Comparison of Intracavitary Brachytherapy and Stereotactic

Brachytherapy - (2012) -

Comparison of intracavitary brachytherapy and stereotactic body radiotherapy dose distribution for cervical cancer Mustafa Cengiz*, Ali Dogan, Gokhan Ozyigit, Ertugrul Erturk, Ferah Yildiz, Ugur Selek, Sukran Ulger, Fatma Colak, Faruk Zorlu Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

ABSTRACT PURPOSE: To compare the dose distribution characteristics of stereotactic body radiotherapy (SBRT) with intracavitary high-dose-rate (HDR) brachytherapy in patients with cervical carcinoma. METHODS AND MATERIALS: HDR intracavitary brachytherapy treatment plans for 11 women with cervical carcinoma were evaluated in this analysis. The total HDR brachytherapy dose was 28 Gy given in four fractions. HDR brachytherapy was delivered with the microSelectron HDR therapy unit (Nucletron B. V., Veenendaal, The Netherlands). SBRT plans for each patient were generated with MultiPlan for CyberKnife Robotic Radiosurgery System (Accuray Inc., Sunnyvale, CA). The dose distributions, doseevolume histograms, and maximum dose points of the target and critical organs were recorded for both plans. RESULTS: SBRT yielded significantly better target coverage; the median target coverage for the 100% isodose line was 50.7% for HDR brachytherapy plans, whereas it was 99.1% for SBRT plans. The dose distributions for critical organs were similar in both types of plans. The exceptions were the 25% isodose being significantly better in brachytherapy plans for rectum, and the 100% isodose exposure being higher in brachytherapy plans for rectum, bladder, and sigmoid colon. Some significant differences were also found in maximum doses received by a 2-cc volume of bladder in favor of SBRT plans. In addition, maximum bone marrow doses were significantly higher in SBRT plans. CONCLUSION: SBRT plans achieved better target coverage and better dose distributions to critical organs except bone marrow compared with HDR brachytherapy plans in patients with locally advanced cervical cancer. Ó 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords: Stereotactic body radiotherapy; Image guidance; Brachytherapy; Cervical cancer; Treatment planning

Introduction survival after irradiation (2, 3). The only randomized trial comparing surgery with radiotherapy for the treatment of Intracavitary brachytherapy is a vital component of cura- Stages IB and IIA cervix carcinoma conﬁrmed that tumor size tive radiotherapy of cervix cancer. The current standard of is an important prognostic factor (3) for pelvic recurrences, care for locally advanced cervical cancers is pelvic external and failure rate was higher in the radiation arm compared with beam radiotherapy (EBRT) and brachytherapy combined surgery arm (30% vs. 20%). The reason for the worse with concurrent chemotherapy. Although 5-year local outcome in the radiation arm may be attributed to inadequate control rates for Stage I disease are reported to be 94% with radiation dose coverage at the edge of the bulky tumor, result- survival rates of nearly 90%, these satisfactory rates deteri- ing in a geographic miss. Several studies, including our recent orate in more advanced stages (1). institutional three-dimensional (3-D) brachytherapy trial, Cervical tumor size is known to be an important indepen- have demonstrated that successful target coverage is a major dent prognostic factor for local control and a close correlation problem particularly for bulky cervical tumors (4e6).The exists between the incidence of pelvic recurrences and Groupe Europeen de Curietherapie and European Society Received 29 November 2009; received in revised form 11 January for Therapeutic Radiology and Oncology (GEC-ESTRO) 2010; accepted 20 August 2010. has recommended the use of interstitial applicators with the * Corresponding author. Department of Radiation Oncology, Faculty intracavitary technique to improve target dose coverage in of Medicine, Hacettepe University, 06100, Sihhiye, Ankara, Turkey. patients with bulky tumors, while keeping critical structures þ þ Tel.: 90-312-305-2918; fax: 90-312-309-2914. below tolerance dose levels (7). E-mail address: [email protected] (M. Cengiz).

1538-4721/$ - see front matter Ó 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.brachy.2011.12.001 2 M. Cengiz et al. / Brachytherapy - (2012) - The serious morbidity rates in patients receiving EBRT compatible applicators were used in all patients according combined with brachytherapy are 2e6% for bladder and to the guidelines of The American Brachytherapy Society rectum (1, 8, 9). Using current techniques, there is a limited (16). Our applicator system consisted of a tandem and two scope to decrease the radiation dose to these critical struc- ovoids. Radio-opaque gauze was used for packing to keep tures without decreasing the dose to the tumor. bladder and rectum wall away from the applicators. Stereotactic body radiotherapy (SBRT) with real-time One set of CT scan images using 5-mm slices was image-guidance capability is a precise way of delivering obtained for each patient (Somatom Emotion Duo, Siemens radiation to a defined target volume, producing steep AG, Munich, Germany). The clinical target volume (CTV) surrounding gradients. In most cases, this technique enables was defined by the whole cervix containing the tumor with the delivery of a large dose to the tumor and provides good an additional 1-cm safety margin superiorly and inferiorly protection for the critical structures surrounding the target. toward the vagina and the uterus. The planning target volume In many respects, SBRT is similar to high-dose-rate (HDR) (PTV) was the same volume as the CTV. Radiation dose was brachytherapy, using hypofractionated large fraction doses prescribed to Point A, as there are no well-established dose and dose distributions with a rapid fall-off around the target, constraints for critical structures for 3-D brachytherapy. but with the ability to sculpt the dose distribution more After critical organ maximum doses were calculated, the efficiently than brachytherapy. The real-time tracking dose coverage of the CTV was increased as far as possible capability associated with advanced SBRT techniques without increasing the critical organ maximum doses. has certain advantages minimizing the possibility of Other critical structures within the pelvisduterus, vagina, a geographical miss. Cheng et al. (10) compared the dosim- urethra, rectum, bladder, sigmoid colon, and small etry of brachytherapy with SBRT in prostate cancer patients intestinesdwere outlined on serial CT images (17). Plato and concluded that image-guided SBRT could reproduce Brachytherapy planning system V14.1 (Nucletron Inc., Vee- HDR plans. Several studies have compared advanced EBRT nendaal, The Netherlands) was used to generate a 3-D treat- techniques with standard and 3-D brachytherapy (11e14), ment plan. butonlyonestudyintheliteraturehascompared SBRT treatment plans for each patient were generated intensity-modulated arc radiotherapy with 3-D brachyther- using MultiPlan Treatment Planning System V2.1 that is apy (15). There is no published data regarding the use of part of the CyberKnife System. Median, maximum doses, SBRT with real-time tracking for the treatment of cervical and doseevolume histograms of all structures were calcu- cancer. This study therefore investigated the dosimetry lated. The maximum dose was described as 1-cc volume with advanced SBRT with CyberKnife (Accuray Inc., receiving the maximum-recorded dose. The maximum Sunnyvale, CA) compared with intracavitary HDR brachy- doses to 2- and 5-cc volumes were also recorded as these therapy in cervical cancer. parameters have, respectively, been previously linked to late complications by the GEC-ESTRO group and with fistula formation (18, 19). The doses and volumes were compared with Wilcoxon signed rank test using the SPSS Methods and materials Statistics 10.0 software (SPSS Inc, Chicago, IL). Eleven patients with Stage IIB cervical cancer referred to Hacettepe University, Department of Radiation Oncology (Ankara, Turkey) for radical radiotherapy were enrolled in Results this dosimetric comparison study. All patients received EBRT with concomitant chemotherapy and intracavitary Median conformity index was 1.27 (range, 1.03e1.38), HDR brachytherapy boost. and median prescription isodose line was 68% (range, In the EBRT phase of the treatment, all patients were 66e70%) for SBRT plans. SBRT plans yielded significantly prescribed an external beam dose of 50.4 Gy in 28 fractions better target coverage with a median 99.1% target coverage using a four-field box technique with 40 mg/m2 cisplatin by the 100% isodose line compared with 50.7% target weekly. After delivery of 45-Gy EBRT, a midline block coverage by the same isodose line in HDR brachytherapy was introduced and the remaining 5.4 Gy were delivered plans ( p!0.05) (Fig. 1). Further details of target coverage using anteroposterior opposing fields. are summarized in Table 1. All reference isodose lines of Brachytherapy was delivered in four fractions prescribed SBRT plans had significantly better tumor coverage. to Point A (7 Gy/fraction/wk), initiated at the third week of Dose distributions to critical organs were similar for both EBRT. HDR brachytherapy was delivered by an 192Ir via SBRT and HDR brachytherapy plans with the exception of microSelectron HDR remote afterloading unit (Nucletron the 25% isodose line for rectum, which was significantly Inc., Veenendaal, The Netherlands). EBRTand cisplatin were better with HDR brachytherapy ( p!0.05) (Table 2). not given on the day of the intracavitary application. All However, the 50% and 75% doses for the rectum were not patients received diazepam and morphine sulfate injections different and there were no significant differences between for sedation and analgesia before application. Computerized the 25%, 50%, and 75% doses received by the sigmoid tomography (CT)/magnetic resonance imaging (MRI) colon or bladder. However, the 100% dose volume was M. Cengiz et al. / Brachytherapy - (2012) - 3

Fig. 1. Dose distribution of high-dose-rate brachytherapy and stereotactic body radiotherapy. significantly larger in HDR brachytherapy plans than SBRT locally advanced cervical carcinoma. The maximum doses plans; 0.9- vs. 0.2-cc volume for rectum, 4.6- vs. 0.8-cc to the critical structures except bone marrow were signifi- volume for bladder, and 1.5- vs. 0.2-cc volume for sigmoid cantly lower and the target coverage was superior with colon (all p!0.05). There were also statistically significant SBRT plans. Although the mean doses for organs at risk differences in maximum doses to 2-cc volume of bladder were similar for both SBRT and HDR brachytherapy plans, (7.99 vs. 6.50 Gy) and rectum (5.30 vs. 4.56 Gy), both in the doses to 1- and 2-cc volumes of critical structures were favor of SBRT plans ( p!0.05) (Table 3). Maximum doses significantly lower in SRBT plans. to the sigmoid colon were similar for the two planning Several authors have demonstrated better target systems (5.46 vs. 5.39 Gy) ( pO0.05), whereas the coverage with intensity-modulated radiotherapy or SBRT maximum dose to 1-cc volume of rectum (5.09 vs. when compared with brachytherapy (11, 13e15). One 6.05 Gy, p 5 0.02) and bladder (6.78 vs. 8.76 Gy, recent study, however, which compared 3-D MRI-guided p 5 0.04) were better with SBRT plans. The maximum dose to 5-cc volume was significantly better with SBRT for Table 1 bladder (5.93 vs. 6.79 Gy, p 5 0.02), whereas sigmoid colon The reference isodose target coverages maximum doses for 1- and 5-cc volumes were similar for Mean volume þ standard Mean volume þ standard both types of treatment plans. The mean total bone marrow Isodose deviation for HDR (%) deviation for SBRT (%) p dose was significantly higher with SBRT (107.7 cGy for D25 63.4 14.9 100.0 0.003 HDR brachytherapy vs. 275.5 cGy for SBRT, p 5 0.023). D50 62.2 14.8 100.0 0.003 D75 58.5 14.3 100.0 0.003 D90 54.3 13.5 99.9 0.008 D95 52.5 13 99.9 0.008 Discussion D100 50.7 12.7 99.1 0.1 0.008

HDR 5 high dose rate; SBRT 5 stereotactic body radiotherapy; Dn 5 This is the first feasibility study of robotic image-guided dose received by n% volume of the target; Vn 5 volume receiving n dose SBRT compared with HDR brachytherapy in patients with of the radiation. 4 M. Cengiz et al. / Brachytherapy - (2012) - Table 2 study, however, no CTV to PTV margin was added for the Doseevolume histograms of critical structures SBRT system because intrafraction target motion was Mean dose and Mean dose and tracked in real time using gold fiducial markers implanted Critical standard deviation standard deviation into the target before the treatment. CyberKnife uses an structure (cc) for HDR (cc) for SBRT p orthogonal X-ray-based tracking system that updates and Bladder V25 79.2 13.5 80.3 3.3 0.59 corrects linear accelerator position continually through Bladder V50 35.6 8.7 36.8 9.8 0.37 a robotic arm to correct for target movement, resulting in Bladder V 13.5 5.2 11.3 3.8 0.72 75 submillimeter target accuracy (21, 22). With proper moni- Bladder V100 4.6 2.8 0.7 0.5 0.03 Rectum V25 29.7 17.7 43.3 16.1 0.05 toring and intervention during treatment, even large pros- Rectum V50 9.2 7.2 14.4 11.0 0.13 tate shifts observed among some patients can be kept Rectum V75 2.9 2.8 3.5 3.2 0.37 within the tracking range of CyberKnife (23), and therefore Rectum V100 0.9 1.0 0.2 0.2 0.02 using similar methods as in this study, equivalent delivery Sigmoid V 58.4 66.5 45.6 18.1 0.93 25 accuracy for cervical cancers should be achievable. Sigmoid V50 18.3 21.1 14.2 9.2 0.72 Sigmoid V75 5.3 6.6 3.5 2.6 0,19 In this study, maximum doses (Dmax) to critical organs Sigmoid V100 1.5 2.2 0.2 0.2 0.03 (Dmax in 1 and 2 cc) and critical organ doseevolume histo- Bone marrow V25 103.5 65.7 158.9 77.6 0.03 grams, median doses, and maximum doses were used for Bone marrow V50 0.2 0.2 5.7 3.3 0.02 the comparison of SBRT and brachytherapy plans. Median Bone marrow V 0.1 0.1 3.5 2.3 0.01 75 radiation doses to critical structures were similar for both Bone marrow V100 001 HDR and SBRT plans. There were significant differences HDR 5 high dose rate; SBRT 5 stereotactic body radiotherapy. Bold indicates statistically signicant values (p ! 0.05). between Dmax of bladder and rectum in favor of the SBRT and values for bone marrow doses were in favor of HDR brachytherapy with intensity-modulated radiotherapy and plans. A correlation between Dmax and toxicity results have intensity-modulated proton therapy has shown better target been previously demonstrated (12). It is worth noting that coverage dose with brachytherapy (12). This study used pelvic radiotherapy given concurrently with chemotherapy interstitial implantation extending into the parametria may also have toxic effects on bone marrow, sometimes during brachytherapy in addition to the intracavitary appli- causing treatment interruptions, and the additive effect of cation to improve tumor coverage using MRI for treatment the SBRT contribution may be important in these patients. planning. The use of additional interstitial implantation to A further dosimetric disadvantage of the CyberKnife plan- sculpt the target dose is a relatively uncomfortable proce- ning system to be considered is the increase in normal dure for the patient and may require general anesthesia. It tissues receiving low-dose radiation, which may increase also carries additional risks from the interstitial procedures, secondary malignancy risk. Another disadvantage of such as infection. The SBRT platform used in this study CyberKnife SBRT sessions is the duration of each treat- does not require any special applicator or procedure to ment and it has been suggested that treatment sessions achieve better tumor coverage. lasting longer than 30 min may be associated with a signif- Studies comparing high-technology EBRT plans with icant loss in cytotoxicity (24e26). These issues require brachytherapy have been criticized for having inadequate further investigation. PTV margins, particularly for the EBRT arms, to account for the large organ motion demonstrated in several studies related to bladder or rectal fullness (20). Bladder fullness Conclusion does not influence target dose distribution during brachytherapy, although it may influence critical structure doses Frameless SBRT is a noninvasive radiotherapy method, (4). Target immobilization with the use of an applicator, which has been shown in this study to achieve better dose patient immobilization, and image-guided verification are distribution in the PTV and lower maximum doses to crit- among the methods used to overcome target motion. In this ical organs at the expense of a greater dose to bone marrow. Future clinical studies are required to test the dosimetric advantages of the frameless SBRT system and evaluate Table 3 the impact of higher bone marrow dose, greater peripheral The maximum dose to 2-cc volume of critical structures low-dose exposure, and prolonged treatment times associ- Mean dose and Mean dose and ated with this technique. Critical standard deviation standard deviation structure (cGy) for HDR (cGy) for SBRT p Bladder 799.7 117.2 650.4 28.6 0.006 Sigmoid 546.5 211.8 539.1 129.6 0.374 Acknowledgment Rectum 530.7 167.5 456.9 133.1 0.033 Bone marrow 107.7 87.9 275.5 98.6 0.023 This study was presented at the 50th ASTRO Meeting, HDR 5 high dose rate; SBRT 5 stereotactic body radiotherapy. 2008, in Boston. Bold indicates statistically signicant values (p ! 0.05). Conflict of interest notification: none. M. Cengiz et al. / Brachytherapy - (2012) - 5 References [13] Low DA, Grigsby PW, Dempsey JF, et al. Applicator-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys [1] Perez CA, Kavanagh B. Uterine cervix. In: Halperin EC, Perez CA, 2002;52:1400e1406. Brady LA, editors. Principles and practice of radiation oncology. [14] Wahab SH, Malyapa RS, Mutic S, et al. A treatment planning study 5th ed. 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