Clinical advantage and outcomes of computed tomography‐based transvaginal hybrid brachytherapy performed only by sedation without general or saddle block anesthesia

Abstract Background Three‐dimensional image‐guided brachytherapy is the standard of care in cervical cancer radiotherapy. In addition, the usefulness of the so‐called “hybrid brachytherapy (HBT)” has been reported, which involves the addition of needle applicators to conventional intracavitary brachytherapy for interstitial irradiation. Aim To evaluate the clinical outcomes of CT‐based HBT consisting of transvaginal insertion of needle applicators (CT‐based transvaginal HBT) and only intravenous sedation without general or saddle block anesthesia. Methods and results This is a retrospective chart review of patients who received definitive radiotherapy, including CT‐based transvaginal HBT, between February 2012 and July 2019. The inclusion criteria were as follows: (i) histologically diagnosed disease, (ii) untreated cervical cancer, (iii) International Federation of Gynecology and Obstetrics (FIGO) stage IB1–IVA disease in the 2008 FIGO staging system, and (iv) patients who underwent CT‐based transvaginal HBT at least once in a series of intracavitary brachytherapy. Overall, 54 patients fulfilled the eligibility criteria in the present study. The median follow‐up period was 32 (IQR, 19–44) months. No patient complained of symptoms such as persistent bleeding or abdominal pain after the treatment. The 3‐year local control (LC), disease‐free survival, and overall survival rates for all 54 patients were 86.6%, 60.3%, and 90.7% (95% CI [81.3%–100.0%]), respectively. The 3‐year LC rate was 87.7% in patients with FIGO III–IVA and 90.4% in tumor size >6.0 cm. The incidence rate of late adverse events, grade ≥3, in the rectum and bladder was 0% and 1.8%, respectively. In the dose‐volume histogram analyses, transvaginal HBT increased the dose of HR‐CTVD90 by ~7.5% without significantly increasing the dose of organs at risk. Conclusion Considering the favorable clinical outcomes, CT‐based transvaginal HBT may be a good option for treating cervical cancer.


| INTRODUCTION
Uterine cervical cancer is one of the most common cancers in women worldwide. 1 Radiotherapy (RT) plays a crucial role as a definitive treatment for patients with stage IB-IVA cervical cancer. Several randomized phase III studies and meta-analyses have established the use of platinum-based concurrent chemoradiotherapy (CCRT) as the standard of care for patients with stage IB-IVA cervical cancer. [2][3][4] Intracavitary brachytherapy is a pivotal treatment for all patients with cervical cancer receiving RT or CCRT. 5 In 2005, the Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology Gynecology proposed the concept of a threedimensional image-guided brachytherapy (3D-IGBT). 6,7 These studies provided the core concepts and defined the terms that would be used in 3D-IGBT. 6,7 Many studies have demonstrated the relationship between local control (LC) probability and dose to the high-risk clinical target volume (HR-CTV) since these concepts were first introduced. [8][9][10] The transition from traditional brachytherapy to 3D-IGBT has led to improved LC rates and reduced late toxicity. [8][9][10] More recently, EMBRACE-I, a prospective multicenter study that employed magnetic resonance imaging (MRI)-guided 3D-IGBT for cervical cancer, has been published. 11 In this study, the actuarial overall 5-year LC rate was 92%, with limited severe toxicity in normal organs. 11 MRI is undoubtedly the ideal imaging modality for 3D-IGBT, owing to its superior visualization in soft tissue compared to computed tomography (CT). 12 However, its availability for 3D-IGBT is still limited in clinical settings. A recent nationwide survey of 3D-IGBT in Japan showed that only 4% of 3D-IGBT was performed using MRI. 13 Similar surveys conducted in the US and Canada report limited use of MRI-based 3D-IGBT (34%-57%). 14,15 Notably, 90% of newly diagnosed cervical cancer occur in low-to middle-income countries, where access to MRI-based 3D-IGBT is difficult. 16 Establishing a beneficial and easily accessible treatment strategy that replaces MRIbased 3D-IGBT is, therefore, crucial to improving treatment outcomes for a larger number of patients with cervical cancer. CT-based 3D-IGBT presents as a viable alternative. Several guidelines or protocols on HR-CTV contouring for CT-based IGBT have been reported hitherto, 17,18 and an international recommendation for CT-based 3D-IGBT has been recently published. 19 With careful consideration of target volume contouring, the LC rates of these studies consisting of CTbased 3D-IGBT are comparable to those of MRI-based IGBT. 10,20,21 For irregularly shaped and/or bulky cervical cancer, the interstitial approach may be an effective treatment method. However, recent National Comprehensive Cancer Network guidelines mention that such interstitial brachytherapy should only be performed by individuals and institutions with appropriate experience and expertise. 22 As a simplified approach, the usefulness of the so-called "hybrid brachytherapy (HBT)," in which needle applicators for interstitial irradiation are added to conventional intracavitary brachytherapy, has been reported. 23,24 Recently, Murakami et al. reported the initial outcomes of CT-based HBT for locally advanced cervical cancer. 24 In this study, additional interstitial needle catheters were inserted perineally or vaginally under transrectal ultrasound guidance using saddle block anesthesia or local anesthesia and intravenous sedation. 25 Although this method is simpler and easier to use than the interstitial approach, it still requires specialized skills and knowledge about the saddle block anesthesia procedure for perineal needle insertion.
Tan et al. proposed a method of HBT in an environment with limited medical resources, such as outpatient set-ups. 26 Although they did not report the oncological outcomes, they reported the feasibility of a combination of oxycodone 5 mg capsules, midazolam, and a paracervical block. As a further simplified approach, we have been performing CT-based HBT consisting of transvaginal insertion of needle applicators (CT-based transvaginal HBT) and only intravenous sedation without general or saddle block anesthesia. Here, we report the clinical outcomes, including the safety of CT-based transvaginal HBT, in patients with cervical cancer in our institution.

| External beam radiotherapy and chemotherapy
External beam radiotherapy (EBRT) involves a combination of whole pelvic (WP) irradiation, and central shielding (CS), similar to traditional methods in Japan and parts of Asia. 27,28 CS has been used as a part of EBRT in anteroposterior/posteroanterior fields to lower the irradiation dose to the bladder and rectum. In brief, up to 50 Gy radiation was delivered to the WP and pelvis sidewall, with a daily fraction dose of 1.8 or 2.0 Gy using 10 megavolt X-rays. After 20, 30, or 40 Gy of WP-EBRT, a 3-cm wide CS was inserted. Boost EBRT of 6-10 Gy in 3-5 fractions were performed for patients with pelvic nodal metastasis. For patients with para-aortic lymph node (PAN) metastases, 40 Gy of prophylactic EBRT to the para-aortic lymph node region was performed, followed by 16-18 Gy in 8-9 fractions of boost EBRT to the metastatic PANs. Weekly cisplatin (40 mg/m 2 , up to five courses) was concurrently administered with EBRT. Patients older than 70 years or with severe concomitant diseases, including renal dysfunction, ischemic heart disease, or severe diabetes, did not receive chemotherapy.

| Brachytherapy
Intracavitary brachytherapy using a 192 Ir remote after loading system (microSelectron, Nucletron, Veenendaal, the Netherlands) was per- After applicator implantation, CT data were acquired with the patient in the supine position. The CT slice thickness was 3 mm, and CT-based treatment planning was performed. HR-CTV contouring was performed with the same delineations as the Japanese Radiation Oncology Study Group recommendations. 17 The findings of the gynecological examinations performed at diagnosis, brachytherapy, and those of MRI examinations performed at diagnosis and just before the first brachytherapy session were used as references.

| Indications for CT-based transvaginal HBT
The transvaginal HBT in our hospital was implemented in cases with one or more of the following criteria: (i) the tumor extended to the pelvic wall on gynecological examination/MRI findings prior to intracavitary irradiation, (ii) tumor remained unevenly distributed on the bladder or rectum side, (iii) ellipticity (ratio of the shortest distance to the longest distance from the center of the uterine lumen to the edge of the tumor on the MRI axial image) was greater than 2, and (iv) (at second or later brachytherapy) insufficient dose or overdose of HR-CTV in organs at risk (OARs) in the previous brachytherapy. Ellipticity was assessed using MRI before the first brachytherapy (Data S2). HBT was not performed if the patient took anticoagulants. The same criteria were consistently used to evaluate all patients who were included in the present study.

| Dose-volume histogram parameters
We estimated the composited dose to HR-CTV D90 and OARs D 2cc (the minimum dose delivered to the highest irradiated 2-cc region). The cumulative EBRT and brachytherapy doses were summarized and normalized to a biological equivalent dose of 2 Gy per fraction (EQD 2 ) using a linear-quadratic model with an alpha/beta of 10 Gy for the HR-CTV and 3 Gy for the OARs. The doses of pelvic irradiation with CS were not added to the EQD 2 , as was done in previous studies. 10,19,20 2.6 | Dose prescription and optimization of HBT All treatment plans were formulated by the Oncentra planning system (Nucletron, Veenendaal, the Netherlands). The initial plan for each patient was generated based on Point A prescription. Dose adaptation by changing the dose at Point A was performed so that a dose >6 Gy was delivered to HR-CTV D90 . Thereafter, the dwell time allocation, including interstitial catheters, was modified. Finally, dose distribution was fine-tuned using "graphical optimization" function. The aiming dose for HR-CTV and OARs in each brachytherapy session in our institution and an actual session of CT-based transvaginal HBT are shown in Figure 1. In each brachytherapy session, the doses aimed for HR-CTV D90 , Rectum D 2cc , and Bladder D 2cc were ≥7.0, <5.5, and <6.5 Gy, respectively. There was no change in the prescription dose for each stage.

| Follow-up and evaluation for clinical outcomes
All patients were carefully monitored after treatment until they awakened and confirmed symptoms such as pain or bleeding after awakening.
Patients' follow-ups were scheduled every 1-3 months for the first 2 years and every 3-6 months thereafter. Gynecological examinations and imaging evaluations, including CT and MRI, were performed regularly.
CT was taken once at the end of treatment, and every 6 months thereafter for the first 2 years. MRIs were taken 1 and 3 months after treatment, and every 6 months thereafter for the first 2 years. After which, CT and MRI were each taken annually. A tumor biopsy was performed for confirmation in cases of suspected local recurrence. Late toxicities in the present study were defined as any toxicity occurring 6 months after the initiation of RT. The grades of late toxicities were assessed in accordance with the toxicity criteria of the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer system. 29

| Statistical analysis
The LC, disease-free survival (DFS), overall survival (OS), and cumulative occurrence rates of late toxicity were evaluated using the Kaplan-Meier method. The LC and survival durations were calculated from the initiation of treatment. The log-rank test was used for univariate analysis.
The clinical factors in the two groups were compared using the Mann-Whitney U test. Statistical significance was set at p < .05, and all statistical tests were two-sided. Statistical calculations were performed using the IBM SPSS Statistics 27 software (IBM, Armonk, NY, United States).

| Patient and treatment characteristics
The patient and treatment characteristics are summarized in Table 1. A total of 54 patients met the eligibility criteria in the present study.

| Clinical outcomes
No patient complained of symptoms such as persistent bleeding or abdominal pain after the treatment.    Table 3 shows the relationship between dose-volume histogram  (Table 3A).

| Relationship between dose-volume histogram parameters and clinical outcomes
Regarding the cumulative dose of rectum D 2cc , the average ± SD values of brachytherapy in patients without and with toxicity were 34.0 ± 8.0 Gy EQD 2 and 37.4 ± 7.2 Gy EQD 2, respectively. There were no statistically significant differences in the mean dose of rectum D 2cc between patients with and without toxicity in any classification, brachytherapy, WP, or brachytherapy plus WP (Table 3B).
Regarding the cumulative dose of bladder D 2cc , the average ± SD values of brachytherapy in patients without and with toxicity were 43.1 ± 9.8 Gy EQD 2 and 47.9 ± 6.8 Gy EQD 2, respectively. There were no statistically significant differences in the mean dose of bladder D 2cc between patients with and without toxicity in any classification, brachytherapy, WP, or brachytherapy plus WP (Table 3C).

| Timing and significance of HBT
For all 54 patients analyzed in the present study, a total of 215 brachytherapy sessions were performed, including conventional brachytherapy, which did not use interstitial catheters, and transvaginal HBT. Table 4 shows the ratio of conventional brachytherapy to transvaginal HBT in each session. Five sessions of brachytherapy were performed on one patient. Except for the fifth session of brachytherapy, transvaginal HBT was performed most frequently in the second session. Next, we compared the dose parameters in HR-CTV and OARs between conventional brachytherapy and transvaginal HBT ( Table 5).

T A B L E 1 Patients and treatment characteristics
The We further assessed the difference in the incidence of local recurrence among patients who did and did not receive HBT at the first session. Of the 37 patients who received HBT at the first session, four had local recurrence. In contrast, of the 17 who did not receive HBT at the first session, two had local recurrence. There was no statistically significant difference in the frequency of recurrence between the two groups (p = .917). Regarding the total dose to the HR-CTV D90 , the group that received HBT for the first time had a significantly higher total dose (4.8% [72.0 ± 4.8 Gy EQD 2 vs. 68.7 ± 4.2 Gy EQD 2 ; p = .020]) compared to the group that did not receive HBT at the first session. However, there were no statistically significant differences in the mean dose of rectum D 2cc or bladder D 2cc between the two groups ( Table 6).  16 The method we have reported here could be implemented with existing applicators and thus can be expected to be implemented in more facilities.

| DISCUSSION
This study has several limitations which include the small cohort of patients and short follow-up periods. The lack of significant differences in DFS and OS in stage and tumor size is probably due to these limitations. In addition, this was a single-institution retrospective analysis. A multicenter prospective study is currently ongoing to determine the clin- In conclusion, we reported the clinical advantages of CT-based transvaginal HBT. With the fact that none of the patients complained of symptoms after the procedure, favorable LC rate, mild toxicity, and possible cost-effectiveness of the series of procedures, our strategy may be a good option for cervical cancer.

ACKNOWLEDGMENTS
We would like to thank the radiology technicians and nurses at the QST Hospital for their support and dedication to this study.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

ETHICS STATEMENT
The study was approved by the Ethical Review Board committee of our institution (QST 20-043, approved on March 11, 2021). Because of the retrospective nature, the need for written informed consent was waived for this study. Instead, patients who refused to be included in this study were given an opt-out policy, which was uploaded on the webpage of our institution. The present study complied with the Declaration of Helsinki.