A Dose–Volume Analysis of Magnetic Resonance Imaging-Aided High-Dose-Rate Image-Based Interstitial Brachytherapy for Uterine Cervical Cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 3, pp. 765–772, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2009.05.027

CLINICAL INVESTIGATION

Cervix

A DOSE–VOLUME ANALYSIS OF MAGNETIC RESONANCE IMAGING-AIDED HIGH-DOSE-RATE IMAGE-BASED INTERSTITIAL BRACHYTHERAPY FOR UTERINE CERVICAL CANCER KEN YOSHIDA, M.D.,* HIDEYA YAMAZAKI, M.D.,y TADASHI TAKENAKA, R.T.T.,* TADAYUKI KOTSUMA, M.D.,* MINEO YOSHIDA, M.D.,* SEIICHI FURUYA, M.D.,z EIICHI TANAKA, M.D.,* TADAAKI UEGAKI, R.T.T.,* KEIKO KURIYAMA, M.D.,* HISANOBU MATSUMOTO, M.D.,x SHIGETOSHI YAMADA, M.D.,x AND CHIAKI BAN, M.D.x y

Departments of *Radiology, x Obstetrics and Gynecology, National Hospital Organization Osaka National Hospital, Osaka; Department of Radiology, Kyoto Prefectural University of Medicine; and z Louis Pasteur Center for Medical Research, Kyoto, Japan Purpose: To investigate the feasibility of our novel image-based high-dose-rate interstitial brachytherapy (HDRISBT) for uterine cervical cancer, we evaluated the dose–volume histogram (DVH) according to the recommendations of the Gynecological GEC-ESTRO Working Group for image-based intracavitary brachytherapy (ICBT). Methods and Materials: Between June 2005 and June 2007, 18 previously untreated cervical cancer patients were enrolled. We implanted magnetic resonance imaging (MRI)-available plastic applicators by our unique ambulatory technique. Total treatment doses were 30–36 Gy (6 Gy per fraction) combined with external beam radiotherapy (EBRT). Treatment plans were created based on planning computed tomography with MRI as a reference. DVHs of the high-risk clinical target volume (HR CTV), intermediate-risk CTV (IR CTV), and the bladder and rectum were calculated. Dose values were biologically normalized to equivalent doses in 2-Gy fractions (EQD2). Results: The median D90 (HR CTV) and D90 (IR CTV) per fraction were 6.8 Gy (range, 5.5–7.5) and 5.4 Gy (range, 4.2–6.3), respectively. The median V100 (HR CTV) and V100 (IR CTV) were 98.4% (range, 83–100) and 81.8% (range, 64–93.8), respectively. When the dose of EBRT was added, the median D90 and D100 of HR CTV were 80.6 Gy (range, 65.5–96.6) and 62.4 Gy (range, 49–83.2). The D2cc of the bladder was 62 Gy (range, 51.4–89) and of the rectum was 65.9 Gy (range, 48.9–76). Conclusions: Although the targets were advanced and difficult to treat effectively by ICBT, MRI-aided imagebased ISBT showed favorable results for CTV and organs at risk compared with previously reported image-based ICBT results. Ó 2010 Elsevier Inc. Interstitial brachytherapy, Uterine cervical cancer, Image-based brachytherapy, Dose-volume histogram.

With the advancement of image and computer technology, the concept of image-based radiotherapy has emerged. Computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI) enable us to visualize precise contours of gross tumor volume, clinical target volume (CTV), and organs at risk (OAR) at the time of brachytherapy (GTVB). Especially, MRI and MRI-compatible applicators lay a path to a new era of image-based brachytherapy. United States (American Brachytherapy Society [ABS] Imageguided Brachytherapy Working Group) and European (Gynecological GEC-ESTRO Working Group) brachyther-

apy groups have tried to establish MRI-based intracavitary brachytherapy (ICBT) (1–3) to achieve better tumor coverage with reduced dose to the OARs. The European Group reported their treatment planning system with preliminary experience of interinstitutional variability (4). Interstitial brachytherapy (ISBT) is also a useful treatment modality for advanced tumors. Because treatment applicators can be implanted in and/or around the CTV, ISBT has the possibility to achieve better tumor coverage regardless of the size of the vaginal and uterine cavity in cases of cervical cancer. The ABS recommends that ISBT should be used in situations such as bulky lesion, narrow vagina, inability to enter the cervical os,

Reprint requests to: Ken Yoshida, M.D., Department of Radiology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka-city, Osaka 540-0006, Japan. Tel: (+81) 6-6942-1331; Fax: (+81) 6-6943-6467; E-mail: kyoshida@ onh.go.jp Supported in part by the Grant-in-Aid for the Osaka Cancer Foundation Award from the Osaka Cancer Foundation. Conflict of interest: none.

Acknowledgment—The authors thank Kazunobu Nakamura, R.T.T.; Mari Mikami, R.T.T.; Toshiaki Tarui, R.T.T.; Hisakazu Okada, D.D.S.; Miyuki Sakemi; Itsuko Kuroda; the staff of the Departments of Radiology, Anesthesiology, and Obstetrics and Gynecology and the operating room for helping us in many ways during the completion of this study. Received Feb 25, 2009, and in revised form May 24, 2009. Accepted for publication May 26, 2009.

INTRODUCTION

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extension to the lateral parametrium or pelvic side wall, and lower vaginal extension (5), and several clinical reports have shown good local control results using low-dose-rate or highdose-rate (HDR) ISBT (6–12). Based on these recommendations, we performed ISBT with metal applicators until May 2005. However, metal applicators cause artifacts on CT images, making it difficult to draw CTV and OAR contours. In addition, we could not use MRI because the applicator was made of magnetic material. We adopted a plastic flexible needle applicator to solve these problems in June 2005, and have since been performing image-based HDR-ISBT using CT and MRI. To evaluate the feasibility of our MRI-aided image-based ISBT, we conducted a dose–volume histogram (DVH) analysis according to that described by the European Gynecological GEC-ESTRO Working Group. METHODS AND MATERIALS Patient characteristics Between June 2005 and June 2007, 18 uterine cervical cancer patients (median age, 56 years; range, 34–79 years) were treated by ISBT at the Department of Radiology, National Hospital Organization Osaka National Hospital (Table 1). The survivors were followed up for a minimum of 1 year (median; 18 months, range; 9–33 months). The eligibility criteria for undergoing ISBT were determined based on ABS recommendations (bulky lesion, narrow vagina, inability to enter the cervical os, extension to the lateral parametrium or pelvic side wall, and lower vaginal extension). Fifteen patients had lateral extension, 5 had lower vaginal extension, 3 had anterior or posterior extension, and 1 presented with the inabilTable 1. Patient characteristics Age (y) Median: Follow-up period (mo) Median: Histology Squamous cell carcinoma Adenocarcinoma Adenosquamous cell carcinoma T stage T3a T3b T4 N stage N0 N1 M stage (paraaortic lymph node) M0 M1 Whole pelvic EBRT (Gy) Median: Center-shielded EBRT (Gy) Median: ISBT (Gy) Median: Chemotherapy + 

56 (34–79) 18 (9–33) 16 1 1 1 13 4 9 9 15 3 30 (30–45) 20 (0–20) 30 (30–36) 14 4

Abbreviations: EBRT = external beam radiotherapy; ISBT = interstitial brachytherapy.

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ity to enter the cervical os (some were overlapping). We used MRI and transrectal ultrasonography (TRUS) to decide between using ICBT or ISBT. Histologic findings showed 16 squamous cell carcinomas, one adenosquamous carcinoma, and one adenocarcinoma. Using the UICC classification of 2002, one T3a, 13 T3b, and 4 T4 lesions were identified. There were 9 N0 and 9 N1 patients, and 3 patients were classified as M1: para-aortic lymph node (PALN) metastasis. All patients received external beam radiotherapy (EBRT) to the whole pelvis with the median prescribed dose of 30 Gy (range, 30–45 Gy). In addition, all but 1 patient underwent center-shielded (CS) EBRT (median, 20 Gy; range, 0–20 Gy). Additional boost irradiation to pelvic lymph node metastasis was performed for 6 patients (median, 6 Gy; range, 0–10 Gy). The EBRT for PALN was performed for 4 patients (45 Gy). The median overall treatment time was 47 days (range, 33–57 days). We performed ISBT after whole pelvic EBRT and before CS EBRT. In principle, a midline block of CS EBRT was decided according to the treatment volume of ISBT. However, when CS EBRT was begun before ISBT, we decided on the extent of the midline block to cover the HR CTV. Fourteen patients (78%) received concurrent (8 patients) or neoadjuvant (2 patients) chemotherapy or both (4 patients). In the concurrent chemotherapy regimen, the patients received intravenous cisplatin. The regimens of neoadjuvant intravenous chemotherapy were a combination of paclitaxel, ifosfamide, and cisplatin for 5 patients and nedaplatin for 1 patient. One patient also received intraarterial chemotherapy (mytomicin-C and cisplatin). The other 4 patients did not receive chemotherapy because of their older age (2 patients) or poor renal function because of tumor-induced bilateral hydronephrosis (2 patients).

Applicator implantation We performed a single applicator implantation with multifractionated HDR irradiations for all patients. Implantation was performed in the operating room with lumbar anesthesia and continuous epidural anesthesia. The implantation was monitored using TRUS (ALOKA, Tokyo, Japan). We adopted flexible needles (ProGuide Sharp Needle, Nucletron, Veenendaal, The Netherlands) for all patients. We implanted 7 to 17 (median, 12) applicators. A single flexible needle applicator (tandemlike needle) was inserted with a curved metallic obturator into the uterine cavity, and the 1- to 1.5-cm tip of the needle was implanted into the uterine fundus. A button stopper was fixed to the tandemlike needle, and it was contacted to the external os. After implantation of the tandemlike needle, a silicone cylinder was inserted into the vagina. This cylinder was custom-made by us using silicone rubber, depending on the patient’s vaginal size. It had five implant holes, and the center hole was used for the tandem-like needle. The concept of our ambulatory implant technique has been described in detail elsewhere (13). Briefly, the tandemlike needle and cylinder complex was sutured to the uterine cervix by a silk thread. After inserting the cylinder, we attached a custom-made vinyl template to the patient’s perineum with holes for needle implantation to aid implantation of the flexible needle applicators. The vinyl template also had five holes for cylinderguided implantation and several additional holes for freehand implantation. The positions of the holes for freehand implantation were defined by preimplantation TRUS, CT, and MRI images. We implanted four cylinder-guided needles into both holes of the cylinder and the vinyl template. Next, we implanted the other applicators using the holes without the cylinder’s holes by freehand implantation.

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The objective of the implantation was to cover the HR CTV with TRUS guidance. After completing implantation, we fixed all needles to the vinyl template and the perineum using silk threads. The silk thread was fixed to a color bead–button complex. The color bead, but not the tandemlike needle, was fixed to the applicator with an adhesive before implantation. This fixation of the bead–button complex determined the needle length, and the bead color codes identified the needle length (e.g., purple, 12 cm; blue, 13 cm; yellow, 14 cm). Because this complex was larger than the holes of cylinder and vinyl template, the tandemlike needle could not be fixed to the complex; therefore, only the button with the silk thread was fixed to the tandemlike needle after implantation. Finally, the protruded connector end of the applicator was cut down short enough to enable the patient to walk (Fig. 1).

Treatment planning and treatment All patients underwent CT and MRI during the planning phase (Fig. 2). The CT-based planning was performed using MRI as a reference to contour the HR CTV and OARs (rectum, bladder). The definition of these contours was based on the recommendation from the Gynecological GEC-ESTRO Working Group for reporting 3D-sectional image assisted brachytherapy of cervix cancer (2, 3). The HR CTV and OARs were delineated with the assistance of axial T2-weighted MR images. Clinical examination and information from the marker seed, which was implanted at the edge of GTVB, were also used for delineation. HR CTV included GTVB and the entire cervix. The rectum and bladder were delineated as structure walls. Intermediate risk CTV (IR CTV) included the HR CTV with a safety margin of 0.5 to 1.5 cm. The treatment planning was performed using the planning system PLATO (software version 14.2, Nucletron) with manual modification after computer optimization (Fig. 3a and b) (14). The single fraction dose was 6 Gy for all patients and the median total prescribed dose was 30 Gy/5 fractions (range, 30–36 Gy). Only two poor responders for EBRT received 36 Gy/6 fractions. Five fractions schedule was finished in 3 days and 6 fractions schedule

Fig. 2. Magnetic resonance image of patient obtained just after implantation, showing the contours of high-risk clinical target volume (arrows), the bladder, and the rectum.

in 4 days. We used the microSelectron-HDR (Nucletron) for treatment and 192 Ir as the treatment source.

DVH analysis The DVH analysis was performed according to the Gynecological GEC-ESTRO Working Group. The DVH was calculated for HR CTV and IR CTV, and the following parameters were reported: the percentage of the CTV covered by the prescribed dose (V100), and the dose that covered 90% and 100% of the target volume (D90, D100). For the OARs, we calculated the minimum dose received by the maximally irradiated 2-cc volume (D2cc). To sum up the EBRT and ISBT doses, we used physical doses and their biologically equivalent doses. The biologically equivalent dose was calculated into equivalent 2-Gy fractions (EQD2) using a linearquadratic model, where a/b = 10 for tumors and a/b = 3 for OARs. In this study, we investigated total radiation doses for the HR CTV, rectum, and bladder. We summed up the ISBT doses (physical dose and EQD2) and isocenter doses of whole pelvic EBRT. Because we had no fusion-soft for EBRT and ISBT, we could not investigate the total irradiated IR CTV dose that was influenced by CS EBRT. We used the Mann-Whitney test, the Kruskal-Wallis test, and the chi-square test to analyze the correlation between the treatment factor and the complication rate.

RESULTS

Fig. 1. The vinyl template-applicator complex was sutured to the perineum. The tandemlike needle was fixed only with the button (arrow), and the other needles were fixed with the button-bead complex. Every button was sutured with silk thread, and this thread was also sutured to the perineal skin and vinyl template. Finally, the protruded connector end of the applicator was cut down short enough to enable to patient to walk.

DVH for CTV The median volumes of HR CTV and IR CTV were 29.8 cc (range, 14.9–56.1 cc) and 63.5 cc (range, 31.3–105.5 cc), respectively. The median D90 and D100 (HR CTV) per fraction was 6.8 Gy (range, 5.5–7.5 Gy) and 4.5 Gy (range, 2.1–6 Gy). The median V100 (HR CTV) was 98.4% (range, 83–100%). The median D90 and D100 (IR CTV) per fraction was 5.4 Gy (range, 4.2–6.3 Gy) and 2.9 Gy (range, 1.2–4.7 Gy). The median V100 (IR CTV) was 81.8% (range, 64– 93.8%). When the EBRT dose was added to the HDR-

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Gy (range, 47.1–71.5 Gy; physical dose) and 62 Gy (range, 51.4–89 Gy; EQD2) (Table 2). The D2cc (rectum) per fraction was 4.4 Gy (range, 3.1–5.4 Gy). The median D2cc (rectum) for all treatments was 54.8 Gy (range, 45.5–65.5 Gy; physical dose) and 65.9 Gy (range, 48.9–76 Gy; EQD2) (Table 2). Local control and survival Local failure occurred in 3 patients (17%), and all died as a result of local and nodal/distant failures. Nodal or distant metastasis without local failure was observed in 3 patients (17%). One of the 3 patients who showed PALN metastasis was treated by radiotherapy and at this writing is in disease-free status. Thirteen of 18 patients (72%) have survived to this writing. Of the 3 patients who experienced local failure, 2 had a T4 lesion and the other had a T3b lesion. Histologic analysis revealed that 1 of the 3 patients with local failure had adenocarcinoma, and the other 2 had squamous cell carcinoma. Local central recurrence occurred in 2 of 3 patients. These regions received more than the prescribed doses. The other patients showed marginal miss (posterior wall of uterine body) (Fig. 4). The median D100 (HR CTV) for the 3 patients was 50.6 Gy (range, 50.1–61 Gy; physical dose) and 53.9 Gy (range, 50.2–64.9 Gy; EQD2). The median D90 (HR CTV) was 71 Gy (range, 59.1–71.1 Gy; physical dose) and 81.9 Gy (range, 67.9–82.4 Gy; EQD2). No statistically significant difference in dosage was observed between patients with locally controlled and those with uncontrolled lesions.

Fig. 3. (a) Computed tomography image of patient in Fig. 2. The dose-distribution curve was calculated by computer optimization with manual modification. High-risk clinical target volume (CTV) was well covered by the 100% prescribed isodose line. (b) Computed tomography image of the same patient as in Figs. 2 and 3a. The dose-distribution curve was calculated by computer optimization with manual modification. Intermediate-risk CTV was well covered by the 80% prescribed isodose line. PD = prescribed dose.

ISBT dose, the median D100 (HR CTV) became 56.1 Gy (range, 47–74 Gy; physical dose) and 62.4 Gy (range, 49– 83.2 Gy; EQD2) (Table 2). The median D90 (HR CTV) became 65.5 Gy (range, 58–81 Gy; physical dose) and 80.6 Gy (range, 65.5–96.6 Gy; EQD2). DVH for OAR The minimum dose to the most irradiated 2 cc of the bladder [D2cc(bladder)] per fraction was 4.2 Gy (range, 3.3–5.3 Gy). The median D2cc (bladder) for all treatments was 52.4

Complications The most severe complication during treatment was bleeding that occurred at implantation and extraction. A blood transfusion was necessary for 2 patients after applicator extraction; hemoglobin decreased from 7.7 to 3.5 g/dL in 1 patient and from 12.1 to 7.6 g/dL in the other. Urinary infection was observed in 2 patients. Both patients presented with hydronephrosis and renal dysfunction by tumor invasion before treatment. In these patients, the D2cc (bladder) was 59.7 and 66.9 Gy, and no significant difference was observed between the D2cc values with or without urinary infection. Grade1 acute rectal morbidity was observed in only 2 patients. The other acute complications (Grade 3 leukopenia, 2 patients; Grade 1 diarrhea, 6 patients) were induced by chemotherapy and/or EBRT. Severe late complication because of ISBT was observed in only 1 patient. This patient had T4 tumor invading the rectum and showed a rectovesicovaginal fistula, and secondary massive bleeding required transarterial embolization (Grade 4) 5 months after ISBT. The tumor decreased rapidly in size by treatment, and the tumor space became a cavity leading to fistula formation and potentially lethal bleeding. She received a colostomy and is disease free at this writing. The D2cc (rectum) of this patient was 5.4 Gy, which was the highest value observed in this study.

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Table 2. Comparison of dose–volume histogram results between the GEC-ESTRO study and our study HR-CTV (EQD2)

ONH (Stage III– IV: 18 patients) GEC-ESTRO* (Stage IIB:3 patients) Viennay (Stage I–II/III–IV: 19/3 patients)

Bladder (D 2 cc)

Rectum (D 2 cc)

D100

D90

V100

EQD2

EQD2

61.4 (49–83.2)

80.6 (65.5–96.6)

98.4 (83–100)

62 (51.4–89)

65.9 (48.9–76)

65 (64–74) 66  7

86 (85–87) 87  10

NA 89  8

81 (70–85) 83  9

62 (53–64) 64  6

Abbreviations: HR-CTV = high-risk clinical target volume; ONH = Osaka National Hospital; GEC-ESTRO = Gynecological ESTRO. * Lang et al. (4). y Kirisits et al. (17).

DISCUSSION Image-based ICBT has emerged after the long-time gold standard Manchester treatment system as a treatment modality for uterine cervical cancer. The ABS and GEC-ESTRO published guidelines (1–3) emphasizing the importance of CTV-based dose prescription rather than dose prescription to point A, which was designed to treat the paracervical triangle before the CT era. MRI is a powerful method of imagebased ICBT. Nag et al. (1) introduced image-based ICBT and MRI that provides superior soft tissue resolution and is the best imaging modality for depicting cervical tumor size

Fig. 4. Magnetic resonance image of the patient who experienced local failure. Dose-distribution curves of interstitial brachytherapy were superimposed. Original tumor location was anterior region of cervix with bladder invasion (T4 stage). However, tumor recurred in posterior wall of uterine body (arrow) that was treated inadequately by brachytherapy. PD = prescribed dose.

and extent compared with ultrasonography and CT. They proposed that T2-weighted MRI should be used for imaging using a pelvic surface coil with image-compatible brachytherapy applicators instead of cervical implants. Po¨tter et al. (15) reported their single institute’s result that MR image-based ICBT with or without ISBT were validated and showed better treatment results and fewer complications than previous treatment methods. They compared treatment results between treatment planning with MRI (2001–2003) and without MRI (1998–2000). The 3-year local control rate for tumors larger than 5 cm improved from 71% (1998–2000) to 90% (2001–2003) with MRI-aided treatment planning. Hatano et al. (16) also reported that MRI imagebased ICBT resulted in better tumor coverage. The mean V100 was 95.85% (range, 80.8–100%) for image-based ICBT, and the mean point A dose was reduced to 85.6% (range, 46.1–106%) of the prescribed dose. There are some limitations in performing image-based ICBT. First, more medical resources are necessary than for conventional ICBT. Nag et al. (1) showed that repeated imaging at each applicator insertion is necessary because the tumor volume may change drastically during the course of the therapy. However, frequent MRI examination may be difficult because of several limitations (e.g., excess patients waiting for MRI examination, medical insurance regulations). Second, the longer treatment planning time is also a burden for patients and institutions. When creating a treatment plan, contours of all types of CTV and OARs for every applicator insertion are drawn before treatment, which requires a longer time interval between applicator insertion and treatment. The ISBT presented has a potential to solve these problems. Only one applicator insertion and MRI are necessary in ISBT. Patients are not restricted to bed rest after lumbar anesthesia, which may permit more comfort during the 3- to 4-day treatment. The shorter overall treatment time for the primary site may be another merit of ISBT for improving local control. In our study, the median treatment time for whole pelvic EBRT and ISBT was only 37 days, which is shorter than that for standard whole pelvic EBRT and ICBT treatment (EBRT, 3 weeks; ICBT, 4 weeks).

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Fig. 5. (a) Computed tomography image of a 66-year-old patient with Stage T3b uterine cervical cancer. We used metal applicators for interstitial brachytherapy. Note strong artifact produced by metallic applicators, which make it difficult to draw a clear delineation of clinical target volume and organs at risk. (b) Computed tomography image of a 45-year-old patient with Stage T3b uterine cervical cancer. We used flexible applicators for interstitial brachytherapy. Note that the flexible applicator diminished the artifact. (c) Magnetic resonance imagng of the same patient.

Image-based brachytherapy can reduce normal tissue morbidity because conventional point-A ICBT treatment results in unnecessary irradiation of normal tissue, especially in cases of small tumor mass. By contrast, image-based ICBT has limitations in treating larger or more lateral extension than the point-A dose specification point. We must increase the dwell times of the three applicators (tandem and two ovoids), which means that the normal tissue morbidity may increase. It is difficult to optimize dose distribution using only three applicators, but ISBT can more easily optimize dose distribution than ICBT because many applicators are located in or around the CTV. The GEC-ESTRO reported the interinstitutional comparison of image-based ICBT (4), and three institutes (Institute Gustav-Roussy, University Hospital Leuven, Medical University of Vienna) showed their DVH results. All three patients were classified as T2b. Their median total D90 (EQD2) of 85–87 Gy for HR CTV (Table 2) concurs with ours (median, 80.6; range, 65.5–96.6 Gy), although all our patients were classified as T3–4 and many of the tumors showed unfavorable topography, and ABS recommends that ISBT should be indicated for such advanced lesions (5). The same GEC-ESTRO report showed that the median D2cc for the bladder was 70–85 Gy, which were higher than our ISBT result. Kirisits et al. (17) reported a DVH result

of ICBT alone that was similar to the result of the GEC-ESTRO study (Table 2). The Vienna group performed image-based ISBT in cases of insufficient CTV coverage by ICBT alone (15, 18, 19). Kirisits et al. (19) reported that large tumors (mean volume of HR CTV: 44 cc) could be treated effectively by additional needle implantation with a tandem and ring applicator, and we strongly agree with their treatment policy. We support this policy because the DVH results of our image-based ISBT were not inferior to those of the GEC-ESTRO ICBT study. Beriwal et al. (6) reported DVH results of ISBT. Beriwal et al investigated 16 patients (uterine cervical cancer, 11; vaginal cancer, 5) including 7 patients with T3–4 cervical lesions. They defined the CTV using CT and clinical examination and also used pretreatment tumor location as a reference. Their acceptable dose value was at least 90% that of the CTV covered by the prescribed dose. They reported that the median biologic effective dose to the target volume was 78.9 Gy10, which concurred with our D90 values. Their local control result was 75% (median follow-up, 22 months; range, 6– 69 months). Although our follow-up time was shorter and further follow-up is necessary, our local control result (83%) seems to be better. All our patients had T3–4 lesions, and MRI assistance may be an important factor. Beriwal et al. (6) did not use MRI for planning, and therefore, poor contour

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definition might be a concern. Until 2004, we had been using metallic needle applicators with the template, which caused an artifact on CT images (Fig. 5a), making it impossible to perform MRI. Adopting flexible nonmetal needle applicators eliminated the artifact (Fig. 5b) and enabled us to perform MRI (Fig. 5c). This image guidance method makes it easier to draw the CTV and OAR contours, and as a result we can produce a more precise dose prescription. Popowski et al. (20) developed a titanium-zirconium needle applicator that can be used during MRI; however, the patient must stay in bed during implantation because this applicator protrudes from the perineum. We adopted our own unique ambulatory implant technique, which has already been reported elsewhere for prostate cancer (13). This technique allows patients to move quite freely after the influence of lumbar anesthesia has diminished. On the second day after implantation, almost all patients could stand and walk from the ward to the treatment room without help. They described having mild perineal pain when they tried to stand, and sitting with direct pressure on the perineum also caused mild pain. The limitation of our multicatheter insertion system was bleeding from vessels near and around the uterus and vagina after implantation, which led to anemia in some cases. Uterine cervical cancer patients often showed massive genital bleeding as a first symptom and preceding chemotherapy

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and EBRT also caused a decrease in hemoglobin. Such background problems were more specific than those of other interstitial implantations for pelvic cancer (e.g., prostate cancer, posthysterectomy recurrence). A few reports have commented about bleeding during implantation (10–12). Demanes et al. (10) reported that 3 of 62 patients showed intraperitoneal hemorrhage requiring transfusions, and Kuipers et al. (11) reported that 2 of 41 patients showed hemorrhage but no transfusion was necessary. Inasmuch as we encountered 2 patients who required blood transfusion, we began to use Doppler ultrasonography to avoid major vascular injury during implantation. We will begin MRI-based image-guided ICBT soon and will compare the DVH evaluation with ISBT. Further study with a larger number of patients and a longer follow-up is necessary to fully evaluate the clinical outcome (recurrence and complication) of this methodology.

CONCLUSIONS Our preliminary method of image-based ISBT using our unique ambulatory method was feasible, and the DVH results were comparable to those of the GEC-ESTRO preliminary report. More investigation is necessary to determine the indications for image-based ICBT and ISBT.

REFERENCES 1. Nag S, Cardenes H, Chang S, et al. Proposed guidelines for image-based intracavitary brachytherapy for cervical carcinoma: Report from image-guided brachytherapy working group. Int J Radiat Oncol Biol Phys 2004;60: 1160–1172. 2. Haie-Meder C, Po¨tter R, Van Limbergen E, et al. Gynaecological (GYN) GEC-ESTRO Working Group. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol 2005;74: 235–245. 3. Po¨tter R, Haie-Meder C, Van Limbergen E, et al. Recommendations from gynaecological (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: 67–77. 4. Lang S, Nulens A, Briot E, et al. Intercomparison of treatment concepts for MR image assisted brachytherapy of cervical carcinoma based on GYN GEC-ESTRO recommendations. Radiother Oncol 2006;78:185–193. 5. Nag S, Erickson B, Thomadsen B, et al. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 2000;48:201–211. 6. Beriwal S, Bhatnagar A, Heron DE, et al. High-dose-rate interstitial brachytherapy for gynecologic malignancies. Brachytherapy 2006;5:218–222. 7. Syed AM, Puthawala AA, Abdelaziz NN, et al. Long-term results of low-dose-rate interstitial-intracavitary brachytherapy

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