT for cervical cancers especially in patients with complete response or residual central disease confined to cervix in the absence of MR imaging. Recently, Peter Macallum Melbourne Group, has shown that US can identify an effective target volume and it is possible to improve technical accuracy, visualize organ boundaries, and with experience, plan conformal treatments, which means that improvements can be made to current treatments based on standardized 2D X-ray image-based planning [26]. In summary, conventional X-ray based ICBT planning although time tested has several limitations. 3D Image Based Brachytherapy Planning with CT/MR and advances in Planning Software are becoming increasingly popular but cannot be widely applied in the majority of the developing countries. As an initial experience we report here the evaluation and validation of US as an alternate imaging modality to outline uterus, cervix, and central disease. This information could be utilized in 3D conformal brachytherapy planning. Our study, demonstrates a reasonably good correlation of US based reference points/distances with MR imaging. Although, posterior wall delineation showed differences >1 cm, this could be resolved with incorporation of newer US systems. Finally, US based conformal intracavitary brachytherapy planning needs further evaluation. Conflict of interest None of the authors have any conflict of interest whatsoever. Acknowledgements
[4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Dr. Kailash Narayan and van Dyk Sylvia, Peter Macallum Cancer Centre, Melbourne for their technical assistance and training in ‘abdominal ultrasound during intracavitary brachytherapy in cervical cancers’.
[17]
Appendix A. Supplementary data
[20]
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.radonc.2011.08.001.
[21]
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