Observation of hemostatic effectiveness and safety of ultrasound-CT guided 3D intracavitary and interstitial brachytherapy in the treatment of larger cervical cancer with bleeding: A retrospective study

Abstract

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women. This study explored the effectiveness and safety of ultrasound-CT guided 3D intracavitary and interstitial brachytherapy (US-CT-3D-IGBT) in the treatment of larger cervical cancer with bleeding. A retrospective study was conducted on 31 patients with larger cervical squamous cell carcinoma (tumor short diameter >4 cm) with vaginal bleeding. US-CT-3D-IGBT was used to deliver a single high-dose prescription of high-risk clinical target volume (HR-CTV) 1000 to 1200 centigray (cGy) to the cervical tumor, followed by conventional intensity-modulated radiation therapy (IMRT) synchronous chemoradiotherapy (45–50 gray (Gy)/25–28 fraction(f)) with weekly cisplatin 25 mg/m². After external radiotherapy, simple intracavitary brachytherapy (BT) combined with manual interstitial BT was administered at 30 Gy/5F or 28 Gy/4F. Within 24 hours after high-dose 3D-IGBT, bleeding stopped in 2 patients (6.4%), and bleeding was reduced in a total of 11 patients (35.4%) within 48 hours. A total of 29 patients achieved hemostasis within 72 hours, with an effective rate of 93.5%. The remaining 2 patients reached the clinical hemostasis requirement on the 4th and 5th day. All patients experienced a significant reduction in vaginal bleeding after the initial BT, with an average reduction of 66 mL (160–20 mL). US-CT-3D-IGBT is effective in rapidly controlling bleeding in patients with larger cervical cancer (tumor short diameter >4 cm), and the treatment is relatively safe and feasible.

1. Introduction

According to Global Cancer Statistics 2020 Data Report,^[1] Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020. The most common symptom of locally advanced cervical cancer is irregular vaginal bleeding. As the tumor grows, new blood vessels form and the amount of bleeding increases. Traditional concepts and poor awareness among women often lead to the presentation of symptoms as massive vaginal bleeding with severe anemia at the time of diagnosis, making it impossible to immediately perform standard chemotherapy and radiation therapy. Previous experience has used drug combination therapy with vaginal packing to stop bleeding and blood transfusion to improve the patient condition before synchronous chemotherapy and radiation therapy.^[2] However, there are issues with the effectiveness of compression to stop bleeding, the effectiveness of blood transfusion, and prolonged treatment time. Rapid and effective relief of massive vaginal bleeding has become a hot topic in the treatment of locally advanced cervical cancer, especially for patients with bulky tumors (tumor diameter >4 cm) and vaginal bleeding (daily bleeding volume >100 mL). When the patients are in critical condition, they urgently require emergency hemostatic treatment.^[3]

Vaginal packing is the most common temporary hemostatic method for cervical cancer with vaginal bleeding, but it cannot achieve hemostasis in a short period due to the incomplete removal of tumor factors and the tumor-induced secretion of vascular endothelial factors, which causes tumor blood vessels to become tortuous and more permeable.^[4] Repeated packing not only carries a high risk of operation but also an infection risk. The standard treatment for advanced cervical cancer is radiotherapy (external radiation + brachytherapy, BT), but there is no unified treatment for patients with larger cervical cancer and vaginal bleeding.^[5] By effective 3-dimensional (3D) treatment planning, BT provides integrated boost dosages to the primary tumor while protecting the nearby organs at risk (OARs). Compared to X-ray-based brachytherapy (BT), image-guided BT (IGBT) that uses computed tomography (CT) or magnetic resonance imaging (MRI) can provide precise individual delineation of the treatment target while minimizing radiation exposure to nearby healthy tissues or OARs.^[6] Imaging-guided BT (IGBT) using CT or MRI is now commonly employed due to the advancement of imaging technology.

The relevant literature and review reports suggest that the goal of achieving hemostasis can be accomplished by delivering high-dose radiation through 1 or multiple sessions of BT or external beam radiation therapy. During BT treatment, the use of hemostatic sponges or gauze packing is employed to ensure patient safety. Tissue interstitial needles can be utilized to improve the dose distribution within the tumor region, and ultrasound guidance during BT insertion offers the advantage of real-time Doppler effect, allowing for avoidance of arterial vessels and major veins. The use of tissue interstitial techniques enables the radiation source to directly enter the tumor tissue through interstitial needles, maximizing the dose delivered within the tumor tissue through the square-inverse distance effect of BT. This approach allows a majority of patients to proceed with subsequent external beam radiation therapy and even transition to curative treatment with long-term survival benefits due to favorable treatment outcomes.^[7,8]

A systematic review and meta-analysis investigated the efficacy and toxic reactions of palliative radiation therapy in terms of pain relief and bleeding control in patients with advanced cervical cancer. The study summarized the hemostatic efficacy of high-dose-rate radiation therapy, whether delivered through external stereotactic body radiation therapy or ICBT. The findings suggest that high-dose-rate BT, as a palliative treatment, can achieve effective bleeding control in patients with bulky cervical cancer.^[9,10]

In order to deliver radiation more precisely and locally, BT includes inserting radioactive sources (BT needle) into or close to the tumor. With this method, radioactive sources are inserted into the tumor under the guidance of a 3D picture. This method uses multiparametric 3D treatment planning to adapt the BT needles, effectively covering the target while preserving the OARs.^[11,12]

Both CT and ultrasound are imaging methods that can be utilized to see the tumor and its surrounding tissues. An improved understanding of the tumor and its location in relation to other body structures can be obtained by combining the 2 imaging methods. Ultrasound and CT could be used in clinical diagnosis as a noninvasive diagnostic approach, which may result in a significant improvement in the accuracy and timing of diagnosis.^[13] Cervical cancer treated with ultrasound-guided conformal BT has shown the best local control (LC) and overall survival.^[14] For the treatment of cancer, 3D image-guided intracavitary and interstitial brachytherapy (IGBT) using ultrasound, CT, and other imaging modalities has various benefits.

This can also aid in directing the positioning of the radioactive sources used in BT, which can enhance the treatment precision and efficacy. A more sophisticated type of BT called 3D-IGBT employs 3D imaging to direct where to place the radioactive sources. This makes it possible to deliver radiation to the tumor more precisely and selectively while protecting neighboring healthy tissues.^[15] According to Liu et al, ultrasound has a sensitivity, specificity, and accuracy of 52.8%, 86.7%, and 68.75%, respectively. CT had 80.3% sensitivity, 90.3% specificity, and 85% accuracy, respectively. The combined use of ultrasound and CT has sensitivity, specificity, and accuracy of 89%, 94.7%, and 91.7%, respectively. The combined application of ultrasound and CT has greater sensitivity, specificity, and accuracy than either ultrasound or CT alone.^[15]

Our department explored the use of ultrasound-CT guided 3D intracavitary and interstitial brachytherapy (US-CT-3D-IGBT) to control bleeding, followed by sequential intensity-modulated radiation therapy (IMRT) + synchronous chemotherapy, and finally radical BT. The hemostasis effectiveness of the US-CT-3D-IGBT was observed, and the safety and short-term toxic and side effects of the overall treatment were evaluated.

2. Materials and methods

This retrospective study explored the effect of the interventional trial, which employed the conventional treatment approach of synchronous chemoradiotherapy combined with BT for patients with a hemorrhage volume of <100 mL. However, for patients with a hemorrhage volume >100 mL, palliative BT was administered first to achieve hemostasis.

2.1. General clinical information

Inclusion criteria: The enrolled patients were those with larger cervical cancer accompanied by vaginal bleeding, admitted to the radiotherapy department of Hainan Cancer Hospital between March 2020 and December 2021, and specifically meeting the following criteria: all patients had histologically confirmed malignant cervical tumors (squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma), MRI T2 assessment showed that the short diameter of the tumor was ≥4 cm, and vaginal bleeding assessment showed bleeding volume >100 mL/day. Patients did not meet the above criteria were excluded.

All patients were informed about the use of BT for hemostasis and subsequent treatment and signed the written informed consent, and the study protocol was approved by the Ethics Committee of Hainan Cancer Hospital (No. 2020 (science) No.10).

2.2. Radiotherapy plan

2.2.1. 3D-IGBT hemostasis.

Insert a urinary catheter and perform retrograde bladder imaging, retaining 150 mL of urine. Dissolve 2 mL of epinephrine hydrochloride in 100 mL of saline and soak a gauze with the solution. Disinfect the surgical field and carefully open the speculum. Fill the vagina with the soaked gauze for 1 minute. After clearing the surgical field, use ultrasound to determine the size of the tumor and the position of the uterus, then quickly insert the applicator into the uterine cavity and insert 4 to 6 BT needles (interstitial needles or intracavitary radiation sources were placed at the center of ICBT, with 4 needles arranged in equal-spacing parallel positions: upper left, lower left, upper right, and lower right. If the tumor was significantly large or showed asymmetrical infiltration, an additional 1 to 2 needles were inserted in the corresponding direction to ensure better coverage of the tumor area), with a parallel distance of 1 cm between the needles and the needle ends marked. Fill the vagina with iodophor-soaked gauze to compress and stop bleeding and separate the needle tails (Fig. 1). All procedures were performed by experienced (>10 years) radiologist Hu MM.

Figure 1.

BT interpolation (BT needle) example diagram. BT = brachytherapy.

2.2.2. Perform 3D-CT scan positioning and adjust the needle depth if necessary.

The final layer thickness was 2.5mm and the images were transmitted to the Varian BT for target area delineation: delineate the high-risk clinical target volume (HR-CTV), including the entire uterine muscle layer and the visible range of the cervical tumor. Delineate OARs (rectum, bladder). The 3D-IGBT device used the Varian radiotherapy machine, and the radiation source (BT needle) was I192. The prescription dose of HR-CTV was 10 to 12 gray (Gy)/fraction (f), and treatment was performed once. Organ at risk limitations were as follows: bladder D2cc < 800 centigray (cGy), small intestine D2cc < 650 cGy, rectum and sigmoid colon D2cc < 800 cGy. After treatment, remove the needles, and perform vaginal packing with fresh gauze. Evaluate the bleeding volume after 24-, 48-, 72-hours (Fig. 2).

Figure 2.

A, B, and C show the US-CT-3D-IGBT BT needle and the prescribed dose from the cross-sectional, sagittal and coronal planes, respectively. BT = brachytherapy. US-CT-3D-IGBT = ultrasound-CT guided 3D intracavitary and interstitial brachytherapy.

2.3. After the 3D-IGBT hemostasis, perform radiotherapy with enhanced positioning

Refer to the Radiation Therapy Oncology Group (RTOG)0418 study and the ICRU89 cervical cancer radiotherapy target delineation consensus. The gross target volume (GTV) includes the cervical mass, and the positive lymph nodes in the pelvis, external iliac and obturator regions, and para-aortic area are evaluated as GTV lymph nodes (GTVnd). The clinical target volume (CTV) includes the common iliac, internal iliac, and partial external iliac lymph node drainage areas, uterus, cervical mass, para-uterine tissue, and the upper 1/3 or 2/3 of the vagina. The planning target volume (PTV) is defined as CTV plus 1 cm margin. The prescription dose was as follows: PTV 45 to 50 Gy/25–28, GTVnd 60 Gy/25–28f.

2.4. After external irradiation

The efficacy was assessed by MRI at the end of external irradiation, while 3D-IGBT was given 4 to 5 times, 1 to 2 times per week. HR-CTV is 6 to 7 Gy/f (24–21 Gy/6–7Fx). The overall principle is to combine the initial 3D-IGBT hemostatic radiation dose, with a rectal D2cc < 7000 cGy, bladder D2cc < 8500 cGy, and intestinal D2cc < 7000 cGy.

ISBT for cervical cancer is typically performed without anesthesia. Patients may receive oral morphine for pain relief. Interstitial needle insertion in the tumor region does not involve nerve tissues. The pain score is usually 3 to 4, tolerable without anesthesia. Needle placement follows a principle of equal spacing around the tumor center. Four needles are commonly used, and additional needles may be inserted for large or asymmetric tumors. In some cases, incomplete needle placement occurs due to patient-induced bleeding.

2.5. Concurrent chemotherapy

For patients who can tolerate it, concurrent chemoradiotherapy is still given. Chemotherapy is given after correcting the patient anemia and evaluating other related hematological and renal functions.

In pelvic external beam radiation therapy for gynecologic malignancies, the standard dose is usually 30 to 40 mg/m² according to NCCN and ASTRO guidelines. However, for Asian patients with severe anemia and limited recovery after blood transfusion and hemostasis, a reduced dose of 30 mg/m² (80% reduction) or 25 mg/m² is administered.^[16] A weekly chemotherapy regimen based on platinum is used with a dose of 25 mg/m².

2.6. Observation indicators and statistical methods

1. Evaluation of short-term therapeutic effect of tumor: After external irradiation, imaging evaluation is given, and a subsequent 3D-IGBT plan is formulated. After all radiotherapy, follow-up visits are scheduled every 3 months, including gynecological examination, blood routine, CT or MRI examination. The therapeutic effect is evaluated according to the RESIST 1.1 standard, including complete response (CR), partial response (PR), local control (LC).

2. Evaluation of bleeding volume: In the case of severe bleeding, the weight method is adopted: bleeding volume (mL) = [wet weight of dressing after bleeding (g) – dry weight of dressing (g)]/1.05 (blood specific gravity). For small amounts of stored blood, the amount of blood loss is roughly estimated based on the area of wet gauze. Daily vaginal bleeding of less than or equal to 20 mL (one large gauze) is defined as minimal bleeding. Effective hemostasis is defined as the transition from heavy vaginal bleeding to minimal bleeding.^[17]

3. Evaluation of radiotherapy plan: External irradiation plan evaluation is based on the RTOG0418 standard, and OARs include the bladder, small intestine, colon, rectum, and femoral head. 3D-IGBT evaluation is based on the ICRU89 document, with D90 > 540 cGy (after US-CT-3D-IGBT), rectal D2cc <420 cGy, bladder < 460 cGy, and small intestinal D2cc < 400 cGy.^[18–20]

4. Evaluation of adverse reactions: Radiation injury standards are based on the RTOG grading standard, with a focus on early damage reactions in the gastrointestinal tract, urinary system, blood system, and vaginal mucosa.^[21] Early (within 3 months after 3D-IGBT hemostatic treatment) and late (within 3 months after radiotherapy) damage reactions are closely observed.

5. Follow up: After hemostatic treatment with US-CT-3D-IGBT, sequential radiotherapy was started the next day using IMRT radiotherapy with a prescribed dose of PTV 45 to 50 Gy/25–28f, PTVnd 60 Gy/25–28f synchronous IMRT radiotherapy. After external irradiation, 3D-IGBT was given total of 30 Gy/5F (6 Gy/f), or a total of 28 Gy/4F (7 Gy/f,), to ensure that GTVit-EDQ2-HRCTV: D90 dose was >100 Gy.

All patients were followed up for 12 months at clinic. All tumor assessments for the patients were conducted via MRI. A total of 35 patients were followed up, but 4 patients either refused or were unable to complete linear accelerator radiation therapy, resulting in a final enrollment of 31 patients.

2.7. Statistical methods

Paired t tests and chi-square tests were performed using SPSS 25 software. A P value <.05 indicates a statistically significant difference. The hemostatic efficiency based on imaging techniques was at 95%. The proposed treatment dose for this trial was HDR 10 Gy/f, BED = 110 Gy, and its effective is expected to be above 90% effective with a 10% loss of visit rate. When P < .05 and β = 0.10, the sample size calculated paired t test yielded n = 30.

3. Results

The patients’ ages ranged from 40 to 71 years old with an average age of 59 years old. The pathological types were 21 cases of squamous cell carcinoma, 6 cases of adenosquamous carcinoma, and 4 cases of adenocarcinoma. The short neck of the cervical mass measured by MRI was all >4 cm (ranging from 4.2 to 8.2 cm). According to the 2019 The International Federation of Gynecology and Obstetrics (FIGO) staging for cervical cancer, there were 7 cases of stage IIb, 9 cases of stage IIIa, 9 cases of stage IIIb, and 6 cases of stage IIIc.

Among the 31 patients, 12 (38.7%) had a hemoglobin level below 80 g/mL (average 73 g/mL). Immediate symptomatic blood transfusion was administered with an average of 4.2 units (420 mL). After treatment, the hemoglobin level reached 80 g/mL. Upon admission, 19 patients (61.2%) had a hemoglobin level above 80 g/mL and did not require transfusion. All patients had varying degrees of bleeding upon admission, ranging from 280 to 100 mL (Table 1).

Table 1.

Patient characteristics.

Cervical cancer (N = 31)
Age (median age [rage] yr)	59 (40–71)
Histological types
Squamous cell carcinoma	21
Sand Adenocarcinoma	6
Adenocarcinoma	4
FIGO 2019 stage
IIb	7
IIIa	9
IIIb	9
IIIc	6
Shortest diameter of cervical mass (cm)	5.92 (4.2–8.2)
Bleeding volume (d)
Bleeding volume >200 mL	2
Bleeding volume 150–200 mL	7
Bleeding volume 100–150 mL	22

3.1. Hemostatic effect

After US-CT-3D-IGBT treatment, 5 patients had vaginal bleeding stopped within 24 hours, 18 patients achieved hemostasis within 48 hours, 29 patients achieved hemostasis within 72 hours, and the remaining 2 patients reached the standard on the 4th and 5th day, respectively (Table 2). According to the paired sample t test, the average bleeding volume of patients before US-CT-3D-IGBT treatment was 137.42 ± 38.81 mL, the average bleeding volume within the first 24 hours after hemostasis was 70.32 ± 41.33 mL, the difference was significant (P < .001, Fig. 3). Within 5 days, all patients gradually transitioned to minimal bleeding, with a 100% hemostatic effective rate. After treatment, the bleeding volume of all patients decreased significantly within 24 hours, with an average decrease of about 60% compared to before treatment, and the average hemostasis time was 2 days.

Table 2.

Bleeding time after US-CT-3D-IGBT.

Radiation therapy dosage (Gy/d)	END bleeding time (N)
	d 1	d 2	d 3	d 4	d 5
10–12 Gy (N = 31)	5	13	11	1	1

Figure 3.

The 24-h bleeding before and after US-CT-3D-IGBT treatments. US-CT-3D-IGBT = ultrasound-CT guided 3D intracavitary and interstitial brachytherapy.

3.2. Hemostatic US-CT-3D-IGBT dose

US-CT-3D-IGBT was used with BT needles ± intrauterine applicator. GTV at initial presentation (GTVinit) was the region where the tumor was located as seen on MRI, and the prescribed dose DT was 1000 to 1200 cGy, with an average GTVinit D90 of about 862.45 cGy (735–1050 cGy, median 857 cGy), and the dose limits for normal tissues were: average bladder D2cc = 744.35 cGy (632–799 cGy, median 770 cGy) with dose maximum (Dmax) < 800 cGy; sigmoid colon/rectum D2cc = 683.45 cGy (514–798 cGy, median 689 cGy) with Dmax < 800 cGy; small intestine D2cc = 550.19 cGy (478–612 cGy, median 549 cGy) with Dmax <650 cGy (Fig. 4).

Figure 4.

The prescription dose for HRCTV D90 is 1000 cGy, with a theoretical maximum dose of Dmax reaching 40473 cGy, and an average dose of 2211 cGy. The D2cc dose of the small intestine, sigmoid colon-rectum, and bladder is evaluated each time, as the dose limit is often required for a particular critical organ due to individualized circumstances.

3.3. Follow-up data

At the 3-month follow-up, 9 patients achieved a complete response (CR) and 22 patients achieved a partial response (PR) (ORR = 100%). At the 6-month follow-up, 14 patients achieved CR and 17 patients achieved PR. At the 12-month follow-up, 14 patients achieved CR, 14 patients achieved PR, and 3 patients had progressive disease (Table 3).

Table 3.

Remission result after US-CT-3D-IGBT.

Remission (mo)	Radiation therapy dosage (Gy/d)
	Remission case at 10–12 Gy (N = 31)
	CR	PR	PD
3	9 (29.03%)	22 (70.97%)	0
6	14 (45.16%)	17 (54.83%)	0
12	14 (45.16%)	14 (45.16%)	3 (9.67%)

CR = complete response, PD = progressive disease, PR = partial response.

3.4. Adverse reaction incidence

After hemostasis with US-CT-3D-IGBT, standard radical dose external pelvic irradiation and 3D-IGBT were given. No perforation or greater bleeding occurred during the 3D-IGBT hemostasis treatment. No cases of vaginal bladder fistula occurred at 3 months or 6 months after treatment.

The most common short term side effect of radiation therapy (from the start of radiation therapy to 90 days after radiation therapy) is cystitis, with 1 person having RTOG grade 0, 14 people with grade 1, 15 people with grade 2, and 1 person with grade 3. Sigmoid/rectal inflammation is reported in 15 people with RTOG grade1 and 15 people with grade 2, and only 1 person with grade 3. Radiation vaginitis is reported in 13 people with RTOG grade 1, 13 people with grade 2, and 5 people with grade 3 (Table 4). Most patients experienced mild to moderate (grade 1–2) radiation therapy-related side effects that were tolerable, and there were no occurrences of grade 4 severe adverse reactions. There was 1 case each of grade 3 radiation cystitis and radiation proctitis (not in the same patient, accounting for 3.02% of cases), and a higher proportion of patients (5 cases, 16.12%) experienced grade 3 ulcerative radiation vaginitis. However, all of these side effects improved after treatment with antibiotics, probiotics for intestinal health, and rectal irrigation.

Table 4.

Observation of toxic and side effects after US-CT-3D-IGBT.

Organ at risk	RTOG grading
	0	1	2	3	4
Cystitis	1	14	15	1	0
Sigmoid/rectal inflammation	0	15	15	1	0
Radiation vaginitis	0	13	13	5	0

RTOG = radiation therapy oncology group.

The long-term toxicity (occurring from 3 months after radiation therapy to 6 months after radiation therapy): Cystitis had different grades as follows: Grade 0 was observed in 15 cases, Grade 1 in 12 cases, Grade 2 in 4 cases, and there were no instances of Grade 3 or Grade 4. Rectal/Sigmoid Colitis had different grades as follows: Grade 0 was observed in 19 cases, Grade 1 in 10 cases, Grade 2 in 1 case, and there were 1 case each of Grade 3 and Grade 4. Vaginal Mucositis had different grades as follows: Grade 0 was observed in 14 cases, Grade 1 in 15 cases, Grade 2 in 1 case, and there were no instances of Grade 3 or Grade 4.

4. Discussion

In 2020, some scholars used external beam radiation therapy with IMRT and dose escalation to achieve good results in stopping bleeding, with an average bleeding cessation time of 1 week after external beam radiation therapy. However, during the external beam radiation therapy process, the use of gauze to stop bleeding can cause significant displacement of the cervix and vagina, and the relative position of the bladder and rectum is not fixed, increasing positioning errors. Ma et al suggest that radiation therapy units equipped with surface tracking technology (OSMS) can be tried.^[22] However, there are limitations in the time required for treatment planning and the inability to achieve immediate bleeding cessation, which may prolong bleeding time for patients. Therefore, our experimental study observed the bleeding cessation effect achieved through BT single high-dose irradiation and observes treatment-related toxic and side effects to evaluate its clinical feasibility.

CT-MRI-guided multi-catheter interstitial BT for bulky (4 cm) and high-risk stage IIB-IVB cervical carcinoma was described by Kokabu et al A total of 18 squamous cell carcinoma patients who had concurrent chemoradiotherapy and ISBT were evaluated. Stage II, III, and IV cervical cancer were identified in 4 (22.2%), 7 (38.9%), and 7 (38.9%) women, respectively.^[23] The percentages of disease-free survival, pelvic control, LC, and overall survival at 4 years were 100%, 100%, 81.6%, and 87.8%, respectively.^[23]

According to the advantages of 3D-IGBT in the past, patients with cervical cancer who had tumors larger than 4 cm, and who had clinical bleeding volume >100 mL that resulted in anemia affecting treatment decisions, or who converted to palliative treatment, were selected for 3D-IGBT hemostasis treatment.^[24] The reason for the vaginal bleeding caused by the rupture of newly formed capillaries due to tumor proliferation also became an indication for IGBT. Although all patients had varying degrees of anemia upon admission, bleeding stopped after treatment and hemoglobin gradually recovered. Therefore, these patients benefited more from hemostasis treatment. All 31 patients were diagnosed with cervical cancer, with a maximum diameter range of 4.1 to 8.1 (mean diameter 5.15 cm, median 5.7 cm), and the overall hemostasis effect was satisfactory.

In the era of 2D-IGBT, treatment was limited by the radiation dose to the source applicator and normal organs. A total of 12 Gy/2F IGBT treatment was given with a dose of 6 Gy per A point,^[25] but due to the lower single dose, the average hemostasis time was 10 to 15 days and the effective rate was lower. Studies by Mathias Onsrud and others found that giving advanced cervical cancer patients a single dose of 10 Gy/week resulted in a high hemostasis effective rate of up to 93%, whether it was external radiation or pure intracavitary BT treatment.^[26] The hemostasis effect of BT was better than that of conventional high-dose fractionated radiotherapy,^[27] and the dose of BT followed the inverse square law of radiation source (BT needle) distance, with the dose at the bleeding point near the center of the tumor reaching a central dose of 3000 cGy. The radiobiological principle of high-dose rate BT is almost zero for re-proliferation and re-population.^[28] Double-stranded DNA breaks in tumor cells are favorable for gradual apoptosis of tumor cells, avoiding an increase in hypoxic cells and avoiding the impact on the subsequent radiotherapy effect. Therefore, in this experiment, the target area HRCTV was defined as the initial GTV of the tumor in the cervical area, especially the visible tumor area on MRI T2/T1 + C; 4 to 6 implantation needles were used for eccentric distribution with a spacing of 1 to 1.5 cm. The purpose was to ensure that HRCTV covered the entire GTVinit. The dose limits for normal organs OARs were based on the constraints of normal organs in 3D pelvic radiotherapy.^[29] The dose limits for the bladder, rectum, and small intestine were D2cc < 800 cGy, D2cc < 800 cGy, and D2cc < 600 cGy, respectively. Although some patients received a higher dose of radiation than conventional BT, the occurrence rates of short-term and long-term toxic and side effects were low based on the experimental conclusions obtained by controlling the angle of interpolation needles (BT needle) or prolonging the total treatment time, and were similar to those of standard cervical cancer radiotherapy and chemotherapy during the same period. The treatment plan was safe and tolerable.^[30] A risk-adapted dose prescription is given to various gross tumor- and clinical target volumes defined at diagnosis and after 40 to 50 Gy external beam radiotherapy, and the treatment method is adjusted in accordance with the topography of the tumor after response and the nearby OARs. This adaptive target volume concept was developed to reflect tumor shrinkage at the end of initial chemoradiation and serves for an image-guided boost delivered through BT.^[31,32]

According to the analysis by Liu et al,^[33] in domestic and foreign published literature related to ISBRT research, about 36% of the units use image-guided 3D-IGBT, CT is still the main guidance method, accounting for about 58%, MRI image guidance has made rapid progress, accounting for about 27% of image guidance, and the rest use X-ray or ultrasound guidance. Traditional CT-guided IGBT treatment requires multiple CT scans, increasing patient radiation dose. After the first treatment, intrauterine BT source (BT needle) treatment should be given immediately after CT scanning, but some patients still experience displacement of the bladder and rectum due to tension, and the position of the uterus changes relative to the small intestine and bladder due to ligament traction and bed movement. Therefore, the implantation of intrauterine BT needle is often unsuccessful due to the asymmetry of information or may cause perforation,^[34] this is especially true for guidance with interpolation needles (BT needle),where real-time guidance with ultrasound can be given throughout the entire interpolation process to avoid accidental occurrences due to uterine movement.^[35] Larger cervical cancer itself has a large amount of bleeding, unclear exposure, and pelvic organs are easily deformed and spasmed due to pain and tension.^[36] The use of ultrasound-guided BT needle (US-CT-3D-IGBT) can avoid large blood vessels and obtain a safer treatment strategy. All patients in this study were guided by ultrasound combined with CT guidance. For patients with larger tumors, CT simulation positioning was performed first, and a BT simulation source insertion needle plan was developed. Then, real-time guidance with ultrasound was used to maximize the restoration of the simulated source insertion needle angle and depth to avoid perforation and (BT needle into larger arteries, which can cause serious bleeding. Therefore, the number of secondary bleeding or perforations caused by the operation was reduced to zero, and the risk caused by the operation was minimized. Recently, the incidence of toxic side effects, especially perforation and bleeding reactions caused by the operation, has decreased significantly compared to other literature.^[37]

The American Brachytherapy Society (ABS) has proposed indications for interstitial brachytherapy (IC/ISBT) as follows^[38]: large tumor volume or poor regression after external beam radiation therapy; tumor location far from the uterine cavity or with significant deviation; irregular tumor morphology; inadequate coverage of the target area with simple ICBT; poor relative positioning of the target area and OARs; parametrial involvement; and recurrent patients. Research results by Assenholt et al^[39] showed that the average dose coverage in ICBT plans was 74%, but by utilizing IC/ISBT, the median coverage of the target area increased to 95%. In the study by Kirisits et al,^[40] the use of additional interstitial needles provided prescription doses at distances of up to 15mm from Point A. For patients with large tumor volumes (average HR-CTV of 44 cm³), IC/ISBT is a favorable choice.

For tumors with a diameter >4 cm, due to their larger size and accompanying intracavitary adhesions and tumor tissue infiltration and compression, the distribution of intracavitary brachytherapy (ICBT) tissue doses may be uneven, with inadequate doses at the edges. The combined use of intracavitary and interstitial brachytherapy (IC/ISBT) or the use of ISBT alone can increase coverage and improve the high-dose distribution in the central region of the tumor at multiple points.

Most patients experienced tolerable mild to moderate (Grade 1–2) short-term side effects from radiation therapy, including cervicitis, proctitis, and vaginitis. Two patients had Grade 3 cervicitis and proctitis separately (3.02% of cases), and a higher proportion of patients (16.12%) experienced Grade 3 ulcerative vaginitis. Fortunately, all these side effects improved with antibiotics, probiotics, and rectal irrigation. The increased incidence of radiation-induced cervical cancer is primarily due to tumor location in the cervical region, with most patients receiving doses over 100 Gy. To achieve better treatment outcomes, higher doses in the tumor area can cause damage to normal cervical tissues. However, the use of protective measures during gynecological treatment prevented severe complications. Anemia and poor nutrition affected ulcer occurrence, despite efforts to reduce concurrent chemotherapy intensity. Nutritional support was provided. Some patients could not complete more than 2 cycles of chemotherapy. No patients had both cervical ulcers and proctitis, as radiation dose to the rectum and bladder was reduced after IMRT to avoid severe complications. Compliance with HRCTV dose adaptation (EQD2_10 > 90 Gy) was important. Protection of organs was prioritized during treatment for diarrhea or urinary symptoms. These measures aimed to adhere to dose limits for normal organs according to guidelines. Overall, these interventions helped manage side effects and improve outcomes.

The defects of this study are also quite apparent, as it is limited to a retrospective analysis and has a small sample size, which presents significant challenges for data analysis. We acknowledge that one of the limitations of our research is that it specifically focused on patients with high-dose vaginal bleeding who received arterial embolization in the emergency department. Therefore, the generalizability of our findings to all patients with bulky cervical cancer experiencing bleeding may be limited. All patients were given vaginal packing and drug treatment on the day of admission, and the amount of bleeding was recorded 24 hours later, after which the vaginal packing was removed and the amount of bleeding was recorded again on the following day. The experiment attempted to exclude fluctuations in bleeding caused by medication, but there was a lack of a control group that received only radiation therapy. In future experimental studies, a retrospective analysis of the rate of bleeding control and efficacy of synchronous radiation and chemotherapy for local advanced patients will be carried out, and a randomized double-blind controlled trial may be conducted to compare the effectiveness of the 2 treatment options and identify the suitable patient population.

5. Conclusion

US-CT-3D-IGBT has advantages for patients with large bleeding caused by larger cervical cancer, including rapid hemostasis and reduction of overall treatment time due to anemia. There are no significant short-term toxic and side effects observed.

Author contributions

Conceptualization: Yuefeng Hu, Yunxiu Luo.

Data curation: Yuefeng Hu, Ying Jin, Dongdong Wang, Yunxiu Luo.

Formal analysis: Yuefeng Hu, Ying Jin, Dongdong Wang, Yunxiu Luo.

Investigation: Yuefeng Hu, Ying Jin, Dongdong Wang.

Methodology: Ying Jin, Yunxiu Luo.

Project administration: Dongdong Wang.

Software: Dongdong Wang.

Writing – original draft: Yuefeng Hu, Yunxiu Luo.

Writing – review & editing: Yuefeng Hu, Yunxiu Luo.