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Intravaginal electronic brachytherapy

A novel technique for intravaginal electronic brachytherapy for endometrial cancer using the INTRABEAM® system is discussed
Tina Reis 
Michael Ehmann
Frank Schneider 
Department of Radiation Oncology
Werner Kleine
Axel Gerhardt
Department of Gynaecology,
University Medical Centre Mannheim, University of Heidelberg, Germany
Endometrial cancer is the sixth most common cancer in women worldwide. The highest age standardised rates of endometrial cancer were found in North America and Central and Eastern Europe. More than 1100 new cases are diagnosed annually in Germany. All medically operable patients should have surgery. Nevertheless, 15–20% of the tumours will recur.(1) The vaginal cuff is the most common side for locoregional failure after hysterectomy in patients with endometrial cancer.(2)
To prevent recurrences, adjuvant radiation will be applied. Dependent on the initial tumour-stage, adjuvant radiotherapy could be applied as combined pelvic external beam radiotherapy (EBRT) and intravaginal brachytherapy (IBT) or intravaginal brachytherapy alone.(3–5) Retrospective studies have reported IBT to have excellent vaginal control rates (95–98%), with low rates of toxicity.
Vaginal brachytherapy is usually performed with 192Ir high-dose rate (HDR) afterloading. Disadvantages of 192Ir HDR afterloading are the high energy, which needs complex radiation protection requirements, and the high cost because the limited half-life of 192Ir requires four source changes each year. Moreover, not all departments have units for HDR-brachytherapy. Therefore, so-called electronic brachytherapy (EBT) is increasingly being used. 
We developed a novel device for intravaginal X-ray brachytherapy using the INTRABEAM® system. Because of the low-energy X-ray source associated with the INTRABEAM® system, the radiation shielding requirements for this electronic brachytherapy are much less than for 192Ir HDR afterloading. Furthermore, the use of the INTRABEAM® is a relatively inexpensive technique, because in contrast to 192Ir HDR afterloading, only one source is needed. 
Physical aspects and technical devices
The INTRABEAM® system is a miniature X-ray generator (X-rays of 30–50kV), which accelerates electrons (Figure 1). The electron beam travels down the evacuated 10cm long drift tube, hits a thin gold target and bremsstrahlung is emitted from the needle tip in a spherically symmetric pattern. To use the INTRABEAM® device for intravaginal X-ray brachytherapy, the spherical dose distribution must be transformed into a cylindrical form. Therefore a cylindrical applicator was developed for a stepwise axial motion of the radiation source along a longitudinal axis. Before first clinical use, dose calculations to create and evaluate a homogeneous cylindrical energy deposition around this newly designed vaginal applicator were carried out.(6)
For vaginal treatment, four applicators (INTRABEAM® Gyn Applicator) with different diameters (2.0, 2.5, 3.0, 3.5cm) and a second inner detonator tube (INTRABEAM® Gyn Probe Guard) for protection of the sensitive drift tube of the INTRABEAM® system were developed (Figure 2). Moreover, a special table attachment with leg rests similar to a gynaecological examination chair for positioning the patient was established (Figure 3a,b). The base plate provides stabilisation of the applicator during simulation and throughout the radiation treatment delivery.
Before first treatment, all patients receive a gynaecological examination and the vagina is measured. Afterwards a computed tomography scan (CT-scan) for treatment planning with an adequate applicator in place is performed (Figure 4). Depending on the length of the radiation field, for homogeneous coverage of the tissue two to four dwell points are needed.
To realise exact distances between the different dwell points, different distance rings (Intrabeam® Gyn Dwell Stepper; width: 20, 37, 54, 71mm) were manufactured (Figure 5a,b). Additional CT-scans directly before every brachytherapy treatment ensure the proper position of the applicator and the correct position of the radiation source within the applicator. 
Because of the low energy, intravaginal brachytherapy with the INTRABEAM® system can be performed without specially radiation protection measurements for example directly in the planning-CT room or simulator suite. 
From April 2011 to October 2012 we treated 11 patients with electronic brachytherapy using the INTRABEAM® system. The median age of the patients was 75 years (range, 53–87 years). Nine patients received postsurgical vaginal cuff irradiation because of endometrial cancer: seven FIGO Stage IB (78%), two FIGO Stage II (22%). One patient received intravaginal brachytherapy because of an intravaginal relapse of endometrial cancer two years after a Wertheim–Meigs operation. Another patient had an intravaginal recurrence of an ovarial cancer seven years after the primary diagnosis. Both patients had intravaginal bleeding over several weeks. 
Electronic brachytherapy dose was prescribed to a depth of 5mm from the applicator surface. The two patients with intravaginal recurrences were treated with IBT in combination with external beam radiotherapy. The treatment applications were: IBT with 1x5Gy to stop bleeding followed by EBRT of the pelvis to a total dose of 39.6Gy and EBRT of the pelvis with a dose total of 45Gy followed by intravaginal brachytherapy with 2x4Gy.
Patients who received post-surgical cuff irradiation were treated with intravaginal brachytherapy alone. When IBT was used alone, the median dose per fraction, number of fractions, and total dose delivered were: 5Gy (range 4–7Gy), four fractions (range 2–4), and 16Gy (range 14–20Gy), respectively. The mean treatment time was 13 minutes per level (range 10–28 minutes). The treatment time for each dwell point was approximately five minutes. Most commonly used were three dwell points (range 1–4 dwell points). Median applicator diameter was 3cm (range 2.5–3.5cm).
The treatment was generally well tolerated. Patients adapted to the setting and the treatment situation very fast and very well. No patient treated with intravaginal brachytherapy alone had any side effects at the time of treatment completion. One patient developed a GI and GU Grade 1 adverse event comprising increased urinary and stool frequency two months after treatment. No severe technical problems or medical complications occurred. No recurrences have been observed so far.
Endometrial carcinoma is the most common gynaecological malignant disease in postmenopausal women in developed countries. Standard treatment includes surgery followed by adjuvant external beam radiation therapy and/or vaginal cuff brachytherapy for women with intermediate or higher risk disease. A randomised prospective trial compared vaginal cuff brachytherapy with EBRT in appropriately selected women.(7)
The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC)-2 trial demonstrated that intravaginal brachytherapy minimises gastrointestinal toxicity and is as effective as EBRT in preventing vaginal relapse in patients with high–intermediate risk endometrial cancer.7 Many hospitals use high-dose rate (HDR) afterloading brachytherapy because of increased convenience and radiation safety, but not all hospitals have access to HDR technology. Therefore alternative forms of internal radiation therapy called electronic brachytherapy are increasingly used.
The INTRABEAM® system requires relatively little shielding compared with the 192Ir HDR unit and can be used in unmodified rooms without particular radiation protection measures.
Until now we have not seen any relevant acute toxicity. Kamrava et al(8) treated 16 patients with electronic brachytherapy (Axxent Brachytherapy system; Xoft Inc, Sunnyvale, CA) alone or combined with external beam radiotherapy. In this study also no Grade 2 or higher acute toxicities were noted in patients treated with EBT alone.
Although multiple fractionation schemes can be found in the literature, the most popular treatment schedules deliver a total dose of 21Gy prescribed at 0.5cm depth in three fractions given one or two weeks apart.(9–11) Our median total dose was 16Gy. This lower dose could be justified considering the difference in the relative biologic effectiveness of electronic brachytherapy and the HDR technique because of the low photon energy of EBT.
It is well established that low energy X-rays have an increased relative biologic effectiveness (RBE) compared to high-energy photons, due to the increased linear energy transfer. RBE values of 1.3 up to 3 have been reported for the INTRABEAM® system, which result in lower maximal biological doses as compared to HDR-brachytherapy.(12–14)
Many studies show excellent control rates after adjuvant intravaginal brachytherapy with local control rates of 94–97%.(8,15) We have also seen no local recurrence so far, even though our follow up is very short. 
Electronic intravaginal brachytherapy using the INTRABEAM® system is a technically feasible and patient-friendly application method, ideal for departments without units for HDR-brachytherapy.
No severe acute toxicity was seen so far. Because long-term experiences with this approach are not available at present, optimisation of the special technical components for brachytherapy treatment is in progress.
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  11. Horowitz NS et al. Adjuvant high dose rate vaginal brachytherapy as treatment of stage I and II endometrial carcinoma. Obstet Gynecol 2002;99:235–40.
  12. Herskind C et al. Sphere of equivalence – a novel target volume concept for intraoperative radiotherapy using low-energy X rays. Int J Radiat Oncol Biol Phys 2008;72:1575–81. 
  13. Herskind C, Wenz F. Radiobiological comparison of hypofractionated accelerated partial-breast irradiation (APBI) and single-dose intraoperative radiotherapy (IORT) with 50-kV X-rays. Strahlenther Onkol 2010;186(8):444–51. 
  14. Herskind C et al. Radiobiological aspects of intraoperative radiotherapy (IORT) with isotropic low-energy X rays for early-stage breast cancer. Radiat Res 2005;163:208–15.
  15. Gaztanaga M et al.  Long-term results of 1-week intravaginal high-dose-rate brachytherapy alone for endometrial cancer. Brachytherapy 2012;11:119–24.