Treatment of cervical cancer with electronic brachytherapy

Abstract Purpose We report the first cervical cancer cases treated with interstitial electronic brachytherapy (eBT) at our hospital and compare them with plans made with high‐dose‐rate interstitial brachytherapy based on Ir192 (HDR‐BT). Materials and methods Eight patients with cervical cancer were treated with the Axxent eBT device (Xoft, Inc.). Planning was with magnetic resonance imaging and computed tomography following the recommendations of the EMBRACE protocol. The dosimetry parameters of organs at risk (OAR) were evaluated for the bladder, rectum, and sigmoid colon (D2cc, D1cc, and D0.1cc). In addition, the V150 and V200 of irradiated tissue were compared for both eBT and HDR‐BT. All patients received intensity‐modulated external beam radiation therapy with a regimen of 23 sessions of 2 Gy followed by four sessions of 7 Gy of eBT performed over 2 weeks (two sessions followed by another two sessions a week later) following the EMBRACE recommendations. Each of the eight patients was followed to assess acute toxicity associated with treatment. Results The doses reaching OAR for eBT plans were lower than for HDR‐BT plans. As for acute toxicity associated with eBT, very few cases of mucositis were detected. No cases of rectal toxicity and one case with grade 1 urinary toxicity were detected. The results at 1 month are equally good, and no relapses have occurred to date. Conclusions The first results of treatment with the Axxent eBT device are promising, as no recurrences have been observed and toxicity is very low. eBT is a good alternative for treating cervical cancer in centers without access to conventional HDR.

(BT) if not. Patients with advanced cancer (IB2-IIA bulky-IIB-III-IVA) receive chemotherapy and radiotherapy concomitantly, as well as BT, irrespective of whether they can undergo surgery. 2 The use of BT as a key component in the treatment of cervical cancer is the main prognostic factor in local control of the disease. 3 As with cancer at other sites, the response of gynecological cancer to radiation is dose-dependent, with improved local control at higher doses. 4 Better knowledge of tumor extension at diagnosis and the response to the treatment received has led to more realistic local treatment of cervical carcinoma, with adapted BT that is tailored depending on the findings at different points during the course of the disease. Therefore, BT has proven to be efficacious as a component of radiation therapy. The dose released by BT in contact with the tumor (4 fractions in 2 weeks) is at least equivalent to the dose administered during external beam radiation therapy (EBRT) on the pelvis for 5 or 6 weeks. 5 Any nonsurgical treatment of gynecologic cancer with curative intent should combine EBRT and BT. 6 The traditional approach has been low-dose rate BT. 7 For the last few years, the type of BT applied has been high-dose rate BT (HDR-BT) with Ir192, 8 which makes it possible to optimize both the dose and patient comfort, since it can be administered on an outpatient basis, even though more sessions are necessary.
Technical advances in imaging and dosimetry have led to the use of computed tomography (CT) and magnetic resonance imaging (MRI) to locate the tumor and organs at risk (OAR) and to plan treatment based on real anatomy. 9 A working group from GEC-ESTRO published recommendations on contouring the target tumor and OAR, as well as on the dose volume parameters to be reported for image-guided BT in definitive radiotherapy for locally advanced cervical cancer. 10 The major advantage of this technique is the possibility of conforming the dose to both volume (3D) and time (4D). Thus, repetitive imaging performed before each BT implant makes it possible to adapt the BT dose to the anatomy of the individual patient, taking into account not only the position of the OAR but also tumor regression, which is often achieved with previous EBRT and chemotherapy.
The EMBRACE study, 11 which was developed some time after publication of the GEC-ESTRO recommendations, attempted to unify all of the processes involved in the management of cervical cancer by providing guidelines for the participating centers. A key feature is the use of MRI to better define the tumor and the OAR volumes. It allows to prescribe higher doses to the region of interest thus increasing the tumor control as shown in the Retro EMBRACE study. 12 All of the participating centers used HDR-BT with Ir192 in their treatments.
Electronic brachytherapy (eBT) has been evolving since the start of the 21st century 13 and has become a treatment option for various tumor sites in different settings. [14][15][16][17][18] The Axxent eBT unit (Xoft, Inc., subsidiary of iCAD, San José, CA, USA) provides treatment to patients with a miniature 50-kVp xray source that irradiates the tumor directly in skin cancer and with different applicators in the case of breast or gynecologic cancer.
The unit is constructed of a disposable mini-x-ray tube inserted into a flexible plastic sheath approximately 5.5 mm in diameter. Water is pumped around the source to reduce heating from the target. The electrons (20-50 keV) are emitted from a filament nearly 1 cm from the anode. The anode is made mainly of a microlayer of tungsten on an yttrium substrate that acts as a buffering layer and a small amount of silver that acts as a constituent of the brazing alloy. The anode transitions are from a spherical tip to a conical-hemisphere section and finally to a cylinder. The source is mounted on a mechanical robot arm that is attached to a movable treatment control console. 19 The unit can be used to treat nonmelanoma skin tumors, intraoperative radiotherapy in breast cancer, and postoperative treatment of endometrial and cervical cancer.
The case of skin tumors is problematic. High doses can reach bone (high atomic number), owing to the predominant photoelectric effect at low energies. 20 Such a situation could arise in cases of cervical cancer, although, to date, we have had no reports of this problem at our center.
It can also be used to treat cervical cancer in protocols that require treatment with HDR-BT after chemotherapy and EBRT with a dedicated applicator (Fig. 1).
The eBT system at our center was acquired in May 2015 for treatment of skin cancer and intraoperative radiotherapy for breast cancer after tumor removal. Retrospective studies on patients treated with Ir192 have compared endometrial cancer, 22,23 cervical cancer, 24 and breast cancer. 25 A lower dose was always found in the OAR in patients whose planning was based on eBT, although the patients in those studies were treated with Ir192. Another study comparing patients with endometrial cancer treated with eBT has reported favorable preliminary results. 26 The objective of treatmenting with eBT is to provide an alternative with a portable device, thus conferring the advantage of mobility and obviating the need for a shielded room: with the energy used by the device, screening equivalent to 0.5 mm of lead on walls and doors is sufficient. Transport is no longer a factor since it does not involve radioactive sources. In addition, the device facilitates quality control and preparation and implementation of the treatment. 27  Planning was performed after a CT study (3-mm slice thickness)

| MATERIALS AND METHODS
and T2-weighted MRI study (5-mm slice thickness). Both sets of images were registered.
CT images are used to reconstruct the applicators appropriately; MRI is used to contour the target volumes and the OAR.
The high-risk clinical target volume (HR-CTV) and the intermediate-risk clinical target volume (IR-CTV) are contoured, and the bladder, rectum, and sigmoid colon as OAR following the recommendations of GEC-ESTRO. 28 After the medical physicist reconstructs the applicators and prepares the plan according to the dosimetric requirements of the EMBRACE protocol 10 (Tables 3 and 4  the two treatment plans in each case, since the same normalization is applied throughout planning. We also determined V150 and V200, both of the HR-CTV and of total tissue (sum of tumor tissue and healthy tissue), which receive 150% and 200% of the prescribed dose.
As for the OAR, the parameters are the same as those recommended in the EMBRACE protocol, and they are determined for all OAR of interest in the study, namely, bladder, rectum, and sigmoid colon. The parameters compared are D2cc (maximum dose, 2 cc), D1cc, and D0.1cc; toxicity is evaluated according to the parameters of the Radiation Therapy Oncology Group (RTOG). 30

| RESULTS
Patients were followed up for a median of 13.4 months (2-

months). Patients planned with eBT received a lower dose in the
OARs than those planned with Ir192. The differences in the energy of both irradiation methods constitute the isodose lines that lead to the dose differences in the OARs (Fig. 2).
In the bladder, the average dose parameters for all the treatments compared (eBT vs Ir192) were 63% of the prescribed dose vs 66% for D2cc, 70% vs 73% for D1cc, and 84% vs 86% for D0.1cc.
By applying these data and the t test, we see that the difference is significant for cases of D2cc and D1cc of the rectum (P < 0.05) (Fig. 3).
Although D90 and D98 for HR-CTV were the values used to standardize the plans, we did observe a small difference in the coverage of IR-CTV-57% of the prescribed dose for eBT vs 59% for HDR-BT-although both were above the objective set by EMBRACE (>46% , Tables 3 and 4). In addition to the differences in the IR-CTV coverage percentage, it is useful to observe the differences in dose equivalent to 2 Gy (EQD2), taking into account the contribution of EBRT and the part of eBT or Ir192 in each case (

| DISCUSSION
We obtained acceptable results after the first 28 months (mean follow-up, 13.4; range, 2-28 months) using the Axxent eBT device for treatment of cervical cancer with EBRT and chemotherapy, thus indicating that this option is a good alternative in BT.
The dose prescribed in each eBT treatment was administered without taking into account the fact that the mean beam energy was much lower than in Ir192 (26 keV vs 355 keV) and, therefore, without taking into account the differences in the relative radiobiological effectiveness (RBE) expected for low-energy radiation. 31,32 One clinical study showed that reducing the dose prescribed for treatment of nodular and superficial basal cell carcinoma using eBT and based on a different RBE reduced control of the tumor from 95% to 90%, thus demonstrating better control for the standard prescription. 33 In our study, we did not modify treatment owing to differences in RBE with respect to Ir192 because of the good results achieved with treatment administered to the endometrium 26  | 83 the prescribed dose continues to be controversial in low-energy cases. 34 We can achieve the same coverage of the cervix as during planning when Ir192 is used in all of the cases presented and the dose to OAR can be reduced, even though V150 and V200 of the planning target volume increase very slightly. This could have led to an increase in the number of cases of acute mucositis in the study population; however, the toxicity results, together with the reduced dose administered to OAR, lead us to conclude that eBT is a good alternative to treatment with Ir192 in cases of cervical cancer.
In their study of 10 patients, Mobit et al. 24  of the prescribed dose), in the rectum (54.9% vs 60.9%), and in the sigmoid colon (44.1% vs 56%). However, in this case, patients were treated with Ir192, and the eBT plans were calculated prospectively.
As for the calculation method used, it is recommended to consider tissue composition and to perform the calculations based on Monte Carlo models. 35 Our calculations were based on TG-43, which was modified for eBT, 29,36 with no correction for heterogeneity, since this was the algorithm used in our TPS and in many other hospitals, for which our results will prove useful.  Table 7).
The differences do not represent an excessive volume in each individual case and, more importantly, do not correspond to an increase in the number of cases of mucositis.
The dose in OAR is slightly lower in the case of eBT, and cases of toxicity associated with doses in OAR are minimal (Table 8).
We did not encounter problems of overdosing in bone, because we used low energies. 20 However, overdosing should be avoided in order to reduce the number of fractions and thus prevent this problem from arising. We believe that the scheme proposed by EMBRACE is adequate in this respect.
Both dosimetry requirements of the EMBRACE protocol were fulfilled for both types of treatment, although D0.1cc in the sigmoid colon would be above tolerance for Ir192. However, as stated above, this does not lead to more cases of mucositis. These results, In areas with a high incidence of cervical cancer and few Ir192based HDR devices, eBT could be a good alternative for patients who live far from a major hospital. In addition, given that treatment does not require a bunker for administration and the device is easily transported, this option is much more economically viable than others.

ACKNOWLEDG MENTS
We thank all the colleagues in the physics and radiation protection service, as well as in radiation oncology, for their support in the preparation of this work and their great daily work, as well as the work of the editor-in-chief of the journal and the reviewers who have participated in the correction of the article. Mean, standard deviation and range of V150, V200: Volume of HR-CTV and Soft tissue with 150% and 200% of the prescribed dose in percentage of the HR-CTV volume. HR-CTV, high-risk clinical target volume.