Patients recruited for this study received three-dimensional brachytherapy in our hospital between January 2020 and June 2021. The inclusion criteria were as follows: (1) normal pretreatment electrocardiogram and routine bloodwork results, including liver and kidney function tests; (2) a 2018 FIGO locally advanced stage Ib–Iva cervical cancer with a histopathological diagnosis of cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma; (3) an ECOG score of 0–1; and (4) no evidence of pretreatment distant metastasis. The exclusion criteria were as follows: (1) evidence of a synchronous primary malignant tumor; (2) a prior history of hysterectomy; (3) active stage of viral hepatitis, HIV, tuberculosis or other infectious diseases; (4) distant hematogenous metastasis was found during treatment; and (5) incomplete treatment data.

Based on these criteria, a total of 224 patients with advanced cervical cancer were included in this study; their demographics are summarized in Table 1. In the past, due to the lack of radiotherapy equipment in our hospital, patients experienced a long waiting time prior to beginning treatment. Our center will assess the waiting time of patients and administer 1–2 cycles of neoadjuvant platinum-containing two-drug chemotherapy to reduce the tumor load. Patients who could tolerate chemotherapy during external irradiation were treated with 4–5 cycles of platinum-based synchronous chemotherapy. The pelvic MRI images were reviewed after 3–4 weeks of radiotherapy and brachytherapy was administered using an appropriate applicator based on the results of the pelvic MRI and gynecologic examination. All patients were treated with brachytherapy after completing external irradiation, which was adjusted according to the tolerance of the individual patient, and the duration of external irradiation and brachytherapy was 6–8 weeks. Following 1 month of treatment, patients’ candidacy for adjuvant chemotherapy was assessed using CT/MRI and serum tumor biomarker results within the context of the tumor pathological subtype; when appropriate, platinum-containing double agents were administered for 21 days.

The primary endpoint of this study was the incidence of hematogenous metastasis in patients with cervical cancer within 2 years after the end of treatment with either type of brachytherapy. Subsequent analysis was performed to determine whether there were differences in the rates of hematogenous metastasis between the 2 brachytherapy groups. This study was approved by the Ethics Committee of Yunnan Cancer Hospital.

The patients received external irradiation therapy, which included intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). All patients underwent routine positioning and target delineation. The CTV included the cervix, uterine body, parametrial tissues, vagina and prophylactic lymphatic drainage areas (common, external and internal iliac; ureter; presacral; and, if necessary, the retroperitoneal lymphatic drainage). Considering the setup error, the PTV was routinely expanded by 7 mm based on the CTV, and the PTV dose was 45–50 Gy/25f, 1.8–2 Gy/f, 5 times/week. Patients with lymph node metastases received concomitant treatment with 55–62.5 Gy/25f or 2.2–2.5 Gy/f in the involved field.

Brachytherapy was administered 1–2 times/week for 2–3 weeks. All patients underwent routine surgical preparation and were placed in the lithotomy position for the procedure. During ICBT, the Fletcher three-channel applicator is placed in the uterine cavity and vaginal fornix and gauze packing and fixation is performed (Fig. 1). During IC/ISBT, the Fletcher tube is placed in the uterine cavity, and the needles are inserted using a freehand technique with a needle inserted into the cervical tissue. (The distance between the inserted needle and the uterine Fletcher tube is generally 1 to 2 cm). The number and depth of the inserted needles are determined according to the size and depth of the tumor, as indicated by CT/MRI images and pelvic examination (Fig. 2).

ICBT. ICBT: three-tube intracavitary brachytherapy(the Fletcher three-channel applicator is placed in the uterine cavity and vaginal fornix and gauze packing and fixation is performed)

IC/ISBT. IC/ISBT: hybrid intracavitary and interstitial brachytherapy(the Fletcher tube is placed in the uterine cavity, and the needles are inserted using a freehand technique with a needle inserted into the cervical tissue. In order to distribute the dose evenly,the distance between the inserted needle and the uterine Fletcher tube is generally 1 to 2 cm)

A 16-row spiral CT machine was used for pelvic scanning during CT positioning; the scanning range was from the upper 2–3 cm of the Fletcher tube to the ischial tuberosity using 3 mm windows. The vagina was filled with an appropriate amount of gauze to fix the position of the inserted needle and avoid changing the applicator position. To better visualize the position and shape of the bladder, our center typically injects 10 ml of contrast agent and 90 ml of saline into the bladder to ensure that the filling state of the bladder is unchanged.

The ICRU Report 89 is referred to for determining high-risk clinical target volume (HR-CTV) target area mapping principles and prescription doses [4]. Using the Oncentra treatment planning system, the treatment plan was designed and reasonably adjusted, and a single dose of HR-CTV was 6 ~ 7 Gy/f, with a total amount of 24 ~ 30 Gy/4 ~ 5 cycles. The three-dimensional dose is optimized so that HR-CTV95% of the volume reaches the prescribed dose. The dosimetric goal is to deliver more than 6 Gy to the HR-CTV D90 (dose covering at least 90% of the HR-CTV) while keeping doses to organs at risk (OARs) as low as possible. The total dose planning aims were HR-CTV EQD2 ≥ 85 Gy, bladder EQD2 ≤ 85 Gy, small intestine and sigmoid colon EQD2 ≤ 75 Gy.

All patients were evaluated weekly for acute adverse events during radiation therapy (RT) by physical examination and blood tests. Computed tomography and/or MRI were performed 3 months after the completion of RT to evaluate the initial tumor response, and imaging was repeated every 3–6 months for the first 5 years and annually thereafter. The clinical treatment effect evaluation standard referred to the solid tumor efficacy evaluation standard [5]. The RT toxicity grading standard formulated in reference to RTOG was used when evaluating adverse events.

SPSS 25.0 was used for statistical analysis of the data. Count data are expressed as cases (%) and were subjected to a χ2 test; measurement data are expressed as x ± s and were subjected to a t test. P ≤ 0.05 was considered statistically significant. Single-factor logistic regression was used to analyze the risk factors for hematogenous metastasis in patients with cervical cancer. Significant variables and baseline characteristics in univariate analysis, including whether patients received adjuvant chemotherapy and tumor size before brachytherapy, were included in multivariate analysis, using a two-tailed P value ≤ 0.05 as the standard of statistical significance, and a 95% confidence interval.