INTRODUCTION PATIENT. J. Radiat. Res., 52, (2011)

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1 J. Radiat. Res., 52, (2011) Regular Paper Intracavitary Combined with CT-guided Interstitial Brachytherapy for Locally Advanced Uterine Cervical Cancer: Introduction of the Technique and a Case Presentation Masaru WAKATSUKI, Tatsuya OHNO*, Daisaku YOSHIDA, Shin-ei NODA, Jun-ichi SAITOH, Kei SHIBUYA, Hiroyuki KATOH, Yoshiyuki SUZUKI, Takeo TAKAHASHI and Takashi NAKANO Interstitial brachytherapy/cervical cancer/radiotherapy/ct-guided brachytherapy/intracavitary brachytherapy. We report a new technique of brachytherapy consisting of intracavitary combined with computed tomography (CT)-guided interstitial brachytherapy for locally advanced cervical cancer. A Fletcher-Suit applicator and trocar point needles were used for performing high-dose rate brachytherapy under in-room CT guidance. First, a tandem and ovoids were implanted into the patient s vagina and uterus by conventional brachytherapy method. Based on clinical examination and MRI/CT imaging, operating radiation oncologists decided the positions of insertion in the tumor and the depth of the needles from the upper surface of the ovoid. Insertion of the needle applicator was performed from the vaginal vault inside the ovoid within the tumor under CT guidance. In treatment planning, dwell positions and time adaptations within the tandem and ovoids were performed first for optimization based on the Manchester system, and then stepwise addition of dwell positions within the needle was continued. Finally, dwell positions and dwell weights were manually modified until dose-volume constraints were optimally matched. In our pilot case, the dose of D90 to high-risk clinical target volume was improved from 3.5 Gy to 6.1 Gy by using our hybrid method on the dose-volume histogram. D1cc of the rectum, bladder and sigmoid colon by our hybrid method was 4.8 Gy, 6.4 Gy and 3.5 Gy, respectively. This method consists of advanced imageguided brachytherapy that can be performed safely and accurately. This approach has the potential of increasing target coverage, treated volume, and total dose without increasing the dose to organs at risk. INTRODUCTION The combination of external beam radiotherapy (RT) and intracavitary brachytherapy (ICBT) is a standard treatment technique of RT for uterine cervical cancer, and concomitant chemotherapy is combined for locally advanced cases. 1 5) ICBT plays an important role because the brachytherapy system allows a much higher dose to the cervix while sparing adjacent bladder and bowels. Local control rates of cervical cancer have been reported at 80 90% for early stages. 6 8) However, those for advanced stages show a range *Corresponding author: Phone: +81(27) , Fax: +81(27) , tohno@gunma-u.ac.jp Department of Radiation Oncology, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma , Japan. Financial disclosure/conflict of interest statement: The authors indicate no financial benefits and conflicts of interest. doi: /jrr of 67 75% and further improvement is needed. 4,5,9) One of the reasons for local failure is inadequate dose coverage to bulky and/or irregular-shape tumors. In order to realize adequate dose coverage to cervical tumors, intracavitary combined with computed tomography (CT)-guided interstitial brachytherapy was developed at Gunma University. We introduce the new technique of hybrid-brachytherapy with a pilot case. PATIENT The patient was a 53-year-old woman with stage IIIB squamous cell carcinoma of the uterine cervix according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. 10) On image diagnosis, CT detected a bulky tumor at the uterine cervix with left hydronephrosis. MRI before treatment revealed a cervical mass measuring mm 3. The tumor extension reaching the pelvic side-wall before RT still existed at the time of brachytherapy (Fig. 1). The patient was treated with a combination of external

$External irradiation to the whole pelvis was performed with antero-posterior and postero-anterior parallel-opposed ports with a total dose of 30 Gy at 2 Gy per fraction, 5 times per week.$

2 Hybrid-brachytherapy for Cervical Cancer 55 Fig. 1. MRI images before treatment and after 30 Gy. beam RT and high-dose rate (HDR) brachytherapy. She did not receive concurrent chemotherapy because of renal dysfunction. External irradiation to the whole pelvis was performed with antero-posterior and postero-anterior parallel-opposed ports with a total dose of 30 Gy at 2 Gy per fraction, 5 times per week. This was followed by a central shielding pelvis field up to a total pelvis irradiation dose of 50 Gy at 2 Gy per fraction, 5 times per week. Along with the central shielding irradiation, she was given HDR brachytherapy by HDR-remote afterloading system (RALS) 5 times using an iridium-192 source. In the first three sessions, she received ICBT without interstitial brachytherapy administered once per week at fraction doses of 7.5, 7 and 7 Gy at Point A, with a total dose of 21.5 Gy. In the remaining two sessions, the hybrid method was used because the tumor showed poor response to radiotherapy. Written informed consent was obtained from the patient before this brachytherapy. METHODS In-Room CT Imaging Brachytherapy was delivered in our unit, comprising HDR- RALS (microselectron HDR; Nucletron, The Netherlands) coupled to a CT scanner and X-ray imager sharing a common couch. The couch rotates 230 at the CT-scanning position or 50 at the X-ray imaging position. During CT scanning, the gantry moves along rails on the floor while the table remains stationary. Applicators are implanted into the patient s vagina and uterus on the couch, and all processes including application, imaging, and irradiation can be performed on the same couch using the in-room CT brachytherapy system. 11,12) Brachytherapy application A set of Fletcher-Suit Asian Pacific applicator (tandem and half-size ovoids) and trocar point needles (Nucletron) was used. This hybrid application was done without general anesthesia or spinal anesthesia. The tandem and ovoids were implanted into the vagina and uterus by the procedure of Fig. 2. X-ray photographs of needle placement after implantation of a tandem and ovoids. conventional brachytherapy. After implantation, CT scans were generated on the same couch at 3-mm slice thickness. Magnetic resonance images (MRI) were taken before brachytherapy and used as reference images of the tumor. Based on clinical examination and MRI/CT imaging, operating radiation oncologists decided the positions of insertion in the tumor and the depth of the needles from the upper surface of the ovoid. The CT-guided insertion of the needle applicator was performed along the inside of the half-size ovoid into the tumor (Fig. 2). After tumor location and needle position were confirmed, anterior and posterior vaginal packing was done in a manner similar to the non-interstitial procedure. CT scans were generated again and used for treatment planning. Then, X-ray images were also taken in the same position while rotating the couch. After completion of irradiation, the applicator was removed in the order of tandem and ovoids, followed by the needles. Treatment Planning The applicator geometry was digitized, reconstructed and registered to the X-ray and CT images. Image registration was performed with the evaluation module of the PLATO Brachytherapy Planning System v (Nucletron). The current brachytherapy planning process starts with a conventional pattern for tandem and ovoids planning based on the Manchester system. Point A was defined on the X- ray as being 2 cm superior to the external os, and 2 cm lateral from the axis of the intrauterine tandem. At first, the dose of point A at the opposite side of needle placement was normalized to 6 Gy. A dwell position and time adaptation were established first to optimize the initial standard dose distribution, and then continued with 2.5-mm stepwise additions as dwell positions within the needle. Dose distribution by the resulting treatment plan was confirmed on CT images for the high-risk clinical target volume (HRCTV), which is

56 M. Wakatsuki et al. defined as the parameter of ICBT in the GYN GEC ESTRO recommendation and for organs at risks (OARs) such as bladder, rectum and sigmoid colon.

3 56 M. Wakatsuki et al. defined as the parameter of ICBT in the GYN GEC ESTRO recommendation and for organs at risks (OARs) such as bladder, rectum and sigmoid colon. 13,14) HRCTV, which is a major risk for local recurrence because of residual macroscopic disease, is defined as the whole cervix and the presumed extracervical tumor extension at the time of brachytherapy. Certain dose coverage values can be defined to describe the specific shape of such a dose-volume histogram (DVH), e.g. D100 and D90, defining the minimum dose delivered to 100 and 90% of the volume of interest, respectively. The OARs were contoured using the external wall contours. Cumulative DVHs were calculated for delineated organs of bladder, rectum and sigmoid colon, and the following parameters were reported: absolute volume and minimum dose to the most irradiated 0.1, 1, 2 cm 3 (D0.1 cc, D1 cc, D2 cc, respectively). 13,14) Dwell positions and dwell weights in the tandem, ovoids and needles were manually modified until the dose distribution was optimally matched to cover HRCTV with a 6-Gy isodose line as much as possible. This planning was com- Fig. 3. Dose distribution by conventional brachytherapy and our hybrid method. : HRCTV Fig. 4. Dose-Volume histograms of conventional brachytherapy planning and our hybrid method planning. : HRCTV : Rectum : Bladder

4 Hybrid-brachytherapy for Cervical Cancer 57 pared with conventional ICBT planning without interstitial needle by using DVH parameters for HRCTV and OARs. In conventional ICBT planning, the same source arrangement and irradiation conditions are used, and the dose distribution was based on the Manchester system. The prescribed dose was generated by the PLATO treatment planning system (TPS) with a dose of 6 Gy normalized to point A. RESULTS Dose distribution and dose volume histogram Figures 3 and 4 show dose distributions and DVHs by our hybrid method and conventional ICBT. D90 to HRCTV by this hybrid method and conventional ICBT were 6.1 Gy and 3.5 Gy, respectively. D1cc of the rectum, bladder and sigmoid colon by this hybrid method were 4.8 Gy, 6.4 Gy and 3.5 Gy, respectively, whereas they were 5.7 Gy, 6.3 Gy and 3.4 Gy by conventional brachytherapy (Table 1, Fig. 4). Table 1. Dose of HRCTV, Rectum, Bladder and Sigmoid Colon. Conventional brachytherapy Treatment Outcome At 12 months after treatment, the tumor in the left parametrium had disappeared almost completely according to pelvic MRI findings. Serum levels of squamous cell carcinoma antigen and cytokeratin fragment 21-1 were reduced to 1.1 ng/ml and 3.3 ng/ml from 2.6 ng/ml and 7.6 ng/ml, respectively. No recurrent lesions and distant metastases were detected at 18 months after the treatment, and she did not experience grade 2 or higher late morbidity. DISCUSSION Our hybridbrachytherapy HRCTV D Gy 3.4 Gy D Gy 6.1 Gy Rectum D0.1cc 5.8 Gy 6.7 Gy D1cc 4.8 Gy 5.7 Gy D2cc 4.4 Gy 5.2 Gy Bladder D0.1cc 8.0 Gy 8.0 Gy D1cc 6.4 Gy 6.3 Gy D2cc 5.8 Gy 5.8 Gy Sigmoid colon D0.1cc 4.5 Gy 4.3 Gy D1cc 3.5 Gy 3.4 Gy D2cc 3.2 Gy 3.2 Gy When bulky and/or irregular-shape cervical cancer is treated with brachytherapy, using increments of the prescribed dose at the reference point is one of the approaches. However, such increments may result in increasing doses to surrounding normal tissues including the bladder, rectum, and small intestine. In recent years, Japanese researchers reported the correlation of rectal bleeding with the dose-volume parameter of rectum in patients with cervical cancer. 15,16) Isohashi et al. reported that the mean biologically equivalent dose in 2-Gy fraction (EQD2) of rectum D1cc for patients with and without rectal bleeding was 76 Gy and 98 Gy, respectively, and there was a significant greater rectal bleeding risk for the high EQD2 group ( 82 Gy of D1cc rectum). 15) In the current case, EQD2 of rectum D1cc was 79.9 Gy, which was calculated as the linear quadratic model for incomplete sublethal damage repair. If the dose prescription at point A could be increased by conventional ICBT until the dose of D90 for HRCTV reached 6 Gy, D1cc of the rectum would increase from 4.8 Gy to 8.2 Gy, and EQD2 of rectum D1cc would increase to 96.8 Gy. This method was able to increase the HRCTV dose while keeping the rectum dose at tolerable levels even in the case of bulky and/or irregular-shape cervical cancer. In the present case, primary tumor was well controlled without severe toxicities. However, further follow-up will be needed to confirm long-term efficacy and toxicities. Historically, interstitial brachytherapy was performed with free hand-placement, and ultrasound-guided, CT-guided and template-guided needles for locally advanced tumor ) To date, transperineal template techniques were the most commonly used methods for interstitial treatment in such cases. However, these techniques have difficulties in achieving accurate positioning of the implant and good parallelism of the needles. In addition, using these methods, the applicators have to be left in place for a few days after implantation. On the other hand, a major part of the procedure in the current hybrid method is derived from conventional brachytherapy. In-room CT-guided insertion of the interstitial needle could be performed after implantation of the Fletcher- Suit applicator. Furthermore, because this insertion is done for each brachytherapy session, the applicators do not need to be left in place. Therefore, this hybrid method is a noncomplicated technique and is safe for patients compared with previous methods. Considering the risk of perforation of the sigmoid colon or intestine, accurate positioning of the needle in interstitial brachytherapy is very important. Several researchers have reported achieving accurate positioning and avoiding perforation by several methods ) With the present hybrid method, CT-guided insertion is performed after implantation of tandem and ovoid applicators. In addition, an in-room CT system is used for the current method. This system enabled implantation of the applicator, CT-guided placement of the needle and irradiation by RALS to be performed on the same couch. Movement of the applicator and needle can be min-

5 58 M. Wakatsuki et al. imized during implantation, planning and irradiation. Because of the CT-guided insertion and in-room system, accurate positioning and safe insertion can be achieved with this hybrid method. Dimopuolos et al. and Kirisits et al. reported a similar technique of intracavitary and interstitial brachytherapy that uses a modified tandem-ring applicator for cervical cancer at Vienna University. 22,23) In their method, needles are inserted through holes in the tandem-ring applicator. As it is limited to moderate lateral expansion of the HRCTV, for cases with involvement up to the pelvic wall, additional interstitial needles are required. Their method was also accurate and safe, based on an MRI-guided approach. However, the Vienna ring applicator is not commercially available, and in Japan the most common type of applicator is the Fletcher-Suit Asian Pacific applicator. In our hybrid method, similar to the Vienna ring applicator, needles can be placed in the tumor located at the posterior parametrium with high flexibility. The current technique of brachytherapy should be further investigated to confirm its safety and efficacy. REFERENCES 1. Nakano T, et al (2005) Long-term results of high-dose rate intracavitary brachytherapy for squamous cell carcinoma of the uterine cervix. Cancer 103: Nakano T, et al (2010) Current advancement in radiation therapy for uterine cervical cancer. J Rad Res 51: Rose PG and Bundy BN (2002) Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20: Eifel PJ, et al (2004) Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for highrisk cervical cancer: an update of radiation therapy oncology group trial (RTOG) J Clin Oncol 22: Pearcey R, et al (2002) Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20: Keys HM, et al (1999) Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340: Goksedef BP, et al (2009) Concurrent cisplatin-based chemoradiation International Federation of Gynecology and Obstetrics stage IB2 cervical carcinoma. Am J Obstet Gynecol 200: 175.e Stehman FB, et al (2007) Radiation therapy with or without weekly cisplatin for bulky stage 1B cervical carcinoma: follow-up of a Gynecologic Oncology Group trial. Am J Obstet Gynecol 197: 503.e Whitney CW, et al (1999) Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17: Shepherd JH (1996) Cervical and vulva cancer: Changes in FIGO definitions of staging. Br J Obstet Gynaecol 103: Owen R, et al (2010) A comparison of in-room computerized tomography options for detection of fiducial markers in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 77: Ma CM, et al (2006) In-room CT techniques for image-guided radiation therapy. Med Dosim 31: Haie-Meder C, et al (2005) 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 74: Pötter R, et al (2006) 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 78: Isohashi F, et al (2010) Rectal dose and source strength of the high-dose-rate iridium-192 both affect late rectal bleeding after intracavitary radiation therapy for uterine cervical carcinoma. Int J Radiat Oncol Biol Phys 77: Kato S, et al (2010) CT-based 3D dose-volume parameter of the rectum and late rectal complication in patients with cervical cancer treated with high-dose-rate intracavitary brachytherapy. J Rad Res 51: Syed AM, et al (2002) Long-term results of low-dose-rate interstitial-intracavitary brachytherapy in the treatment of carcinoma of the cervix. Int J Radiat Oncol Biol Phys 54: Martinez A, et al (1985) Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynaecologic malignancies. Int J Radiat Oncol Biol Phys 11: Nag S, et al (1998) Interstitial brachytherapy in the management of primary carcinoma of the cervix and vagina. Gynecol Oncol 70: Kuipers T, et al (2001) HDR brachytherapy applied to cervical carcinoma with moderate lateral expansion: modified principles of treatment. Radiother Oncol 58: Erickson B and Gillin MT (1997) Interstitial implantation of gynaecologic malignancies. J Surg Oncol 66: Kirisits C, et al (2006) The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: design, application, treatment planning, and dosimetric results. Int J Radiat Oncol Biol Phys 65: Dimopoulos JC, et al (2006) The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: clinical feasibility and preliminary results. Int J Radiat Oncol Biol Phys 66: Received on July 16, 2010 Revision received on October 13, 2010 Accepted on October 21, 2010

3D ANATOMY-BASED PLANNING OPTIMIZATION FOR HDR BRACHYTHERAPY OF CERVIX CANCER

SAUDI JOURNAL OF OBSTETRICS AND GYNECOLOGY VOLUME 11 NO. 2 1430 H - 2009 G 3D ANATOMY-BASED PLANNING OPTIMIZATION FOR HDR BRACHYTHERAPY OF CERVIX CANCER DR YASIR BAHADUR 1, DR CAMELIA CONSTANTINESCU 2,