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Intermediate-term results of image-guided brachytherapy and high-technology external beam radiotherapy in cervical cancer: Chiang Mai University experience
Gynecologic Oncology 130 (2013) 81–85
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Intermediate-term results of image-guided brachytherapy and high-technology external beam radiotherapy in cervical cancer: Chiang Mai University experience Ekkasit Tharavichitkul a,⁎, Somvilai Chakrabandhu a, Somsak Wanwilairat a, Damrongsak Tippanya a, Wannapha Nobnop a, Nantaka Pukanhaphan a, Razvan M. Galalae b, Imjai Chitapanarux a a b
The division of therapeutic radiology and oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Faculty of Medicine, Christian-Albrechts-University, Kiel, Germany
H I G H L I G H T S • Image-guided brachytherapy showed promising intermediate-term results in the treatment of cervical cancer. • Image-guided brachytherapy caused a low incidence of grade 3–4 toxicity in treated study patients.
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Article history: Received 27 December 2012 Accepted 10 April 2013 Available online 17 April 2013 Keywords: Cervical cancer IGBT Results
a b s t r a c t Objective. To evaluate the outcomes of image-guided brachytherapy combined with 3D conformal or intensity modulated external beam radiotherapy (3D CRT/IMRT) in cervical cancer at Chiang Mai University. Methods. From 2008 to 2011, forty-seven patients with locally advanced cervical cancer were enrolled in this study. All patients received high-technology (3D CRT/IMRT) whole pelvic radiotherapy with a total dose of 45–46 Gy plus image-guided High-Dose-Rate intracavitary brachytherapy 6.5–7 Gy × 4 fractions to a HighRisk Clinical Target Volume (HR-CTV) according to GEC-ESTRO recommendations. The dose parameters of the HR-CTV for bladder, rectum and sigmoid colon were recorded, as well as toxicity profiles. In addition, the endpoints for local control, disease-free, metastasis-free survival and overall survival were calculated. Results. At the median follow-up time of 26 months, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. In terms of late toxicity, the incidence of grade 3–4 bladder and rectum morbidity was 2.1% and 2.1%, respectively. Conclusions. A combination of image-guided brachytherapy and IMRT/3D CRT showed very promising results of local control, disease-free survival, metastasis-free survival and overall survival rates. It also caused a low incidence of grade 3–4 toxicity in treated study patients. © 2013 Elsevier Inc. All rights reserved.
Introduction Cervix carcinoma is one of the most frequent cancer entities in Northern Thailand. According to the report of Kamnerdsupaphon et al., the age-standardized incidence rates were 22.7 and there were 234 new cases of cervix cancer diagnosed in 2005 [1]. The treatment options of cervical cancer are composed of surgery, radiotherapy and chemotherapy according to the stage and performance status of the patients. Radiotherapy plays an important role in early and advanced stages of the disease. For early disease, radical radiotherapy is a good alternative option to surgery for medically ⁎ Corresponding author at: The division of therapeutic radiology and oncology, Department of radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Fax: +66 53945491. E-mail address: [email protected] (E. Tharavichitkul). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.04.018
operable patients. For locally advanced disease, radical radiochemotherapy is the standard treatment, and combined modalities improve treatment results [2–4]. Radical radiotherapy constitutes external beam radiotherapy (EBRT) and brachytherapy (BT). EBRT (45–50.4 Gy) aims to reduce gross tumors and control microscopic disease in the pelvic area, while BT is used to boost the dose to the local lesion up to 75–90 Gy. For conventional brachytherapy planning, simple orthogonal X-rays are usually obtained to evaluate the position of the applicator in relation to musculoskeletal pelvic anatomy and the dose is prescribed to a fixed reference point 2 cm superior and 2 cm lateral to the distal end of the applicator/tandem (Point A), regardless of tumor characteristics or the individual patient anatomy [5]. Computed tomography (CT) or MRI (magnetic resonance imaging) is increasingly used in the diagnosis/staging of cervical cancer [6]. Errors in clinical staging have been reported in up to 22% of patients with stage I disease and in up
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to 75% with stage III disease. These errors arise from a failure to recognize infiltration of the parametrium, the pelvic sidewall, or the bladder/rectal wall and metastatic spread. CT and MRI can aid in the staging and follow-up of patients with advanced cervical cancer [7]. In this new era of advanced imaging technology, therefore, Gross Tumor Volume (GTV) or Clinical Target Volume (CTV) and organs at risk (bladder, rectum and others) can be superiorly identified. Schöppel et al. reported the use of magnetic resonance imaging (MRI) for brachytherapy in cervical cancer in 1992 [8] when the concept of image-guided brachytherapy was developed. With the emergence of Groupe Européen de Curiethérapie — European Society for Therapeutic Radiology and Oncology (GEC-GESTRO) recommendations, volume-based tumor concepts (Gross Tumor Volume; GTV and Clinical Target Volume; CTV) for organs at risk (bladder, rectum and sigmoid colon) with dose constraints in terms of Dose-volume-histograms (DVHs) have significantly improved brachytherapy in the treatment of cervical cancer [9,10]. After the preliminary results of IGBT for cervical cancer by Pötter et al. were reported [11], the concepts of IGBT were addressed by other research groups. Many studies reported the disadvantages of X-ray based planning in the treatment of cervical cancer by using brachytherapy in the modern imaging era [12–15]. Additionally, previous preliminary studies from our group at Chiang Mai University in Thailand showed that image (CT/ MRI)-based brachytherapy could reduce the dose to OARs significantly (except for rectum in CT-based brachytherapy) while maintaining target dose coverage in comparison to standard planning in terms of EQD2, according to GEC-ESTRO recommendations [16,17]. All data supports the use of image-guided brachytherapy (IGBT) and volume-based planning in clinical practice. However, the developments of modern radiotherapy techniques such as IGBT, and their potential benefits, should be further tested. Our division had started this prospective project of image-guided brachytherapy in 2008. Evaluation of the continued results of newly introduced IGBT remains essential at longer follow-up periods. Thus, we performed this study to evaluate the long term results and treatment-related toxicities of image-guided (with CT or MRI) brachytherapy in cervical carcinoma and we focused on a prospective approach for locally advanced cervical cancer (FIGO IIB–IIIB), which may potentially benefit the most from these technology advances.
Materials and methods Patients After approval of the institutional review board, forty-seven patients with carcinoma of cervix uteri from July 2008 to December 2011were included in this study. All cervical cancer patients were classified as IIB and IIIB using FIGO clinical staging, were at ages ranging from 18 to 70 years old, and had a Karnofsky performance status >70%. Patients with a severe co-morbidity, an emergency condition (e.g. bleeding that could not allow for treatment initiation thereby causing delay and a complex planning process), pregnancy, previous irradiation or history of allergies were excluded from the study. Informed consents were signed by all patients before treatment. All patients received whole pelvis irradiation with 3D conformal radiotherapy (3D CRT) or intensity-modulated radiation therapy (IMRT) to a total dose of 45–46 Gy in 23–25 fractions. In 3D-CRT, a parametrial boost to 50.4–56 Gy was considered individually when parametrial involvement was found per vaginal examination after the fourth week of EBRT. For IMRT, the dose of 45 Gy in 25 fractions was prescribed to the dose at 98% of clinical target volume (CTV). CTV was defined as an area of potential microscopic disease and included the Gross Tumor Volume, whole cervix, entire uterus, parametrial tissue, and the upper vagina [18,19]. The pelvic lymph node groups (common iliac nodes, external iliac nodes, internal iliac nodes, obturator nodes, and pre-sacral lymph nodes) were identified and included to the CTV [20,21].
Concomitant radiochemotherapy Concomitant radiochemotherapy with weekly cisplatin doses of 40 mg/m 2 for a maximum of six courses was given to patients with sufficient kidney and bone marrow function. Complete blood counts and renal function tests (serum blood urea nitrogen and creatinine) were evaluated weekly before consideration of chemotherapy. The dose of chemotherapy was modified according to a weekly assessment of creatinine clearance prior to each applied dose. Chemotherapy was held back when creatinine clearance was less than 40 ml/min, and considered to be stopped when creatinine clearance was less than 30 ml/mn. Brachytherapy Four fractions of intracavitary brachytherapy were designed for all patients. The first brachytherapy application was assigned to be performed after the fourth week of EBRT. A dose of 6.5–7 Gy per fraction (with a total of four fractions) to High-Risk Clinical Target Volume (HR-CTV) was applied as per the routine prescribed schedule of the division of therapeutic radiology and oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand [22]. Standard tandem/ ovoid or CT/MR applicators were used. A Foley's catheter was placed in the bladder and filled with 7 cc of diluted contrast media. A normal saline solution (50 cc) plus 10 cc of contrast media were added into the bladder to identify the bladder volume for imaging planning. The vagina was packed with gauze to increase the distance between the radiation source, and the rectum and bladder. The EBRT was interrupted for each day of HDR brachytherapy insertion. After application, all patients were transferred to imaging devices, and the pelvic region from the iliac crest to the ischial tuberosity was scanned without intravenous contrast to obtain appropriate images with the patients in a supine treatment position with their legs relaxed on the table. The slice thickness of the MRI and CT scans was 5 mm without an interslice gap. After the imaging was performed the position of the applicators was checked and imaging data was collected by the radiation oncologist before being transferred to the planning system. Patients were then transferred to the brachytherapy treatment room and adjusted to the same position as in the imaging devices. Computed tomography or magnetic resonance imaging was used and GEC-ESTRO definitions were applied to identify target volumes e.g. Gross Tumor Volume (GTV) or High-Risk Clinical Target Volume (HR-CTV), and organs at risk (OARs) [9,10,23]. Dose-volume histograms were calculated to consider the adequate dose to HR-CTV and limitations of OARs. The D90 (minimum dose covering 90% of volumes) of the HR-CTV and D2cc (representing the maximum doses calculated at the most irradiated 2 cc volumes) of OARs were recorded according to GEC-ESTRO recommendations. The prescribed dose to HR-CTV was 6.5–7 Gy × 4 fractions. Dosevolume histograms were calculated for the HR-CTV, rectum, bladder, and sigmoid colon. Optimization by adjustment of dwell weight and dwell time was performed for the dose distribution of HR-CTV, bladder, rectum and sigmoid colon according to GEC-ESTRO recommendations. The cumulative target and OAR doses (EBRT plus IGBT) were calculated to the equivalent dose in 2-Gy fractions (EQD2) using the linearquadratic model and assuming α/β ratio = 10 for the tumors and α/β = 3 for OARs [24]. Outcomes After the treatment was completed, patients were appointed to visits for vaginal examination (PV exam) in a follow-up program. The follow-up program schedule was performed every 3 months in the first 3 years after treatment was finished. In the 4th–5th year, the appointment was every 6 months and then annually after the 5th year. A vaginal examination was performed to evaluate the disease status according to World Health Organization (WHO) criteria. Investigations
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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 (RTOG/EORTC) late toxicity
criteria. All descriptive and survival data were calculated using SPSS software version 17.0. The Kaplan–Meier method and log-rank tests were used to evaluate local control, disease-free survival, metastasisfree survival and overall survival rates [25,26].
Fig. 1. Kaplan–Meier curves showed local control, disease-free survival and overall survival rate.
Fig. 2. Kaplan–Meier curves showed the local control, disease-free survival and overall survival rates in stages IIB and IIIB.
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Table 1 Patient characteristic data. Parameters
Numbers (N = 47)
Age Stage IIB IIIB WP-IMRT WP-3DCRT CT-based planning MRI-Guided planning (at 1st fraction) Pathological results SCCA Adenocarcinoma Total treatment time
52.4 years (36–63 years) 32 15 15 32 32 15 42 5 54 (42–85 days)
Results From July 2008 to December 2011, 47 patients were enrolled into the present study. Thirty-two patients had stage IIB and 15 patients had stage IIIB, according to FIGO staging. Fifteen patients were treated by IMRT in the EBRT phase, and MRI at the first application of brachytherapy was performed in 15 patients with the CT-based plan in other fractions. All patient characteristics are shown in Table 1. At the median follow-up time of 26 months (range; 5–57 months), one patient developed a local recurrence and six patients developed distant metastases. Three patients died due to metastasis. Thus, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. All treatment results accordingly are shown in Table 2, Figs. 1 and 2. The mean doses in EQD2 of HRCTV, bladder, rectum and sigmoid were 93.1 Gy, 88.2 Gy, 69.6 Gy, and 72 Gy, respectively (Table 3). For late toxicity, one patient developed grade 3 GU toxicity and GI toxicity. For G1–2 toxicities, there were 0 events for skin, 2 events for subcutaneous tissue, 6 events for GI and 2 events for GU toxicity. All data are shown in Table 4. Discussions Image-guided brachytherapy provides detailed anatomical information and variations in each patient of individual clinical target volumes and organs at risk. In the year of 2005–2006, GEC-ESTRO published the recommendations of target volume and organs at risk definitions for image-guided brachytherapy [9,10]. First studies of image-guided brachytherapy tested the concepts of three-dimensional treatment planning systems. In the largest study consisting of a Vienna group, 156 patients were included. All patients received whole pelvis radiotherapy 45 Gy/25fractions plus MRI-guided brachytherapy in 7 Gy to HR-CTV in 4 fractions. The mean D90-HRCTV, D2cc bladder, D2cc rectum and D2cc sigmoid were 93, 86, 65 and 64 Gy, respectively. The overall 3-year local control, cancer-specific survival and overall survival rates were 95%, 74% and 68%, respectively. The local control, cancerspecific survival and overall survival rates were lower in tumor sizes more than 5 cm versus b5 cm (92% vs. 98%, 70% vs. 83% and 65% v. 72%; respectively) [11,27]. In addition, Tan et al. reported treatment results using computed tomography (CT) based brachytherapy in 28 cervical cancer patients. The authors showed a 3-year cancer-specific survival rate of 81%, with a pelvic control rate of 96%. Twenty-four patients had a D90 of at least 74 Gy in EQD2 (α/β = 10) while in Table 2 Treatment results in patients and in divided stages. Parameters
Overall
Stage IIB
Stage IIIB
Local control rate Disease-free survival rate Overall survival rate
97.9% 85.1% 93.6%
96.9% 87.5% 96.9%
100% 80% 86.7%
Table 3 Dose distributions to HR-CTV, Bladder, rectum and sigmoid colon in terms of means ± standard deviation. Parameters
Mean doses (Gy) in EQD2
D90 HR-CTV (α/β = 10) D2cc bladder (α/β = 3) D2cc rectum (α/β = 3) D2cc sigmoid (α/β = 3)
93.1 88.2 69.6 72.0
± ± ± ±
7.7 7.2 6.6 6.9
patients with local recurrence a D90 equal to 63.8 Gy was only reached. Late morbidity was 14%. Seventeen patients had satisfactory OAR doses using a standard loading pattern and in 7 patients planning had to be optimized to reduce risk of toxicity [28]. The study of IGBT by Beriwal et al. also showed promising results. Forty-four cervical cancer patients were treated with EBRT 45/25 Fractions plus IGBT (hybrid CT/MR; MRI 1st fraction/CT in others) 5–6 Gy × 5 fractions. The study showed a mean D90 for the HR-CTV of 83.3 Gy, and means for D2cc of bladder, rectum and sigmoid colon were 79.7 Gy, 57.5 Gy and 66.8 Gy, respectively. Forty-three patients (97.7%) had complete response after treatment. Positron emission tomography/computed tomography (PET/CT) at 3 months showed complete response in 38 patients (in 3 pts it was not performed) and local recurrences at the 6th and 8th month in 2 pts. The 2-year local control, disease-specific survival and overall survival rates were 88%, 85% and 86%, respectively [29]. In our study, the local control, disease-free and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. The present study results show a high concordance when compared to previous literature reports (see also Table 5). No patient developed grade 3–4 late toxicity except two patients with grade 3 gastrointestinal toxicity (recto-sigmoiditis) and genitourinary toxicity (dysuria). Overall, our intermediate-term results show excellent local control in all enrolled patients and low treatment-related late morbidity supporting the use of IGBT for treatment planning, delivery and evaluation. There was just one event for grade 3 gastrointestinal (GI) toxicity and one episode for grade 3 genitourinary (GU) morbidity. The toxicity profiles in the present study resemble the results of Pötter et al. which can be considered as a reference which reported 3 events for grade 3– 4 GI and 5 events for grade 3–4 GU, respectively [27]. In addition, a Japanese study which reported a relationship between rectal dose in EQD2 and rectal toxicity showed a cut point of 60 Gy [31]. The same tendency was found in our institutional analysis of rectal dose with a cut point at 65 Gy in EQD2 [Meungwong P, unpublished data]. Image-guided brachytherapy (IGBT) could improve the quality of treatment in both the target and OARs. However, the implementation of IGBT in our cancer center concerned many aspects. Firstly, the total workload was increased due to the process of imaging, contouring and optimization. In our experience, conventional planning was associated with approximately 0.5–1 h of time consumption in the entire process of one fraction, in comparison with 1–2 h for CT-based, and 3–4 h for MRI-guided planning, respectively. Taking into account our high cancer center brachytherapy workload of 6–8 patients per day, the implementation of image-guided brachytherapy is a serious concern. Table 4 Late toxicity profiles of treated patients. Parameters
Numbers
Skin G1–2 Skin G1–2 Subcutaneous tissue G1–2 Subcutaneous tissue G3–4 Gastrointestinal G1–2 Gastrointestinal G3–4 Genitourinary G1–2 Genitourinary G3–4
0 0 2 0 6 1 2 1
E. Tharavichitkul et al. / Gynecologic Oncology 130 (2013) 81–85 Table 5 Literature comparison: cumulative doses in EQD2 for HR-CTV, bladder, rectum and sigmoid. Study
HR-CTV (D90)
Bladder (D2cc)
Rectum (D2cc)
Sigmoid (D2cc)
Pötter et al. [26] 93 ± 13 Gy 86 ± 17 Gy 65 ± 9 Gy 64 ± 6 Gy Beriwal et al. [28] 82.3 ± 3 Gy 79.7 ± 5.1 Gy 57.5 ± 4.4 Gy 66.8 ± 5.7 Gy De Brabandere 82 ± 10 Gy 85 ± 8 Gy 63 ± 6 Gy 66 ± 10 Gy et al. [12] Lindegaard et al. 91 ± 7 Gy 73 ± 6 Gy 65 ± 5 Gy 68 ± 6 Gy [30] Present study 93.1 ± 7.7 Gy 88.2 ± 7.2 Gy 69.6 ± 6.6 Gy 72.0 ± 6.9 Gy
Therefore, a sensitive triage with focus on patients with the most potential benefit is necessary for an optimum utilization of limited resources. Secondly, the imaging approach and the corresponding infrastructure may differ in each hospital. In our institute, the CT-simulator is an integral part of our department and very closely located to our brachytherapy operating room which facilitates its use significantly at high temporal efficiency. The implementation, however, of advanced imaging, especially MRI for technology advanced brachytherapy, has to be well judged in order to outbalance the resource use with the potential outcome benefit. Logistics should be considered globally on an institutional level and not in the affected department only. Conclusion By using GEC-ESTRO recommendations, target volumes and OARs could be identified with higher quality and precision with advanced technology imaging. Image-guided brachytherapy by MRI or CT has shown, in our experience, promising intermediate-term results in the treatment of cervical cancer. Conflict of interest statement All authors declared no conflicts of interest.
Acknowledgments The author offers many thanks to the NRU-CMU in the Gynecologic Oncology Cluster, the Research Unit of Faculty of Medicine, Chiang Mai University and Nucletron for partial support. Definitely, the author conveys many thanks to our staff at the division of therapeutic radiology and oncology-Faculty of medicine-Chiang Mai University, for supporting this study. References [1] Kamnerdsupaphon P, Srisukho S, Sumitsawan Y, Lorvidhaya V, Sukthomya V. Cancers in Northern Thailand. Biomed Imaging Interv J 2008;4:e46. [2] Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53. [3] Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs III CL, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–61. [4] Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of Radiation Therapy Oncology Group trial (RTOG) 90-01. J Clin Oncol 2004;22:872–80. [5] Chassagne D, Duterix A, Almond P, Burgers J, Busch M, Joslin C. Dose and volume specification for reporting intracavitary therapy in gynaecology. International Commission on Radiation Units and Measurements, ICRU Report 38; 1985. [6] Hricak H, Yu KK. Radiology in invasive cervical cancer. AJR Am J Roentgenol 1996;167:1101–8. [7] Van Nagell Jr JR, Roddick Jr JW, Lowin DM. The staging of cervical cancer: inevitable discrepancies between clinical and pathological findings. Am J Obstet Gynecol 1971;110:973–8.
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Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Intermediate-term results of image-guided brachytherapy and high-technology external beam radiotherapy in cervical cancer: Chiang Mai University experience Ekkasit Tharavichitkul a,⁎, Somvilai Chakrabandhu a, Somsak Wanwilairat a, Damrongsak Tippanya a, Wannapha Nobnop a, Nantaka Pukanhaphan a, Razvan M. Galalae b, Imjai Chitapanarux a a b
The division of therapeutic radiology and oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand Faculty of Medicine, Christian-Albrechts-University, Kiel, Germany
H I G H L I G H T S • Image-guided brachytherapy showed promising intermediate-term results in the treatment of cervical cancer. • Image-guided brachytherapy caused a low incidence of grade 3–4 toxicity in treated study patients.
a r t i c l e
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Article history: Received 27 December 2012 Accepted 10 April 2013 Available online 17 April 2013 Keywords: Cervical cancer IGBT Results
a b s t r a c t Objective. To evaluate the outcomes of image-guided brachytherapy combined with 3D conformal or intensity modulated external beam radiotherapy (3D CRT/IMRT) in cervical cancer at Chiang Mai University. Methods. From 2008 to 2011, forty-seven patients with locally advanced cervical cancer were enrolled in this study. All patients received high-technology (3D CRT/IMRT) whole pelvic radiotherapy with a total dose of 45–46 Gy plus image-guided High-Dose-Rate intracavitary brachytherapy 6.5–7 Gy × 4 fractions to a HighRisk Clinical Target Volume (HR-CTV) according to GEC-ESTRO recommendations. The dose parameters of the HR-CTV for bladder, rectum and sigmoid colon were recorded, as well as toxicity profiles. In addition, the endpoints for local control, disease-free, metastasis-free survival and overall survival were calculated. Results. At the median follow-up time of 26 months, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. In terms of late toxicity, the incidence of grade 3–4 bladder and rectum morbidity was 2.1% and 2.1%, respectively. Conclusions. A combination of image-guided brachytherapy and IMRT/3D CRT showed very promising results of local control, disease-free survival, metastasis-free survival and overall survival rates. It also caused a low incidence of grade 3–4 toxicity in treated study patients. © 2013 Elsevier Inc. All rights reserved.
Introduction Cervix carcinoma is one of the most frequent cancer entities in Northern Thailand. According to the report of Kamnerdsupaphon et al., the age-standardized incidence rates were 22.7 and there were 234 new cases of cervix cancer diagnosed in 2005 [1]. The treatment options of cervical cancer are composed of surgery, radiotherapy and chemotherapy according to the stage and performance status of the patients. Radiotherapy plays an important role in early and advanced stages of the disease. For early disease, radical radiotherapy is a good alternative option to surgery for medically ⁎ Corresponding author at: The division of therapeutic radiology and oncology, Department of radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Fax: +66 53945491. E-mail address: [email protected] (E. Tharavichitkul). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.04.018
operable patients. For locally advanced disease, radical radiochemotherapy is the standard treatment, and combined modalities improve treatment results [2–4]. Radical radiotherapy constitutes external beam radiotherapy (EBRT) and brachytherapy (BT). EBRT (45–50.4 Gy) aims to reduce gross tumors and control microscopic disease in the pelvic area, while BT is used to boost the dose to the local lesion up to 75–90 Gy. For conventional brachytherapy planning, simple orthogonal X-rays are usually obtained to evaluate the position of the applicator in relation to musculoskeletal pelvic anatomy and the dose is prescribed to a fixed reference point 2 cm superior and 2 cm lateral to the distal end of the applicator/tandem (Point A), regardless of tumor characteristics or the individual patient anatomy [5]. Computed tomography (CT) or MRI (magnetic resonance imaging) is increasingly used in the diagnosis/staging of cervical cancer [6]. Errors in clinical staging have been reported in up to 22% of patients with stage I disease and in up
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to 75% with stage III disease. These errors arise from a failure to recognize infiltration of the parametrium, the pelvic sidewall, or the bladder/rectal wall and metastatic spread. CT and MRI can aid in the staging and follow-up of patients with advanced cervical cancer [7]. In this new era of advanced imaging technology, therefore, Gross Tumor Volume (GTV) or Clinical Target Volume (CTV) and organs at risk (bladder, rectum and others) can be superiorly identified. Schöppel et al. reported the use of magnetic resonance imaging (MRI) for brachytherapy in cervical cancer in 1992 [8] when the concept of image-guided brachytherapy was developed. With the emergence of Groupe Européen de Curiethérapie — European Society for Therapeutic Radiology and Oncology (GEC-GESTRO) recommendations, volume-based tumor concepts (Gross Tumor Volume; GTV and Clinical Target Volume; CTV) for organs at risk (bladder, rectum and sigmoid colon) with dose constraints in terms of Dose-volume-histograms (DVHs) have significantly improved brachytherapy in the treatment of cervical cancer [9,10]. After the preliminary results of IGBT for cervical cancer by Pötter et al. were reported [11], the concepts of IGBT were addressed by other research groups. Many studies reported the disadvantages of X-ray based planning in the treatment of cervical cancer by using brachytherapy in the modern imaging era [12–15]. Additionally, previous preliminary studies from our group at Chiang Mai University in Thailand showed that image (CT/ MRI)-based brachytherapy could reduce the dose to OARs significantly (except for rectum in CT-based brachytherapy) while maintaining target dose coverage in comparison to standard planning in terms of EQD2, according to GEC-ESTRO recommendations [16,17]. All data supports the use of image-guided brachytherapy (IGBT) and volume-based planning in clinical practice. However, the developments of modern radiotherapy techniques such as IGBT, and their potential benefits, should be further tested. Our division had started this prospective project of image-guided brachytherapy in 2008. Evaluation of the continued results of newly introduced IGBT remains essential at longer follow-up periods. Thus, we performed this study to evaluate the long term results and treatment-related toxicities of image-guided (with CT or MRI) brachytherapy in cervical carcinoma and we focused on a prospective approach for locally advanced cervical cancer (FIGO IIB–IIIB), which may potentially benefit the most from these technology advances.
Materials and methods Patients After approval of the institutional review board, forty-seven patients with carcinoma of cervix uteri from July 2008 to December 2011were included in this study. All cervical cancer patients were classified as IIB and IIIB using FIGO clinical staging, were at ages ranging from 18 to 70 years old, and had a Karnofsky performance status >70%. Patients with a severe co-morbidity, an emergency condition (e.g. bleeding that could not allow for treatment initiation thereby causing delay and a complex planning process), pregnancy, previous irradiation or history of allergies were excluded from the study. Informed consents were signed by all patients before treatment. All patients received whole pelvis irradiation with 3D conformal radiotherapy (3D CRT) or intensity-modulated radiation therapy (IMRT) to a total dose of 45–46 Gy in 23–25 fractions. In 3D-CRT, a parametrial boost to 50.4–56 Gy was considered individually when parametrial involvement was found per vaginal examination after the fourth week of EBRT. For IMRT, the dose of 45 Gy in 25 fractions was prescribed to the dose at 98% of clinical target volume (CTV). CTV was defined as an area of potential microscopic disease and included the Gross Tumor Volume, whole cervix, entire uterus, parametrial tissue, and the upper vagina [18,19]. The pelvic lymph node groups (common iliac nodes, external iliac nodes, internal iliac nodes, obturator nodes, and pre-sacral lymph nodes) were identified and included to the CTV [20,21].
Concomitant radiochemotherapy Concomitant radiochemotherapy with weekly cisplatin doses of 40 mg/m 2 for a maximum of six courses was given to patients with sufficient kidney and bone marrow function. Complete blood counts and renal function tests (serum blood urea nitrogen and creatinine) were evaluated weekly before consideration of chemotherapy. The dose of chemotherapy was modified according to a weekly assessment of creatinine clearance prior to each applied dose. Chemotherapy was held back when creatinine clearance was less than 40 ml/min, and considered to be stopped when creatinine clearance was less than 30 ml/mn. Brachytherapy Four fractions of intracavitary brachytherapy were designed for all patients. The first brachytherapy application was assigned to be performed after the fourth week of EBRT. A dose of 6.5–7 Gy per fraction (with a total of four fractions) to High-Risk Clinical Target Volume (HR-CTV) was applied as per the routine prescribed schedule of the division of therapeutic radiology and oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand [22]. Standard tandem/ ovoid or CT/MR applicators were used. A Foley's catheter was placed in the bladder and filled with 7 cc of diluted contrast media. A normal saline solution (50 cc) plus 10 cc of contrast media were added into the bladder to identify the bladder volume for imaging planning. The vagina was packed with gauze to increase the distance between the radiation source, and the rectum and bladder. The EBRT was interrupted for each day of HDR brachytherapy insertion. After application, all patients were transferred to imaging devices, and the pelvic region from the iliac crest to the ischial tuberosity was scanned without intravenous contrast to obtain appropriate images with the patients in a supine treatment position with their legs relaxed on the table. The slice thickness of the MRI and CT scans was 5 mm without an interslice gap. After the imaging was performed the position of the applicators was checked and imaging data was collected by the radiation oncologist before being transferred to the planning system. Patients were then transferred to the brachytherapy treatment room and adjusted to the same position as in the imaging devices. Computed tomography or magnetic resonance imaging was used and GEC-ESTRO definitions were applied to identify target volumes e.g. Gross Tumor Volume (GTV) or High-Risk Clinical Target Volume (HR-CTV), and organs at risk (OARs) [9,10,23]. Dose-volume histograms were calculated to consider the adequate dose to HR-CTV and limitations of OARs. The D90 (minimum dose covering 90% of volumes) of the HR-CTV and D2cc (representing the maximum doses calculated at the most irradiated 2 cc volumes) of OARs were recorded according to GEC-ESTRO recommendations. The prescribed dose to HR-CTV was 6.5–7 Gy × 4 fractions. Dosevolume histograms were calculated for the HR-CTV, rectum, bladder, and sigmoid colon. Optimization by adjustment of dwell weight and dwell time was performed for the dose distribution of HR-CTV, bladder, rectum and sigmoid colon according to GEC-ESTRO recommendations. The cumulative target and OAR doses (EBRT plus IGBT) were calculated to the equivalent dose in 2-Gy fractions (EQD2) using the linearquadratic model and assuming α/β ratio = 10 for the tumors and α/β = 3 for OARs [24]. Outcomes After the treatment was completed, patients were appointed to visits for vaginal examination (PV exam) in a follow-up program. The follow-up program schedule was performed every 3 months in the first 3 years after treatment was finished. In the 4th–5th year, the appointment was every 6 months and then annually after the 5th year. A vaginal examination was performed to evaluate the disease status according to World Health Organization (WHO) criteria. Investigations
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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 (RTOG/EORTC) late toxicity
criteria. All descriptive and survival data were calculated using SPSS software version 17.0. The Kaplan–Meier method and log-rank tests were used to evaluate local control, disease-free survival, metastasisfree survival and overall survival rates [25,26].
Fig. 1. Kaplan–Meier curves showed local control, disease-free survival and overall survival rate.
Fig. 2. Kaplan–Meier curves showed the local control, disease-free survival and overall survival rates in stages IIB and IIIB.
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Table 1 Patient characteristic data. Parameters
Numbers (N = 47)
Age Stage IIB IIIB WP-IMRT WP-3DCRT CT-based planning MRI-Guided planning (at 1st fraction) Pathological results SCCA Adenocarcinoma Total treatment time
52.4 years (36–63 years) 32 15 15 32 32 15 42 5 54 (42–85 days)
Results From July 2008 to December 2011, 47 patients were enrolled into the present study. Thirty-two patients had stage IIB and 15 patients had stage IIIB, according to FIGO staging. Fifteen patients were treated by IMRT in the EBRT phase, and MRI at the first application of brachytherapy was performed in 15 patients with the CT-based plan in other fractions. All patient characteristics are shown in Table 1. At the median follow-up time of 26 months (range; 5–57 months), one patient developed a local recurrence and six patients developed distant metastases. Three patients died due to metastasis. Thus, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. All treatment results accordingly are shown in Table 2, Figs. 1 and 2. The mean doses in EQD2 of HRCTV, bladder, rectum and sigmoid were 93.1 Gy, 88.2 Gy, 69.6 Gy, and 72 Gy, respectively (Table 3). For late toxicity, one patient developed grade 3 GU toxicity and GI toxicity. For G1–2 toxicities, there were 0 events for skin, 2 events for subcutaneous tissue, 6 events for GI and 2 events for GU toxicity. All data are shown in Table 4. Discussions Image-guided brachytherapy provides detailed anatomical information and variations in each patient of individual clinical target volumes and organs at risk. In the year of 2005–2006, GEC-ESTRO published the recommendations of target volume and organs at risk definitions for image-guided brachytherapy [9,10]. First studies of image-guided brachytherapy tested the concepts of three-dimensional treatment planning systems. In the largest study consisting of a Vienna group, 156 patients were included. All patients received whole pelvis radiotherapy 45 Gy/25fractions plus MRI-guided brachytherapy in 7 Gy to HR-CTV in 4 fractions. The mean D90-HRCTV, D2cc bladder, D2cc rectum and D2cc sigmoid were 93, 86, 65 and 64 Gy, respectively. The overall 3-year local control, cancer-specific survival and overall survival rates were 95%, 74% and 68%, respectively. The local control, cancerspecific survival and overall survival rates were lower in tumor sizes more than 5 cm versus b5 cm (92% vs. 98%, 70% vs. 83% and 65% v. 72%; respectively) [11,27]. In addition, Tan et al. reported treatment results using computed tomography (CT) based brachytherapy in 28 cervical cancer patients. The authors showed a 3-year cancer-specific survival rate of 81%, with a pelvic control rate of 96%. Twenty-four patients had a D90 of at least 74 Gy in EQD2 (α/β = 10) while in Table 2 Treatment results in patients and in divided stages. Parameters
Overall
Stage IIB
Stage IIIB
Local control rate Disease-free survival rate Overall survival rate
97.9% 85.1% 93.6%
96.9% 87.5% 96.9%
100% 80% 86.7%
Table 3 Dose distributions to HR-CTV, Bladder, rectum and sigmoid colon in terms of means ± standard deviation. Parameters
Mean doses (Gy) in EQD2
D90 HR-CTV (α/β = 10) D2cc bladder (α/β = 3) D2cc rectum (α/β = 3) D2cc sigmoid (α/β = 3)
93.1 88.2 69.6 72.0
± ± ± ±
7.7 7.2 6.6 6.9
patients with local recurrence a D90 equal to 63.8 Gy was only reached. Late morbidity was 14%. Seventeen patients had satisfactory OAR doses using a standard loading pattern and in 7 patients planning had to be optimized to reduce risk of toxicity [28]. The study of IGBT by Beriwal et al. also showed promising results. Forty-four cervical cancer patients were treated with EBRT 45/25 Fractions plus IGBT (hybrid CT/MR; MRI 1st fraction/CT in others) 5–6 Gy × 5 fractions. The study showed a mean D90 for the HR-CTV of 83.3 Gy, and means for D2cc of bladder, rectum and sigmoid colon were 79.7 Gy, 57.5 Gy and 66.8 Gy, respectively. Forty-three patients (97.7%) had complete response after treatment. Positron emission tomography/computed tomography (PET/CT) at 3 months showed complete response in 38 patients (in 3 pts it was not performed) and local recurrences at the 6th and 8th month in 2 pts. The 2-year local control, disease-specific survival and overall survival rates were 88%, 85% and 86%, respectively [29]. In our study, the local control, disease-free and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. The present study results show a high concordance when compared to previous literature reports (see also Table 5). No patient developed grade 3–4 late toxicity except two patients with grade 3 gastrointestinal toxicity (recto-sigmoiditis) and genitourinary toxicity (dysuria). Overall, our intermediate-term results show excellent local control in all enrolled patients and low treatment-related late morbidity supporting the use of IGBT for treatment planning, delivery and evaluation. There was just one event for grade 3 gastrointestinal (GI) toxicity and one episode for grade 3 genitourinary (GU) morbidity. The toxicity profiles in the present study resemble the results of Pötter et al. which can be considered as a reference which reported 3 events for grade 3– 4 GI and 5 events for grade 3–4 GU, respectively [27]. In addition, a Japanese study which reported a relationship between rectal dose in EQD2 and rectal toxicity showed a cut point of 60 Gy [31]. The same tendency was found in our institutional analysis of rectal dose with a cut point at 65 Gy in EQD2 [Meungwong P, unpublished data]. Image-guided brachytherapy (IGBT) could improve the quality of treatment in both the target and OARs. However, the implementation of IGBT in our cancer center concerned many aspects. Firstly, the total workload was increased due to the process of imaging, contouring and optimization. In our experience, conventional planning was associated with approximately 0.5–1 h of time consumption in the entire process of one fraction, in comparison with 1–2 h for CT-based, and 3–4 h for MRI-guided planning, respectively. Taking into account our high cancer center brachytherapy workload of 6–8 patients per day, the implementation of image-guided brachytherapy is a serious concern. Table 4 Late toxicity profiles of treated patients. Parameters
Numbers
Skin G1–2 Skin G1–2 Subcutaneous tissue G1–2 Subcutaneous tissue G3–4 Gastrointestinal G1–2 Gastrointestinal G3–4 Genitourinary G1–2 Genitourinary G3–4
0 0 2 0 6 1 2 1
E. Tharavichitkul et al. / Gynecologic Oncology 130 (2013) 81–85 Table 5 Literature comparison: cumulative doses in EQD2 for HR-CTV, bladder, rectum and sigmoid. Study
HR-CTV (D90)
Bladder (D2cc)
Rectum (D2cc)
Sigmoid (D2cc)
Pötter et al. [26] 93 ± 13 Gy 86 ± 17 Gy 65 ± 9 Gy 64 ± 6 Gy Beriwal et al. [28] 82.3 ± 3 Gy 79.7 ± 5.1 Gy 57.5 ± 4.4 Gy 66.8 ± 5.7 Gy De Brabandere 82 ± 10 Gy 85 ± 8 Gy 63 ± 6 Gy 66 ± 10 Gy et al. [12] Lindegaard et al. 91 ± 7 Gy 73 ± 6 Gy 65 ± 5 Gy 68 ± 6 Gy [30] Present study 93.1 ± 7.7 Gy 88.2 ± 7.2 Gy 69.6 ± 6.6 Gy 72.0 ± 6.9 Gy
Therefore, a sensitive triage with focus on patients with the most potential benefit is necessary for an optimum utilization of limited resources. Secondly, the imaging approach and the corresponding infrastructure may differ in each hospital. In our institute, the CT-simulator is an integral part of our department and very closely located to our brachytherapy operating room which facilitates its use significantly at high temporal efficiency. The implementation, however, of advanced imaging, especially MRI for technology advanced brachytherapy, has to be well judged in order to outbalance the resource use with the potential outcome benefit. Logistics should be considered globally on an institutional level and not in the affected department only. Conclusion By using GEC-ESTRO recommendations, target volumes and OARs could be identified with higher quality and precision with advanced technology imaging. Image-guided brachytherapy by MRI or CT has shown, in our experience, promising intermediate-term results in the treatment of cervical cancer. Conflict of interest statement All authors declared no conflicts of interest.
Acknowledgments The author offers many thanks to the NRU-CMU in the Gynecologic Oncology Cluster, the Research Unit of Faculty of Medicine, Chiang Mai University and Nucletron for partial support. Definitely, the author conveys many thanks to our staff at the division of therapeutic radiology and oncology-Faculty of medicine-Chiang Mai University, for supporting this study. References [1] Kamnerdsupaphon P, Srisukho S, Sumitsawan Y, Lorvidhaya V, Sukthomya V. Cancers in Northern Thailand. Biomed Imaging Interv J 2008;4:e46. [2] Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53. [3] Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs III CL, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–61. [4] Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of Radiation Therapy Oncology Group trial (RTOG) 90-01. J Clin Oncol 2004;22:872–80. [5] Chassagne D, Duterix A, Almond P, Burgers J, Busch M, Joslin C. Dose and volume specification for reporting intracavitary therapy in gynaecology. International Commission on Radiation Units and Measurements, ICRU Report 38; 1985. [6] Hricak H, Yu KK. Radiology in invasive cervical cancer. AJR Am J Roentgenol 1996;167:1101–8. [7] Van Nagell Jr JR, Roddick Jr JW, Lowin DM. The staging of cervical cancer: inevitable discrepancies between clinical and pathological findings. Am J Obstet Gynecol 1971;110:973–8.
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