Development and assessment of interstitial brachytherapy using individual curved-needle in treatment of recurrent gynecological tumors after external beam radiotherapy

Development and assessment of interstitial brachytherapy using individual curved-needle in treatment of recurrent gynecological tumors after external beam radiotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development and assessment of interstitial brachytherapy using individual curved-needle in treatment of recurrent gynecological tumors after external beam radiotherapy Zheng Zeng, Yining Chen, Jie Zhang, Chunli Luo, Lang Yu, Yuliang Sun, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6728229/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: To evaluate the efficacy and safety of individualized curved-needle interstitial brachytherapy (ISBT) using 3D printing for recurrent gynecologic tumors. Method: This study enrolled patients with pelvic recurrent gynecologic tumors from March 2022 to April 2024. All patients received external beam radiotherapy (EBRT) (40-60 Gy, 20-30 fractions), followed by individualized curved-needle ISBT using a 3D-printed applicator (12-30 Gy, 2-5 fractions). Concurrent systemic therapy was administered when necessary. Dosimetric parameters (V100%, V200%, D100%, D98%, D90%, D50%, D5cc, D2cc, D0.1cc) were assessed. Clinical outcomes and treatment-related complications were analyzed. Results: 45 fractions of ISBT were analyzed. Central and non-central pelvic recurrences occurred in 46.2% and 53.8% of patients, respectively. Eight patients received concurrent systemic therapy. The cumulative equivalent dose to the gross tumor volume of recurrence treatment was 64.87 ± 7.16 Gy for patients with prior radiation and 73.03 ± 9.95 Gy for others. The cumulative equivalent dose to D2cc in brachytherapy for patients with vs. without prior radiation was 19.75 ± 8.92 Gy vs. 21.65 ± 9.49 Gy for the bladder, 13.23 ± 2.81 Gy vs. 15.25 ± 6.82 Gy for the rectum, and 9.09 ± 5.85 Gy vs. 8.23 ± 5.09 Gy for the sigmoid colon. At a median follow-up of 25 months, 100% of patients were alive. The objective response rate was 84.6%, with 91.7% local control at 2 years. Acute Grade 3 toxicity was observed in 30.8%, and late Grade 3 toxicity in 7.7%. Conclusion: Individualized curved-needle ISBT with a 3D-printed applicator provides high-quality treatment for recurrent gynecologic tumors with favorable outcomes and acceptable toxicity. Recurrent gynecological tumor Interstitial brachytherapy Individual curved-needles Clinical outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Gynecological malignancies, which include uterine, cervical, ovarian, vaginal, and vulvar cancers, continue to pose a significant global public health burden, particularly in transitioning countries. 1 Standard treatment protocols have been established for each type of gynecological malignancy, and satisfactory prognoses have been achieved in recent decades. 2 , 3 However, pelvic recurrence occurs in 5%-40% of cases, 4 , 5 and selecting an appropriate treatment approach—whether surgery, radiotherapy, or systemic therapy—remains challenging due to the lack of widely recognized recommendations. Additionally, the prognosis for patients with recurrence is generally poor. 6 Pelvic recurrence can be categorized into central and noncentral types. 7 Pelvic exenteration is the primary salvage therapy for central pelvic recurrence, with a 5-year overall survival (OS) rate of 20%-60%; 8 however, its surgical indication is limited to carefully selected patients and is generally associated with significant postoperative complications and diminished quality of life. 9 For patients who are not candidates for surgery, radiation offers a reasonable alternative, though its efficacy often depends on the history of prior treatments and radiation 6 Salvage radiation is considered safe and effective for out-field recurrence, but re-irradiation for in-field recurrence presents more challenges. 10 Recent studies have suggested that re-irradiation could be a viable salvage treatment option, with favorable clinical outcomes and acceptable toxicity, especially when external beam radiotherapy (EBRT) is followed by high-dose-rate (HDR) intracavity brachytherapy (with or without interstitial brachytherapy, ISBT). These studies have largely focused on central pelvic recurrence. 11 , 12 For noncentral recurrence, the National Comprehensive Cancer Network guidelines recommend individualized EBRT as a treatment option. 13 However, its therapeutic efficacy remains limited, with a 5-year survival rate of less than 10% compared to approximately 63% for central recurrence, 14 , 15 indicating an urgent need for more effective treatment strategies. ISBT could play a more significant role in improving treatment outcomes, with accurate needle insertion being a key factor in enhancing tumor response while minimizing radiation exposure to surrounding healthy tissues. 16 , 17 Despite this, current interstitial needles used in ISBT are generally straight or oblique, rigid, and inflexible. Most studies have focused on developing applicators or templates to improve the flexibility and efficiency of ISBT. 18 There remains a strong demand for both safe and effective treatment options for pelvic recurrence of gynecological malignancies. In this study, we focus on the combination of EBRT and ISBT for treating pelvic recurrence, particularly in cases of in-field recurrence, noncentral recurrence, and other refractory cases, where there is limited evidence supporting the efficacy and safety of current treatments. We developed individualized curved-needle ISBT with a 3D-printed applicator, hypothesizing that this method would improve targeting accuracy and reduce radiation injury to surrounding tissues compared to existing needle designs. We also investigated the clinical outcomes of this approach, as the current literature primarily consists of case reports or focuses mainly on dosimetric considerations. Method and materials Patient selection The study initially included 13 patients with recurrent gynecological malignancies treated at our institution between March 2022 and April 2024. The inclusion criteria were as follows: 1) pathologic confirmation of gynecological cancer, 2) pelvic recurrence, 3) inability to use standard brachytherapy applicators, and 4) the need for ISBT. The ethics committee of Peking Union Medical College Hospital approved the study (Approval No. K3121). The requirement for written informed consent was waived because of the retrospective nature of the study. EBRT For treatment planning, imaging studies such as positron emission tomography-computed tomography (PET-CT), magnetic resonance imaging (MRI), and computed tomography (CT) were performed to assess the extent of the disease and define the target volume during pre-planning. Detailed descriptions of the specific radiation techniques used can be found in our previous studies. 19 , 20 The clinical target volume (CTV) was treated with volumetric modulated arc therapy to a median dose of 45 Gy (interquartile range [IQR] 45–50.4 Gy) in 1.8–2 Gy per fraction. The CTV was determined based on the location of the lesions and the patient’s radiotherapy history. A 0.6–1 cm expansion was applied to the CTV to create the planning target volume to account for daily treatment setup variations. For patients without prior radiation, the treatment field covered the recurrent lesion, with expansion to high-risk regions and whole pelvic lymph node drainage. For the three patients with metastatic lymph nodes, a total dose of 60.2 Gy in 28 fractions (or 60 Gy in 25 fractions) was delivered to the planning gross tumor volume of the nodes, with a simultaneous integrated boost. The gross tumor volume of the nodes received a 5 mm margin to create the planning gross tumor volume. For patients with a history of radiation, the CTV included the recurrent lesion and the involved lymph node drainage. No patient underwent lymph node metastasis, then no lymph node boost was delivered. Brachytherapy Customized 3D-printed applicators (Stratasys Ltd., Rehovot, Israel) were used for all patients undergoing brachytherapy. The vagina was packed with a thin contrast-soaked gauze strip, pre-soaked in diluted diatrizoate meglumine, ensuring it was thin enough to fill any gaps within the vaginal cavity. The patient underwent CT imaging, with or without MRI, depending on clinical indication. If MRI was performed, image fusion was utilized. The gross tumor volume and CTV were contoured by an experienced radiation oncologist. Catheters and needle paths were designed and optimized by experienced physicists based on the evaluation of the lesion after the CTV images were contoured. The 3D-printed applicators were fabricated, and quality assurance was performed through physical evaluation of material attenuation, path patency checks, and disinfection. Once the 3D-printed applicator was placed in the vagina, both pelvic CT and MRI simulations were performed to confirm the applicator's position. The HDR brachytherapy plan was then generated using the Oncentra brachytherapy treatment planning system (Elekta, Stockholm, Sweden), and the precise insertion depth from the applicator surface to the CTV delineation was estimated. ISBT was performed using individually curved needles (Elekta, Stockholm, Sweden), guided by the applicator. These needles are designed to be flexible and manually shaped and curved during the brachytherapy procedure. For each patient, individual needle with different insertion direction and angle could be adjusted according to the corresponding needle path design through evaluation of recurrence lesion. Examples of individual curved-needles and brachytherapy procedure were illustrated in Fig. 1. The total doses (EBRT and brachytherapy) were converted to the biologically equivalent doses in 2-Gy fractions (EQD2) using the linear-quadratic model with an α/β of 10 Gy for tumor control and 3 Gy for late normal tissue damage. The goal for organs at risk (OARs) was a cumulative dose to D2cc of bladder ≤ 90 Gy, sigmoid ≤ 75 Gy, and rectum ≤ 75 Gy. Considering the interval between two radiations and tissue recovery, a dose reduction of 50% is allowed for re-irradiation if it occurs 12 months after the last treatment. For re-irradiation between 6 and 12 months, a 25% dose reduction is recommended, while re-irradiation within 6 months should be avoided 21 , 22 . Therefore, the study suggests that a D2cc of ≤ 110 Gy for the bladder, ≤ 100 Gy for the sigmoid, and ≤ 100 Gy for the rectum is considered safe for re-irradiation 21 . CT or MRI guided 3D brachytherapy with a dose schedule of 10–30 Gy in 2–5 fractions began after EBRT. The delineation of the clinical target volume - brachytherapy (CTV-B) was based on imaging results and clinical findings, where lymph nodes would not be included. The following dose-volume parameters were calculated for the CTV-B and OARs: the percentage of the CTV receiving 100% of the prescribed dose (V100) and the dose covering 90%, 98%, and 100% of the target volume (D90, D98, and D100, respectively). Additionally, the D0.1cc, D2cc, and D5cc values were calculated for the rectum, sigmoid and bladder. Systemic therapy Some patients received concurrent systemic therapy. Systemic therapy was delivered in two phases: during radiation (concurrent), and following radiation (maintain). Maintenance systemic therapy as planned treatment administered after radiation completion. Concurrent systemic therapy was provided as needed. The most common regimen was weekly cisplatin. The remaining regimens included cisplatin and paclitaxel, carboplatin and paclitaxel, targeted therapy, and immunotherapy. Followup Following the completion of treatment, the first follow-up evaluation was conducted one month after treatment. Patients were then examined every three months for the first two years, followed by every six months for the next two years, and annually thereafter. Routine follow-up assessments included gynecological examinations, complete blood count, liver and kidney function tests, thoracic and abdominal CT scans, pelvic MRI or CT scans, and serum tumor marker tests (squamous cell carcinoma antigen, carcinoembryonic antigen, cancer antigen 125, or cancer antigen 199). If recurrence or metastasis is suspected, a PET-CT scan will be performed if necessary. Statistical analysis SPSS 27.0 (IBM. Corp, New York, USA) and Prism 9.0 (GraphPad Software, USA) were utilized for data analysis. The Kaplan-Meier method was used to analyze OS, progression-free survival (PFS) and local failure free survival (LFFS). OS was calculated from the date of recurrence to the date of death from any cause or of the last clinical follow-up. PFS was defined as the time interval between the start of recurrence treatment and any disease progression. LFFS was defined as the time interval between the start of recurrence treatment and the local failure. The independent samples t-test was utilized to compare normally distributed quantitative data. All statistics were two-sided tests, and the level of significance was 0.05. Local tumor response after radiotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. 24 Treatment-related complications were graded according to the Common Terminology Criteria for Adverse Events version 5.0. 25 Result Patient and treatment characteristics The final analysis included 13 patients with a 100% follow-up. The clinical characteristics of the patients related to their primary tumor treatment are detailed in Table 1. The primary tumor types were cervical cancer [9, 69.2%; International Federation of Gynecology and Obstetrics (FIGO) stage: 2 for IA, 2 for IB, 2 for IIB, 2 for IIIA, 1 for IIIB], endometrial cancer (2, 15.4%; FIGO stage: 1 for IA, 1 for IIIA), vaginal cancer (1, 7.7%, FIGO stage II) and endometrial sarcoma (1, 7.7%; high grade endomerial stromal sarcoma). Of the patients, for the treatment of their primary tumor, 9 (69.2%) underwent surgery, 6 (46.2%) received systemic therapy, and 4 (30.8%) were treated with radiation therapy. The median interval between primary diagnosis and recurrence was 29 (range 5–420) months. The recurrent gynecological cancer treatment characteristics were detailed in Table 2. Among the included patients, 4 (30.7%) patients receiving re-irradiation, the recurrence were all in-field recurrence. As regard to the classification of recurrence, there were 6 central recurrence and 7 noncentral recurrence. For recurrence site, 9 patients (69.2%) had vaginal recurrence, 6 patients (46.2%) had parametrial recurrence, 5 patients (38.5%) had pelvic LN metastasis, 3 patients (23.1%) had cervical recurrence, and one patient (7.7%) had recurrence at uterine body. 10 patients (76.9%) had multiple recurrence location, including uterine body, cervix, parametria, vagina, and pelvic LN. The mean distance between the farthest margin of recurrence site and center of the vaginal stump was 4.33 cm (range 3.28-5.47 cm). All patients were treated with EBRT. The median total external radiation dose was 45 Gy (IQR 45–50.4) given in 1.8 Gy per fraction (IQR 1.8–2.0). During brachytherapy the number of needles for each patient ranged from 2 to 6 with a median of 3, while the option of type of needles was based on actual clinical situation, and individual curved-needles account for 92.7% in the total 41 insertion needles. 76.9% patient used all individual curved-needles for insertion while the other (3 patients, 23.1%) used both individual curved-needles and rigid needles. The median total insertion depth of needles was 10.6 cm per fraction, ranging from 2.4-16.7 cm. The median insertion depth of individual curved-needles was 3.1 cm (range 1-5cm) with maximum angles ranging from 7 to 40 degrees, while the median insertion depth of rigid needles was 1.5 cm. A representative interstitial brachytherapy case for individual curved-needles design and real practice was illustrated in Figure 2. A majority of patients (92.3%) were treated with CT guided brachytherapy, while 69.2% treatment plan was designed in accordance with MRI. The median total brachytherapy dose was 20 Gy (IQR 13.5–23.5) given in 6 Gy per fraction (IQR 5.3–6.0). 5 patients (38.5%) received concurrent chemotherapy, 1 patient (7.7%) received concurrent chemotherapy combined with targeted therapy, and 1 patient (7.7%) received concurrent chemotherapy combined with immunotherapy. Only 1 patient (7.7%) received immunotherapy as maintenance treatment. Dosimetric outcomes A total of 45 brachytherapy fractions were administered to 13 patients. The mean cumulative EQD2 to the CTV for recurrence treatment was 64.87 ± 7.16 Gy for patients with a history of prior radiation and 73.03 ± 9.95 Gy for those without prior radiation. Among the cohort, 9 patients (69.2%) received doses greater than 65 Gy, with 8 of these patients belonging to the group without prior radiation history. Among the remaining 4 patients receiving a cumulative EQD2 for recurrence treatment of less than 65 Gy, three of them had prior radiation history and the dose delivery was restricted under consideration of the OARs. For the 4 patients with prior radiation history and the 9 patients without, the mean cumulative EQD2 to the D2cc of the OARs for recurrence treatment were as follows: for the bladder, 63.98±11.37 Gy and 79.00±12.34 Gy; for the rectum, 61.93±8.90 Gy and 68.44±9.93 Gy; and for the sigmoid, 41.22±20.79 Gy and 54.49±7.45 Gy, respectively. For brachytherapy, the average per fraction and EQD2 values for D100%, D98%, D90%, and D50% for CTV-B, as well as D5cc, D2cc, and D0.1cc for OARs, are detailed in Tables 3 and 4 for patients with and without prior radiation history, respectively. During brachytherapy, the average CTV-B D90% per fraction was 5.61 ± 0.67 Gy for patients with prior radiation history and 5.78 ± 0.64 Gy for those without. The corresponding average CTV-B EQD2 values were 22.90 ± 6.04 Gy and 24.98 ± 9.61 Gy, respectively. These doses were found to meet the clinical prescription requirements, as illustrated in Figure 3. Tumor response and survival All patients are alive at a median follow-up of 25 months (range 9-40). Of these, 10 (76.9%) remain in continuous complete remission, 1 (7.7%) shows a partial response without progression, and 2 (15.4%) have progressive disease. Regarding local tumor control, 11 (84.6%) are in continuous complete remission, 1 (7.7%) shows a partial response, and 1 (7.7%) has progressive disease. One patient developed lung metastasis and a new in-field vaginal recurrence, while another had multiple out-field metastases. The 1-year local control (LC) rate was 100%, with a 2-year LC rate of 91.7%. The 1-year and 2-year OS rates were both 100%. The 1-year PFS rate was 92.3%, and the 2-year PFS rate was 83.9%, as shown in Figure 4. All 4 patients who underwent re-irradiation achieved complete response, with 100% 1-year OS and PFS rates. Toxicities No significant bleeding, infection, or other major complications related to the insertion procedure were observed during or after brachytherapy. Acute and late toxicities from the treatment are summarized in Table 5. The most common acute toxicity observed in these patients was hematologic toxicity, particularly leukopenia. Four patients (30.8%) experienced grade 3 hematological toxicities, and only 1 patient (4%) developed grade 3 urinary toxicity. No grade 3–5 acute gastrointestinal or genital toxicities occurred. For late toxicities, no grade >3 toxicities were observed. The only reported grade 3 late toxicity was a vesicovaginal fistula in 1 case (7.7%). Grade 2 toxicities were observed in 3 (23.1%) patients. A trend was observed where, after the initiation of brachytherapy, adverse events were reduced to a lower grade compared to the duration of EBRT. The detailed incidences of adverse events during EBRT and brachytherapy are summarized in Table 6. During EBRT, diarrhea was reported in 5 (38.4%) patients: 2 (15.4%) had grade 1, and 3 (23.1%) had grade 2. After brachytherapy began, the incidence of diarrhea reduced to 7.7% (n=1, grade 1). No genital toxicity was observed during brachytherapy, and grade 1 pelvic pain, vaginal hemorrhage, vaginal dryness, and vaginal discharge reported during EBRT in 3 (23.1%) patients were relieved. Brachytherapy was performed without acute complications in 5 (38.5%) patients, and no acute grade ≥3 toxicities occurred, except for one case of grade 3 urinary tract obstruction, which was not observed during EBRT. Re-irradiation Among the 4 patients who underwent re-irradiation, one reported no acute or late toxicities, one reported no late toxicity but experienced grade 1–2 acute toxicities, one reported grade 1–2 adverse events for both acute and late toxicities, and the remaining patient reported grade 1–2 acute toxicities and grade 3 late toxicity. The only grade 3 late toxicity observed among all 13 patients was a case of vesicovaginal fistula in a re-irradiated patient. There was a significant difference in the incidence of radiocystitis between patients who received re-irradiation and those without a history of radiation (p = 0.027) (Figure 5A). The rates of factitial proctitis were higher in patients receiving re-irradiation than in those without a radiation history, although the difference was not statistically significant (p = 0.174) (Figure 5B). Discussion Failure of primary treatment for gynecological tumors is associated with a poor prognosis for subsequent recurrence treatment. 26 Recurrence can be classified into intra-pelvic and extra-pelvic types. Treatment for pelvic recurrence is particularly challenging due to the proximity of surrounding OARs and the large, complex shape of the recurrent tumor. There is no optimal or standard approach for managing pelvic recurrence, especially for patients who are inoperable or have a history of radiation. 27 Treatment options typically include salvage surgery, radiotherapy, chemotherapy, and other systemic therapies. 4 Most patients are not recommended for surgery. Pelvic exenteration is suggested for select patients, offering a 5-year survival rate ranging from 21–73%, but the resectability rate is less than 20%, and postoperative complications are frequent. 27 EBRT, with or without chemotherapy, is generally better tolerated by patients, but the outcomes are often unsatisfactory. 28 However, when combined with brachytherapy, it holds potential for both tumor remission and the preservation of OARs. 29 The current improvements in ISBT accuracy in previous studies have primarily focused on templates, applicators, and various image guidance technologies to adapt to straight and oblique needles, but not to individually curved needles. Our prior studies concentrated on the development and evaluation of a 3D-printed applicator with rigid, straight needles. A previous study reported that the use of the 3D-printed applicator in patients with gynecological cancer post-hysterectomy since 2017 resulted in superior CTV coverage and dose distribution compared to the multichannel cylinder in intracavity brachytherapy. Specifically, it achieved higher CTV and CTV-1cm V100% of 90.02% and 81.85%, and lower bladder and rectum D0.1cc doses of 4.63 Gy and 4.57 Gy, respectively. 30 The 3D-printed applicator in intracavity ± ISBT also showed satisfactory clinical outcomes with acceptable toxicities, but it mainly focused on central pelvic recurrence and patients who underwent primary hysterectomy, with ISBT performed using straight metal needles. 31 This study further developed individually curved needles capable of adjusting angles for more flexible insertions. For each patient, the insertion direction, curvature angle, and needle path were tailored in real time based on the location, depth, and geometry of the recurrent tumor, as assessed by pre-procedural imaging and intraoperative findings. This flexibility allowed for more precise coverage of irregularly shaped or anatomically challenging lesions, while minimizing damage to adjacent organs at risk. The introduction of individually curved needles addresses the limitations of straight, rigid needles, which are difficult to use for noncentral recurrences or recurrences at the uterine body, where the insertion must bypass the bladder. With these curved needles, this study included 13 patients with recurrent gynecological tumors, 53.8% of whom had noncentral recurrence. The study also included patients with no surgery history or a history of prior radiation. Compared to our prior study using straight metal needles with insertion depths ranging from 1.8 to 3 cm, this study achieved deeper insertion depths, with a median of 3.1 cm at variable angles (7 to 40 degrees) in the 45 ISBT fractions. In this study, the use of individual curved-needle ISBT with 3D-printed applicators resulted in excellent tumor control. The 2-year LC, PFS, and OS rates were 91.7%, 83.9%, and 100%, respectively. The objective response rate was 84.6% for all patients and 92.3% for local tumors during the follow-up period. The mean cumulative EQD2 to CTV D90 was 64.87 ± 7.16 Gy for patients with a history of radiation and 73.03 ± 9.95 Gy for those without prior radiation. Previous studies on brachytherapy for pelvic recurrence reported a 2-year LC rate ranging from 60–87.8%, with a CTV D90 of > 65 Gy being associated with favorable LC outcomes. 29 , 31 , 32 In our study, the LC rate was higher compared to previous studies, and the mean cumulative EQD2 of CTV D90 exceeded 65 Gy, particularly in patients without prior radiation therapy. Intra-pelvic recurrences can be further categorized into central and non-central recurrences, based on whether there is invasion to the pelvic wall or other tissues outside the gynecological system. For central recurrence, previous studies have reported a LC rate of 76.9% after HDR ISBT, with a median post-recurrence survival of 32 months. 33 In contrast, the average survival for non-central pelvic recurrences is much worse, ranging from 7 to 9 months, and the 5-year survival rate can drop to 0%. 17 To date, no satisfactory or standardized salvage treatment for non-central recurrence has been established. 34 Although HDR ISBT has shown efficacy in about one-third of non-central recurrences, 35 pelvic exenteration for these cases has a high mortality rate, limiting its clinical application. 34 , 36 ISBT has been recommended for non-central recurrence, but its application has been restricted due to inadequate dosimetry. 37 Some studies suggest stereotactic body radiotherapy as an alternative for non-central recurrence, with 2-year OS, LFFS, and disease-free survival rates of 43%, 65%, and 52%, respectively. 38 , 39 In our study, 7 patients exhibited non-central recurrence patterns. With the development of individual curved-needles, the 1-year PFS and LC rates reached 100%, while the 2-year PFS and LC rates were 85.7%. These results suggest that the use of individual curved-needles, which provide greater flexibility in insertion angles, combined with EBRT and individual curved-needle interstitial high-dose rate brachytherapy using a 3D-printed applicator, represents an effective approach for treating non-central pelvic recurrence. In this study, patients did not experience severe toxicities after salvage treatment. No Grade > 3 acute toxicities were reported, which is lower than the 8% Grade > 3 toxicity observed in a previous study. 29 In our study, Grade 3 acute toxicities were observed in 30.8% of patients, which is acceptable compared to other studies. These included 23.1% hematological acute toxicities and 7.7% urinary toxicity, specifically urinary tract obstruction. Acute hematological, genital, and gastrointestinal toxicities tended to resolve from the duration of EBRT to brachytherapy. Furthermore, no Grade > 3 late toxicities were observed in this study. The use of individual curved-needles ISBT with a 3D-printed applicator demonstrated advantages in terms of late toxicities. Grade 1 to 2 late hematological, gastrointestinal, and urinary toxicities were observed in 38.5% of patients, while Grade 3 late genital toxicity occurred in 7.7% of patients during follow-up. In comparison, the median incidence of Grade ≥ 3 late toxicities was 18.5% in a systematic review by Bockel et al. on recurrent gynecological tumors treated with brachytherapy. 40 Additionally, Ren et al. 41 reported that 39.1% of patients experienced Grade 3 or 4 late toxicities after receiving image-guided HDR ISBT with or without EBRT. Among patients with recurrent cervical carcinoma, those who underwent re-irradiation had a higher likelihood of achieving favorable clinical outcomes. However, in-field recurrence tends to have a worse prognosis and unsatisfactory tumor response, with a median survival of 8 to 12.6 months. 42 , 43 Re-irradiation, with or without concurrent chemotherapy, is the first-line treatment option for patients with recurrent cervical cancer who have a history of radiation, 44 while surgery typically results in poor prognosis. 45 In this study, the 4 patients who underwent re-irradiation with EBRT and individual curved-needle ISBT using a 3D-printed applicator demonstrated good treatment efficacy, even though all of them had in-field recurrence. Their LFFS, with a median of 25 months (range 9–40 months), was superior to previously reported survival rates, with a 100% complete response. Regarding toxicities, comparisons of dosimetric results and the incidence of radiocystitis and factitial proctitis between patients with or without prior radiation suggest that re-irradiation carries a higher risk of late toxicities when similar doses are delivered. Receiving a higher parametrial dose during brachytherapy may contribute to the development of factitial proctitis, with a Grade 2–4 proctitis incidence rate of 27%. 46 In our study, 75% of the 4 re-irradiated patients received a parametrial boost through ISBT, and only Grade 2 proctitis was observed. Among the 4 re-irradiated patients, two reported no late toxicities, one reported Grade 1 to 2 late toxicities, and the remaining patient experienced Grade 3 late toxicity, a case of vesicovaginal fistula. Fistula formation is a known complication in re-irradiated patients with recurrent gynecological tumors, occurring in up to 51% of cases, with the incidence of Grade 4 fistula ranging from 6.7–27%. 47,48 In this study, one case of Grade 3 fistula was reported among the 4 re-irradiated patients, and the incidence and severity of fistula were relatively acceptable. Overall, the toxicities observed in the re-irradiated patients were relatively low and acceptable. To our knowledge, this is the first study to evaluate the efficacy and safety of individual curved-needles for ISBT in gynecological recurrence, particularly in refractory recurrent cases. However, there are several limitations to this study, including the relatively small sample size and the fact that it was conducted at a single center. Potential selection bias may have been introduced during the determination of treatment strategies. Additionally, patients' and tumors' characteristics, as well as the primary treatment approaches, varied significantly, making salvage treatments for recurrence highly individualized rather than uniform. This variability is more reflective of a real-world setting. Future studies should aim to identify favorable prognostic factors and ensure adequate local dose coverage, which could improve local control and offer survival benefits. Furthermore, the requirement for experienced oncologists and physicists, the use of 3D-printed applicators, and the challenges related to quality assurance cannot be overlooked, as these contribute to the high cost of the procedure. There is still room for improvement. In our study, only one patient underwent MRI-guided brachytherapy, and 69.2% of patients were contoured using CT images fused with MRI. MRI would be valuable for more precise positioning, providing clearer tumor delineation and better visualization of surrounding organs. This can lead to reduced procedure-related side effects and less reliance on the operator’s skills and experience. When using individual curved-needles, which allow for more precise and adjustable insertion, the incorporation of MRI may offer additional benefits compared to rigid needles. 16 , 49 Conclusion For patients with recurrent gynecologic cancers, the combination of EBRT and ISBT appears to be a relatively effective and safe treatment option. More importantly, the use of individual curved-needle ISBT with a 3D-printed applicator, which was first developed and evaluated in our study, may provide a solution for non-central recurrences or other complex recurrent cases. Initial outcomes and dosimetric results have shown promising findings, with good LC and acceptable toxicity. However, these results require further evaluation over the long term and validation through large-scale studies. Abbreviations three-dimensional (3D) clinical target volume (CTV) clinical target volume-brachytherapy (CTV-B) organs at risk (OARs) high-dose-rate (HDR) interstitial brachytherapy (ISBT) external beam radiation therapy (EBRT) equivalent doses in 2-Gy fractions (EQD2) overall survival (OS) progression-free survival (PFS) local failure free survival (LFFS) local control (LC) positron emission tomography-computed tomography (PET-CT) Magnetic resonance imaging (MRI) computed tomography (CT) International Federation of Gynecology and Obstetrics (FIGO) interquartile range (IQR) Declarations Ethics approval and consent to participate The ethics committee of Peking Union Medical College Hospital approved this study (Approval No. K3121) and waived the requirement for informed patient consent, as it was a retrospective analysis. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed for the present study are available from the corresponding author on reasonable request. Declaration of competing interest The authors state that they have no recognized financial conflicts or personal relationships that could have influenced the work presented in this paper. Funding This work was supported by National Key R&D Program of China, Ministry of Science and Technology of the People's Republic of China (Grant No. 2022YFC2407100, 2022YFC2407101) and National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-B-052 and 2022-PUMCH-B-127). Authors' contributions Z.Z. and Y.C. wrote the original draft of the manuscript. J.Z., C.L., and L.Y. conducted the investigation. All authors reviewed the manuscript. J.Y. conceptualized the study and supervised the project along with K.H. and F.Z. 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Radiat Oncol. 2024;19(1):70. Marar M, Niedermayr T, Kidd EA. Developing Next-Generation 3-Dimensional Printing for Cervical Cancer Hybrid Brachytherapy: A Guided Interstitial Technique Enabling Improved Flexibility, Dosimetry, and Efficiency. Int J Radiat Oncol Biol Phys. 2023;117(2):312–20. Zeng Z, Wang W, Liu X, et al. Optimal cisplatin cycles in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy. Clin Transl Oncol. 2023;25(10):2892–900. Wang W, Zhang F, Hu K, Hou X. Image-guided, intensity-modulated radiation therapy in definitive radiotherapy for 1433 patients with cervical cancer. Gynecol Oncol. 2018;151(3):444–8. Abusaris H, Storchi PR, Brandwijk RP, Nuyttens JJ. Second re-irradiation: efficacy, dose and toxicity in patients who received three courses of radiotherapy with overlapping fields. Radiother Oncol. 2011;99(2):235–9. Zolciak-Siwinska A, Bijok M, Jonska-Gmyrek J, et al. HDR brachytherapy for the reirradiation of cervical and vaginal cancer: analysis of efficacy and dosage delivered to organs at risk. Gynecol Oncol. 2014;132(1):93–7. Goto T, Kino N, Shirai T, Fujimura M, Takahashi M, Shiromizu K. Late recurrence of invasive cervical cancer: twenty years' experience in a single cancer institute. J Obstet Gynaecol Res. 2005;31(6):514–9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. services USdohah. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017. Cibula D, Dostalek L, Jarkovsky J, et al. Post-recurrence survival in patients with cervical cancer. Gynecol Oncol. 2022;164(2):362–9. Peiretti M, Zapardiel I, Zanagnolo V, Landoni F, Morrow CP, Maggioni A. Management of recurrent cervical cancer: a review of the literature. Surg Oncol. 2012;21(2):e59–66. Maneo A, Landoni F, Cormio G, et al. 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Li J, Huang L, Wu H, Li J, Cao X, Liu Z. Re-irradiation for recurrent cervical cancer: A single institutional experience. Clin Translational Radiation Oncol 2023; 43. Moolenaar LR, van Rangelrooij LE, van Poelgeest MIE, et al. Clinical outcomes of pelvic exenteration for gynecologic malignancies. Gynecol Oncol. 2023;171:114–20. Jurado M, Alcázar JL, Martinez-Monge R. Resectability rates of previously irradiated recurrent cervical cancer (PIRCC) treated with pelvic exenteration: Is still the clinical involvement of the pelvis wall a real contraindication? A twenty-year experience. Gynecol Oncol. 2010;116(1):38–43. Chiantera V, Rossi M, De Iaco P, et al. Survival after curative pelvic exenteration for primary or recurrent cervical cancer: a retrospective multicentric study of 167 patients. Int J Gynecol Cancer. 2014;24(5):916–22. Liu Y, Jiang P, Zhang H, Wang J. Safety and efficacy of 3D-printed templates assisted CT-guided radioactive iodine-125 seed implantation for the treatment of recurrent cervical carcinoma after external beam radiotherapy. J Gynecol Oncol. 2021;32(2):e15. Llewelyn M, Taylor A. Re-irradiation of cervical and endometrial cancer. Curr Opin Oncol. 2017;29(5):343–50. Seo Y, Kim M-S, Yoo H-J, et al. Salvage stereotactic body radiotherapy for locally recurrent uterine cervix cancer at the pelvic sidewall: Feasibility and complication. Asia-Pac J Clin Oncol. 2016;12(2):e280–8. Bockel S, Espenel S, Sun R et al. Image-Guided Brachytherapy for Salvage Reirradiation: A Systematic Review. Cancers (Basel) 2021; 13(6). Ren X, Fu Y, Liu Z, et al. Image-guided interstitial brachytherapy for recurrent cervical cancer after radiotherapy: A single institution experience. Front Oncol. 2022;12:943703. Beadle BM, Jhingran A, Yom SS, Ramirez PT, Eifel PJ. Patterns of Regional Recurrence After Definitive Radiotherapy for Cervical Cancer. Int J Radiation Oncology*Biology*Physics. 2010;76(5):1396–403. Yoshida K, Kajiyama H, Utsumi F, et al. A post-recurrence survival-predicting indicator for cervical cancer from the analysis of 165 patients who developed recurrence. Mol Clin Oncol. 2018;8(2):281–5. Small W, Bacon MA, Bajaj A, et al. Cervical cancer: A global health crisis. Cancer. 2017;123(13):2404–12. Hong JH, Tsai CS, Lai CH, et al. Recurrent squamous cell carcinoma of cervix after definitive radiotherapy. Int J Radiat Oncol Biol Phys. 2004;60(1):249–57. Huang E-Y, Lin H, Hsu H-C, et al. High External Parametrial Dose Can Increase the Probability of Radiation Proctitis in Patients with Uterine Cervix Cancer. Gynecol Oncol. 2000;79(3):406–10. Martínez-Monge R, Cambeiro M, Rodríguez-Ruiz ME, et al. Phase II trial of image-based high-dose-rate interstitial brachytherapy for previously irradiated gynecologic cancer. Brachytherapy. 2014;13(3):219–24. Murakami N, Kasamatsu T, Sumi M, et al. Vaginal tolerance of CT based image-guided high-dose rate interstitial brachytherapy for gynecological malignancies. Radiat Oncol. 2014;9:31. Sullivan T, Yacoub JH, Harkenrider MM, Small W, Surucu M, Shea SM. Providing MR Imaging for Cervical Cancer Brachytherapy: Lessons for Radiologists. RadioGraphics 2018; 38(3): 932 – 44. Tables Tables 1 to 6 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.docx Table5.docx Table6.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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10:41:36","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":14953,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.docx","url":"https://assets-eu.researchsquare.com/files/rs-6728229/v1/43bb0ff5e4d2c838892dad3b.docx"},{"id":85755048,"identity":"65a4d145-2cc1-4cdc-b92d-217c77449329","added_by":"auto","created_at":"2025-07-01 10:41:36","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":15124,"visible":true,"origin":"","legend":"","description":"","filename":"Table6.docx","url":"https://assets-eu.researchsquare.com/files/rs-6728229/v1/9b5c50d53b8b7fde7470fbeb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Development and assessment of interstitial brachytherapy using individual curved-needle in treatment of recurrent gynecological tumors after external beam radiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGynecological malignancies, which include uterine, cervical, ovarian, vaginal, and vulvar cancers, continue to pose a significant global public health burden, particularly in transitioning countries.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Standard treatment protocols have been established for each type of gynecological malignancy, and satisfactory prognoses have been achieved in recent decades.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e However, pelvic recurrence occurs in 5%-40% of cases, \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e and selecting an appropriate treatment approach\u0026mdash;whether surgery, radiotherapy, or systemic therapy\u0026mdash;remains challenging due to the lack of widely recognized recommendations. Additionally, the prognosis for patients with recurrence is generally poor.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Pelvic recurrence can be categorized into central and noncentral types.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Pelvic exenteration is the primary salvage therapy for central pelvic recurrence, with a 5-year overall survival (OS) rate of 20%-60%;\u003csup\u003e8\u003c/sup\u003e however, its surgical indication is limited to carefully selected patients and is generally associated with significant postoperative complications and diminished quality of life.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e For patients who are not candidates for surgery, radiation offers a reasonable alternative, though its efficacy often depends on the history of prior treatments and radiation \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSalvage radiation is considered safe and effective for out-field recurrence, but re-irradiation for in-field recurrence presents more challenges.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Recent studies have suggested that re-irradiation could be a viable salvage treatment option, with favorable clinical outcomes and acceptable toxicity, especially when external beam radiotherapy (EBRT) is followed by high-dose-rate (HDR) intracavity brachytherapy (with or without interstitial brachytherapy, ISBT). These studies have largely focused on central pelvic recurrence.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e For noncentral recurrence, the National Comprehensive Cancer Network guidelines recommend individualized EBRT as a treatment option.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e However, its therapeutic efficacy remains limited, with a 5-year survival rate of less than 10% compared to approximately 63% for central recurrence,\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e indicating an urgent need for more effective treatment strategies. ISBT could play a more significant role in improving treatment outcomes, with accurate needle insertion being a key factor in enhancing tumor response while minimizing radiation exposure to surrounding healthy tissues.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Despite this, current interstitial needles used in ISBT are generally straight or oblique, rigid, and inflexible. Most studies have focused on developing applicators or templates to improve the flexibility and efficiency of ISBT.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere remains a strong demand for both safe and effective treatment options for pelvic recurrence of gynecological malignancies. In this study, we focus on the combination of EBRT and ISBT for treating pelvic recurrence, particularly in cases of in-field recurrence, noncentral recurrence, and other refractory cases, where there is limited evidence supporting the efficacy and safety of current treatments. We developed individualized curved-needle ISBT with a 3D-printed applicator, hypothesizing that this method would improve targeting accuracy and reduce radiation injury to surrounding tissues compared to existing needle designs. We also investigated the clinical outcomes of this approach, as the current literature primarily consists of case reports or focuses mainly on dosimetric considerations.\u003c/p\u003e"},{"header":"Method and materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eThe study initially included 13 patients with recurrent gynecological malignancies treated at our institution between March 2022 and April 2024. The inclusion criteria were as follows: 1) pathologic confirmation of gynecological cancer, 2) pelvic recurrence, 3) inability to use standard brachytherapy applicators, and 4) the need for ISBT. The ethics committee of Peking Union Medical College Hospital approved the study (Approval No. K3121). The requirement for written informed consent was waived because of the retrospective nature of the study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEBRT\u003c/h3\u003e\n\u003cp\u003eFor treatment planning, imaging studies such as positron emission tomography-computed tomography (PET-CT), magnetic resonance imaging (MRI), and computed tomography (CT) were performed to assess the extent of the disease and define the target volume during pre-planning. Detailed descriptions of the specific radiation techniques used can be found in our previous studies.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe clinical target volume (CTV) was treated with volumetric modulated arc therapy to a median dose of 45 Gy (interquartile range [IQR] 45\u0026ndash;50.4 Gy) in 1.8\u0026ndash;2 Gy per fraction. The CTV was determined based on the location of the lesions and the patient\u0026rsquo;s radiotherapy history. A 0.6\u0026ndash;1 cm expansion was applied to the CTV to create the planning target volume to account for daily treatment setup variations.\u003c/p\u003e \u003cp\u003eFor patients without prior radiation, the treatment field covered the recurrent lesion, with expansion to high-risk regions and whole pelvic lymph node drainage. For the three patients with metastatic lymph nodes, a total dose of 60.2 Gy in 28 fractions (or 60 Gy in 25 fractions) was delivered to the planning gross tumor volume of the nodes, with a simultaneous integrated boost. The gross tumor volume of the nodes received a 5 mm margin to create the planning gross tumor volume.\u003c/p\u003e \u003cp\u003eFor patients with a history of radiation, the CTV included the recurrent lesion and the involved lymph node drainage. No patient underwent lymph node metastasis, then no lymph node boost was delivered.\u003c/p\u003e\n\u003ch3\u003eBrachytherapy\u003c/h3\u003e\n\u003cp\u003eCustomized 3D-printed applicators (Stratasys Ltd., Rehovot, Israel) were used for all patients undergoing brachytherapy. The vagina was packed with a thin contrast-soaked gauze strip, pre-soaked in diluted diatrizoate meglumine, ensuring it was thin enough to fill any gaps within the vaginal cavity. The patient underwent CT imaging, with or without MRI, depending on clinical indication. If MRI was performed, image fusion was utilized. The gross tumor volume and CTV were contoured by an experienced radiation oncologist. Catheters and needle paths were designed and optimized by experienced physicists based on the evaluation of the lesion after the CTV images were contoured. The 3D-printed applicators were fabricated, and quality assurance was performed through physical evaluation of material attenuation, path patency checks, and disinfection. Once the 3D-printed applicator was placed in the vagina, both pelvic CT and MRI simulations were performed to confirm the applicator's position. The HDR brachytherapy plan was then generated using the Oncentra brachytherapy treatment planning system (Elekta, Stockholm, Sweden), and the precise insertion depth from the applicator surface to the CTV delineation was estimated. ISBT was performed using individually curved needles (Elekta, Stockholm, Sweden), guided by the applicator. These needles are designed to be flexible and manually shaped and curved during the brachytherapy procedure. For each patient, individual needle with different insertion direction and angle could be adjusted according to the corresponding needle path design through evaluation of recurrence lesion. Examples of individual curved-needles and brachytherapy procedure were illustrated in Fig.\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eThe total doses (EBRT and brachytherapy) were converted to the biologically equivalent doses in 2-Gy fractions (EQD2) using the linear-quadratic model with an α/β of 10 Gy for tumor control and 3 Gy for late normal tissue damage. The goal for organs at risk (OARs) was a cumulative dose to D2cc of bladder\u0026thinsp;\u0026le;\u0026thinsp;90 Gy, sigmoid\u0026thinsp;\u0026le;\u0026thinsp;75 Gy, and rectum\u0026thinsp;\u0026le;\u0026thinsp;75 Gy. Considering the interval between two radiations and tissue recovery, a dose reduction of 50% is allowed for re-irradiation if it occurs 12 months after the last treatment. For re-irradiation between 6 and 12 months, a 25% dose reduction is recommended, while re-irradiation within 6 months should be avoided\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Therefore, the study suggests that a D2cc of \u0026le;\u0026thinsp;110 Gy for the bladder, \u0026le; 100 Gy for the sigmoid, and \u0026le;\u0026thinsp;100 Gy for the rectum is considered safe for re-irradiation\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCT or MRI guided 3D brachytherapy with a dose schedule of 10\u0026ndash;30 Gy in 2\u0026ndash;5 fractions began after EBRT. The delineation of the clinical target volume - brachytherapy (CTV-B) was based on imaging results and clinical findings, where lymph nodes would not be included. The following dose-volume parameters were calculated for the CTV-B and OARs: the percentage of the CTV receiving 100% of the prescribed dose (V100) and the dose covering 90%, 98%, and 100% of the target volume (D90, D98, and D100, respectively). Additionally, the D0.1cc, D2cc, and D5cc values were calculated for the rectum, sigmoid and bladder.\u003c/p\u003e\n\u003ch3\u003eSystemic therapy\u003c/h3\u003e\n\u003cp\u003eSome patients received concurrent systemic therapy. Systemic therapy was delivered in two phases: during radiation (concurrent), and following radiation (maintain). Maintenance systemic therapy as planned treatment administered after radiation completion. Concurrent systemic therapy was provided as needed. The most common regimen was weekly cisplatin. The remaining regimens included cisplatin and paclitaxel, carboplatin and paclitaxel, targeted therapy, and immunotherapy.\u003c/p\u003e\n\u003ch3\u003eFollowup\u003c/h3\u003e\n\u003cp\u003eFollowing the completion of treatment, the first follow-up evaluation was conducted one month after treatment. Patients were then examined every three months for the first two years, followed by every six months for the next two years, and annually thereafter. Routine follow-up assessments included gynecological examinations, complete blood count, liver and kidney function tests, thoracic and abdominal CT scans, pelvic MRI or CT scans, and serum tumor marker tests (squamous cell carcinoma antigen, carcinoembryonic antigen, cancer antigen 125, or cancer antigen 199). If recurrence or metastasis is suspected, a PET-CT scan will be performed if necessary.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSPSS 27.0 (IBM. Corp, New York, USA) and Prism 9.0 (GraphPad Software, USA) were utilized for data analysis. The Kaplan-Meier method was used to analyze OS, progression-free survival (PFS) and local failure free survival (LFFS). OS was calculated from the date of recurrence to the date of death from any cause or of the last clinical follow-up. PFS was defined as the time interval between the start of recurrence treatment and any disease progression. LFFS was defined as the time interval between the start of recurrence treatment and the local failure. The independent samples t-test was utilized to compare normally distributed quantitative data. All statistics were two-sided tests, and the level of significance was 0.05. Local tumor response after radiotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Treatment-related complications were graded according to the Common Terminology Criteria for Adverse Events version 5.0.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cstrong\u003ePatient and treatment characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe final analysis included 13 patients with a 100% follow-up. The clinical characteristics of the patients related to their primary tumor treatment are detailed in Table 1. The primary tumor types were cervical cancer [9, 69.2%; International Federation of Gynecology and Obstetrics (FIGO) stage: 2 for IA, 2 for IB, 2 for IIB, 2 for IIIA, 1 for IIIB], endometrial cancer (2, 15.4%; FIGO stage: 1 for IA, 1 for IIIA), vaginal cancer (1, 7.7%, FIGO stage II) and endometrial sarcoma (1, 7.7%; high grade endomerial stromal sarcoma). Of the patients, for the treatment of their primary tumor, 9 (69.2%) underwent surgery, 6 (46.2%) received systemic therapy, and 4 (30.8%) were treated with radiation therapy.\u003c/p\u003e\n\u003cp\u003eThe median interval between primary diagnosis and recurrence was 29 (range 5–420) months. The recurrent gynecological cancer treatment characteristics were detailed in Table 2. Among the included patients, 4 (30.7%) patients receiving re-irradiation, the recurrence were all in-field recurrence. As regard to the classification of recurrence, there were 6 central recurrence and 7 noncentral recurrence.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor recurrence site, 9 patients (69.2%) had vaginal recurrence, 6 patients (46.2%) had parametrial recurrence, 5 patients (38.5%) had pelvic LN metastasis, 3 patients (23.1%) had cervical recurrence, and one patient (7.7%) had recurrence at uterine body. 10 patients (76.9%) had multiple recurrence location, including uterine body, cervix, parametria, vagina, and pelvic LN. The mean distance between the farthest margin of recurrence site and center of the vaginal stump was 4.33 cm (range 3.28-5.47 cm).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients were treated with EBRT. The median total external radiation dose was 45 Gy (IQR 45–50.4) given in 1.8 Gy per fraction (IQR 1.8–2.0). During brachytherapy the number of needles for each patient ranged from 2 to 6 with a median of 3, while the option of type of needles was based on actual clinical situation, and individual curved-needles account for 92.7% in the total 41 insertion needles. 76.9% patient used all individual curved-needles for insertion while the other (3 patients, 23.1%) used both individual curved-needles and rigid needles. The median total insertion depth of needles was 10.6 cm per fraction, ranging from 2.4-16.7 cm. The median insertion depth of individual curved-needles was 3.1 cm (range 1-5cm) with maximum angles ranging from 7 to 40 degrees, while the median insertion depth of rigid needles was 1.5 cm. A representative interstitial brachytherapy case for individual curved-needles design and real practice was illustrated in Figure 2. A majority of patients (92.3%) were treated with CT guided brachytherapy, while 69.2% treatment plan was designed in accordance with MRI. The median total brachytherapy dose was 20 Gy (IQR 13.5–23.5) given in 6 Gy per fraction (IQR 5.3–6.0).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5 patients (38.5%) received concurrent chemotherapy, 1 patient (7.7%) received concurrent chemotherapy combined with targeted therapy, and 1 patient (7.7%) received concurrent chemotherapy combined with immunotherapy. Only 1 patient (7.7%) received immunotherapy as maintenance treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDosimetric outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 45 brachytherapy fractions were administered to 13 patients. The mean cumulative EQD2 to the CTV for recurrence treatment was 64.87 ± 7.16 Gy for patients with a history of prior radiation and 73.03 ± 9.95 Gy for those without prior radiation. Among the cohort, 9 patients (69.2%) received doses greater than 65 Gy, with 8 of these patients belonging to the group without prior radiation history. Among the remaining 4 patients receiving a cumulative EQD2 for recurrence treatment of less than 65 Gy, three of them had prior radiation history and the dose delivery was restricted under consideration of the OARs. For the 4 patients with prior radiation history and the 9 patients without, the mean cumulative EQD2 to the D2cc of the OARs for recurrence treatment were as follows: for the bladder, 63.98±11.37 Gy and 79.00±12.34 Gy; for the rectum, 61.93±8.90 Gy and 68.44±9.93 Gy; and for the sigmoid, 41.22±20.79 Gy and 54.49±7.45 Gy, respectively. For brachytherapy, the average per fraction and EQD2 values for D100%, D98%, D90%, and D50% for CTV-B, as well as D5cc, D2cc, and D0.1cc for OARs, are detailed in Tables 3 and 4 for patients with and without prior radiation history, respectively.\u003c/p\u003e\n\u003cp\u003eDuring brachytherapy, the average CTV-B D90% per fraction was 5.61 ± 0.67 Gy for patients with prior radiation history and 5.78 ± 0.64 Gy for those without. The corresponding average CTV-B EQD2 values were 22.90 ± 6.04 Gy and 24.98 ± 9.61 Gy, respectively. These doses were found to meet the clinical prescription requirements, as illustrated in Figure 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor response and survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients are alive at a median follow-up of 25 months (range 9-40). Of these, 10 (76.9%) remain in continuous complete remission, 1 (7.7%) shows a partial response without progression, and 2 (15.4%) have progressive disease. Regarding local tumor control, 11 (84.6%) are in continuous complete remission, 1 (7.7%) shows a partial response, and 1 (7.7%) has progressive disease. One patient developed lung metastasis and a new in-field vaginal recurrence, while another had multiple out-field metastases. The 1-year local control (LC) rate was 100%, with a 2-year LC rate of 91.7%. The 1-year and 2-year OS rates were both 100%. The 1-year PFS rate was 92.3%, and the 2-year PFS rate was 83.9%, as shown in Figure 4. All 4 patients who underwent re-irradiation achieved complete response, with 100% 1-year OS and PFS rates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToxicities\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant bleeding, infection, or other major complications related to the insertion procedure were observed during or after brachytherapy. Acute and late toxicities from the treatment are summarized in Table 5. The most common acute toxicity observed in these patients was hematologic toxicity, particularly leukopenia. Four patients (30.8%) experienced grade 3 hematological toxicities, and only 1 patient (4%) developed grade 3 urinary toxicity. No grade 3–5 acute gastrointestinal or genital toxicities occurred. For late toxicities, no grade \u0026gt;3 toxicities were observed. The only reported grade 3 late toxicity was a vesicovaginal fistula in 1 case (7.7%). Grade 2 toxicities were observed in 3 (23.1%) patients.\u003c/p\u003e\n\u003cp\u003eA trend was observed where, after the initiation of brachytherapy, adverse events were reduced to a lower grade compared to the duration of EBRT. The detailed incidences of adverse events during EBRT and brachytherapy are summarized in Table 6. During EBRT, diarrhea was reported in 5 (38.4%) patients: 2 (15.4%) had grade 1, and 3 (23.1%) had grade 2. After brachytherapy began, the incidence of diarrhea reduced to 7.7% (n=1, grade 1). No genital toxicity was observed during brachytherapy, and grade 1 pelvic pain, vaginal hemorrhage, vaginal dryness, and vaginal discharge reported during EBRT in 3 (23.1%) patients were relieved. Brachytherapy was performed without acute complications in 5 (38.5%) patients, and no acute grade ≥3 toxicities occurred, except for one case of grade 3 urinary tract obstruction, which was not observed during EBRT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRe-irradiation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 4 patients who underwent re-irradiation, one reported no acute or late toxicities, one reported no late toxicity but experienced grade 1–2 acute toxicities, one reported grade 1–2 adverse events for both acute and late toxicities, and the remaining patient reported grade 1–2 acute toxicities and grade 3 late toxicity. The only grade 3 late toxicity observed among all 13 patients was a case of vesicovaginal fistula in a re-irradiated patient. There was a significant difference in the incidence of radiocystitis between patients who received re-irradiation and those without a history of radiation (p = 0.027) (Figure 5A). The rates of factitial proctitis were higher in patients receiving re-irradiation than in those without a radiation history, although the difference was not statistically significant (p = 0.174) (Figure 5B).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFailure of primary treatment for gynecological tumors is associated with a poor prognosis for subsequent recurrence treatment.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Recurrence can be classified into intra-pelvic and extra-pelvic types. Treatment for pelvic recurrence is particularly challenging due to the proximity of surrounding OARs and the large, complex shape of the recurrent tumor. There is no optimal or standard approach for managing pelvic recurrence, especially for patients who are inoperable or have a history of radiation.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Treatment options typically include salvage surgery, radiotherapy, chemotherapy, and other systemic therapies.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Most patients are not recommended for surgery. Pelvic exenteration is suggested for select patients, offering a 5-year survival rate ranging from 21\u0026ndash;73%, but the resectability rate is less than 20%, and postoperative complications are frequent.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e EBRT, with or without chemotherapy, is generally better tolerated by patients, but the outcomes are often unsatisfactory.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e However, when combined with brachytherapy, it holds potential for both tumor remission and the preservation of OARs.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe current improvements in ISBT accuracy in previous studies have primarily focused on templates, applicators, and various image guidance technologies to adapt to straight and oblique needles, but not to individually curved needles. Our prior studies concentrated on the development and evaluation of a 3D-printed applicator with rigid, straight needles. A previous study reported that the use of the 3D-printed applicator in patients with gynecological cancer post-hysterectomy since 2017 resulted in superior CTV coverage and dose distribution compared to the multichannel cylinder in intracavity brachytherapy. Specifically, it achieved higher CTV and CTV-1cm V100% of 90.02% and 81.85%, and lower bladder and rectum D0.1cc doses of 4.63 Gy and 4.57 Gy, respectively.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e The 3D-printed applicator in intracavity\u0026thinsp;\u0026plusmn;\u0026thinsp;ISBT also showed satisfactory clinical outcomes with acceptable toxicities, but it mainly focused on central pelvic recurrence and patients who underwent primary hysterectomy, with ISBT performed using straight metal needles.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study further developed individually curved needles capable of adjusting angles for more flexible insertions. For each patient, the insertion direction, curvature angle, and needle path were tailored in real time based on the location, depth, and geometry of the recurrent tumor, as assessed by pre-procedural imaging and intraoperative findings. This flexibility allowed for more precise coverage of irregularly shaped or anatomically challenging lesions, while minimizing damage to adjacent organs at risk. The introduction of individually curved needles addresses the limitations of straight, rigid needles, which are difficult to use for noncentral recurrences or recurrences at the uterine body, where the insertion must bypass the bladder. With these curved needles, this study included 13 patients with recurrent gynecological tumors, 53.8% of whom had noncentral recurrence. The study also included patients with no surgery history or a history of prior radiation. Compared to our prior study using straight metal needles with insertion depths ranging from 1.8 to 3 cm, this study achieved deeper insertion depths, with a median of 3.1 cm at variable angles (7 to 40 degrees) in the 45 ISBT fractions.\u003c/p\u003e \u003cp\u003eIn this study, the use of individual curved-needle ISBT with 3D-printed applicators resulted in excellent tumor control. The 2-year LC, PFS, and OS rates were 91.7%, 83.9%, and 100%, respectively. The objective response rate was 84.6% for all patients and 92.3% for local tumors during the follow-up period. The mean cumulative EQD2 to CTV D90 was 64.87\u0026thinsp;\u0026plusmn;\u0026thinsp;7.16 Gy for patients with a history of radiation and 73.03\u0026thinsp;\u0026plusmn;\u0026thinsp;9.95 Gy for those without prior radiation. Previous studies on brachytherapy for pelvic recurrence reported a 2-year LC rate ranging from 60\u0026ndash;87.8%, with a CTV D90 of \u0026gt;\u0026thinsp;65 Gy being associated with favorable LC outcomes.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e In our study, the LC rate was higher compared to previous studies, and the mean cumulative EQD2 of CTV D90 exceeded 65 Gy, particularly in patients without prior radiation therapy.\u003c/p\u003e \u003cp\u003eIntra-pelvic recurrences can be further categorized into central and non-central recurrences, based on whether there is invasion to the pelvic wall or other tissues outside the gynecological system. For central recurrence, previous studies have reported a LC rate of 76.9% after HDR ISBT, with a median post-recurrence survival of 32 months.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e In contrast, the average survival for non-central pelvic recurrences is much worse, ranging from 7 to 9 months, and the 5-year survival rate can drop to 0%.\u003csup\u003e17\u003c/sup\u003e To date, no satisfactory or standardized salvage treatment for non-central recurrence has been established.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e Although HDR ISBT has shown efficacy in about one-third of non-central recurrences,\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e pelvic exenteration for these cases has a high mortality rate, limiting its clinical application.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e ISBT has been recommended for non-central recurrence, but its application has been restricted due to inadequate dosimetry.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e Some studies suggest stereotactic body radiotherapy as an alternative for non-central recurrence, with 2-year OS, LFFS, and disease-free survival rates of 43%, 65%, and 52%, respectively.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e In our study, 7 patients exhibited non-central recurrence patterns. With the development of individual curved-needles, the 1-year PFS and LC rates reached 100%, while the 2-year PFS and LC rates were 85.7%. These results suggest that the use of individual curved-needles, which provide greater flexibility in insertion angles, combined with EBRT and individual curved-needle interstitial high-dose rate brachytherapy using a 3D-printed applicator, represents an effective approach for treating non-central pelvic recurrence.\u003c/p\u003e \u003cp\u003eIn this study, patients did not experience severe toxicities after salvage treatment. No Grade\u0026thinsp;\u0026gt;\u0026thinsp;3 acute toxicities were reported, which is lower than the 8% Grade\u0026thinsp;\u0026gt;\u0026thinsp;3 toxicity observed in a previous study.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e In our study, Grade 3 acute toxicities were observed in 30.8% of patients, which is acceptable compared to other studies. These included 23.1% hematological acute toxicities and 7.7% urinary toxicity, specifically urinary tract obstruction. Acute hematological, genital, and gastrointestinal toxicities tended to resolve from the duration of EBRT to brachytherapy. Furthermore, no Grade\u0026thinsp;\u0026gt;\u0026thinsp;3 late toxicities were observed in this study. The use of individual curved-needles ISBT with a 3D-printed applicator demonstrated advantages in terms of late toxicities. Grade 1 to 2 late hematological, gastrointestinal, and urinary toxicities were observed in 38.5% of patients, while Grade 3 late genital toxicity occurred in 7.7% of patients during follow-up. In comparison, the median incidence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 late toxicities was 18.5% in a systematic review by Bockel et al. on recurrent gynecological tumors treated with brachytherapy. \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Additionally, Ren et al.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e reported that 39.1% of patients experienced Grade 3 or 4 late toxicities after receiving image-guided HDR ISBT with or without EBRT.\u003c/p\u003e \u003cp\u003eAmong patients with recurrent cervical carcinoma, those who underwent re-irradiation had a higher likelihood of achieving favorable clinical outcomes. However, in-field recurrence tends to have a worse prognosis and unsatisfactory tumor response, with a median survival of 8 to 12.6 months.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Re-irradiation, with or without concurrent chemotherapy, is the first-line treatment option for patients with recurrent cervical cancer who have a history of radiation,\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e while surgery typically results in poor prognosis.\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e In this study, the 4 patients who underwent re-irradiation with EBRT and individual curved-needle ISBT using a 3D-printed applicator demonstrated good treatment efficacy, even though all of them had in-field recurrence. Their LFFS, with a median of 25 months (range 9\u0026ndash;40 months), was superior to previously reported survival rates, with a 100% complete response. Regarding toxicities, comparisons of dosimetric results and the incidence of radiocystitis and factitial proctitis between patients with or without prior radiation suggest that re-irradiation carries a higher risk of late toxicities when similar doses are delivered. Receiving a higher parametrial dose during brachytherapy may contribute to the development of factitial proctitis, with a Grade 2\u0026ndash;4 proctitis incidence rate of 27%.\u003csup\u003e46\u003c/sup\u003e In our study, 75% of the 4 re-irradiated patients received a parametrial boost through ISBT, and only Grade 2 proctitis was observed. Among the 4 re-irradiated patients, two reported no late toxicities, one reported Grade 1 to 2 late toxicities, and the remaining patient experienced Grade 3 late toxicity, a case of vesicovaginal fistula. Fistula formation is a known complication in re-irradiated patients with recurrent gynecological tumors, occurring in up to 51% of cases, with the incidence of Grade 4 fistula ranging from 6.7\u0026ndash;27%.\u003csup\u003e47,48\u003c/sup\u003e In this study, one case of Grade 3 fistula was reported among the 4 re-irradiated patients, and the incidence and severity of fistula were relatively acceptable. Overall, the toxicities observed in the re-irradiated patients were relatively low and acceptable.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study to evaluate the efficacy and safety of individual curved-needles for ISBT in gynecological recurrence, particularly in refractory recurrent cases. However, there are several limitations to this study, including the relatively small sample size and the fact that it was conducted at a single center. Potential selection bias may have been introduced during the determination of treatment strategies. Additionally, patients' and tumors' characteristics, as well as the primary treatment approaches, varied significantly, making salvage treatments for recurrence highly individualized rather than uniform. This variability is more reflective of a real-world setting. Future studies should aim to identify favorable prognostic factors and ensure adequate local dose coverage, which could improve local control and offer survival benefits. Furthermore, the requirement for experienced oncologists and physicists, the use of 3D-printed applicators, and the challenges related to quality assurance cannot be overlooked, as these contribute to the high cost of the procedure. There is still room for improvement. In our study, only one patient underwent MRI-guided brachytherapy, and 69.2% of patients were contoured using CT images fused with MRI. MRI would be valuable for more precise positioning, providing clearer tumor delineation and better visualization of surrounding organs. This can lead to reduced procedure-related side effects and less reliance on the operator\u0026rsquo;s skills and experience. When using individual curved-needles, which allow for more precise and adjustable insertion, the incorporation of MRI may offer additional benefits compared to rigid needles.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFor patients with recurrent gynecologic cancers, the combination of EBRT and ISBT appears to be a relatively effective and safe treatment option. More importantly, the use of individual curved-needle ISBT with a 3D-printed applicator, which was first developed and evaluated in our study, may provide a solution for non-central recurrences or other complex recurrent cases. Initial outcomes and dosimetric results have shown promising findings, with good LC and acceptable toxicity. However, these results require further evaluation over the long term and validation through large-scale studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ethree-dimensional (3D)\u003c/p\u003e\n\u003cp\u003eclinical target volume (CTV)\u003c/p\u003e\n\u003cp\u003eclinical target volume-brachytherapy (CTV-B)\u003c/p\u003e\n\u003cp\u003eorgans at risk (OARs)\u003c/p\u003e\n\u003cp\u003ehigh-dose-rate (HDR)\u003c/p\u003e\n\u003cp\u003einterstitial brachytherapy (ISBT)\u003c/p\u003e\n\u003cp\u003eexternal beam radiation therapy (EBRT)\u003c/p\u003e\n\u003cp\u003eequivalent doses in 2-Gy fractions (EQD2)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eoverall survival (OS)\u003c/p\u003e\n\u003cp\u003eprogression-free survival (PFS)\u003c/p\u003e\n\u003cp\u003elocal failure free survival (LFFS)\u003c/p\u003e\n\u003cp\u003elocal control (LC)\u003c/p\u003e\n\u003cp\u003epositron emission tomography-computed tomography (PET-CT)\u003c/p\u003e\n\u003cp\u003eMagnetic resonance imaging (MRI)\u003c/p\u003e\n\u003cp\u003ecomputed tomography\u0026nbsp;(CT)\u003c/p\u003e\n\u003cp\u003eInternational Federation of Gynecology and Obstetrics (FIGO)\u003c/p\u003e\n\u003cp\u003einterquartile range (IQR)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethics committee of Peking Union Medical College Hospital approved this study\u0026nbsp;(Approval No. K3121)\u0026nbsp;and waived the requirement for informed patient consent, as it was a retrospective analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed for the present study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors state that they have no recognized financial conflicts or personal relationships that could have influenced the work presented in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by National Key R\u0026amp;D Program of China, Ministry of Science and Technology of the People's Republic of China (Grant No. 2022YFC2407100, 2022YFC2407101) and National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-B-052 and 2022-PUMCH-B-127).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZ.Z. and Y.C. wrote the original draft of the manuscript. J.Z., C.L., and L.Y. conducted the investigation. All authors reviewed the manuscript. J.Y. conceptualized the study and supervised the project along with K.H. and F.Z. Z.Z. and Y.C. performed the formal analysis and developed the methodology. Data were curated by Z.Z., Y.C., and J.Z. Resources were provided by Y.S., B.Z., and L.Y.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2024;74(3):229\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNCCN Clinical Practice. 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Asia-Pac J Clin Oncol. 2016;12(2):e280\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBockel S, Espenel S, Sun R et al. Image-Guided Brachytherapy for Salvage Reirradiation: A Systematic Review. Cancers (Basel) 2021; 13(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRen X, Fu Y, Liu Z, et al. Image-guided interstitial brachytherapy for recurrent cervical cancer after radiotherapy: A single institution experience. Front Oncol. 2022;12:943703.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeadle BM, Jhingran A, Yom SS, Ramirez PT, Eifel PJ. Patterns of Regional Recurrence After Definitive Radiotherapy for Cervical Cancer. Int J Radiation Oncology*Biology*Physics. 2010;76(5):1396\u0026ndash;403.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida K, Kajiyama H, Utsumi F, et al. A post-recurrence survival-predicting indicator for cervical cancer from the analysis of 165 patients who developed recurrence. Mol Clin Oncol. 2018;8(2):281\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmall W, Bacon MA, Bajaj A, et al. Cervical cancer: A global health crisis. Cancer. 2017;123(13):2404\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHong JH, Tsai CS, Lai CH, et al. Recurrent squamous cell carcinoma of cervix after definitive radiotherapy. Int J Radiat Oncol Biol Phys. 2004;60(1):249\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang E-Y, Lin H, Hsu H-C, et al. High External Parametrial Dose Can Increase the Probability of Radiation Proctitis in Patients with Uterine Cervix Cancer. Gynecol Oncol. 2000;79(3):406\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;nez-Monge R, Cambeiro M, Rodr\u0026iacute;guez-Ruiz ME, et al. Phase II trial of image-based high-dose-rate interstitial brachytherapy for previously irradiated gynecologic cancer. Brachytherapy. 2014;13(3):219\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurakami N, Kasamatsu T, Sumi M, et al. Vaginal tolerance of CT based image-guided high-dose rate interstitial brachytherapy for gynecological malignancies. Radiat Oncol. 2014;9:31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSullivan T, Yacoub JH, Harkenrider MM, Small W, Surucu M, Shea SM. Providing MR Imaging for Cervical Cancer Brachytherapy: Lessons for Radiologists. \u003cem\u003eRadioGraphics\u003c/em\u003e 2018; 38(3): 932\u0026thinsp;\u0026ndash;\u0026thinsp;44.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Recurrent gynecological tumor, Interstitial brachytherapy, Individual curved-needles, Clinical outcomes","lastPublishedDoi":"10.21203/rs.3.rs-6728229/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6728229/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo evaluate the efficacy and safety of individualized curved-needle interstitial brachytherapy (ISBT) using 3D printing for recurrent gynecologic tumors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod:\u003c/strong\u003e This study enrolled patients with pelvic recurrent gynecologic tumors from March 2022 to April 2024. All patients received external beam radiotherapy (EBRT) (40-60 Gy, 20-30 fractions), followed by individualized curved-needle ISBT using a 3D-printed applicator (12-30 Gy, 2-5 fractions). Concurrent systemic therapy was administered when necessary. Dosimetric parameters (V100%, V200%, D100%, D98%, D90%, D50%, D5cc, D2cc, D0.1cc) were assessed. Clinical outcomes and treatment-related complications were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e45 fractions of ISBT were analyzed. Central and non-central pelvic recurrences occurred in 46.2% and 53.8% of patients, respectively. Eight patients received concurrent systemic therapy. The cumulative equivalent dose to the gross tumor volume of recurrence treatment was 64.87 ± 7.16 Gy for patients with prior radiation and 73.03 ± 9.95 Gy for others. The cumulative equivalent dose to D2cc in brachytherapy for patients with vs. without prior radiation was 19.75 ± 8.92 Gy vs. 21.65 ± 9.49 Gy for the bladder, 13.23 ± 2.81 Gy vs. 15.25 ± 6.82 Gy for the rectum, and 9.09 ± 5.85 Gy vs. 8.23 ± 5.09 Gy for the sigmoid colon. At a median follow-up of 25 months, 100% of patients were alive. The objective response rate was 84.6%, with 91.7% local control at 2 years. Acute Grade 3 toxicity was observed in 30.8%, and late Grade 3 toxicity in 7.7%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIndividualized curved-needle ISBT with a 3D-printed applicator provides high-quality treatment for recurrent gynecologic tumors with favorable outcomes and acceptable toxicity.\u003c/p\u003e","manuscriptTitle":"Development and assessment of interstitial brachytherapy using individual curved-needle in treatment of recurrent gynecological tumors after external beam radiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 10:33:31","doi":"10.21203/rs.3.rs-6728229/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"836e04c7-41e2-4e69-9466-3b4d10e407b0","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-15T13:55:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-01 10:33:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6728229","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6728229","identity":"rs-6728229","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}