Incidence of pelvic fractures after definitive radiotherapy for cervical cancer: A retrospective multi-center cohort study: IPFAR study

Incidence of pelvic fractures after definitive radiotherapy for cervical cancer: A retrospective multi-center cohort study: IPFAR study | 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 Incidence of pelvic fractures after definitive radiotherapy for cervical cancer: A retrospective multi-center cohort study: IPFAR study Shinsuke Shirakawa, Shoji Nagao, Kotaro Yoshio, Toshiharu Mitsuhashi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5779783/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 Background This multicenter study aimed to identify risk factors for pelvic insufficiency fractures (PIFs) in women who received definitive radiotherapy (RT) as initial treatment for cervical cancer and to were examine differences in the incidence of PIFs across institutions. Methods Medical records of 208 women who received definitive RT as the initial treatment for cervical cancer at four institutions between January 2016 and December 2018 reviewed. Results The median age was 61.5 years (range: 29–93 years). Overall, 59 patients (28.4%) developed PIF, 48 (81.4%) of them within two years from completion of RT. Multivariate analysis identified menopausal status, as well as the institution where RT was performed, as independent risk factors for PIF. The incidences of PIF were 19.8%, 33.9%, 18.9%, and 50% in Institution A, B, C, and D, respectively. The hazard ratio for Institution D (based on Institution A) was 1.214 (95% confident interval: 1.015–1.412). However, no statistically significant differences in patient backgrounds or RT details were observed among institutions. Conclusions Despite targeting the same population and implementing similar RT treatment protocols, significant differences in PIF rates were observed among institutions. Caution should be exercised when making direct comparisons between institutions. cervical cancer radiotherapy pelvic insufficiency fracture risk factor Figures Figure 1 Figure 2 1. Introduction Radiotherapy (RT) for cervical cancer causes pelvic insufficiency fractures (PIFs) in 10–29% of patients [ 1 – 5 ]. More than 80% of them develop PIF within 2 years after completion of RT, and more than half of whom have symptoms such as chronic pain [ 6 ]. The chronic pain significantly impairs patient quality of life long following completion of cancer treatment, and narcotic painkillers are generally required for pain relief [ 6 ]. Previous research has suggested that age, menopausal status, and a lower BMI are risk factors for PIF [ 6 – 9 ]. Additionally, definitive RT has been identified as a risk factor for PIF [ 6 , 9 ]. As aforementioned, previous studies regarding “PIF after RT for cervical cancer” showed a wide variation in PIF incidence. Most of these reports were from single institutions, and differences in patients’ backgrounds likely caused such large variations. Factors that may have contributed include age distribution, race, region, medical history, RT protocols, and diagnostic methods for PIF. Therefore, we decided to investigate PIF caused by RT for cervical cancer in a multicenter setting, considering these background factors. This study involved four institutions in a relatively small area of Japan that provide RT under a similar protocol, and the diagnosis of PIF was reconfirmed based on strictly defined diagnostic criteria. The purpose of this study was to determine whether there were any inter-institutional differences in the incidence of PIF after adjusting for background conditions, and, if so, to clarify the causes of such differences. 2. Patients and methods This study is a multi-center case-control study targeting patients who have undergone RT for cervical cancer. 2.1. Patients Four institutions—Okayama University, Hiroshima City Hospital, Fukuyama Medical Center, and Kagawa Prefectural Central Hospital (58, 38, 19, and 16 patients treated for cervical cancer in 2018, respectively)—participated in this multicenter study. We reviewed medical records of women diagnosed with cervical cancer through pathological examination and received definitive RT as initial treatment at four institutions between January 2016 and December 2018. The participating institutions are all located within the same medical region and have distinct teams of gynecologic oncologists and radiologists. All patients who received RT alone or concurrent chemoradiotherapy (CCRT) were eligible for inclusion, regardless of whether they received a lymph node boost, underwent high-dose-rate intracavitary brachytherapy (HDR-ICBT), used center shield, or were treated volumetric modulated arc therapy (VMAT) or intensity modulated radiation therapy (IMRT). Patients who received RT as adjuvant RT after surgery, those who received RT for recurrent disease, those who could not complete the scheduled RT, and those who did not receive appropriate follow-up after treatment were excluded. 2.2. Method of data collection We reviewed the medical records of eligible women and extracted the necessary information including patient background, disease status, treatment details, and occurrence of PIF and analyzed. 2.3. Follow-up and diagnosis of PIF After the completion of RT, all patients received medical examination approximately every 3 months for the first 2 years, every 6 months for the next 3 years. Radiological imaging tests including computed tomography (CT) and magnetic resonance imaging (MRI) were performed every 6 months for the first 2 years, then every 12 months for the next 3 years. In conducting this study, all CT or MRI images were reviewed under the uniform PIF diagnostic criteria by diagnostic imaging specialists at each institution; the diagnosis of PIF was made by CT or MRI when a PIF was identified in the RT field. Slight changes in bone colouration within the irradiated field were also diagnosed as PIF, regardless of the presence of absence of clinical symptoms such as back or pelvic pain. Fractures secondary to bone metastasis were excluded. 2.4. Data analysis The collected data was analyzed under the supervision of a biostatistician. Descriptive statistics were calculated for both the PIF and non-PIF groups. The Mann-Whitney U tests were applied for comparison. We further performed descriptive statistics for the number of patients, age, menopausal status, BMI, medical history, drug history, FIGO stage (2018), combination with chemotherapy, PIF rate, and painkiller use at each institution. We calculated the PIF rate after RT at each institution and analyzed them using the Kaplan–Meier method. PIF was treated as an event, and in cases of death or disease progression were treated as dropouts. Each factor was assessed using a Cox regression analysis with hazard models (multivariate analysis). Inverse Probability Weighting was used to correct for bias in multivariate analysis. Statistical analyses were performed using IBM SPSS Statistics (version 29.0; IBM Corp., Armonk, NY). Statistical significance was set at p-value < 0.05. 2.5. Ethics This study was conducted in accordance with the declaration of Helsinki. In this study, we are careful to ensure that individual names will not be identified by third parties, and participation is voluntary, with the opportunity to refuse participation in the study. This study has been approved by the Clinical Research Ethics Review Committee of Okayama University Hospital (No.2203-045). 3. Results 3.1. RT Table 1 shows the basic RT conditions of each institution. All institutions performed RT in accordance with the Japanese guidelines for RT, and there was no significant difference in the equipment used [ 10 ]. The patients were treated with a combination of external irradiation and intracavitary brachytherapy (ICBT) in principle. In all institutions, RT was delivered using 10-MV photons. The clinical target volume (CTV) for External Beam Radiation Therapy (EBRT) included sites such as the primary tumor, whole uterus, bilateral parametrium, upper half of the vagina, and pelvic lymph nodes including common, internal, and external iliac, obturator, and presacral lymph nodes. The four-field box was used for whole-pelvic (WP) irradiation. Following WP irradiation, the anterior-posterior parallel-opposed field with the Center Shield (CS) was performed. The total pelvic dose (WP-dose plus CS-dose) administered was 46.8 to 54.0 Gy, and the HDR-ICBT was at most 24 Gy/4 times. Four-field box or VMAT was used for para-aortic lymph nodes (PAN) irradiation. Table 1 Basic RT conditions of each facility Facility A Facility B Facility C Facility ༤ Upper edge of WP irradiation field Aortic bifurcation (L4-5 level) Aortic bifurcation (L4-5 level) Aortic bifurcation (L4-5 level) Aortic bifurcation (L4-5 level) Upper edge of PAN irradiation field Upper edge of left renal vein Upper edge of L1 Upper edge of L1 Upper edge of left renal vein Lower edge of PAN irradiation field Aortic bifurcation Aortic bifurcation Aortic bifurcation Aortic bifurcation Left and right edges of PAN irradiation field 10-20mm expansion from aorta/IVC laterally About 10mm expansion from aorta/IVC laterally 10mm expansion from aorta/IVC laterally 10-20mm expansion from aorta/IVC laterally Ventral edge of PAN irradiation field 10-20mm expansion from aorta/IVC laterally About 10mm expansion from aorta/IVC forward 10mm expansion from aorta/IVC laterally 10-20mm expansion from aorta/IVC laterally Dorsal edge of PAN irradiation field 10-20mm expansion from aorta/IVC laterally About 10mm expansion from aorta/IVC dorsal side 10mm expansion from aorta/IVC laterally 10-20mm expansion from aorta/IVC laterally WP irradiation field method 4-field box technique 4-field box technique 4-field box technique 4-field box technique PAN irradiation field method 4-field box technique 4-field box technique VMAT 4-field box technique or VMAT The position of CS S2/3 level to cover the presacral area S2/3 level to cover the presacral area S2/3 level to cover the presacral area S2/3 level to cover the presacral area Type of instrument Primus; Canon Medical Systems, Tochigi, Japan CLINAC iX; Varian Medical Systems, USA True Beam; Varian Medical Systems, USA Synergy; Elekta Medical Systems, Stockholm. Sweden WP, whole pelvis; PAN, para-aortic lymph nodes; IVC, inferior vena cava; VMAT, volumetric modulated arc therapy; IMRT, intensity modulated radiation therapy; CS, center shield. 3.2. Incidence of PIF Two hundred and eight patients who underwent definitive RT as initial treatment for cervical cancer between January 2016 and December 2018 were enrolled in this study (81, 56, 37, and 34 patients in Institutions A, B, C, and D, respectively). The median follow-up period was 36 months (range: 1–72 months). Overall, 28.4% (59/208) of patients developed PIF in the irradiated field. Patient characteristics of woman with and without PIF are presented in Table 2 . The median age of the whole study cohort was 61.5 years, and 69.7% of the patients were menopausal. Only a few patients received oral medications (including female hormones (such as estradiol) and drugs for osteoporosis) at the initiation of RT. There were statistically significant differences between PIF and non-PIF groups in terms of age, menopausal status, and institution. The distribution of PIFs was as follows: pelvis, 34 (57.6%); lumbar vertebra, 13 (22.0%); and femoral head/neck, 4 (6.8%); and unknown 8 (13.6%). Among 59 women with PIF, 31 (52.5%) had chronic pain and required long-term painkillers. Table 2 Patient characteristics PIF (N = 59) Non-PIF (N = 149) p-value Median age (range) 71 (42–90) 54 (29–93) <0.001 Postmenopausal state 55 (93.2%) 90 (60.4%) <0.001 BMI<23 kg/m 2 16 (27.1%) 60 (40.3%) 0.081 Medical history Rheumatoid arthritis Osteoporosis Breast cancer Insufficiency fracture 1 (1.7%) 0 0 4 (6.8%) 2 (1.4%) 3 (2.1%) 1 (0.7%) 7 (4.7%) FIGO stage Ⅰ Ⅱ Ⅲ Ⅳ 8 (13.6%) 14 (23.7%) 28 (47.4%) 9 (15.3%) 21 (14.1%) 57 (38.3%) 50 (33.6%) 21 (14.1%) 0.192 Histopathology Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma Unknown 45 (76.3%) 13 (22.0%) 0 1 (1.7%) 126 (84.6%) 18 (12.1%) 2 (1.4%) 3 (2.1%) Combination chemotherapy 41 (69.5%) 118 (79.2%) 0.275 Irradiation range, Using HDR-ICBT WP WP་PAN WP་HDR-ICBT WP་PAN་HDR-ICBT 5 (8.5%) 4 (6.8%) 39 (66.1%) 11 (18.6%) 15 (10.1%) 2 (1.4%) 112 (75.2%) 20 (13.4%) 0.124 Facility A B C D 16 (27.1%) 19 (32.2%) 7 (11.9%) 17 (28.8%) 65 (43.6%) 37 (24.8%) 30 (20.1%) 17 (11.4%) 0.005 PIF, pelvic insufficiency fracture; WP, whole pelvis; PAN, para-aortic lymph nodes; HDR-ICBT, high-dose-rate intracavitary brachytherapy. Mann-Whitney U test was applied for comparison. Table 3 shows the patient characteristics of each institution. The number of patients who developed PIF was 19.8% (16/81), 33.9% (19/56), 18.9% (7/37), and 50% (17/34) at Institution A, B, C, D, respectively; with significant differences between institutions (p-value = 0.004). Overall, Institutions B and C had more patients with advanced FIGO stage. On the other hand, there were no significant differences in menopausal status or BMI, which are known risk factors for PIF, at each facility. 3.3. Risk factors of PIF Potential risk factors including menopausal status, BMI, histological type, presence or absence of CCRT, PAN irradiation, use of HDR-CBT, and institutions, they are thought to be uncorrelated with each other, were included in the multivariate analysis using COX regression analysis. We excluded other medical conditions (rheumatoid arthritis, osteoporosis, breast cancer, and existing insufficiency fractures) or medication (hormones and osteoporosis drugs) from the analysis, as there were only a few patients with each risk factor. The significant risk factors for PIF were menopausal status and institution (Table 4 ). The hazard ratios (HRs) for menopause, and Institution D (based on A) were 7.391 (95%CI: 2.63-20.79), and 1.214 (95%CI: 1.015།1.412), respectively. The hazard ratio for PIF was 1.8 when comparing high incidence institutions (Institution B, D) with low incidence institutions (Institution A, C). Institutions B and D, which had a high incidence of PIF, and especially Institution D, had a high proportion of patients who received PAN irradiation (Table 5 ). There were no clear differences between institutions in the timing of centers shield or the implementation of lymph boost. Table 4 Multivariate analysis of risk factors associated with PIF (N = 208) Factors HR 95%CI p-value Postmenopausal state 7.391 2.63–20.79 <0.001 BMI<23 kg/m 2 0.673 0.741–1.572 0.156 FIGO stage (Ⅲ/Ⅳ vs. Ⅰ/Ⅱ) 1.057 0.609–1.836 0.843 Concurrent chemotherapy 0.857 0.483–1.521 0.599 Histopathology (SCC vs non-SCC) 1.818 0.983–3.362 0.057 Irradiation, including PAN 1.665 0.878–3.155 0.118 HDR-ICBT 1.225 0.519–2.893 0.643 Facility (vs. A) Facility B Facility C Facility D 0.916 1.045 1.214 0.864–1.120 0.892-1.200 1.015–1.412 0.897 0.566 0.035 Facility (B/D vs. A/C) 1.870 1.069–3.269 0.028 PIF, pelvic insufficiency fracture; HR, hazard ratio; SCC, squamous cell carcinoma; PAN, para-aortic lymph nodes; HDR-ICBT, high-dose-rate intracavitary brachytherapy. Table 5 Treatment characteristics of each facility Facility A (N = 81) Facility B (N = 56) Facility C (N = 37) Facility ༤ (N = 34) p-value Irradiation range, Using HDR-ICBT WP WP་PAN WP་HDR-ICBT WP་PAN་HDR-ICBT 4 (4.9%) 0 67 (82.7%) 10 (12.3%) 6 (10.7%) 2 (3.6%) 41 (73.2%) 7 (12.5%) 8 (21.6%) 2 (4.4%) 25 (67.6%) 2 (5.4%) 2 (5.9%) 2 (5.9%) 18 (52.9%) 12 (35.3%) 0.001 WP/CS Gy 30/20 40/10 50/0 70 (86.4%) 6 (7.4%) 5 (6.2%) 6 (10.7%) 30 (53.8%) 20 (35.7%) 2 (5.4%) 25 (67.6%) 10 (27.0%) 9 (26.5%) 18 (52.9%) 7 (20.6%) 0.341 Lymph boost Yes No 14 (12.3%) 67 (82.7%) 27 (48.2%) 29 (51.8%) 19 (51.4%) 18 (48.6%) 14 (41.2%) 20 (58.8%) 0.593 WP, whole pelvis; PAN, para-aortic lymph nodes; HDR-ICBT, high-dose-rate intracavitary brachytherapy; CS, center shield. Mann-Whitney U test was applied for comparison. 3.4. Onset of PIF Within 2 years after the end of RT, 81.4% of the patients developed PIF (Fig. 1 ). PIF was diagnosed a median of 12 months (range: 1–51 months) after the end of RT. In Institution A and C, almost all patients developed PIF within 2 years after the completion of RT, with no significant difference. Conversely, in Institution B and D, patients developed PIF within 4 years after the completion of RT (Fig. 2 ). 4. Discussion This study is a multi-center study collaborative research study investigating the incidence of PIFs in patients with advanced cervical cancer who undergone definitive RT. The four participating institutions, located in close proximity within Japan, followed nearly identical protocols (Table 1 ). PIFs occurred in 28.4% of all patients, with nearly 70% of these cases occurring in postmenopausal patients. Additionally, there were significant differences in the incidence of PIFs among the institutions (Institution A: 19.8%, B: 33.9%, C: 18.9%, D: 50%). The differences in PIF incidence among the institutions are likely attributable to variations in factors such as patient age distribution, the proportion of postmenopausal patients, baseline bone mineral density prior to treatment, and the stage of disease progression. These findings suggest that direct comparisons of PIF incidence rates between different institutions may be misleading if the characteristics of the patient populations and baseline conditions at the start of treatment are not taken into account. To further investigate the differences in PIF incidence, we conducted a detailed analysis of patient backgrounds and treatment protocols across the institutions. As shown in Table 3, there were no significant differences among the institutions regarding known patient background risk factors for PIF, such as age, postmenopausal status, or a history of conditions like rheumatoid arthritis. On the other hand, there were significant differences between institutions in terms of FIGO stage and RT protocols. However, multivariate analysis revealed that factors such as HDR-ICBT and PAN irradiation were not associated with an increased risk of PIF (Tables3, 4 ). In addition to the incidence of PIF, as shown in Fig. 2 , there were also clear differences between institutions in the timing of PIF onset. At Institution A and C, the majority of PIF cases occurred within two years after completing RT, whereas at Institution B and D, around 80% of cases developed within two years, with the remainder occurring between two- and four-years post-treatment. Although there were no statistically significant differences in the median age or age distribution, the slight variations in age distribution between Institutions A, C and B, D may have contributed to these differences. The limitation of this study, although strict diagnostic criteria for PIF were established, no central review was conducted. Additionally, intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT) were not used in whole-pelvic irradiation across all participating institutions. Moreover, as this study is retrospective, data on bone mineral density prior to the initiation of treatment were not available, which may have contributed to the differences observed between institutions. In this study, 38 patients (52.5%) who developed PIF reported experiencing chronic pain. From the perspective of improving quality of life (QOL) for patients after RT for cervical cancer, the necessity of preventing PIF has become increasingly evident. Currently, we are developing a PIF prevention program specifically for postmenopausal cervical cancer patients who have undergone definitive RT, and its effectiveness is being evaluated through prospective cohort study. Additionally, based on the finding of this study, we have decided to include “treatment institution” as an adjustment factor in future data analyses. This study newly identified “treatment institution” as a risk factor for PIFs associated with RT in patients with locally advanced cervical cancer. When interpreting data on RT-induced PIFs, it is essential to consider the still unexplained inter-institutional differences. Further investigation into the factors underlying these differences may lead to the identification of new PIF risk factors, a deeper understanding of the mechanisms of PIF development, and ultimately, the formulation of effective prevention strategies. Declarations Acknowledgments We would like to express our gratitude to Hiroshima City Hiroshima Citizens Hospital , Fukuyama Medical Center and Kagawa Prefectural Central Hospital, for their participation in this study. Disclosure The authors have no conflicts of interest to disclose. 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Cancer 116(3):625–630 Yamamoto K, Nagao S, Suzuki K et al (2017) Pelvic fractures after definitive and postoperative radiotherapy for cervical cancer: A retrospective analysis of risk factors. Gynecol Oncol 147(3):585–588 Ramlov A, Pedersen EM, Røhl L et al (2017) Risk factors for pelvic insufficiency fractures in locally advanced cervical cancer following intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 97(5):1032–1039 Bazire L, Xu H, Foy JP et al (2017) Pelvic insufficiency fracture (PIF) incidence in patients treated with intensity-modulated radiation therapy (IMRT) for gynecological or anal cancer: Single-institution experience and review of the literature. Br J Radiol 90(1073):20160885 Sapienza LG, Salcedo MP, Ning MS et al (2020) Pelvic insufficiency fractures after external beam radiation therapy for gynecologic cancers: A meta-analysis and meta-regression of 3929 patients. Int J Radiat Oncol Biol Phys 106(3):475–484 Japanese Society for Radiation Oncology (JASTRO) (2020) JASTRO Guidelines 2020 for Radiotherapy Treatment Planning Tables Table 3 is available in the Supplementary Files section. Supplementary Files Table3.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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5779783","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":400162995,"identity":"fe602971-86a2-4944-9b72-a22956f5b6b0","order_by":0,"name":"Shinsuke Shirakawa","email":"","orcid":"","institution":"Okayama University: Okayama Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Shinsuke","middleName":"","lastName":"Shirakawa","suffix":""},{"id":400162996,"identity":"8b149e67-2fad-410c-b4b3-300048599053","order_by":1,"name":"Shoji 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09:15:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5779783/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5779783/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73784718,"identity":"ea58c8d9-2dc0-41ad-a9da-693edb72d19f","added_by":"auto","created_at":"2025-01-14 16:02:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29213,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence of PIF after the end of RT for cervical cancer (N=59)\u003c/p\u003e\n\u003cp\u003eWe investigated the timing of PIF onset in 59 patients who developed PIF. The horizontal axis represents the months following the completion of RT, while the vertical axis indicates the percentage of patients who developed PIF. Within 2 years after the end of RT, 81.4% of the patients developed PIF.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5779783/v1/e478d418c85674ae1d44717a.png"},{"id":73784724,"identity":"bf0db0f6-4370-4a96-bfa8-57ac04246513","added_by":"auto","created_at":"2025-01-14 16:02:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45611,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence of pelvic insufficiency fracture in each facility\u003c/p\u003e\n\u003cp\u003eAmong patients who developed pelvic insufficiency fracture (PIF), this figure shows when the PIF occurred in patients in each facility. The horizontal axis represents the month PIF occurred, and the vertical axis represents the percentage of PIFs. In Facility A and C, almost all patients developed PIF within 2 years after RT, with no significant difference. On the other hand, in Facility B and D, patients developed PIF within 4 years after RT.\u003c/p\u003e\n\u003cp\u003eA) Facility A (N=16)\u003c/p\u003e\n\u003cp\u003eB) Facility B (N=19)\u003c/p\u003e\n\u003cp\u003eC) Facility C (N=7)\u003c/p\u003e\n\u003cp\u003eFacility D (N=17)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5779783/v1/0f1f4add0efc643d4a255421.png"},{"id":76953514,"identity":"6fb5ba89-6e9a-46cb-b68f-29e89c4167ec","added_by":"auto","created_at":"2025-02-23 08:58:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":733404,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5779783/v1/99b03d0f-234c-4acb-87bc-63f95ac582e1.pdf"},{"id":73785623,"identity":"c13144cc-ec59-42b4-aed2-65ae27d1786e","added_by":"auto","created_at":"2025-01-14 16:10:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16913,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-5779783/v1/57144eb35cd6fb6eccd1dc08.docx"}],"financialInterests":"","formattedTitle":"Incidence of pelvic fractures after definitive radiotherapy for cervical cancer: A retrospective multi-center cohort study: IPFAR study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eRadiotherapy (RT) for cervical cancer causes pelvic insufficiency fractures (PIFs) in 10\u0026ndash;29% of patients [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. More than 80% of them develop PIF within 2 years after completion of RT, and more than half of whom have symptoms such as chronic pain [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The chronic pain significantly impairs patient quality of life long following completion of cancer treatment, and narcotic painkillers are generally required for pain relief [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Previous research has suggested that age, menopausal status, and a lower BMI are risk factors for PIF [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Additionally, definitive RT has been identified as a risk factor for PIF [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs aforementioned, previous studies regarding \u0026ldquo;PIF after RT for cervical cancer\u0026rdquo; showed a wide variation in PIF incidence. Most of these reports were from single institutions, and differences in patients\u0026rsquo; backgrounds likely caused such large variations. Factors that may have contributed include age distribution, race, region, medical history, RT protocols, and diagnostic methods for PIF.\u003c/p\u003e \u003cp\u003eTherefore, we decided to investigate PIF caused by RT for cervical cancer in a multicenter setting, considering these background factors. This study involved four institutions in a relatively small area of Japan that provide RT under a similar protocol, and the diagnosis of PIF was reconfirmed based on strictly defined diagnostic criteria. The purpose of this study was to determine whether there were any inter-institutional differences in the incidence of PIF after adjusting for background conditions, and, if so, to clarify the causes of such differences.\u003c/p\u003e"},{"header":"2. Patients and methods","content":"\u003cp\u003eThis study is a multi-center case-control study targeting patients who have undergone RT for cervical cancer.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Patients\u003c/h2\u003e \u003cp\u003e Four institutions\u0026mdash;Okayama University, Hiroshima City Hospital, Fukuyama Medical Center, and Kagawa Prefectural Central Hospital (58, 38, 19, and 16 patients treated for cervical cancer in 2018, respectively)\u0026mdash;participated in this multicenter study. We reviewed medical records of women diagnosed with cervical cancer through pathological examination and received definitive RT as initial treatment at four institutions between January 2016 and December 2018. The participating institutions are all located within the same medical region and have distinct teams of gynecologic oncologists and radiologists.\u003c/p\u003e \u003cp\u003eAll patients who received RT alone or concurrent chemoradiotherapy (CCRT) were eligible for inclusion, regardless of whether they received a lymph node boost, underwent high-dose-rate intracavitary brachytherapy (HDR-ICBT), used center shield, or were treated volumetric modulated arc therapy (VMAT) or intensity modulated radiation therapy (IMRT). Patients who received RT as adjuvant RT after surgery, those who received RT for recurrent disease, those who could not complete the scheduled RT, and those who did not receive appropriate follow-up after treatment were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Method of data collection\u003c/h2\u003e \u003cp\u003e We reviewed the medical records of eligible women and extracted the necessary information including patient background, disease status, treatment details, and occurrence of PIF and analyzed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Follow-up and diagnosis of PIF\u003c/h2\u003e \u003cp\u003eAfter the completion of RT, all patients received medical examination approximately every 3 months for the first 2 years, every 6 months for the next 3 years. Radiological imaging tests including computed tomography (CT) and magnetic resonance imaging (MRI) were performed every 6 months for the first 2 years, then every 12 months for the next 3 years. In conducting this study, all CT or MRI images were reviewed under the uniform PIF diagnostic criteria by diagnostic imaging specialists at each institution; the diagnosis of PIF was made by CT or MRI when a PIF was identified in the RT field. Slight changes in bone colouration within the irradiated field were also diagnosed as PIF, regardless of the presence of absence of clinical symptoms such as back or pelvic pain. Fractures secondary to bone metastasis were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Data analysis\u003c/h2\u003e \u003cp\u003eThe collected data was analyzed under the supervision of a biostatistician. Descriptive statistics were calculated for both the PIF and non-PIF groups. The Mann-Whitney U tests were applied for comparison. We further performed descriptive statistics for the number of patients, age, menopausal status, BMI, medical history, drug history, FIGO stage (2018), combination with chemotherapy, PIF rate, and painkiller use at each institution. We calculated the PIF rate after RT at each institution and analyzed them using the Kaplan\u0026ndash;Meier method. PIF was treated as an event, and in cases of death or disease progression were treated as dropouts. Each factor was assessed using a Cox regression analysis with hazard models (multivariate analysis). Inverse Probability Weighting was used to correct for bias in multivariate analysis. Statistical analyses were performed using IBM SPSS Statistics (version 29.0; IBM Corp., Armonk, NY). Statistical significance was set at p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Ethics\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the declaration of Helsinki. In this study, we are careful to ensure that individual names will not be identified by third parties, and participation is voluntary, with the opportunity to refuse participation in the study. This study has been approved by the Clinical Research Ethics Review Committee of Okayama University Hospital (No.2203-045).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1. RT\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the basic RT conditions of each institution. All institutions performed RT in accordance with the Japanese guidelines for RT, and there was no significant difference in the equipment used [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. The patients were treated with a combination of external irradiation and intracavitary brachytherapy (ICBT) in principle. In all institutions, RT was delivered using 10-MV photons. The clinical target volume (CTV) for External Beam Radiation Therapy (EBRT) included sites such as the primary tumor, whole uterus, bilateral parametrium, upper half of the vagina, and pelvic lymph nodes including common, internal, and external iliac, obturator, and presacral lymph nodes. The four-field box was used for whole-pelvic (WP) irradiation. Following WP irradiation, the anterior-posterior parallel-opposed field with the Center Shield (CS) was performed. The total pelvic dose (WP-dose plus CS-dose) administered was 46.8 to 54.0 Gy, and the HDR-ICBT was at most 24 Gy/4 times. Four-field box or VMAT was used for para-aortic lymph nodes (PAN) irradiation.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBasic RT conditions of each facility\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility A\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility B\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility C\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility ༤\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper edge of WP irradiation field\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation (L4-5 level)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation (L4-5 level)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation (L4-5 level)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation (L4-5 level)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper edge of PAN irradiation field\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper edge of left renal vein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper edge of L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper edge of L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper edge of left renal vein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLower edge of PAN irradiation field\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAortic bifurcation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLeft and right edges of PAN irradiation field\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10-20mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbout 10mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10-20mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVentral edge of PAN irradiation field\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10-20mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbout 10mm expansion from aorta/IVC forward\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10-20mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDorsal edge of PAN irradiation field\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10-20mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbout 10mm expansion from aorta/IVC dorsal side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10-20mm expansion from aorta/IVC laterally\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWP irradiation\u003c/p\u003e\n \u003cp\u003efield method\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePAN irradiation field method\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVMAT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4-field box technique or VMAT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThe position of CS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS2/3 level to cover the presacral area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS2/3 level to cover the presacral area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS2/3 level to cover the presacral area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eS2/3 level to cover the presacral area\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eType of instrument\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrimus; Canon Medical Systems, Tochigi, Japan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCLINAC iX; Varian Medical Systems, USA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTrue Beam; Varian Medical Systems, USA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSynergy; Elekta Medical Systems, Stockholm. Sweden\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eWP, whole pelvis; PAN, para-aortic lymph nodes; IVC, inferior vena cava; VMAT, volumetric modulated arc therapy; IMRT, intensity modulated radiation therapy; CS, center shield.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2. Incidence of PIF\u003c/h2\u003e\n \u003cp\u003eTwo hundred and eight patients who underwent definitive RT as initial treatment for cervical cancer between January 2016 and December 2018 were enrolled in this study (81, 56, 37, and 34 patients in Institutions A, B, C, and D, respectively). The median follow-up period was 36 months (range: 1\u0026ndash;72 months). Overall, 28.4% (59/208) of patients developed PIF in the irradiated field. Patient characteristics of woman with and without PIF are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The median age of the whole study cohort was 61.5 years, and 69.7% of the patients were menopausal. Only a few patients received oral medications (including female hormones (such as estradiol) and drugs for osteoporosis) at the initiation of RT. There were statistically significant differences between PIF and non-PIF groups in terms of age, menopausal status, and institution. The distribution of PIFs was as follows: pelvis, 34 (57.6%); lumbar vertebra, 13 (22.0%); and femoral head/neck, 4 (6.8%); and unknown 8 (13.6%). Among 59 women with PIF, 31 (52.5%) had chronic pain and required long-term painkillers.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePIF (N\u0026thinsp;=\u0026thinsp;59)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNon-PIF (N\u0026thinsp;=\u0026thinsp;149)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian age (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71 (42\u0026ndash;90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 (29\u0026ndash;93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostmenopausal state\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (93.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (60.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI\u0026lt;23 kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (27.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (40.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedical history\u003c/p\u003e\n \u003cp\u003eRheumatoid arthritis\u003c/p\u003e\n \u003cp\u003eOsteoporosis\u003c/p\u003e\n \u003cp\u003eBreast cancer\u003c/p\u003e\n \u003cp\u003eInsufficiency fracture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e1 (1.7%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e4 (6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (1.4%)\u003c/p\u003e\n \u003cp\u003e3 (2.1%)\u003c/p\u003e\n \u003cp\u003e1 (0.7%)\u003c/p\u003e\n \u003cp\u003e7 (4.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFIGO stage\u003c/p\u003e\n \u003cp\u003eⅠ\u003c/p\u003e\n \u003cp\u003eⅡ\u003c/p\u003e\n \u003cp\u003eⅢ\u003c/p\u003e\n \u003cp\u003eⅣ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e8 (13.6%)\u003c/p\u003e\n \u003cp\u003e14 (23.7%)\u003c/p\u003e\n \u003cp\u003e28 (47.4%)\u003c/p\u003e\n \u003cp\u003e9 (15.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e21 (14.1%)\u003c/p\u003e\n \u003cp\u003e57 (38.3%)\u003c/p\u003e\n \u003cp\u003e50 (33.6%)\u003c/p\u003e\n \u003cp\u003e21 (14.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.192\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistopathology\u003c/p\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003cp\u003eAdenosquamous carcinoma\u003c/p\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e45 (76.3%)\u003c/p\u003e\n \u003cp\u003e13 (22.0%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e126 (84.6%)\u003c/p\u003e\n \u003cp\u003e18 (12.1%)\u003c/p\u003e\n \u003cp\u003e2 (1.4%)\u003c/p\u003e\n \u003cp\u003e3 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombination chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (69.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e118 (79.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.275\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIrradiation range, Using HDR-ICBT\u003c/p\u003e\n \u003cp\u003eWP\u003c/p\u003e\n \u003cp\u003eWP་PAN\u003c/p\u003e\n \u003cp\u003eWP་HDR-ICBT\u003c/p\u003e\n \u003cp\u003eWP་PAN་HDR-ICBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e5 (8.5%)\u003c/p\u003e\n \u003cp\u003e4 (6.8%)\u003c/p\u003e\n \u003cp\u003e39 (66.1%)\u003c/p\u003e\n \u003cp\u003e11 (18.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e15 (10.1%)\u003c/p\u003e\n \u003cp\u003e2 (1.4%)\u003c/p\u003e\n \u003cp\u003e112 (75.2%)\u003c/p\u003e\n \u003cp\u003e20 (13.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFacility\u003c/p\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003cp\u003eD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e16 (27.1%)\u003c/p\u003e\n \u003cp\u003e19 (32.2%)\u003c/p\u003e\n \u003cp\u003e7 (11.9%)\u003c/p\u003e\n \u003cp\u003e17 (28.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e65 (43.6%)\u003c/p\u003e\n \u003cp\u003e37 (24.8%)\u003c/p\u003e\n \u003cp\u003e30 (20.1%)\u003c/p\u003e\n \u003cp\u003e17 (11.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003ePIF, pelvic insufficiency fracture; WP, whole pelvis; PAN, para-aortic lymph nodes; HDR-ICBT, high-dose-rate intracavitary brachytherapy.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eMann-Whitney U test was applied for comparison.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eTable\u0026nbsp;3 shows the patient characteristics of each institution. The number of patients who developed PIF was 19.8% (16/81), 33.9% (19/56), 18.9% (7/37), and 50% (17/34) at Institution A, B, C, D, respectively; with significant differences between institutions (p-value\u0026thinsp;=\u0026thinsp;0.004). Overall, Institutions B and C had more patients with advanced FIGO stage. On the other hand, there were no significant differences in menopausal status or BMI, which are known risk factors for PIF, at each facility.\u003c/p\u003e\n\u003c/div\u003e\n\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3. Risk factors of PIF\u003c/h2\u003e\n \u003cp\u003ePotential risk factors including menopausal status, BMI, histological type, presence or absence of CCRT, PAN irradiation, use of HDR-CBT, and institutions, they are thought to be uncorrelated with each other, were included in the multivariate analysis using COX regression analysis. We excluded other medical conditions (rheumatoid arthritis, osteoporosis, breast cancer, and existing insufficiency fractures) or medication (hormones and osteoporosis drugs) from the analysis, as there were only a few patients with each risk factor. The significant risk factors for PIF were menopausal status and institution (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The hazard ratios (HRs) for menopause, and Institution D (based on A) were 7.391 (95%CI: 2.63-20.79), and 1.214 (95%CI: 1.015།1.412), respectively. The hazard ratio for PIF was 1.8 when comparing high incidence institutions (Institution B, D) with low incidence institutions (Institution A, C). Institutions B and D, which had a high incidence of PIF, and especially Institution D, had a high proportion of patients who received PAN irradiation (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). There were no clear differences between institutions in the timing of centers shield or the implementation of lymph boost.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMultivariate analysis of risk factors associated with PIF (N\u0026thinsp;=\u0026thinsp;208)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostmenopausal state\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.391\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.63\u0026ndash;20.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI\u0026lt;23 kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.673\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.741\u0026ndash;1.572\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFIGO stage (Ⅲ/Ⅳ vs. Ⅰ/Ⅱ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.609\u0026ndash;1.836\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.843\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConcurrent chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.483\u0026ndash;1.521\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistopathology (SCC vs non-SCC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.818\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.983\u0026ndash;3.362\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.057\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIrradiation, including PAN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.878\u0026ndash;3.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHDR-ICBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.519\u0026ndash;2.893\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.643\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFacility (vs. A)\u003c/p\u003e\n \u003cp\u003eFacility B\u003c/p\u003e\n \u003cp\u003eFacility C\u003c/p\u003e\n \u003cp\u003eFacility D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.916\u003c/p\u003e\n \u003cp\u003e1.045\u003c/p\u003e\n \u003cp\u003e1.214\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.864\u0026ndash;1.120\u003c/p\u003e\n \u003cp\u003e0.892-1.200\u003c/p\u003e\n \u003cp\u003e1.015\u0026ndash;1.412\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.897\u003c/p\u003e\n \u003cp\u003e0.566\u003c/p\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFacility (B/D vs. A/C)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.870\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.069\u0026ndash;3.269\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003ePIF, pelvic insufficiency fracture; HR, hazard ratio; SCC, squamous cell carcinoma; PAN, para-aortic lymph nodes; HDR-ICBT, high-dose-rate intracavitary brachytherapy.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment characteristics of each facility\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility A\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;81)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility B\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility C\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFacility ༤\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIrradiation range, Using HDR-ICBT\u003c/p\u003e\n \u003cp\u003eWP\u003c/p\u003e\n \u003cp\u003eWP་PAN\u003c/p\u003e\n \u003cp\u003eWP་HDR-ICBT\u003c/p\u003e\n \u003cp\u003eWP་PAN་HDR-ICBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e4 (4.9%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e67 (82.7%)\u003c/p\u003e\n \u003cp\u003e10 (12.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6 (10.7%)\u003c/p\u003e\n \u003cp\u003e2 (3.6%)\u003c/p\u003e\n \u003cp\u003e41 (73.2%)\u003c/p\u003e\n \u003cp\u003e7 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e8 (21.6%)\u003c/p\u003e\n \u003cp\u003e2 (4.4%)\u003c/p\u003e\n \u003cp\u003e25 (67.6%)\u003c/p\u003e\n \u003cp\u003e2 (5.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (5.9%)\u003c/p\u003e\n \u003cp\u003e2 (5.9%)\u003c/p\u003e\n \u003cp\u003e18 (52.9%)\u003c/p\u003e\n \u003cp\u003e12 (35.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWP/CS Gy\u003c/p\u003e\n \u003cp\u003e30/20\u003c/p\u003e\n \u003cp\u003e40/10\u003c/p\u003e\n \u003cp\u003e50/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e70 (86.4%)\u003c/p\u003e\n \u003cp\u003e6 (7.4%)\u003c/p\u003e\n \u003cp\u003e5 (6.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e6 (10.7%)\u003c/p\u003e\n \u003cp\u003e30 (53.8%)\u003c/p\u003e\n \u003cp\u003e20 (35.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e2 (5.4%)\u003c/p\u003e\n \u003cp\u003e25 (67.6%)\u003c/p\u003e\n \u003cp\u003e10 (27.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e9 (26.5%)\u003c/p\u003e\n \u003cp\u003e18 (52.9%)\u003c/p\u003e\n \u003cp\u003e7 (20.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.341\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymph boost\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e14 (12.3%)\u003c/p\u003e\n \u003cp\u003e67 (82.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e27 (48.2%)\u003c/p\u003e\n \u003cp\u003e29 (51.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e19 (51.4%)\u003c/p\u003e\n \u003cp\u003e18 (48.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e14 (41.2%)\u003c/p\u003e\n \u003cp\u003e20 (58.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.593\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eWP, whole pelvis; PAN, para-aortic lymph nodes; HDR-ICBT, high-dose-rate intracavitary brachytherapy; CS, center shield.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eMann-Whitney U test was applied for comparison.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4. Onset of PIF\u003c/h2\u003e\n \u003cp\u003eWithin 2 years after the end of RT, 81.4% of the patients developed PIF (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). PIF was diagnosed a median of 12 months (range: 1\u0026ndash;51 months) after the end of RT. In Institution A and C, almost all patients developed PIF within 2 years after the completion of RT, with no significant difference. Conversely, in Institution B and D, patients developed PIF within 4 years after the completion of RT (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study is a multi-center study collaborative research study investigating the incidence of PIFs in patients with advanced cervical cancer who undergone definitive RT. The four participating institutions, located in close proximity within Japan, followed nearly identical protocols (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). PIFs occurred in 28.4% of all patients, with nearly 70% of these cases occurring in postmenopausal patients. Additionally, there were significant differences in the incidence of PIFs among the institutions (Institution A: 19.8%, B: 33.9%, C: 18.9%, D: 50%). The differences in PIF incidence among the institutions are likely attributable to variations in factors such as patient age distribution, the proportion of postmenopausal patients, baseline bone mineral density prior to treatment, and the stage of disease progression. These findings suggest that direct comparisons of PIF incidence rates between different institutions may be misleading if the characteristics of the patient populations and baseline conditions at the start of treatment are not taken into account.\u003c/p\u003e \u003cp\u003eTo further investigate the differences in PIF incidence, we conducted a detailed analysis of patient backgrounds and treatment protocols across the institutions. As shown in Table\u0026nbsp;3, there were no significant differences among the institutions regarding known patient background risk factors for PIF, such as age, postmenopausal status, or a history of conditions like rheumatoid arthritis. On the other hand, there were significant differences between institutions in terms of FIGO stage and RT protocols. However, multivariate analysis revealed that factors such as HDR-ICBT and PAN irradiation were not associated with an increased risk of PIF (Tables3,\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition to the incidence of PIF, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, there were also clear differences between institutions in the timing of PIF onset. At Institution A and C, the majority of PIF cases occurred within two years after completing RT, whereas at Institution B and D, around 80% of cases developed within two years, with the remainder occurring between two- and four-years post-treatment. Although there were no statistically significant differences in the median age or age distribution, the slight variations in age distribution between Institutions A, C and B, D may have contributed to these differences.\u003c/p\u003e \u003cp\u003eThe limitation of this study, although strict diagnostic criteria for PIF were established, no central review was conducted. Additionally, intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT) were not used in whole-pelvic irradiation across all participating institutions. Moreover, as this study is retrospective, data on bone mineral density prior to the initiation of treatment were not available, which may have contributed to the differences observed between institutions.\u003c/p\u003e \u003cp\u003eIn this study, 38 patients (52.5%) who developed PIF reported experiencing chronic pain. From the perspective of improving quality of life (QOL) for patients after RT for cervical cancer, the necessity of preventing PIF has become increasingly evident. Currently, we are developing a PIF prevention program specifically for postmenopausal cervical cancer patients who have undergone definitive RT, and its effectiveness is being evaluated through prospective cohort study. Additionally, based on the finding of this study, we have decided to include \u0026ldquo;treatment institution\u0026rdquo; as an adjustment factor in future data analyses.\u003c/p\u003e \u003cp\u003e This study newly identified \u0026ldquo;treatment institution\u0026rdquo; as a risk factor for PIFs associated with RT in patients with locally advanced cervical cancer. When interpreting data on RT-induced PIFs, it is essential to consider the still unexplained inter-institutional differences. Further investigation into the factors underlying these differences may lead to the identification of new PIF risk factors, a deeper understanding of the mechanisms of PIF development, and ultimately, the formulation of effective prevention strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to Hiroshima City Hiroshima Citizens Hospital\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003eFukuyama Medical Center and Kagawa Prefectural Central Hospital, for their participation in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOgino I, Okamoto N, Ono Y, Kitamura T, Nakayama H (2003) Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy. Radiother Oncol 68(1):61\u0026ndash;67\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIkushima H, Osaki K, Furutani S et al (2006) Pelvic bone complications following radiation therapy of gynecologic malignancies: clinical evaluation of radiation-induced pelvic insufficiency fractures. Gynecol Oncol 103(3):1100\u0026ndash;1104\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOh D, Huh SJ, Nam H et al (2008) Pelvic insufficiency fracture after pelvic radiotherapy for cervical cancer: analysis of risk factors. Int J Radiat Oncol Biol Phys 70(4):1183\u0026ndash;1188\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwon JW, Huh SJ, Yoon YC et al (2008) Pelvic bone complications after radiation therapy of uterine cervical cancer: evaluation with MRI. AJR Am J Roentgenol 191(4):987\u0026ndash;994\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmeler KM, Jhingran A, Iyer RB et al (2010) Pelvic fractures after radiotherapy for cervical cancer: implication for survivors. Cancer 116(3):625\u0026ndash;630\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamamoto K, Nagao S, Suzuki K et al (2017) Pelvic fractures after definitive and postoperative radiotherapy for cervical cancer: A retrospective analysis of risk factors. Gynecol Oncol 147(3):585\u0026ndash;588\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamlov A, Pedersen EM, R\u0026oslash;hl L et al (2017) Risk factors for pelvic insufficiency fractures in locally advanced cervical cancer following intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 97(5):1032\u0026ndash;1039\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBazire L, Xu H, Foy JP et al (2017) Pelvic insufficiency fracture (PIF) incidence in patients treated with intensity-modulated radiation therapy (IMRT) for gynecological or anal cancer: Single-institution experience and review of the literature. Br J Radiol 90(1073):20160885\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSapienza LG, Salcedo MP, Ning MS et al (2020) Pelvic insufficiency fractures after external beam radiation therapy for gynecologic cancers: A meta-analysis and meta-regression of 3929 patients. Int J Radiat Oncol Biol Phys 106(3):475\u0026ndash;484\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapanese Society for Radiation Oncology (JASTRO) (2020) JASTRO Guidelines 2020 for Radiotherapy Treatment Planning\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 3 is 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":true,"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":"cervical cancer, radiotherapy, pelvic insufficiency fracture, risk factor","lastPublishedDoi":"10.21203/rs.3.rs-5779783/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5779783/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis multicenter study aimed to identify risk factors for pelvic insufficiency fractures (PIFs) in women who received definitive radiotherapy (RT) as initial treatment for cervical cancer and to were examine differences in the incidence of PIFs across institutions.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e Medical records of 208 women who received definitive RT as the initial treatment for cervical cancer at four institutions between January 2016 and December 2018 reviewed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median age was 61.5 years (range: 29\u0026ndash;93 years). Overall, 59 patients (28.4%) developed PIF, 48 (81.4%) of them within two years from completion of RT. Multivariate analysis identified menopausal status, as well as the institution where RT was performed, as independent risk factors for PIF. The incidences of PIF were 19.8%, 33.9%, 18.9%, and 50% in Institution A, B, C, and D, respectively. The hazard ratio for Institution D (based on Institution A) was 1.214 (95% confident interval: 1.015\u0026ndash;1.412). However, no statistically significant differences in patient backgrounds or RT details were observed among institutions.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eDespite targeting the same population and implementing similar RT treatment protocols, significant differences in PIF rates were observed among institutions. Caution should be exercised when making direct comparisons between institutions.\u003c/p\u003e","manuscriptTitle":"Incidence of pelvic fractures after definitive radiotherapy for cervical cancer: A retrospective multi-center cohort study: IPFAR study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-14 16:02:31","doi":"10.21203/rs.3.rs-5779783/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":"d1ef0c9f-989d-434b-814e-92019167b613","owner":[],"postedDate":"January 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-23T08:50:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-14 16:02:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5779783","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5779783","identity":"rs-5779783","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}