Brachytherapy 14 (2015) 238e244
Two-year results of transabdominal ultrasound-guided brachytherapy for cervical cancer Ekkasit Tharavichitkul1,*, Damrongsak Tippanya1, Rungtip Jayavasti1, Somvilai Chakrabandhu1, Pitchayaponne Klunklin1, Wimrak Onchan1, Somsak Wanwilairat1, Razvan M. Galalae2, Imjai Chitapanarux1 1
Division of Therapeutic Radiology and Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 2 Faculty of Medicine, Christian-Albrecht-University, Kiel, Germany
ABSTRACT
PURPOSE: To report the preliminary results of transabdominal ultrasound (TAUS)eguided brachytherapy (BT) in cervical cancer. METHODS AND MATERIALS: Twenty-nine patients with cervical cancer Stage IBeIVA according to The International Federation of Gynecology and Obstetrics staging were treated by radical radiotherapy from February 2012 to December 2012. Treatment was composed of WPRT to 50 Gy in 25 fractions and central shielding after 44 Gy in combination with TAUS-guided BT to optimize the total dose (equivalent dose of 2 Gy [EQD2]) to the minimal dose at cervical points (in EQD2 concepts) defined by TAUS $80 Gy while maintaining low doses to the ICRU report no. 38 bladder and rectal points. The treatment results and toxicity profiles were reported. RESULTS: At median followup time of 19 months (range, 17e27), the local control and diseasefree survival rates were 93.1% and 86.2%, respectively. One episode of Grade 3 vaginal toxicity was observed in this followup period. The mean applied doses to cervix, bladder, and rectal points were 82.6, 72.5, and 75 Gy, respectively. TAUS-guided planning reduced bladder (defined as O80 Gy in EQD2) and rectal overdose (defined as O75 Gy in EQD2) in 44.9% and 34.5% of patients, respectively. CONCLUSION: The 2-year results demonstrate that TAUS-guided BT is feasible and associated with excellent tumor control/toxicity rates in cervical cancer. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cervical cancer; Brachytherapy; Transabdominal ultrasound (TAUS)
Introduction Cervical cancer is one of the most common gynecologic cancers in Asia. In Northern Thailand, the incidence rate of cervical cancer was 22.7 per 100,000 in 2005 (1). In patients who are categorized inoperable, a combination of whole pelvic radiation therapy (WPRT) and brachytherapy (BT) is commonly used. High-dose-rate (HDR) intracavitary brachytherapy (ICBT) is used to escalate the
Received 24 August 2014; received in revised form 28 October 2014; accepted 3 November 2014. Conflict of interest: All authors declared no conflicts of interest. * Corresponding author. Division of Therapeutic Radiology and Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: þ66-53-945456; fax: þ66-53-945491. E-mail address: [email protected] (E. Tharavichitkul).
dose to the tumor or cervix to total doses of minimum 80 Gy at Point A. The point-based approach according to Manchester system is extensively applied and works with orthogonal x-rays for calculation and prescription of ICBT (2, 3). In this context, Point A is the major critical point for dose specification of conventional ICBT and is rigidly calculated ignoring the specific tumor anatomy or volume in each individual patient. However, this may cause underdosage to the target volume and/or overdosage to organs at risk (OARs) (4e6). In contrast to conventional planning, the utilization of image-guided brachytherapy (IGBT) with MRI and/or CT is increasingly described in the recent literature and shows a clear benefit of volume-based IGBT to significantly improve treatment results in terms of dose escalation to high-risk clinical target volume O80 Gy and reduction of treatment-related morbidity (7e12).
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2014.11.001
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In addition to CT and MRI, ultrasound (US) technology already plays an important role in BT and may also serve as an additional method for IGBT treatment planning. Application of US guidance during BT for cervical cancer has been used extensively in the past to reduce the complications, especially from uterine perforation that have been reported to occur in 3e10% of applications (13, 14). The use of US in BT planning for cervical cancer is in clinical practice and documented in a few publications. The largest study by Van Dyk et al. (15, 16) reports very promising first results and treatment-related toxicities. Based on these published data, we performed a study using a portable US device that was installed in January 2012. The aim was to analyze the use of portable US in multiple places, BT theater, loading room, and to evaluate the early results of transabdominal ultrasound (TAUS)eguided BT planning and treatment in cervical cancer in the Faculty of Medicine, Chiang Mai University.
Methods and materials After approval by institutional review board, patients with histologically verified cervical cancer were enrolled. The inclusion criteria were cervical cancer Stage IBeIVA according to The International Federation of Gynecology and Obstetrics (FIGO) classification, biopsy-proven squamous cell carcinoma or adenocarcinoma of cervix, no uncontrolled medical condition, age 18e70 years, no previous surgery or radiotherapy, and signed informed consent. The treatment method included a combination of WPRT and concurrent platinum-based chemotherapy with HDR ICBT and is described in the next section. External beam radiation therapy WPRT with 6 or 10 MV photons was applied to treat the primary tumor and pelvic lymph nodes to the dose of 50 Gy in 25 fractions and with central shielding (after 44 Gy) in cN0 stages. A parametrial boost (additional dose of 6 Gy in three fractions) was performed in the case of advanced parametrial or pelvic sidewall involvement. Concurrent chemoradiation When concurrent chemotherapy was indicated (e.g., squamous cell carcinoma), either cisplatin (40 mg/m2; maximum dose 5 70 mg) or carboplatin (area under the curve 5 2; maximum dose 5 200 mg) was prescribed in weekly schedule. Laboratory investigations (complete blood count, blood urea nitrogen, and serum creatinine) were evaluated before consideration of chemotherapy. In cisplatin regimen, chemotherapy was performed when creatinine clearance was more than 50 mL/min and stopped when it was less than 30 mL/min. In carboplatin regimen, it was stopped when creatinine clearance was less than 30 mL/min.
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Brachytherapy HDR ICBT was used in all patients. Four applications with 6.5e7 Gy per fraction were applied, and TAUS was used to guide and plan all fractions. The first ICBT application was usually scheduled after the fourth week of WPRT. Standard tandem/ovoid or CT/MRI applicators were used. A Foley catheter was placed in the bladder and filled with 7 cm3 of diluted contrast media. A normal saline solution 150e200 cm3 was added into the bladder to enhance US visibility of uterus and OARs and maintain reproducible bladder geometry. The vagina was packed with gauze to stabilize the applicator. The WPRT was interrupted for each day of HDR BT insertion. Three steps of TAUS (BK Medical Flex Focus 400, Analogic Ultrasound, Boston, MA) were performed by the radiation oncologist. Primarily, TAUS was used during the BT application to prevent uterine perforation. The uterine tandem was identified, and the relationship to the uterus was evaluated. In the second step, patients were transferred to the loading room and adjusted to supine position with their legs relaxed on the flat table. The rectal probe was inserted to identify the anterior rectal wall. Then, TAUS was performed again for each application to verify the position of applicator. The tandem and uterus were also defined in this step. In the third step, the tandem was used as reference, and, at the level of cervical os and 2 cm superiorly, the distances from tandem to the uterine wall in anterior and posterior directions were measured by TAUS in sagittal view. At the level of cervical os, the measurements of the distances from the tandem to the lateral walls were also evaluated. These measurements were performed as described by Van Dyk and Bernshaw (17). After these three steps, orthogonal radiographs were taken to start the planning process. The TAUS-measured distances from the tandem to the uterine wall were used to define the following cervical points (Fig. 1): L1 5 the distance from tandem to posterior wall of uterus at the level of cervical os L2 5 the distance from tandem to anterior wall of uterus at the level of cervical os L3 5 the distance from tandem to posterior wall of uterus at the level of 2 cm superior to the cervical os along the tandem L4 5 the distance from tandem to anterior wall of uterus at the level of 2 cm superior to the cervical os along the tandem A1 5 the distance from tandem to right lateral wall of cervix at the level of cervical os A2 5 the distance from tandem to left lateral wall of cervix at the level of cervical os
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Fig. 1. Transabdominal ultrasound images with inserted applicator showing the structures (tandem, uterus, and bladder) and measurements of cervix in sagittal and transverse directions to define the cervical points (L1, L2, L3, L4, A1, and A2).
A3 5 the distance from tandem to right lateral wall of cervix at the level of 2 cm from cervical os or isthmus A4 5 the distance from tandem to left lateral wall of cervix at the level of 2 cm from cervical os or isthmus All cervical points (L1, L2, L3, L4, A1, A2, A3, and A4) defined by TAUS were marked into the orthogonal radiographs correlating to the tandem position (Fig. 2). Point A (R and L), rectum, and bladder points were also digitized according to the International Commission on Radiation Units and Measurements (ICRU) report no. 38 (2). All information was then digitized into PLATO TPS (Nucletron, an Elekta company, Stockholm, Sweden). The prescribed dose was 6.5e7 Gy per fraction to Point A for all patients, and the calculated doses to cervical, bladder, and rectal points were recorded. When estimated cumulative doses
to bladder and rectal points indicated overdoses (more than 80 Gy for bladder and 75 Gy for rectum), optimizations by adjustment of dwell weight and dwell time were performed to reduce the overdose to bladder and rectum as low as possible and achieve a sufficient minimal dose to the cervical points (L1, L2, L3, L4, A1, A2, A3, and A4) at least 6.5e7 Gy per fraction (Fig. 3). The cumulative doses from WPRT and BT to minimum cervical, rectal, and bladder points were reported in equivalent dose of 2 Gy (EQD2) using the linearequadratic model. The assumed a/b values were 10 for the tumor and three for OARs (18). Followup program After the treatment was completed, patients were scheduled to visit for per vaginal examination in the followup
Fig. 2. Orthogonal radiographs showing the marked Point As (AR and AL), ICRU 38 bladder, ICRU 38 rectum, additional rectal, L1eL4, and A1eA4 points in lateral and anterioreposterior (AP) films, respectively. (Note: in AP film, AR/AL 5 red and A1eA4 5 black cross). In lateral film, L1eL4 5 black cross, ICRU bladder 5 blue dot, ICRU rectum 5 red dot, and additional rectal points along the anterior surface of rectal probe 5 green dot. ICRU 5 International Commission on Radiation Units and Measurements. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
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Fig. 3. PLATO images in TAUS-guided planning. (a) standard ‘‘point-A’’ plan and (b) TAUS-guided plan. In TAUS-guided plan, the dose distribution was optimized to keep the minimal dose for the cervical point (L1eL4 and A1eA4) to be at least prescribed dose (red line). Point As, cervix points, bladder ICRU 38, and rectal ICRU 38 points were digitized in the planning system. TAUS 5 transabdominal ultrasound; ICRU 5 International Commission on Radiation Units and Measurements. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
(FU) program. The FU program schedule is every 3 months in the first 3 years after treatment, six monthly in fourth and fifth years, then annually after 5 years. A vaginal examination was performed to evaluate the disease status according to the World Health Organization criteria. Investigations (tissue biopsy, medical imaging, or laboratories) for disease progression were performed as indicated when patients presented with suggested symptoms. Late toxicities were evaluated according to the Radiation Therapy Oncology Group/ European Organization of Research and Treatment of Cancer late toxicity criteria. Statistical analysis All statistical analyses were evaluated by Statistical Package of Social Sciences (SPSS; IBM, Armonk, NY, USA) version 17.0. Descriptive statistics were calculated and reported in terms of mean and interquartile range. The comparisons between doses of TAUS-guided plans vs. standard (Point A) plans according to the defined cervical,
bladder, and rectum points were performed by paired t test (two-tailed test) to identify a statistical significance level of p ! 0.05. The KaplaneMeier method and log-rank tests were used to evaluate local control, disease-free survival, and overall survival (OS) rates (19, 20).
Results From February 2012 to December 2012, 29 patients were evaluated. Fifty-nine percent of patients were Stage IIB by FIGO classification. The mean total treatment time was 50.2 days. Patients’ characteristics are shown in Table 1. At median FU time of 19 months (range, 17e27), 2 of the evaluated 29 patients (6.9%) had persistent disease proven by biopsy at third month after treatment completion. These patients were presented to the gynecologic oncologist for radical surgery. Two of 29 patients (6.9%) developed distant metastases and received chemotherapy. One patient died because of metastatic disease. The mean
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Table 1 Patients’ characteristics Parameters
N (range)
Age Stage IB, IIA IIB IIIB Histology Squamous cell carcinoma Adenocarcinoma Total treatment time
56.7 y (range, 34e78) 3 17 9 25 4 51.4 d (range, 42e69)
dose in terms of EQD2 concepts for standard plans to cervical, bladder, and rectal points were 81.43 9.4, 68.84 8.0, and 84.32 11.6 Gy, respectively. At median FU time of 19 months, the local control, disease-free survival, and OS rates according to Kaplane Meier were 93.1%, 86.2%, and 96.6%, respectively. At mean FU time of 18 months, only 1 patient had Grade 3 vaginal toxicity. The toxicity profiles are shown in Table 3.
Discussion transverse diameter (A1 þ A2) of uterine cervix measured by TAUS at the first application of BT was 3.6 cm (range, 2.8e5.2), whereas the mean anteroposterior uterine diameter (L1 þ L2) measured by TAUS at the first application of BT was 2.8 cm (range, 2e4.9). The mean volume of cervix was 11.1 cm3 (range, 6e25). The mean cumulative doses in terms of EQD2 for TAUS-guided plans at the cervical (the minimal dose), bladder, and rectum points were 82.6, 71.6, and 74.8 Gy, respectively. The mean standard deviation of cumulative dose in EQD2 concepts to Point A was 76 10 Gy. The mean cumulative dose in EQD2 concepts for standard plans to bladder and rectum points were 87.5 and 85.2 Gy, respectively. TAUS-guided plans decreased the dose to the ICRU bladder and rectal points. After standard planning, the total bladder dose exceeded 80 Gy (EQD2) in 62.1% of patients. This was reduced to 17.2% of patients after TAUS-based planning. Similarly, after standard planning, the total rectal dose exceeded 75 Gy (EQD2) in 79.3% of patients. This was reduced to 44.8% after TAUS planning. All data are shown in Table 2. When we considered 7 patients who had transverse diameter at the first application O4 cm, the means and standard deviations of cumulative dose in terms of EQD2 for TAUS-guided plan at the cervical, bladder, and rectal points were 82.59 1.4, 65.02 4.6, and 81.85 5.7 Gy, respectively. The means and standard deviations of cumulative Table 2 Dose characteristics in patients treated by TAUS-guided brachytherapy in comparison with standard Point A-based planning Target dose Minimal dose at defined cervical points (mean cumulative EQD2 dose), in Gy The mean cumulative dose to Point A in EQD2 dose, in Gy Organs at risk Proportion of patients with bladder dose O80 Gy in EQD2 Proportion of patients with rectal dose O75 Gy in EQD2
TAUS plans
Standard plans
82.6 1.3
93.2 11
76.3 10.3 N (%)
83.7 N (%)
5/29 (17.2)
18/29 (62.1)
13/29 (44.8)
23/29 (79.3)
TAUS 5 transabdominal ultrasound; EQD2 5 equivalent dose of 2 Gy.
IGBT for cervical cancer has been used for more than 5 years. The Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology published recommendations in 2005e2006 facilitating the use of IGBT (21, 22). The promising benefits of IGBT with MRI or CT guidance in terms of treatment results and toxicity profiles were reported in a series of publications (7e12). Although use of US has been proven to prevent uterine perforation during BT applications (13, 14), the potential benefit of US in BT planning aspects has only been addressed in a few publications mainly focusing on comparisons of the uterine dimensions measured by US and MRI. However, Van Dyk et al. were the first to report on 71 patients with locoregionally advanced cervical cancer treated with chemoradiation and BT with US-assisted tandem insertion and conformal US-based planning. Orthogonal films for applicator reconstruction were also taken. A standard plan (STD) was modified to suit the US-based volume, and treatment was delivered based on modified plans. The patients then underwent MRI scan with the applicators in situ. Standard plans had higher doses to Point A, target volume, ICRU 38 bladder and rectal points, and individualized bowel point compared with US and MRI plans. There was a statistically significant difference between standard plans and image-based plans, STD vs. US, and STD vs. MRI ( p # 0.001), respectively, for target volume, Point A, ICRU 38 bladder, and bowel point. US plans vs. two-dimensional MRI were comparable for target volume ( p 5 0.11), rectal point ( p 5 0.8), and vaginal mucosa ( p 5 0.19). The local Table 3 Toxicity profiles in patients (N 5 29) treated by TAUS-guided brachytherapy for cervical cancer Toxicity (RTOG/EORTC late toxicity criteria)
Grade 0
Grade 1
Grade 2
Grade 3 and higher
GI GU Skin Subcutaneous tissue Vaginal obstruction
24 25 22 21 24
5 4 7 5 3
0 0 0 3 1
0 0 0 0 1
TAUS 5 transabdominal ultrasound; RTOG 5 Radiation Therapy Oncology Group; EORTC 5 European Organization of Research and Treatment of Cancer; GI 5 gastrointestinal; GU 5 genitourinary.
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control was 90%, and late bowel morbidity (G3 and G4) was !2% (16, 17). These first reports of US-guided planning of ICBT for cervical cancer also showed the agreement between different imaging modalities (MRI/US) and demonstrated very promising preliminary results of TAUS-guided planning in terms of disease control and late toxicity. In addition, the updated study of this first series reported on comparison between MRI and US in 192 patients with mean differences of measurements between TAUS and MRI at the anterior and posterior uterine surfaces ranging from 1.5 (3.353) to 3.7 (3.856) mm and 1.46 (3.308) to 0.47 (3.502) mm, respectively. In conclusion of this study, the mean detected differences were less than 3 mm in the cervix and less than 1.5 mm at all measurement points on the posterior surface (15). However, TAUS was also tested in other centers. Mahantshetty et al. (23) from Tata Memorial Hospital published the use of TAUS for BT and correlations to MRI in 20 cervical cancer patients. The D1 and D3 (anterior surface) strongly correlated in TAUS and MRI with R 5 0.92 and 0.94 ( p ! 0.01), whereas D2 and D4 references (posterior surface) revealed moderate correlations with R 5 0.62 and 0.82 ( p ! 0.01). The D5 reference (fundal thickness) also showed a strong correlation between TAUS and US with R 5 0.98. The D2 references showed the lowest correlations between the two imaging modalities. Another approach by transrectal ultrasound (TRUS) was performed by Schmid et al. (24) reporting TRUSand MRI-guided correlations for conformal intracavitary interstitial BT in cervical cancer. The study identified a mean maximum target width of 4.2 0.83 and 4.2 0.79 cm for MRI and TRUS, respectively. The mean maximum target thickness was 3.3 1.03 and 3.1 1.15 cm for MRI and TRUS, respectively. Linear regression analysis for target width and thickness between TRUS and MRI demonstrated a correlation with R(2) 5 0.842 and R(2) 5 0.943, respectively. The authors concluded that the comparison of the target width and thickness showed a high correlation between TRUS and MRI, indicating the potential of TRUS for target definition in image-guided adaptive BT (24). All studies published to date in the literature supported that US measurements fit well with measurements performed by MRI in cervical cancer BT. The latest report by Narayan et al. (25) also showed promising clinical results. Three hundred nine patients with cervical cancer were treated between January 1999 and December 2008 with external beam radiotherapy and HDR conformal TAUS-guided BT with curative intent. Two hundred ninety-two patients were available for analyses. The median FU time was 4.1 years (range, 2.4e6.1). The 5-year failure-free survival and OS rates were 66% and 65%, respectively. Local failure rates according to FIGO Stage I, II, and III were 12%, 10%, and 17%, respectively. In toxicity profiles, the rate of Grade
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3e4 toxicities of bladder, rectum, and vagina was 0.3, 0.99, and 0.69 per 100 person-years of FU, respectively (25). Our present study reports the first utilization of TAUSguided BT for cervical cancer in Thailand. TAUS-guided planning for ICBT in cervical cancer has been confirmed in our data to improve the treatment quality by decreasing the OAR doses of ICRU bladder and rectal points. In addition, TAUS-guided optimization maintained a sufficient high minimal dose to the cervix of at least 80 Gy in EQD2 concept. However, there were some circumstances that we had to choose the adequate dose to target or limited doses to OARs. As curative intent, we decided to keep the adequate dose to the target (at least 80 Gy in EQD2). The mean transverse diameter of uterine cervix measured by TAUS in our study was 3.5 cm (range, 2.8e5.2), and 22 of them (75.8%) were up to 4 cm. After a mean FU time of 18 months, 93.1% of patients developed no recurrence and had only one incidence of severe vaginal obstruction (Grade 3). Not only is US beneficial during applicator insertion and treatment planning but also had other advantages. First, the investment and running costs of US technology are clearly more economical than MRI or CT alternatives. Second, US is portable and thus can be used in the loading room for verification in addition to in-room imaging. Third, the time duration of one application of TAUS-guided ICBT is about 40e60 min compared with 2 h for CT-based BT and 4 h for MRI-based BT (26, 27). These advantages are essential in the context of a developing country with a very high volume of patients to be treated of more than 250 patients per year. However, there are some limitations in the present study. TAUS-guided BT does not allow full volumetric analysis of tumor coverage or doses to OARs and may be considered as ‘‘2.5D’’ point-based planning. Therefore, this demonstrated approach could not entirely incorporate the volume-based concepts of The Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology recommendations (14, 15). Second, at present, TAUS cannot evaluate the residual tumor or the vaginal extension as accurately as MRI. Therefore, clinical evaluation and/or pretreatment imaging by MRI are very important to guide the treatment by TAUS-based BT. And finally, TAUS cannot assess the cumulative doses to sigmoid colon because of its imaging limitations in comparison to CT or MRI. In addition, US-guided planning requires more individual experience and expertise, and no published guidelines for this specific US use are available to date. However, the benefit of TAUS-guided cervical cancer BT planning vs. conventional Point Aebased BT became evident in the present study. The further advantages of lower costs and reduced workload/duration suggest that TAUS-guided BT may be used as a surrogate of hightechnology imaging (MRI/CT) in radiotherapy centers with limited resources and high workload to improve the treatment quality of BT for cervical cancer and its efficacy.
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Conclusion TAUS-guided BT significantly improved the dose distribution for target (uterine cervix) and OARs in comparison with conventional Point-Aebased planning. The described approach proved feasible and makes image-guided conformal BT possible in limited resource settings.
[12]
[13]
[14]
Acknowledgments This study was supported by the National Research University Project, under Thailand’s Office of the Higher Education Commission and Faculty of Medicine, Chiang Mai University.
[15]
[16]
References [17] [1] Kamnerdsupaphon P, Srisukho S, Sumitsawan Y, et al. Cancers in Northern Thailand. Biomed Imaging Interv J 2008;4:e46. [2] International Commission on Radiation Units and Measurements. ICRU report 38: Dose and volume specification for reporting intracavitary therapy in gynecology. Bethesda, MD: International Commission on Radiation Units and Measurements; 1985. [3] Tod M, Meredith WJ. Treatment of cancer of the cervix uteri, a revised Manchester method. Br J Radiol 1953;26:252e257. [4] De Brabandere M, Mousa AG, Nulens A, et al. Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma. Radiother Oncol 2008;88:217e226. [5] Tanderup K, Nielsen SK, Nyvang GB, et al. From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer. Radiother Oncol 2010;94:173e180. [6] Wander as AD, Sundset M, Langdal I, et al. Adaptive brachytherapy of cervical cancer, comparison of conventional point A and CT based individual treatment planning. Acta Oncol 2012;51:345e354. [7] P€ otter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116e123. [8] Beriwal S, Kannan N, Kim H, et al. Three-dimensional high dose rate intracavitary image-guided brachytherapy for the treatment of cervical cancer using a hybrid magnetic resonance imaging/computed tomography approach: Feasibility and early results. Clin Oncol (R Coll Radiol) 2011;23:685e690. [9] Charra-Brunaud C, Harter V, Delannes M, et al. Impact of 3D imagebased PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study. Radiother Oncol 2012;103:305e313. [10] Tan LT, Coles CE, Hart C, et al. Clinical impact of computed tomography-based image-guided brachytherapy for cervix cancer using the tandem-ring applicatordThe Addenbrooke’s experience. Clin Oncol 2009;21:175e182. [11] Tharavichitkul E, Chakrabandhu S, Wanwilairat S, et al. Intermediateterm results of image-guided brachytherapy and high-technology
[18] [19] [20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
external beam radiotherapy in cervical cancer: Chiang Mai University experience. Gynecol Oncol 2013;130:81e85. Mazeron R, Gilmore J, Dumas I, et al. Adaptive 3D image-guided brachytherapy: A strong argument in the debate on systematic radical hysterectomy for locally advanced cervical cancer. Oncologist 2013; 18:415e433. Makin WP, Hunter RD. CT scanning in intracavitary therapy: Unexpected findings in ‘‘straightforward’’ insertions. Radiother Oncol 1988;13:253e255. Davidson MT, Yuen J, D’Souza DP, et al. Optimization of high-doserate cervix brachytherapy applicator placement: The benefits of intraoperative ultrasound guidance. Brachytherapy 2008;7:248e253. Van Dyk S, Kondalsamy-Chennakesavan S, Schneider M, et al. Comparison of measurements of the uterus and cervix obtained by magnetic resonance and transabdominal ultrasound imaging to identify the brachytherapy target in patients with cervix cancer. Int J Radiat Oncol Biol Phys 2014;88:860e865. Van Dyk S, Narayan K, Fisher R, et al. Conformal brachytherapy planning for cervical cancer using transabdominal ultrasound. Int J Radiat Oncol Biol Phys 2009;75:64e70. Van Dyk S, Bernshaw D. Ultrasound-based conformal planning for gynaecological brachytherapy. J Med Imaging Radiat Oncol 2008; 52:77e84. Joiner M, VanDer Kogel A. Basic clinical radiobiology. 4th ed. London, England: Edward Arnold; 2009. p. 120e134. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457e481. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50: 163e170. Haie-Meder C, P€otter R, Van Limbergen E, 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;74:235e245. P€otter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynecological (GYN) GEC ESTRO Working Group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67e77. Mahantshetty U, Khanna N, Swamidas J, et al. Trans-abdominal ultrasound (US) and magnetic resonance imaging (MRI) correlation for conformal intracavitary brachytherapy in carcinoma of the uterine cervix. Radiother Oncol 2012;102:130e134. Schmid MP, P€otter R, Brader P, et al. Transrectal ultrasonography for assessment of cervical cancer. Strahlenther Onkol 2013;189: 123e128. Narayan K, Van Dyk S, Bernshaw D, et al. Ultrasound guided conformal brachytherapy of cervix cancer: Survival, patterns of failure, and late complications. J Gynecol Oncol 2014;25:206e213. Tharavichitkul E, Mayurasakorn S, Lorvidhaya V, et al. Preliminary results of conformal computed tomography (CT)-based intracavitary brachytherapy (ICBT) for locally advanced cervical cancer: A single institution’s experience. J Radiat Res 2011;52:634e640. Tharavichitkul E, Sivasomboon C, Wanwilairat S, et al. Preliminary results of MRI-guided brachytherapy in cervical carcinoma: The Chiangmai University experience. J Radiat Res 2012;53:313e318.
Two-year results of transabdominal ultrasound-guided brachytherapy for cervical cancer Ekkasit Tharavichitkul1,*, Damrongsak Tippanya1, Rungtip Jayavasti1, Somvilai Chakrabandhu1, Pitchayaponne Klunklin1, Wimrak Onchan1, Somsak Wanwilairat1, Razvan M. Galalae2, Imjai Chitapanarux1 1
Division of Therapeutic Radiology and Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 2 Faculty of Medicine, Christian-Albrecht-University, Kiel, Germany
ABSTRACT
PURPOSE: To report the preliminary results of transabdominal ultrasound (TAUS)eguided brachytherapy (BT) in cervical cancer. METHODS AND MATERIALS: Twenty-nine patients with cervical cancer Stage IBeIVA according to The International Federation of Gynecology and Obstetrics staging were treated by radical radiotherapy from February 2012 to December 2012. Treatment was composed of WPRT to 50 Gy in 25 fractions and central shielding after 44 Gy in combination with TAUS-guided BT to optimize the total dose (equivalent dose of 2 Gy [EQD2]) to the minimal dose at cervical points (in EQD2 concepts) defined by TAUS $80 Gy while maintaining low doses to the ICRU report no. 38 bladder and rectal points. The treatment results and toxicity profiles were reported. RESULTS: At median followup time of 19 months (range, 17e27), the local control and diseasefree survival rates were 93.1% and 86.2%, respectively. One episode of Grade 3 vaginal toxicity was observed in this followup period. The mean applied doses to cervix, bladder, and rectal points were 82.6, 72.5, and 75 Gy, respectively. TAUS-guided planning reduced bladder (defined as O80 Gy in EQD2) and rectal overdose (defined as O75 Gy in EQD2) in 44.9% and 34.5% of patients, respectively. CONCLUSION: The 2-year results demonstrate that TAUS-guided BT is feasible and associated with excellent tumor control/toxicity rates in cervical cancer. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Cervical cancer; Brachytherapy; Transabdominal ultrasound (TAUS)
Introduction Cervical cancer is one of the most common gynecologic cancers in Asia. In Northern Thailand, the incidence rate of cervical cancer was 22.7 per 100,000 in 2005 (1). In patients who are categorized inoperable, a combination of whole pelvic radiation therapy (WPRT) and brachytherapy (BT) is commonly used. High-dose-rate (HDR) intracavitary brachytherapy (ICBT) is used to escalate the
Received 24 August 2014; received in revised form 28 October 2014; accepted 3 November 2014. Conflict of interest: All authors declared no conflicts of interest. * Corresponding author. Division of Therapeutic Radiology and Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: þ66-53-945456; fax: þ66-53-945491. E-mail address: [email protected] (E. Tharavichitkul).
dose to the tumor or cervix to total doses of minimum 80 Gy at Point A. The point-based approach according to Manchester system is extensively applied and works with orthogonal x-rays for calculation and prescription of ICBT (2, 3). In this context, Point A is the major critical point for dose specification of conventional ICBT and is rigidly calculated ignoring the specific tumor anatomy or volume in each individual patient. However, this may cause underdosage to the target volume and/or overdosage to organs at risk (OARs) (4e6). In contrast to conventional planning, the utilization of image-guided brachytherapy (IGBT) with MRI and/or CT is increasingly described in the recent literature and shows a clear benefit of volume-based IGBT to significantly improve treatment results in terms of dose escalation to high-risk clinical target volume O80 Gy and reduction of treatment-related morbidity (7e12).
1538-4721/$ - see front matter Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2014.11.001
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In addition to CT and MRI, ultrasound (US) technology already plays an important role in BT and may also serve as an additional method for IGBT treatment planning. Application of US guidance during BT for cervical cancer has been used extensively in the past to reduce the complications, especially from uterine perforation that have been reported to occur in 3e10% of applications (13, 14). The use of US in BT planning for cervical cancer is in clinical practice and documented in a few publications. The largest study by Van Dyk et al. (15, 16) reports very promising first results and treatment-related toxicities. Based on these published data, we performed a study using a portable US device that was installed in January 2012. The aim was to analyze the use of portable US in multiple places, BT theater, loading room, and to evaluate the early results of transabdominal ultrasound (TAUS)eguided BT planning and treatment in cervical cancer in the Faculty of Medicine, Chiang Mai University.
Methods and materials After approval by institutional review board, patients with histologically verified cervical cancer were enrolled. The inclusion criteria were cervical cancer Stage IBeIVA according to The International Federation of Gynecology and Obstetrics (FIGO) classification, biopsy-proven squamous cell carcinoma or adenocarcinoma of cervix, no uncontrolled medical condition, age 18e70 years, no previous surgery or radiotherapy, and signed informed consent. The treatment method included a combination of WPRT and concurrent platinum-based chemotherapy with HDR ICBT and is described in the next section. External beam radiation therapy WPRT with 6 or 10 MV photons was applied to treat the primary tumor and pelvic lymph nodes to the dose of 50 Gy in 25 fractions and with central shielding (after 44 Gy) in cN0 stages. A parametrial boost (additional dose of 6 Gy in three fractions) was performed in the case of advanced parametrial or pelvic sidewall involvement. Concurrent chemoradiation When concurrent chemotherapy was indicated (e.g., squamous cell carcinoma), either cisplatin (40 mg/m2; maximum dose 5 70 mg) or carboplatin (area under the curve 5 2; maximum dose 5 200 mg) was prescribed in weekly schedule. Laboratory investigations (complete blood count, blood urea nitrogen, and serum creatinine) were evaluated before consideration of chemotherapy. In cisplatin regimen, chemotherapy was performed when creatinine clearance was more than 50 mL/min and stopped when it was less than 30 mL/min. In carboplatin regimen, it was stopped when creatinine clearance was less than 30 mL/min.
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Brachytherapy HDR ICBT was used in all patients. Four applications with 6.5e7 Gy per fraction were applied, and TAUS was used to guide and plan all fractions. The first ICBT application was usually scheduled after the fourth week of WPRT. Standard tandem/ovoid or CT/MRI applicators were used. A Foley catheter was placed in the bladder and filled with 7 cm3 of diluted contrast media. A normal saline solution 150e200 cm3 was added into the bladder to enhance US visibility of uterus and OARs and maintain reproducible bladder geometry. The vagina was packed with gauze to stabilize the applicator. The WPRT was interrupted for each day of HDR BT insertion. Three steps of TAUS (BK Medical Flex Focus 400, Analogic Ultrasound, Boston, MA) were performed by the radiation oncologist. Primarily, TAUS was used during the BT application to prevent uterine perforation. The uterine tandem was identified, and the relationship to the uterus was evaluated. In the second step, patients were transferred to the loading room and adjusted to supine position with their legs relaxed on the flat table. The rectal probe was inserted to identify the anterior rectal wall. Then, TAUS was performed again for each application to verify the position of applicator. The tandem and uterus were also defined in this step. In the third step, the tandem was used as reference, and, at the level of cervical os and 2 cm superiorly, the distances from tandem to the uterine wall in anterior and posterior directions were measured by TAUS in sagittal view. At the level of cervical os, the measurements of the distances from the tandem to the lateral walls were also evaluated. These measurements were performed as described by Van Dyk and Bernshaw (17). After these three steps, orthogonal radiographs were taken to start the planning process. The TAUS-measured distances from the tandem to the uterine wall were used to define the following cervical points (Fig. 1): L1 5 the distance from tandem to posterior wall of uterus at the level of cervical os L2 5 the distance from tandem to anterior wall of uterus at the level of cervical os L3 5 the distance from tandem to posterior wall of uterus at the level of 2 cm superior to the cervical os along the tandem L4 5 the distance from tandem to anterior wall of uterus at the level of 2 cm superior to the cervical os along the tandem A1 5 the distance from tandem to right lateral wall of cervix at the level of cervical os A2 5 the distance from tandem to left lateral wall of cervix at the level of cervical os
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Fig. 1. Transabdominal ultrasound images with inserted applicator showing the structures (tandem, uterus, and bladder) and measurements of cervix in sagittal and transverse directions to define the cervical points (L1, L2, L3, L4, A1, and A2).
A3 5 the distance from tandem to right lateral wall of cervix at the level of 2 cm from cervical os or isthmus A4 5 the distance from tandem to left lateral wall of cervix at the level of 2 cm from cervical os or isthmus All cervical points (L1, L2, L3, L4, A1, A2, A3, and A4) defined by TAUS were marked into the orthogonal radiographs correlating to the tandem position (Fig. 2). Point A (R and L), rectum, and bladder points were also digitized according to the International Commission on Radiation Units and Measurements (ICRU) report no. 38 (2). All information was then digitized into PLATO TPS (Nucletron, an Elekta company, Stockholm, Sweden). The prescribed dose was 6.5e7 Gy per fraction to Point A for all patients, and the calculated doses to cervical, bladder, and rectal points were recorded. When estimated cumulative doses
to bladder and rectal points indicated overdoses (more than 80 Gy for bladder and 75 Gy for rectum), optimizations by adjustment of dwell weight and dwell time were performed to reduce the overdose to bladder and rectum as low as possible and achieve a sufficient minimal dose to the cervical points (L1, L2, L3, L4, A1, A2, A3, and A4) at least 6.5e7 Gy per fraction (Fig. 3). The cumulative doses from WPRT and BT to minimum cervical, rectal, and bladder points were reported in equivalent dose of 2 Gy (EQD2) using the linearequadratic model. The assumed a/b values were 10 for the tumor and three for OARs (18). Followup program After the treatment was completed, patients were scheduled to visit for per vaginal examination in the followup
Fig. 2. Orthogonal radiographs showing the marked Point As (AR and AL), ICRU 38 bladder, ICRU 38 rectum, additional rectal, L1eL4, and A1eA4 points in lateral and anterioreposterior (AP) films, respectively. (Note: in AP film, AR/AL 5 red and A1eA4 5 black cross). In lateral film, L1eL4 5 black cross, ICRU bladder 5 blue dot, ICRU rectum 5 red dot, and additional rectal points along the anterior surface of rectal probe 5 green dot. ICRU 5 International Commission on Radiation Units and Measurements. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
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Fig. 3. PLATO images in TAUS-guided planning. (a) standard ‘‘point-A’’ plan and (b) TAUS-guided plan. In TAUS-guided plan, the dose distribution was optimized to keep the minimal dose for the cervical point (L1eL4 and A1eA4) to be at least prescribed dose (red line). Point As, cervix points, bladder ICRU 38, and rectal ICRU 38 points were digitized in the planning system. TAUS 5 transabdominal ultrasound; ICRU 5 International Commission on Radiation Units and Measurements. (For interpretation of references to color in this figure legend, the reader is referred to the web version of this article.)
(FU) program. The FU program schedule is every 3 months in the first 3 years after treatment, six monthly in fourth and fifth years, then annually after 5 years. A vaginal examination was performed to evaluate the disease status according to the World Health Organization criteria. Investigations (tissue biopsy, medical imaging, or laboratories) for disease progression were performed as indicated when patients presented with suggested symptoms. Late toxicities were evaluated according to the Radiation Therapy Oncology Group/ European Organization of Research and Treatment of Cancer late toxicity criteria. Statistical analysis All statistical analyses were evaluated by Statistical Package of Social Sciences (SPSS; IBM, Armonk, NY, USA) version 17.0. Descriptive statistics were calculated and reported in terms of mean and interquartile range. The comparisons between doses of TAUS-guided plans vs. standard (Point A) plans according to the defined cervical,
bladder, and rectum points were performed by paired t test (two-tailed test) to identify a statistical significance level of p ! 0.05. The KaplaneMeier method and log-rank tests were used to evaluate local control, disease-free survival, and overall survival (OS) rates (19, 20).
Results From February 2012 to December 2012, 29 patients were evaluated. Fifty-nine percent of patients were Stage IIB by FIGO classification. The mean total treatment time was 50.2 days. Patients’ characteristics are shown in Table 1. At median FU time of 19 months (range, 17e27), 2 of the evaluated 29 patients (6.9%) had persistent disease proven by biopsy at third month after treatment completion. These patients were presented to the gynecologic oncologist for radical surgery. Two of 29 patients (6.9%) developed distant metastases and received chemotherapy. One patient died because of metastatic disease. The mean
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Table 1 Patients’ characteristics Parameters
N (range)
Age Stage IB, IIA IIB IIIB Histology Squamous cell carcinoma Adenocarcinoma Total treatment time
56.7 y (range, 34e78) 3 17 9 25 4 51.4 d (range, 42e69)
dose in terms of EQD2 concepts for standard plans to cervical, bladder, and rectal points were 81.43 9.4, 68.84 8.0, and 84.32 11.6 Gy, respectively. At median FU time of 19 months, the local control, disease-free survival, and OS rates according to Kaplane Meier were 93.1%, 86.2%, and 96.6%, respectively. At mean FU time of 18 months, only 1 patient had Grade 3 vaginal toxicity. The toxicity profiles are shown in Table 3.
Discussion transverse diameter (A1 þ A2) of uterine cervix measured by TAUS at the first application of BT was 3.6 cm (range, 2.8e5.2), whereas the mean anteroposterior uterine diameter (L1 þ L2) measured by TAUS at the first application of BT was 2.8 cm (range, 2e4.9). The mean volume of cervix was 11.1 cm3 (range, 6e25). The mean cumulative doses in terms of EQD2 for TAUS-guided plans at the cervical (the minimal dose), bladder, and rectum points were 82.6, 71.6, and 74.8 Gy, respectively. The mean standard deviation of cumulative dose in EQD2 concepts to Point A was 76 10 Gy. The mean cumulative dose in EQD2 concepts for standard plans to bladder and rectum points were 87.5 and 85.2 Gy, respectively. TAUS-guided plans decreased the dose to the ICRU bladder and rectal points. After standard planning, the total bladder dose exceeded 80 Gy (EQD2) in 62.1% of patients. This was reduced to 17.2% of patients after TAUS-based planning. Similarly, after standard planning, the total rectal dose exceeded 75 Gy (EQD2) in 79.3% of patients. This was reduced to 44.8% after TAUS planning. All data are shown in Table 2. When we considered 7 patients who had transverse diameter at the first application O4 cm, the means and standard deviations of cumulative dose in terms of EQD2 for TAUS-guided plan at the cervical, bladder, and rectal points were 82.59 1.4, 65.02 4.6, and 81.85 5.7 Gy, respectively. The means and standard deviations of cumulative Table 2 Dose characteristics in patients treated by TAUS-guided brachytherapy in comparison with standard Point A-based planning Target dose Minimal dose at defined cervical points (mean cumulative EQD2 dose), in Gy The mean cumulative dose to Point A in EQD2 dose, in Gy Organs at risk Proportion of patients with bladder dose O80 Gy in EQD2 Proportion of patients with rectal dose O75 Gy in EQD2
TAUS plans
Standard plans
82.6 1.3
93.2 11
76.3 10.3 N (%)
83.7 N (%)
5/29 (17.2)
18/29 (62.1)
13/29 (44.8)
23/29 (79.3)
TAUS 5 transabdominal ultrasound; EQD2 5 equivalent dose of 2 Gy.
IGBT for cervical cancer has been used for more than 5 years. The Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology published recommendations in 2005e2006 facilitating the use of IGBT (21, 22). The promising benefits of IGBT with MRI or CT guidance in terms of treatment results and toxicity profiles were reported in a series of publications (7e12). Although use of US has been proven to prevent uterine perforation during BT applications (13, 14), the potential benefit of US in BT planning aspects has only been addressed in a few publications mainly focusing on comparisons of the uterine dimensions measured by US and MRI. However, Van Dyk et al. were the first to report on 71 patients with locoregionally advanced cervical cancer treated with chemoradiation and BT with US-assisted tandem insertion and conformal US-based planning. Orthogonal films for applicator reconstruction were also taken. A standard plan (STD) was modified to suit the US-based volume, and treatment was delivered based on modified plans. The patients then underwent MRI scan with the applicators in situ. Standard plans had higher doses to Point A, target volume, ICRU 38 bladder and rectal points, and individualized bowel point compared with US and MRI plans. There was a statistically significant difference between standard plans and image-based plans, STD vs. US, and STD vs. MRI ( p # 0.001), respectively, for target volume, Point A, ICRU 38 bladder, and bowel point. US plans vs. two-dimensional MRI were comparable for target volume ( p 5 0.11), rectal point ( p 5 0.8), and vaginal mucosa ( p 5 0.19). The local Table 3 Toxicity profiles in patients (N 5 29) treated by TAUS-guided brachytherapy for cervical cancer Toxicity (RTOG/EORTC late toxicity criteria)
Grade 0
Grade 1
Grade 2
Grade 3 and higher
GI GU Skin Subcutaneous tissue Vaginal obstruction
24 25 22 21 24
5 4 7 5 3
0 0 0 3 1
0 0 0 0 1
TAUS 5 transabdominal ultrasound; RTOG 5 Radiation Therapy Oncology Group; EORTC 5 European Organization of Research and Treatment of Cancer; GI 5 gastrointestinal; GU 5 genitourinary.
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control was 90%, and late bowel morbidity (G3 and G4) was !2% (16, 17). These first reports of US-guided planning of ICBT for cervical cancer also showed the agreement between different imaging modalities (MRI/US) and demonstrated very promising preliminary results of TAUS-guided planning in terms of disease control and late toxicity. In addition, the updated study of this first series reported on comparison between MRI and US in 192 patients with mean differences of measurements between TAUS and MRI at the anterior and posterior uterine surfaces ranging from 1.5 (3.353) to 3.7 (3.856) mm and 1.46 (3.308) to 0.47 (3.502) mm, respectively. In conclusion of this study, the mean detected differences were less than 3 mm in the cervix and less than 1.5 mm at all measurement points on the posterior surface (15). However, TAUS was also tested in other centers. Mahantshetty et al. (23) from Tata Memorial Hospital published the use of TAUS for BT and correlations to MRI in 20 cervical cancer patients. The D1 and D3 (anterior surface) strongly correlated in TAUS and MRI with R 5 0.92 and 0.94 ( p ! 0.01), whereas D2 and D4 references (posterior surface) revealed moderate correlations with R 5 0.62 and 0.82 ( p ! 0.01). The D5 reference (fundal thickness) also showed a strong correlation between TAUS and US with R 5 0.98. The D2 references showed the lowest correlations between the two imaging modalities. Another approach by transrectal ultrasound (TRUS) was performed by Schmid et al. (24) reporting TRUSand MRI-guided correlations for conformal intracavitary interstitial BT in cervical cancer. The study identified a mean maximum target width of 4.2 0.83 and 4.2 0.79 cm for MRI and TRUS, respectively. The mean maximum target thickness was 3.3 1.03 and 3.1 1.15 cm for MRI and TRUS, respectively. Linear regression analysis for target width and thickness between TRUS and MRI demonstrated a correlation with R(2) 5 0.842 and R(2) 5 0.943, respectively. The authors concluded that the comparison of the target width and thickness showed a high correlation between TRUS and MRI, indicating the potential of TRUS for target definition in image-guided adaptive BT (24). All studies published to date in the literature supported that US measurements fit well with measurements performed by MRI in cervical cancer BT. The latest report by Narayan et al. (25) also showed promising clinical results. Three hundred nine patients with cervical cancer were treated between January 1999 and December 2008 with external beam radiotherapy and HDR conformal TAUS-guided BT with curative intent. Two hundred ninety-two patients were available for analyses. The median FU time was 4.1 years (range, 2.4e6.1). The 5-year failure-free survival and OS rates were 66% and 65%, respectively. Local failure rates according to FIGO Stage I, II, and III were 12%, 10%, and 17%, respectively. In toxicity profiles, the rate of Grade
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3e4 toxicities of bladder, rectum, and vagina was 0.3, 0.99, and 0.69 per 100 person-years of FU, respectively (25). Our present study reports the first utilization of TAUSguided BT for cervical cancer in Thailand. TAUS-guided planning for ICBT in cervical cancer has been confirmed in our data to improve the treatment quality by decreasing the OAR doses of ICRU bladder and rectal points. In addition, TAUS-guided optimization maintained a sufficient high minimal dose to the cervix of at least 80 Gy in EQD2 concept. However, there were some circumstances that we had to choose the adequate dose to target or limited doses to OARs. As curative intent, we decided to keep the adequate dose to the target (at least 80 Gy in EQD2). The mean transverse diameter of uterine cervix measured by TAUS in our study was 3.5 cm (range, 2.8e5.2), and 22 of them (75.8%) were up to 4 cm. After a mean FU time of 18 months, 93.1% of patients developed no recurrence and had only one incidence of severe vaginal obstruction (Grade 3). Not only is US beneficial during applicator insertion and treatment planning but also had other advantages. First, the investment and running costs of US technology are clearly more economical than MRI or CT alternatives. Second, US is portable and thus can be used in the loading room for verification in addition to in-room imaging. Third, the time duration of one application of TAUS-guided ICBT is about 40e60 min compared with 2 h for CT-based BT and 4 h for MRI-based BT (26, 27). These advantages are essential in the context of a developing country with a very high volume of patients to be treated of more than 250 patients per year. However, there are some limitations in the present study. TAUS-guided BT does not allow full volumetric analysis of tumor coverage or doses to OARs and may be considered as ‘‘2.5D’’ point-based planning. Therefore, this demonstrated approach could not entirely incorporate the volume-based concepts of The Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology recommendations (14, 15). Second, at present, TAUS cannot evaluate the residual tumor or the vaginal extension as accurately as MRI. Therefore, clinical evaluation and/or pretreatment imaging by MRI are very important to guide the treatment by TAUS-based BT. And finally, TAUS cannot assess the cumulative doses to sigmoid colon because of its imaging limitations in comparison to CT or MRI. In addition, US-guided planning requires more individual experience and expertise, and no published guidelines for this specific US use are available to date. However, the benefit of TAUS-guided cervical cancer BT planning vs. conventional Point Aebased BT became evident in the present study. The further advantages of lower costs and reduced workload/duration suggest that TAUS-guided BT may be used as a surrogate of hightechnology imaging (MRI/CT) in radiotherapy centers with limited resources and high workload to improve the treatment quality of BT for cervical cancer and its efficacy.
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Conclusion TAUS-guided BT significantly improved the dose distribution for target (uterine cervix) and OARs in comparison with conventional Point-Aebased planning. The described approach proved feasible and makes image-guided conformal BT possible in limited resource settings.
[12]
[13]
[14]
Acknowledgments This study was supported by the National Research University Project, under Thailand’s Office of the Higher Education Commission and Faculty of Medicine, Chiang Mai University.
[15]
[16]
References [17] [1] Kamnerdsupaphon P, Srisukho S, Sumitsawan Y, et al. Cancers in Northern Thailand. Biomed Imaging Interv J 2008;4:e46. [2] International Commission on Radiation Units and Measurements. ICRU report 38: Dose and volume specification for reporting intracavitary therapy in gynecology. Bethesda, MD: International Commission on Radiation Units and Measurements; 1985. [3] Tod M, Meredith WJ. Treatment of cancer of the cervix uteri, a revised Manchester method. Br J Radiol 1953;26:252e257. [4] De Brabandere M, Mousa AG, Nulens A, et al. Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma. Radiother Oncol 2008;88:217e226. [5] Tanderup K, Nielsen SK, Nyvang GB, et al. From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer. Radiother Oncol 2010;94:173e180. [6] Wander as AD, Sundset M, Langdal I, et al. Adaptive brachytherapy of cervical cancer, comparison of conventional point A and CT based individual treatment planning. Acta Oncol 2012;51:345e354. [7] P€ otter R, Georg P, Dimopoulos JC, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol 2011;100:116e123. [8] Beriwal S, Kannan N, Kim H, et al. Three-dimensional high dose rate intracavitary image-guided brachytherapy for the treatment of cervical cancer using a hybrid magnetic resonance imaging/computed tomography approach: Feasibility and early results. Clin Oncol (R Coll Radiol) 2011;23:685e690. [9] Charra-Brunaud C, Harter V, Delannes M, et al. Impact of 3D imagebased PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study. Radiother Oncol 2012;103:305e313. [10] Tan LT, Coles CE, Hart C, et al. Clinical impact of computed tomography-based image-guided brachytherapy for cervix cancer using the tandem-ring applicatordThe Addenbrooke’s experience. Clin Oncol 2009;21:175e182. [11] Tharavichitkul E, Chakrabandhu S, Wanwilairat S, et al. Intermediateterm results of image-guided brachytherapy and high-technology
[18] [19] [20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
external beam radiotherapy in cervical cancer: Chiang Mai University experience. Gynecol Oncol 2013;130:81e85. Mazeron R, Gilmore J, Dumas I, et al. Adaptive 3D image-guided brachytherapy: A strong argument in the debate on systematic radical hysterectomy for locally advanced cervical cancer. Oncologist 2013; 18:415e433. Makin WP, Hunter RD. CT scanning in intracavitary therapy: Unexpected findings in ‘‘straightforward’’ insertions. Radiother Oncol 1988;13:253e255. Davidson MT, Yuen J, D’Souza DP, et al. Optimization of high-doserate cervix brachytherapy applicator placement: The benefits of intraoperative ultrasound guidance. Brachytherapy 2008;7:248e253. Van Dyk S, Kondalsamy-Chennakesavan S, Schneider M, et al. Comparison of measurements of the uterus and cervix obtained by magnetic resonance and transabdominal ultrasound imaging to identify the brachytherapy target in patients with cervix cancer. Int J Radiat Oncol Biol Phys 2014;88:860e865. Van Dyk S, Narayan K, Fisher R, et al. Conformal brachytherapy planning for cervical cancer using transabdominal ultrasound. Int J Radiat Oncol Biol Phys 2009;75:64e70. Van Dyk S, Bernshaw D. Ultrasound-based conformal planning for gynaecological brachytherapy. J Med Imaging Radiat Oncol 2008; 52:77e84. Joiner M, VanDer Kogel A. Basic clinical radiobiology. 4th ed. London, England: Edward Arnold; 2009. p. 120e134. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457e481. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50: 163e170. Haie-Meder C, P€otter R, Van Limbergen E, 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;74:235e245. P€otter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynecological (GYN) GEC ESTRO Working Group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol 2006;78:67e77. Mahantshetty U, Khanna N, Swamidas J, et al. Trans-abdominal ultrasound (US) and magnetic resonance imaging (MRI) correlation for conformal intracavitary brachytherapy in carcinoma of the uterine cervix. Radiother Oncol 2012;102:130e134. Schmid MP, P€otter R, Brader P, et al. Transrectal ultrasonography for assessment of cervical cancer. Strahlenther Onkol 2013;189: 123e128. Narayan K, Van Dyk S, Bernshaw D, et al. Ultrasound guided conformal brachytherapy of cervix cancer: Survival, patterns of failure, and late complications. J Gynecol Oncol 2014;25:206e213. Tharavichitkul E, Mayurasakorn S, Lorvidhaya V, et al. Preliminary results of conformal computed tomography (CT)-based intracavitary brachytherapy (ICBT) for locally advanced cervical cancer: A single institution’s experience. J Radiat Res 2011;52:634e640. Tharavichitkul E, Sivasomboon C, Wanwilairat S, et al. Preliminary results of MRI-guided brachytherapy in cervical carcinoma: The Chiangmai University experience. J Radiat Res 2012;53:313e318.
