Risk Factors for Venous Thromboembolism Induced by Prolonged Bed Rest during Interstitial Brachytherapy for Gynecological Cancer: A Retrospective Study

Risk Factors for Venous Thromboembolism Induced by Prolonged Bed Rest during Interstitial Brachytherapy for Gynecological Cancer: A Retrospective 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 Risk Factors for Venous Thromboembolism Induced by Prolonged Bed Rest during Interstitial Brachytherapy for Gynecological Cancer: A Retrospective Study Keiko Murofushi, Tetsuya Tomita, Kayoko Ohnishi, Kei Nakai, Azusa Akiyama, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-138401/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: Screening and management of venous thromboembolism (VTE) after surgery is important in preventing sublethal VTE. However, the risk factors for VTE during interstitial brachytherapy (ISBT) remain unknown, and appropriate screening and management strategies are yet to be established. This study therefore aimed to evaluate the risk factors for VTE resulting from requisite bed rest during ISBT for gynecologic cancers. Methods: We retrospectively analyzed 47 patients. For patients without definitive preceding radiotherapy, whole pelvic irradiation (30-50 Gy) followed by ISBT of 12-30 Gy/2-5 fx/1-3 days was administered to CTV D90. For patients with preceding radiotherapy, 36-42 Gy/6-7 fx/3-4 days was delivered by ISBT alone. D-dimer (DD) was measured at initial presentation, 1 week before ISBT, pre-ISBT, on the day of, and the day following needle removal. Patients were divided into three groups according to the risk of VTE and were managed accordingly. Group 1: DD was not detected (negative) before ISBT. Group 2: VTE was not detected on venous ultrasound imaging, although DD was positive before ISBT. Group 3: VTE was detected (positive) before ISBT. An intermittent pneumatic compression device was used during ISBT; for this, patients without VTE before ISBT required to remain in the supine position. Heparin or oral anticoagulants were administered to patients with VTE before ISBT. Results: Overall, the median values of DD pre-ISBT, on the day of, and on the day following needle removal were 1.0 (0.4-5.8), 1.1 (0.5-88.9), and 1.5 (0.7-40.6) μg/mL, respectively. After ISBT, no patients had deep vein thrombosis (DVT) in groups 1 and 2. In group 3, 7 of 14 patients experienced worsening of VTE but remained asymptomatic. In univariate analysis, DVT diagnosed before ISBT, Caprini score ≥5, and difference in DD values between pre-ISBT and the day of or the day following needle removal ≥1 were associated with the incidence or worsening of VTE. Conclusion: DD should be measured before and after ISBT to detect the incidence or worsening of VTE in patients with DVT. The Caprini score may help in the prediction of VTE during or after ISBT. Oncology Cancer Biology Gynecological cancer image-guided adaptive brachytherapy interstitial brachytherapy venous thromboembolism deep vein thrombosis Figures Figure 1 Figure 2 Figure 3 Background Silent or subclinical venous thromboembolism (VTE) before treatment occurs in 6.7–23.6% of gynecological cancer patients [ 1 – 3 ]. Abdominal and pelvic surgery, or a prior history of VTE, is associated with the incidence of VTE following surgery [ 4 ]. D-dimer (DD), which is a degradation product of fibrin and is reflective of fibrin concentration, is useful for the screening of VTE [ 5 , 6 ]. Geerts et al. reported that pulmonary embolism (PE) was observed in 30% of patients with deep vein thrombosis (DVT), and one third of the cases of PE were fatal [ 7 ]. The screening and management of VTE following surgery has an important role in the prevention of sublethal VTE. Hence, the American College of Chest Physicians Evidence-based Clinical Practice Guidelines recommends the use of thromboprophylaxis for the occurence of VTE after surgery, according to the risk classification of the patient [ 4 ]. The risk stratification for VTE following surgery is primarily based on the Rogers score, which consists of patient factors, preoperative laboratory values, and operative characteristics [ 8 ], and/or the Caprini score, which consists of patient factors and operative characteristics [ 9 ]. Interstitial brachytherapy (ISBT) can deliver an adequate dose for the treatment of irregularly-shaped cervical cancer, such as severe vaginal invasion or asymmetrical tumors, resulting in good local control (LC) [ 10 ]. Given that 2–3 days of bed rest are necessary to perform ISBT, patients may be more likely to develop VTE during ISBT. However, the risk factors of VTE during ISBT are unknown, and appropriate screening and management has yet to be established. The present study sought to analyze the incidence of VTE during ISBT, and to determine the risk factors for VTE in gynecological cancer patients treated with ISBT. Methods Patient characteristics A total of 52 patients with gynecological cancer received high dose rate (HDR) ISBT between June 2017 and December 2019 at (blinded for review). We included 47 patients as per following criteria: (1) the screening and management of VTE in this study were adhered; (2) atrial fibrillation was not observed; (3) anticoagulant was not administered for cardiovascular disease, cerebrovascular disease, or other reasons besides VTE. The protocol for this study was approved by the institutional review board at (blinded for review) (IRB No. H30-302), and informed consent was waived due to the retrospective nature of the study. Measurement of plasma D-dimer levels Peripheral blood samples were collected from all patients at initial presentation, 1 week before ISBT, pre-ISBT (0–3 days before needle insertion), on the day of needle removal, and the day following needle removal. Blood samples were collected from an antecubital vein into plastic tubes. 0.11 M sodium citrate was added to whole blood in a 9:1 dilution as an anticoagulant, and citrated plasma was then separated by centrifugation at 3000 rpm for 10 minutes. Plasma DD levels were measured using nanopia DD (Sekisui Medical, Tokyo, Japan) sensitized with anti-DD mouse monoclonal antibodies to induce a latex coagulation reaction. Turbidity was then quantified by spectrophotometry using the CP3000 automated coagulation system (CP3000; Sekisui Medical, Tokyo, Japan). The cutoff value for the measure of plasma DD was 1.0 µg/mL. Detection of VTE Venous ultrasound imaging (VUI) was performed to detect deep vein thrombosis (DVT). Ultrasonography was performed using Aplio500 or Aplio a 450 (Canon Medical Systems Corporation, Otawara, Japan) with a 3.5-MHz convex and a 7.5-MHz linear transducer. Power, pulse repetition frequency and wall thump filter settings were adjusted for venous vascular studies. Femoral, popliteal, peroneal, anterior and posterior tibial, and soleal veins were evaluated bilaterally. Femoral veins were assessed in a supine position and other veins were assessed in a sitting position. All veins were imaged on transverse and long axis views. Venous lumina were observed while searching for thrombus by manual compression with transducer and color Doppler imaging (Thrombus was searched by transducer compression and color Doppler imaging). For the patients, who had a DVT on the proximal side beyond the popliteal fossa, intrapelvic DVT and PE were evaluated by contrast-enhanced CT. Screening and management of patients with VTE at peri-ISBT period DD was measured in all patients at first presentation, 1 week before ISBT, pre-ISBT, on the day of needle removal and on the day following needle removal. Patients were divided into 3 groups based on the risks and management of VTE during the peri-ISBT period (Fig. 1 ). Patients in Group 1 were negative for DD (< 1.0 µg/mL) 1 week before ISBT. In this group, an intermittent pneumatic compression device (IPCD) was used during the supine position, and VUI (± CT) was performed if DD levels exceeded a standard value of 1.0 µg/mL on the day of or the day following needle removal. In Group 2, VTE was not detected in VUI (± CT), although patients were positive for DD (≥ 1.0 µg/mL) 1 week before ISBT. IPCD was used during the supine position in this group. VUI (± CT) was performed if DD levels on the day of or the day following needle removal exceeded the pre-ISBT value + 0.5 µg/mL. In Group 3, VTE was detected at first presentation and/or 1 week before ISBT. A graduated compression stocking was used during ISBT to maintain the supine position for patients in this group. VUI (± CT) was performed if DD on the day of or the day following needle removal was positive in patients who had negative DD levels pre-ISBT, or exceeded the pre-ISBT value + 0.5 µg/mL in patients that had a positive DD level pre-ISBT. The patients with DVT at first presentation received VUI 1 week before ISBT. Patients with acute or subacute DVT detected by VUI 1 week before ISBT, or with PE detected by enhanced CT before ISBT were given unfractionated heparin (UFH), which was subsequently interrupted at midnight on the day of needle insertion. Oral anticoagulant was interrupted 2 days before ISBT for patients with chronic DVT. A bolus injection of 5000 units (80–100 unit/kg) of UFH was initially administered, followed by continuous administration of 750–1000 units/h (15–20 units/kg/h) under monitoring for the activated partial thromboplastin time (aPTT) (target value: 1.5–2.5 x normal value). Radiotherapy and brachytherapy protocol Patients that did not receive preceding radiotherapy underwent external beam radiotherapy (EBRT) and HDR ISBT. The EBRT was delivered using the three-dimensional conformal technique with a linear accelerator (Clinac iX; Varian Medical System, Palo Alto, CA) and a 10-MV photon beam. Whole-pelvic EBRT was initially administered at a dose of 30.0–50.0 Gy in 15–25 fractions using the four-field technique, and an additional dose of 0–20.0 Gy in 0–10 fractions was administered using EBRT with a 3-cm midline block (MB) and the anterior-posterior/posterior-anterior technique. In cases where the shortest diameter of a pelvic lymph node was ≥ 1 cm, a boost EBRT dose of 6–10 Gy was administered in 3–5 fractions. Brachytherapy was performed using an iridium-192 ( 192 Ir) remote afterloading system (MicroSelectron HDRTM; Nucletron, Veenendaal, The Netherlands), and the first HDR ISBT treatment was performed within 7 days after the MB insertion. For patients that did not undergo preceding radiotherapy, ISBT was delivered at a dose of 12–30 Gy in 2–5 fractions on 1–3 consecutive days (prescribed as D90 to high-risk clinical target volume [HRCTV]). For the patients that did receive preceding radiotherapy, ISBT was delivered at a dose of 36–42 Gy in 6–7 fractions on 3–4 consecutive days. ISBT was planned based on CT with a 2.5-mm slice thickness and either the Oncentra system (version 4.0, Nucletron). The HRCTV included the macroscopic residual tumor, which was imaged as the high T2WI area on the pre-brachytherapy magnetic resonance imaging, and the entire cervix. During ISBT, the Martinez Universal Perineal Interstitial Template was used for all patients. Spinal anesthesia and epidural anesthesia were the principal methods of anesthesia for ISBT. In cases where epidural anesthesia was difficult to perform, intravenous patient-controlled anesthesia was used. Bed rest in the supine position was maintained for all patients during ISBT. From the time of needle removal to the next morning, the standing position was prohibited, and bed rest was maintained. Chemotherapy During the radiotherapy period, a weekly regimen of cisplatin (CDDP; 40 mg/m 2 ) was generally administered for the patients receiving both EBRT and ISBT. Concurrent chemotherapy with radiotherapy (CCRT) was not performed for patients who met any of the following conditions: 1) ISBT alone, 2) preceding radiotherapy, 3) insufficient renal function, or 4) ≥ 75 years old. A total of 14 patients ultimately received radiotherapy alone and 33 patients received CCRT. Statistical analysis The incidence of VTE was defined as a newly appearing thrombosis within in a specific region where VTE was not present before ISBT. The worsening of VTE was defined as a thrombosis that was larger than the thrombosis observed on VUI or CT before ISBT. For the patients receiving EBRT, the equivalent dose in 2 Gy fractions (EQD2) was calculated to sum the dose of ISBT plus EBRT before the insertion of the MB, based on the linear-quadratic model [ 11 ]. For the patients treated with ISBT alone, the EQD2 was calculated to determine the dose of ISBT. The tumor dose was calculated using an α/β ratio of 10 Gy. For calculation of the dose-volume parameters of the organ at risk (OAR) (i.e., D2.0 cc), the α/β ratio was assumed to be 3 Gy. The paired t -test was used to compare DD values between pre-ISBT levels and levels on the day of and the day following needle removal. The difference between pre-ISBT DD values and those on the day of needle removal was determined by subtracting the pre-ISBT DD value from the DD level on the day of needle removal. The difference between pre-ISBT DD values and those on the day following needle removal was determined by subtracting the pre-ISBT DD value from the DD level on the day following needle removal. The Student t -test was used to compare these differences. The risk factors for incidence or worsening of VTE and/or PE caused by prolonged bed rest during ISBT were assessed by the Chi-square test. The chi-square test was performed using the SPSS Base System software program version 24.0.0.0 (SPSS, Chicago, IL) and the SAS software version 9.4 (SAS Institute, Cary, NC), and differences were considered statistically significant at p -values of < 0.05. Results The patient characteristics are shown in Table 1 . The median age was 61 years old. Recurrent tumors were present in 14 patients. Of these, 11 patients had a postoperative recurrence, and the remaining 3 patients experienced recurrence after definitive radiotherapy. Six of the fourteen patients received preceding radiotherapy. Table 1 Patient and tumor characteristics Median age (years) 61 (range: 30˗86) Primary Cervix 37 (79%) Corpus 7 (15%) Vagina 2 (4%) Vulva 1 (2%) Histology Squamous cell carcinoma 36 (77%) Adenocarcinoma 11 (23%) Median tumor size, mm 62 (range: 9˗140) Initial onset/recurrence Initial onset 33 (70%) Recurrence 14 (30%) FIGO for 33 patients with initial onset III 18 (55%) IVA 15 (45%) PLN metastasis at the time of pre-radiotherapy Negative 17 (36%) Positive 30 (64%) PALN metastasis at the time of pre-radiotherapy Negative 35 (74%) Positive 12 (26%) Median Caprini score at the time of pre-ISBT 5 (range: 3˗10) Median Rogers score at the time of pre-ISBT 4 (range: 1˗5) Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; PLN, pelvic lymph node; PALN, para aortic lymph node; ISBT, interstitial brachytherapy. Treatment characteristics are shown in Table 2 . A total of 41 patients received EBRT plus ISBT, and ISBT alone was performed on 6 patients with preceding radiotherapy. The median duration of bed rest was 2 days (range: 1–4 days). The median number of needles inserted during ISBT was 15 (range: 7–23). Table 2 Treatment characteristics Radiotherapy EBRT plus ISBT 41 ISBT alone 6 Anesthesia for ISBT Spinal and epidural aesthesia 32 Spinal anesthesia and IVPCA 15 Median duration of bed rest, day (range) 2 (1–4) Median number of inserted needles, needle (range) 15 (7–23) Mean volume of CTV (cc) 54.9 ± 32.4 Mean EQD2 for CTV and OARs (Gy) CTV D90 (α/β = 10) 71.0 ± 6.7 Bladder D2cc (α/β = 3) 61.7 ± 15.6 Sigmoid D2cc 44.2 ± 17.1 Rectum D2cc 58.5 ± 11.9 Abbreviations: EBRT, external beam radiotherapy; ISBT, interstitial brachytherapy; IVPCA, intravenous patients-control anesthesia; CTV, clinical target volume; EQD2, equivalent dose in 2 Gy fractions; OAR, organ at risk. VTE and DD status during ISBT, according to the patients’ assigned group, is shown in Fig. 2 . There were no VTEs detected before ISBT in 33 patients. Of these, 18 patients were in group 1 and 15 patients were in group 2. In group 3, 12 of 14 patients with VTE before ISBT had DVT alone, and the remaining 2 patients had both DVT and PE. Of the 14 patients in group 3, VTE was detected at first consultation in 8 patients and was detected 1 week before ISBT in 6 patients. In the VUI findings 1 week before ISBT, 1 patient was diagnosed with acute DVT, 6 patients were diagnosed with subacute DVT, and 7 patients had chronic DVT. Administration of heparin was provided for 8 patients, including 7 patients with acute or subacute DVT, and 1 patient with PE and chronic DVT. VUI ± CT was performed after needle removal in 22 patients. Of these, 18 patients received VUI alone, 3 received VUI and CT, and 1 received CT alone. VUI was omitted in this patient because DD levels were extremely high on the day of needle removal. We observed no incidence of VTE related to ISBT in 33 patients in group 1 and 2. Among the 14 patients in group 3, we observed an incidence and/or worsening of VTE in 7 patients. None of these 7 patients had symptomatic VTE. In one patient, administration of heparin was initiated 3 hours after needle removal, due to new presentation of VTE in multiple sites including the lungs, and the DD level was extremely high (88.9 µg/mL). Another patient, in whom VTE extended to the inferior vena cava, was administered heparin on the day following needle removal. The remaining patients in group 3 received oral coagulants. During or after ISBT, none of the patients experienced bleeding requiring treatment. The DD values obtained pre-ISBT, on the day of, and on the day following needle removal are shown in Fig. 3 . For all patients, the median pre-ISBT DD value was 1.0 µg/mL (range: 0.4–5.8 µg/mL), the median value on the day of needle removal was 1.1 (0.5–88.9), and the median value on the day following needle removal was 1.5 (0.7–40.6). For all patients, DD values on the day following needle removal were significantly higher than those measured pre-ISBT ( p = 0.04); however, there was no significant difference in DD values between the pre-ISBT levels and those on the day of needle removal ( p = 0.22). The median difference in DD values between the pre-ISBT level and the day of needle removal was 0.0 µg/mL (-4.4–85.5 µg/mL). For patients without VTE before ISBT, the median difference was 0.0 (-4.4–3.1), for those with VTE it was 0.2 (-0.5–85.5), and among 7 patients without and 7 with incidence or worsening of VTE, the median difference was − 0.2 (-0.5–0.4) and 6.1 (-0.1–85.5), respectively. There was no significant difference between patients without VTE before ISBT vs. those with ( p = 0.21), and between patients without incidence or worsening of VTE compared to those with ( p = 0.22). The median difference between pre-ISBT DD values and the day following needle removal among all patients was 0.3 µg/mL (-3.3–37.2 µg/mL), while among patients without VTE before ISBT the median difference was 0.2 (-3.3–4.6), and among patients with VTE it was 2.0 (-0.2–37.2). Among 7 patients without and 7 with incidence or worsening of VTE, the median difference was 0.1 (-0.2–2.9) and 7.7 (1.3–37.2), respectively. There was a borderline significant difference between patients without VTE before ISBT vs those with ( p = 0.07), and between patients without incidence or worsening of VTE vs. those with ( p = 0.07). The univariate analysis revealed that the incidence or worsening of VTE was significantly related to a diagnosis of DVT before ISBT ( p < 0.01), a Caprini score ≥ 6 ( p < 0.01), a difference in DD values between pre-ISBT and the day of needle removal ≥ 1 ( p < 0.01), and a difference between DD values pre-ISBT and on the day following needle removal ≥ 1 ( p < 0.01) (Table 3 ). However, longer duration of bed rest and Rogers score were not significantly associated with the incidence or worsening of VTE ( p = 0.08 and p = 0.40, respectively). Table 3 Univariate analysis for the incidence or worsening of venous thromboembolism Patients Incidence or worsening of VTE p -value Age < 61 years 23 2 0.23 ≥ 61 years 24 5 Primary Cervix 37 7 0.16 Others 10 0 Tumor size < 61 mm 23 3 0.53 ≥ 61 mm 24 4 PLN metastasis Negative 17 3 0.50 Positive 30 4 PALA metastasis Negative 35 6 0.42 Positive 12 1 Initial onset/recurrence Initial onset 33 5 0.65 Recurrence 14 2 Duration of bed rest ≤ 2 days 34 3 0.08 ≥ 3 days 13 4 Number of inserted needles ≤ 15 29 4 0.55 ≥ 16 18 3 Volume of CTV ≤ 54.9 cc 24 3 0.48 > 54.9 cc 23 4 VTE before ISBT Negative 33 0 < 0.01 Positive 14 7 Caprini score ≤ 5 25 0 < 0.01 ≥ 6 22 7 Rogers score ≤ 4 31 6 0.40 ≥ 5 16 1 Difference of D-dimer value between pre-ISBT and the day of needle removal ≤+1 µg/mL 41 2 +1 6 5 Difference of D-dimer value between pre-ISBT and the day following needle removal ≤+1 µg/mL 34 0 +1 13 7 Abbreviations: VTE, venous thromboembolism; SCC, squamous cell carcinoma; PLN, pelvic lymph node metastasis; PALA, para-aortic lymph node; CCRT, concurrent chemoradiotherapy; RT, radiotherapy; EBRT, external beam radiotherapy; ISBT, interstitial brachytherapy; CTV, clinical target volume; DVT, deep vein thrombosis. Discussion It has been previously reported that without thromboprophylaxis, the incidence of symptomatic VTE following major surgery was 1.5-6.0% [ 12 , 13 ]. In surgical patients with mechanical prophylaxis, administration of heparin, or both of these, the incidence of symptomatic VTE was 0.9–3.4%, 0.5–1.9%, or 0.2–0.9%, respectively [ 12 – 16 ]. These studies also reported that major bleeding was observed in 1.2–4.5% of patients [ 12 , 14 , 15 ]. The incidence of fatal PE in the patients with thromboprophylaxis was reduced to 0.1–0.5%, compared to 0.3–1.2% in the patients without thromboprophylaxis [ 4 ]. In the clinical practice guidelines reported by the American College of Chest Physicians and the American Society of Clinical Oncology, the type of thromboprophylaxis was determined according to the risk stratification of VTE and bleeding complications. For patients with a moderate risk of VTE, administration of heparin or mechanical prophylaxis was recommended, while for the patients at a high risk of VTE, the administration of heparin with the addition of IPCD was recommended [ 4 , 17 ]. However, if the patients were at high risk for major bleeding complications, the administration of heparin was avoided. In this study, all patients were classified as moderate or high risk, as evaluated by the Caprini score. Heparin was only administered to patients with acute or subacute DVT, or with PE before ISBT. This was because ISBT, in which 10 or more needles were placed for 2–3 days, was considered to be a procedure that had a potential for major bleeding. As a result, the incidence of VTE was observed in 2 (4.2%) out of 47 patients, and worsening of VTE was observed in 5 (10.6%) out of 47 patients. However, there was no occurrence of symptomatic VTE, and no major bleeding complications occurred during or after ISBT under thromboprophylaxis in this study. The risk of VTE appeared to be highest for patients undergoing abdominal or pelvic surgery for malignancy [ 4 , 18 , 19 ]. In addition, advanced age (especially 60 years or older), prior VTE, bed rest (4 days or longer), and longer length of hospital stay were also considered to be risk factors for VTE following surgery [ 4 , 13 , 20 – 22 ]. Tasaka et al. reported that the risk factors for VTE at pretreatment were advanced age (60 years or older) and bulky tumors (40 mm or greater) for cervical cancer patients, and advanced age, stage III/IV disease, and bulky tumors (60 mm or greater) for endometrial cancer patients [ 23 ]. In univariate analysis of this study, advanced age, bulky tumors, and long bed rest were not significantly related to the incidence or worsening of VTE (Table 3 ). However, the presence of VTE before ISBT, a Caprini score ≥ 6, a difference in DD values between pre-ISBT and the day of needle removal ≥ 1, and a difference between pre-ISBT and the day following needle removal ≥ 1 were risk factors for VTE. The risk stratification for VTE following surgery was mainly evaluated according to the Rogers score [ 4 , 8 ] and the Caprini score [ 4 , 9 ]. The Rogers score was established based on the analysis of VTE incidence in 183,069 patients undergoing vascular and general surgery [ 8 ] and consists of patient factors (female gender, higher American Society of Anesthesiologists class, ventilator dependence, preoperative dyspnea and transfusion in the 72 hours before operation), preoperative laboratory values (albumin, bilirubin, sodium and hematocrit), and surgical characteristics (type of surgical procedure, work relative value units, and infected/contaminated wounds). In this study, all patients were categorized as very low risk, because the Rogers score is composed of factors that are less affected by ISBT. In contrast, the Caprini score, which was mainly established by referring to the medical literature, contains patient factors (age, body mass index, prior VTE, family history of VTE, coagulation factors such as Factor V Reiden and Lupus anticoagulant, malignancy, and bed rest) and surgical characteristics (type of surgical procedure). In this study, the incidence or worsening of VTE was significantly higher in the high-risk group, as determined by a Caprini score ≥ 6, than in the high risk group (Caprini score 5) or the moderate risk group (Caprini score 3–4) ( p < 0.01). Because factors such as age, bed rest, and prior VTE were included in the Caprini score, it was considered more suitable than the Rogers score to evaluate a risk for the incidence or worsening of VTE during ISBT. To predict the incidence or worsening of VTE during ISBT, changes in DD values detected by close monitoring and a diagnosis of VTE before ISBT are necessary to screen gynecological cancer patients treated with ISBT. The Caprini score may be useful to predict the incidence or worsening of VTE, not only for the surgical patients but also for the patients treated with ISBT. Additionally, the close monitoring of DD values and the management of VTE that was modelled in this study could be suggested as a novel approach for thromboprophylaxis in gynecological cancer patients treated with ISBT. Conclusions The limitations of this study include its single-center retrospective design. Thus, further studies with multicenter prospective designs are needed to establish the efficacy of screening and thromboprophylaxis for VTE during ISBT. DD levels should be closely measured before and after ISBT to detect the incidence or worsening of VTE for patients diagnosed with DVT before ISBT. The Caprini score may be useful to evaluate the risks for the incidence or worsening of VTE induced by prolonged bed rest during ISBT. List Of Abbreviations venous thromboembolism (VTE), D-dimer (DD), pulmonary embolism (PE), Interstitial brachytherapy (ISBT), local control (LC), high dose rate (HDR), Venous ultrasound imaging (VUI), deep vein thrombosis (DVT), activated partial thromboplastin time (aPTT), external beam radiotherapy (EBRT), midline block (MB), high-risk clinical target volume (HRCTV), concurrent chemotherapy with radiotherapy (CCRT), organ at risk (OAR), external beam radiotherapy (EBRT) Declarations Ethics approval and consent to participate This retrospective study was approved by the institutional review board of Tsukuba University and was conducted according to the tenets of the 1975 Declaration of Helsinki. The need for informed consent was waived owing to the retrospective nature of the study. Consent for publication Not applicable (our manuscript did not contain any individual person’s data in any form). Availability of data and materials The datasets supporting the conclusions of this article are available upon reasonable request. Competing interests: The authors declare that they have no competing interests Funding Not Applicable Author’s Contributions KNM, TT, OK, AA, and KN: Conceptualization, Methodology, Formal Analysis, Investigation TS and TO: Writing – Original Draft, Writing – Review & Editing KK, TS, and HS: Writing – Review & Editing KNM: Validation, Supervision, Project administration All authors read and approved the final manuscript. Acknowledgement This research was supported by the University of Tsukuba. References Satoh T, Matsumoto K, Tanaka YO, Akiyama A, Nakao S, Sakurai M, et al. Incidence of venous thromboembolism before treatment in cervical cancer and the impact of management on venous thromboembolism after commencement of treatment. 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Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Eng J Med. 2003;349:1227-35. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell C, et al. Prevention of venous thromboembolism: the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(Suppl 3):338S-400S. Rogers SO Jr, Kilaru RK, Hosokawa P, Henderson WG, Zinner MJ, Khuri SF. Multivariable predictors of postoperative venous thromboembolic events after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg. 2007;204:1211-21. Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon. 2005;51:70-8. Mendez LC, Weiss Y, D’Souza D, Ravi A, Barbera L, Leung E. Three-dimensional-guided perineal-based interstitial brachytherapy in cervical cancer: A systematic review of technique, local control, and toxicities. Radiother Oncol. 2017;123:312-8. Dale RG. 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Prevention of venous thromboembolism in neurosurgery: a metaanalysis. Chest 2008;134:237-49. Pezzuoli G, Neri Serneri GG, Settembrini P, Coggi G, Olivari N, Buzzetti G, et al. Prophylaxis of fatal pulmonary embolism in general surgery using low-molecular weight heparin Cy 216: a multicenter, double-blind, randomized, controlled, clinical trial versus placebo (STEP). STEP-Study Group. Int Surg. 1989;74:205-10. Lyman GH, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189-204. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90:446-55. Alcalay A, Wun T, Khatri V, Chew HK, Harvey D, Zhou H, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol . 2006;24:1112-8. Clarke-Pearson DL, Synan IS, Coleman RE, Hinshaw W, Creasman WT. The natural history of postoperative venous thromboli in gynecologic oncology: a prospective study of 382 patients. Am J Obstet Gynecol. 1984;148:1051-4. Agnelli G, Bolis G, Capussotti L, carpa RM, Tonelli F, Bonizzoni E, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg. 2006;243:89-95. Spyropoulos AC, Hussein M, Lin J, Battleman D. Rates of venous thromboembolism occurrence in medical patients among the insured population. Thromb Haemost. 2009;102:951-7. Tasaka N, Minaguchi T, Hosokawa Y, Takao W, Itagaki H, Nishida K, et al. Prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer. J Obstet Gynaecol Res. 2020;46:765-73. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 29 May, 2021 Review # 1 received at journal 10 Apr, 2021 Reviewer # 1 agreed at journal 25 Jan, 2021 Reviewers invited by journal 24 Jan, 2021 First submitted to journal 28 Dec, 2020 Editor assigned by journal 28 Dec, 2020 Submission checks completed at journal 28 Dec, 2020 Editor invited by journal 28 Dec, 2020 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-138401","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":7291476,"identity":"c66cdee2-7005-4b6e-b164-79cdee6f76a8","order_by":0,"name":"Keiko Murofushi","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-5439-172X","institution":"Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital: Tokyo Toritsu Komagome Byoin","correspondingAuthor":true,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Murofushi","suffix":""},{"id":7291477,"identity":"bef4de20-1352-46e2-8979-09d7896f350d","order_by":1,"name":"Tetsuya Tomita","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Tetsuya","middleName":"","lastName":"Tomita","suffix":""},{"id":7291478,"identity":"a46c7c2c-0ec7-4290-9124-c8fa4e573f49","order_by":2,"name":"Kayoko Ohnishi","email":"","orcid":"","institution":"International University of Health and Welfare","correspondingAuthor":false,"prefix":"","firstName":"Kayoko","middleName":"","lastName":"Ohnishi","suffix":""},{"id":7291479,"identity":"ae96d718-1f61-4cf5-a53c-4475af27b386","order_by":3,"name":"Kei Nakai","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Nakai","suffix":""},{"id":7291480,"identity":"2a4ba764-75b2-44d4-8720-af5e41525524","order_by":4,"name":"Azusa Akiyama","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Azusa","middleName":"","lastName":"Akiyama","suffix":""},{"id":7291481,"identity":"a39aa8e6-1fa2-4c87-92d0-cdf0adde0863","order_by":5,"name":"Tsukasa Saida Sasaki","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Tsukasa","middleName":"Saida","lastName":"Sasaki","suffix":""},{"id":7291482,"identity":"1fc4dbc9-93a9-4f41-a9db-4c3dfa2e7d0b","order_by":6,"name":"Toshiyuki Okumura","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Toshiyuki","middleName":"","lastName":"Okumura","suffix":""},{"id":7291483,"identity":"a20a9198-4012-44c3-af1e-37cf0f4ce739","order_by":7,"name":"Katsuyuki Karasawa","email":"","orcid":"","institution":"Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital: Tokyo Toritsu Komagome Byoin","correspondingAuthor":false,"prefix":"","firstName":"Katsuyuki","middleName":"","lastName":"Karasawa","suffix":""},{"id":7291484,"identity":"53234a11-c433-433a-a3e1-412e60717bd1","order_by":8,"name":"Toyomi Satoh","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Toyomi","middleName":"","lastName":"Satoh","suffix":""},{"id":7291485,"identity":"66982067-6083-4977-bd8e-f2c44a7cd62b","order_by":9,"name":"Hideyuki Sakurai","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"prefix":"","firstName":"Hideyuki","middleName":"","lastName":"Sakurai","suffix":""}],"badges":[],"createdAt":"2020-12-30 16:00:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-138401/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-138401/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":4720408,"identity":"f13e8858-742d-4f2d-9492-78d0f1f96c29","added_by":"auto","created_at":"2021-01-05 16:53:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":389270,"visible":true,"origin":"","legend":"Screening and management of venous thromboembolism\nISBT, interstitial brachytherapy; VUI, venous ultrasound imaging; DVT, deep venous thrombosis.\n","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-138401/v1/e2ae60eb4d3b1366120b3e20.jpg"},{"id":4720291,"identity":"9c206a08-844c-4737-a5fa-d44be25c1af9","added_by":"auto","created_at":"2021-01-05 16:50:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":406655,"visible":true,"origin":"","legend":"Incidence and worsening of venous thromboembolism after interstitial brachytherapy in each group\nISBT, interstitial brachytherapy; VUI, venous ultrasound imaging; CT, computed tomography; VTE, venous thromboembolism; DVT, deep venous thrombosis; PE, pulmonary embolism.\n","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-138401/v1/3fbfa53334b906af73facc57.jpg"},{"id":4720409,"identity":"4928e0ce-e689-45e7-b438-820ed4c98a57","added_by":"auto","created_at":"2021-01-05 16:53:38","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":149986,"visible":true,"origin":"","legend":"D-dimer values \nD-dimer values pre-interstitial brachytherapy, on the day of and day following needle removal for all patients (a), values in patients without venous thromboembolism before interstitial brachytherapy (Groups 1 and 2) (b) and values in patients with venous thromboembolism before interstitial brachytherapy (Group 3) (c)\n","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-138401/v1/88d25115f223612641f57f78.jpg"},{"id":13643084,"identity":"6f236860-ba27-4a25-8dbc-0a1eb14ebe8a","added_by":"auto","created_at":"2021-09-17 09:10:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":695683,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-138401/v1/3147d982-67d9-43b5-bc1e-570b528acc29.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eRisk Factors for Venous Thromboembolism Induced by Prolonged Bed Rest during Interstitial Brachytherapy for Gynecological Cancer: A Retrospective Study\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eSilent or subclinical venous thromboembolism (VTE) before treatment occurs in 6.7\u0026ndash;23.6% of gynecological cancer patients [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Abdominal and pelvic surgery, or a prior history of VTE, is associated with the incidence of VTE following surgery [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. D-dimer (DD), which is a degradation product of fibrin and is reflective of fibrin concentration, is useful for the screening of VTE [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Geerts et al. reported that pulmonary embolism (PE) was observed in 30% of patients with deep vein thrombosis (DVT), and one third of the cases of PE were fatal [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The screening and management of VTE following surgery has an important role in the prevention of sublethal VTE. Hence, the American College of Chest Physicians Evidence-based Clinical Practice Guidelines recommends the use of thromboprophylaxis for the occurence of VTE after surgery, according to the risk classification of the patient [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The risk stratification for VTE following surgery is primarily based on the Rogers score, which consists of patient factors, preoperative laboratory values, and operative characteristics [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and/or the Caprini score, which consists of patient factors and operative characteristics [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterstitial brachytherapy (ISBT) can deliver an adequate dose for the treatment of irregularly-shaped cervical cancer, such as severe vaginal invasion or asymmetrical tumors, resulting in good local control (LC) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Given that 2\u0026ndash;3 days of bed rest are necessary to perform ISBT, patients may be more likely to develop VTE during ISBT. However, the risk factors of VTE during ISBT are unknown, and appropriate screening and management has yet to be established. The present study sought to analyze the incidence of VTE during ISBT, and to determine the risk factors for VTE in gynecological cancer patients treated with ISBT.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eA total of 52 patients with gynecological cancer received high dose rate (HDR) ISBT between June 2017 and December 2019\u0026nbsp;at (blinded for review). We included 47 patients as per following criteria: (1) the screening and management of VTE in this study were adhered; (2) atrial fibrillation was not observed; (3) anticoagulant was not administered for cardiovascular disease, cerebrovascular disease, or other reasons besides VTE. The protocol for this study was approved by the institutional review board at (blinded for review) (IRB No. H30-302), and informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMeasurement of plasma D-dimer levels\u003c/h2\u003e \u003cp\u003ePeripheral blood samples were collected from all patients at initial presentation, 1 week before ISBT, pre-ISBT (0\u0026ndash;3 days before needle insertion), on the day of needle removal, and the day following needle removal. Blood samples were collected from an antecubital vein into plastic tubes. 0.11\u0026nbsp;M sodium citrate was added to whole blood in a 9:1 dilution as an anticoagulant, and citrated plasma was then separated by centrifugation at 3000\u0026nbsp;rpm for 10 minutes. Plasma DD levels were measured using nanopia DD (Sekisui Medical, Tokyo, Japan) sensitized with anti-DD mouse monoclonal antibodies to induce a latex coagulation reaction. Turbidity was then quantified by spectrophotometry using the CP3000 automated coagulation system (CP3000; Sekisui Medical, Tokyo, Japan). The cutoff value for the measure of plasma DD was 1.0\u0026nbsp;\u0026micro;g/mL.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDetection of VTE\u003c/h2\u003e \u003cp\u003eVenous ultrasound imaging (VUI) was performed to detect deep vein thrombosis (DVT). Ultrasonography was performed using Aplio500 or Aplio a 450 (Canon Medical Systems Corporation, Otawara, Japan) with a 3.5-MHz convex and a 7.5-MHz linear transducer. Power, pulse repetition frequency and wall thump filter settings were adjusted for venous vascular studies. Femoral, popliteal, peroneal, anterior and posterior tibial, and soleal veins were evaluated bilaterally. Femoral veins were assessed in a supine position and other veins were assessed in a sitting position. All veins were imaged on transverse and long axis views. Venous lumina were observed while searching for thrombus by manual compression with transducer and color Doppler imaging (Thrombus was searched by transducer compression and color Doppler imaging). For the patients, who had a DVT on the proximal side beyond the popliteal fossa, intrapelvic DVT and PE were evaluated by contrast-enhanced CT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eScreening and management of patients with VTE at peri-ISBT period\u003c/h2\u003e \u003cp\u003eDD was measured in all patients at first presentation, 1 week before ISBT, pre-ISBT, on the day of needle removal and on the day following needle removal. Patients were divided into 3 groups based on the risks and management of VTE during the peri-ISBT period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients in Group 1 were negative for DD (\u0026lt;\u0026thinsp;1.0\u0026nbsp;\u0026micro;g/mL) 1 week before ISBT. In this group, an intermittent pneumatic compression device (IPCD) was used during the supine position, and VUI (\u0026plusmn;\u0026thinsp;CT) was performed if DD levels exceeded a standard value of 1.0\u0026nbsp;\u0026micro;g/mL on the day of or the day following needle removal. In Group 2, VTE was not detected in VUI (\u0026plusmn;\u0026thinsp;CT), although patients were positive for DD (\u0026ge;\u0026thinsp;1.0\u0026nbsp;\u0026micro;g/mL) 1 week before ISBT. IPCD was used during the supine position in this group. VUI (\u0026plusmn;\u0026thinsp;CT) was performed if DD levels on the day of or the day following needle removal exceeded the pre-ISBT value\u0026thinsp;+\u0026thinsp;0.5\u0026nbsp;\u0026micro;g/mL. In Group 3, VTE was detected at first presentation and/or 1 week before ISBT. A graduated compression stocking was used during ISBT to maintain the supine position for patients in this group. VUI (\u0026plusmn;\u0026thinsp;CT) was performed if DD on the day of or the day following needle removal was positive in patients who had negative DD levels pre-ISBT, or exceeded the pre-ISBT value\u0026thinsp;+\u0026thinsp;0.5\u0026nbsp;\u0026micro;g/mL in patients that had a positive DD level pre-ISBT.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patients with DVT at first presentation received VUI 1 week before ISBT. Patients with acute or subacute DVT detected by VUI 1 week before ISBT, or with PE detected by enhanced CT before ISBT were given unfractionated heparin (UFH), which was subsequently interrupted at midnight on the day of needle insertion. Oral anticoagulant was interrupted 2 days before ISBT for patients with chronic DVT. A bolus injection of 5000 units (80\u0026ndash;100 unit/kg) of UFH was initially administered, followed by continuous administration of 750\u0026ndash;1000 units/h (15\u0026ndash;20 units/kg/h) under monitoring for the activated partial thromboplastin time (aPTT) (target value: 1.5\u0026ndash;2.5 x normal value).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRadiotherapy and brachytherapy protocol\u003c/h2\u003e \u003cp\u003ePatients that did not receive preceding radiotherapy underwent external beam radiotherapy (EBRT) and HDR ISBT. The EBRT was delivered using the three-dimensional conformal technique with a linear accelerator (Clinac iX; Varian Medical System, Palo Alto, CA) and a 10-MV photon beam. Whole-pelvic EBRT was initially administered at a dose of 30.0\u0026ndash;50.0\u0026nbsp;Gy in 15\u0026ndash;25 fractions using the four-field technique, and an additional dose of 0\u0026ndash;20.0\u0026nbsp;Gy in 0\u0026ndash;10 fractions was administered using EBRT with a 3-cm midline block (MB) and the anterior-posterior/posterior-anterior technique. In cases where the shortest diameter of a pelvic lymph node was \u0026ge;\u0026thinsp;1\u0026nbsp;cm, a boost EBRT dose of 6\u0026ndash;10\u0026nbsp;Gy was administered in 3\u0026ndash;5 fractions.\u003c/p\u003e \u003cp\u003eBrachytherapy was performed using an iridium-192 (\u003csup\u003e192\u003c/sup\u003eIr) remote afterloading system (MicroSelectron HDRTM; Nucletron, Veenendaal, The Netherlands), and the first HDR ISBT treatment was performed within 7 days after the MB insertion. For patients that did not undergo preceding radiotherapy, ISBT was delivered at a dose of 12\u0026ndash;30\u0026nbsp;Gy in 2\u0026ndash;5 fractions on 1\u0026ndash;3 consecutive days (prescribed as D90 to high-risk clinical target volume [HRCTV]). For the patients that did receive preceding radiotherapy, ISBT was delivered at a dose of 36\u0026ndash;42\u0026nbsp;Gy in 6\u0026ndash;7 fractions on 3\u0026ndash;4 consecutive days. ISBT was planned based on CT with a 2.5-mm slice thickness and either the Oncentra system (version 4.0, Nucletron). The HRCTV included the macroscopic residual tumor, which was imaged as the high T2WI area on the pre-brachytherapy magnetic resonance imaging, and the entire cervix. During ISBT, the Martinez Universal Perineal Interstitial Template was used for all patients. Spinal anesthesia and epidural anesthesia were the principal methods of anesthesia for ISBT. In cases where epidural anesthesia was difficult to perform, intravenous patient-controlled anesthesia was used. Bed rest in the supine position was maintained for all patients during ISBT. From the time of needle removal to the next morning, the standing position was prohibited, and bed rest was maintained.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eChemotherapy\u003c/h2\u003e \u003cp\u003eDuring the radiotherapy period, a weekly regimen of cisplatin (CDDP; 40\u0026nbsp;mg/m\u003csup\u003e2\u003c/sup\u003e) was generally administered for the patients receiving both EBRT and ISBT. Concurrent chemotherapy with radiotherapy (CCRT) was not performed for patients who met any of the following conditions: 1) ISBT alone, 2) preceding radiotherapy, 3) insufficient renal function, or 4)\u0026thinsp;\u0026ge;\u0026thinsp;75\u0026nbsp;years old. A total of 14 patients ultimately received radiotherapy alone and 33 patients received CCRT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe incidence of VTE was defined as a newly appearing thrombosis within in a specific region where VTE was not present before ISBT. The worsening of VTE was defined as a thrombosis that was larger than the thrombosis observed on VUI or CT before ISBT.\u003c/p\u003e \u003cp\u003eFor the patients receiving EBRT, the equivalent dose in 2\u0026nbsp;Gy fractions (EQD2) was calculated to sum the dose of ISBT plus EBRT before the insertion of the MB, based on the linear-quadratic model [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. For the patients treated with ISBT alone, the EQD2 was calculated to determine the dose of ISBT. The tumor dose was calculated using an α/β ratio of 10\u0026nbsp;Gy. For calculation of the dose-volume parameters of the organ at risk (OAR) (i.e., D2.0\u0026nbsp;cc), the α/β ratio was assumed to be 3\u0026nbsp;Gy.\u003c/p\u003e \u003cp\u003eThe paired \u003cem\u003et\u003c/em\u003e-test was used to compare DD values between pre-ISBT levels and levels on the day of and the day following needle removal. The difference between pre-ISBT DD values and those on the day of needle removal was determined by subtracting the pre-ISBT DD value from the DD level on the day of needle removal. The difference between pre-ISBT DD values and those on the day following needle removal was determined by subtracting the pre-ISBT DD value from the DD level on the day following needle removal. The Student \u003cem\u003et\u003c/em\u003e-test was used to compare these differences. The risk factors for incidence or worsening of VTE and/or PE caused by prolonged bed rest during ISBT were assessed by the Chi-square test. The chi-square test was performed using the SPSS Base System software program version 24.0.0.0 (SPSS, Chicago, IL) and the SAS software version 9.4 (SAS Institute, Cary, NC), and differences were considered statistically significant at \u003cem\u003ep\u003c/em\u003e-values of \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cp\u003eThe patient characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 61\u0026nbsp;years old. Recurrent tumors were present in 14 patients. Of these, 11 patients had a postoperative recurrence, and the remaining 3 patients experienced recurrence after definitive radiotherapy. Six of the fourteen patients received preceding radiotherapy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient and tumor characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e61 (range: 30˗86)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCervix\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (79%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCorpus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVagina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVulva\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (77%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (23%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian tumor size, mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e62 (range: 9˗140)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial onset/recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInitial onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (70%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (30%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIGO for 33 patients with initial onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (55%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (45%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLN metastasis at the time of pre-radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (64%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePALN metastasis at the time of pre-radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (74%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (26%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Caprini score at the time of pre-ISBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5 (range: 3˗10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Rogers score at the time of pre-ISBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4 (range: 1˗5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: FIGO, International Federation of Gynecology and Obstetrics; PLN, pelvic lymph node; PALN, para aortic lymph node; ISBT, interstitial brachytherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTreatment characteristics are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A total of 41 patients received EBRT plus ISBT, and ISBT alone was performed on 6 patients with preceding radiotherapy. The median duration of bed rest was 2 days (range: 1\u0026ndash;4 days). The median number of needles inserted during ISBT was 15 (range: 7\u0026ndash;23).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEBRT plus ISBT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eISBT alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnesthesia for ISBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpinal and epidural aesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSpinal anesthesia and IVPCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMedian duration of bed rest, day (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMedian number of inserted needles, needle (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (7\u0026ndash;23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMean volume of CTV (cc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.9\u0026thinsp;\u0026plusmn;\u0026thinsp;32.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean EQD2 for CTV and OARs (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCTV D90 (α/β\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBladder D2cc (α/β\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.7\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSigmoid D2cc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.2\u0026thinsp;\u0026plusmn;\u0026thinsp;17.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRectum D2cc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: EBRT, external beam radiotherapy; ISBT, interstitial brachytherapy; IVPCA, intravenous patients-control anesthesia; CTV, clinical target volume; EQD2, equivalent dose in 2\u0026nbsp;Gy fractions; OAR, organ at risk.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eVTE and DD status during ISBT, according to the patients\u0026rsquo; assigned group, is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. There were no VTEs detected before ISBT in 33 patients. Of these, 18 patients were in group 1 and 15 patients were in group 2. In group 3, 12 of 14 patients with VTE before ISBT had DVT alone, and the remaining 2 patients had both DVT and PE. Of the 14 patients in group 3, VTE was detected at first consultation in 8 patients and was detected 1 week before ISBT in 6 patients. In the VUI findings 1 week before ISBT, 1 patient was diagnosed with acute DVT, 6 patients were diagnosed with subacute DVT, and 7 patients had chronic DVT. Administration of heparin was provided for 8 patients, including 7 patients with acute or subacute DVT, and 1 patient with PE and chronic DVT. VUI\u0026thinsp;\u0026plusmn;\u0026thinsp;CT was performed after needle removal in 22 patients. Of these, 18 patients received VUI alone, 3 received VUI and CT, and 1 received CT alone. VUI was omitted in this patient because DD levels were extremely high on the day of needle removal. We observed no incidence of VTE related to ISBT in 33 patients in group 1 and 2. Among the 14 patients in group 3, we observed an incidence and/or worsening of VTE in 7 patients. None of these 7 patients had symptomatic VTE. In one patient, administration of heparin was initiated 3 hours after needle removal, due to new presentation of VTE in multiple sites including the lungs, and the DD level was extremely high (88.9\u0026nbsp;\u0026micro;g/mL). Another patient, in whom VTE extended to the inferior vena cava, was administered heparin on the day following needle removal. The remaining patients in group 3 received oral coagulants. During or after ISBT, none of the patients experienced bleeding requiring treatment.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe DD values obtained pre-ISBT, on the day of, and on the day following needle removal are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. For all patients, the median pre-ISBT DD value was 1.0\u0026nbsp;\u0026micro;g/mL (range: 0.4\u0026ndash;5.8\u0026nbsp;\u0026micro;g/mL), the median value on the day of needle removal was 1.1 (0.5\u0026ndash;88.9), and the median value on the day following needle removal was 1.5 (0.7\u0026ndash;40.6). For all patients, DD values on the day following needle removal were significantly higher than those measured pre-ISBT (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04); however, there was no significant difference in DD values between the pre-ISBT levels and those on the day of needle removal (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.22). The median difference in DD values between the pre-ISBT level and the day of needle removal was 0.0\u0026nbsp;\u0026micro;g/mL (-4.4\u0026ndash;85.5\u0026nbsp;\u0026micro;g/mL). For patients without VTE before ISBT, the median difference was 0.0 (-4.4\u0026ndash;3.1), for those with VTE it was 0.2 (-0.5\u0026ndash;85.5), and among 7 patients without and 7 with incidence or worsening of VTE, the median difference was \u0026minus;\u0026thinsp;0.2 (-0.5\u0026ndash;0.4) and 6.1 (-0.1\u0026ndash;85.5), respectively. There was no significant difference between patients without VTE before ISBT vs. those with (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.21), and between patients without incidence or worsening of VTE compared to those with (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.22). The median difference between pre-ISBT DD values and the day following needle removal among all patients was 0.3\u0026nbsp;\u0026micro;g/mL (-3.3\u0026ndash;37.2\u0026nbsp;\u0026micro;g/mL), while among patients without VTE before ISBT the median difference was 0.2 (-3.3\u0026ndash;4.6), and among patients with VTE it was 2.0 (-0.2\u0026ndash;37.2). Among 7 patients without and 7 with incidence or worsening of VTE, the median difference was 0.1 (-0.2\u0026ndash;2.9) and 7.7 (1.3\u0026ndash;37.2), respectively. There was a borderline significant difference between patients without VTE before ISBT vs those with (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.07), and between patients without incidence or worsening of VTE vs. those with (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.07).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe univariate analysis revealed that the incidence or worsening of VTE was significantly related to a diagnosis of DVT before ISBT (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), a Caprini score\u0026thinsp;\u0026ge;\u0026thinsp;6 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), a difference in DD values between pre-ISBT and the day of needle removal\u0026thinsp;\u0026ge;\u0026thinsp;1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and a difference between DD values pre-ISBT and on the day following needle removal\u0026thinsp;\u0026ge;\u0026thinsp;1 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, longer duration of bed rest and Rogers score were not significantly associated with the incidence or worsening of VTE (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.40, respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis for the incidence or worsening of venous thromboembolism\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncidence or worsening of VTE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;61\u0026nbsp;years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;61\u0026nbsp;years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCervix\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;61\u0026nbsp;mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;61\u0026nbsp;mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLN metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePALA metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial onset/recurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInitial onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of bed rest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;2 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNumber of inserted needles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVolume of CTV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;54.9\u0026nbsp;cc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;54.9\u0026nbsp;cc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVTE before ISBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaprini score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRogers score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDifference of D-dimer value between pre-ISBT and the day of needle removal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;+1\u0026nbsp;\u0026micro;g/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;+1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDifference of D-dimer value between pre-ISBT and the day following needle removal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;+1\u0026nbsp;\u0026micro;g/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;+1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: VTE, venous thromboembolism; SCC, squamous cell carcinoma; PLN, pelvic lymph node metastasis; PALA, para-aortic lymph node; CCRT, concurrent chemoradiotherapy; RT, radiotherapy; EBRT, external beam radiotherapy; ISBT, interstitial brachytherapy; CTV, clinical target volume; DVT, deep vein thrombosis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eIt has been previously reported that without thromboprophylaxis, the incidence of symptomatic VTE following major surgery was 1.5-6.0% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In surgical patients with mechanical prophylaxis, administration of heparin, or both of these, the incidence of symptomatic VTE was 0.9\u0026ndash;3.4%, 0.5\u0026ndash;1.9%, or 0.2\u0026ndash;0.9%, respectively [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These studies also reported that major bleeding was observed in 1.2\u0026ndash;4.5% of patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The incidence of fatal PE in the patients with thromboprophylaxis was reduced to 0.1\u0026ndash;0.5%, compared to 0.3\u0026ndash;1.2% in the patients without thromboprophylaxis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the clinical practice guidelines reported by the American College of Chest Physicians and the American Society of Clinical Oncology, the type of thromboprophylaxis was determined according to the risk stratification of VTE and bleeding complications. For patients with a moderate risk of VTE, administration of heparin or mechanical prophylaxis was recommended, while for the patients at a high risk of VTE, the administration of heparin with the addition of IPCD was recommended [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, if the patients were at high risk for major bleeding complications, the administration of heparin was avoided. In this study, all patients were classified as moderate or high risk, as evaluated by the Caprini score. Heparin was only administered to patients with acute or subacute DVT, or with PE before ISBT. This was because ISBT, in which 10 or more needles were placed for 2\u0026ndash;3 days, was considered to be a procedure that had a potential for major bleeding. As a result, the incidence of VTE was observed in 2 (4.2%) out of 47 patients, and worsening of VTE was observed in 5 (10.6%) out of 47 patients. However, there was no occurrence of symptomatic VTE, and no major bleeding complications occurred during or after ISBT under thromboprophylaxis in this study.\u003c/p\u003e \u003cp\u003eThe risk of VTE appeared to be highest for patients undergoing abdominal or pelvic surgery for malignancy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In addition, advanced age (especially 60\u0026nbsp;years or older), prior VTE, bed rest (4\u0026nbsp;days or longer), and longer length of hospital stay were also considered to be risk factors for VTE following surgery [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Tasaka et al. reported that the risk factors for VTE at pretreatment were advanced age (60\u0026nbsp;years or older) and bulky tumors (40\u0026nbsp;mm or greater) for cervical cancer patients, and advanced age, stage III/IV disease, and bulky tumors (60\u0026nbsp;mm or greater) for endometrial cancer patients [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In univariate analysis of this study, advanced age, bulky tumors, and long bed rest were not significantly related to the incidence or worsening of VTE (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, the presence of VTE before ISBT, a Caprini score\u0026thinsp;\u0026ge;\u0026thinsp;6, a difference in DD values between pre-ISBT and the day of needle removal\u0026thinsp;\u0026ge;\u0026thinsp;1, and a difference between pre-ISBT and the day following needle removal\u0026thinsp;\u0026ge;\u0026thinsp;1 were risk factors for VTE.\u003c/p\u003e \u003cp\u003eThe risk stratification for VTE following surgery was mainly evaluated according to the Rogers score [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and the Caprini score [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The Rogers score was established based on the analysis of VTE incidence in 183,069 patients undergoing vascular and general surgery [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and consists of patient factors (female gender, higher American Society of Anesthesiologists class, ventilator dependence, preoperative dyspnea and transfusion in the 72 hours before operation), preoperative laboratory values (albumin, bilirubin, sodium and hematocrit), and surgical characteristics (type of surgical procedure, work relative value units, and infected/contaminated wounds). In this study, all patients were categorized as very low risk, because the Rogers score is composed of factors that are less affected by ISBT. In contrast, the Caprini score, which was mainly established by referring to the medical literature, contains patient factors (age, body mass index, prior VTE, family history of VTE, coagulation factors such as Factor V Reiden and Lupus anticoagulant, malignancy, and bed rest) and surgical characteristics (type of surgical procedure). In this study, the incidence or worsening of VTE was significantly higher in the high-risk group, as determined by a Caprini score\u0026thinsp;\u0026ge;\u0026thinsp;6, than in the high risk group (Caprini score 5) or the moderate risk group (Caprini score 3\u0026ndash;4) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Because factors such as age, bed rest, and prior VTE were included in the Caprini score, it was considered more suitable than the Rogers score to evaluate a risk for the incidence or worsening of VTE during ISBT.\u003c/p\u003e \u003cp\u003eTo predict the incidence or worsening of VTE during ISBT, changes in DD values detected by close monitoring and a diagnosis of VTE before ISBT are necessary to screen gynecological cancer patients treated with ISBT. The Caprini score may be useful to predict the incidence or worsening of VTE, not only for the surgical patients but also for the patients treated with ISBT. Additionally, the close monitoring of DD values and the management of VTE that was modelled in this study could be suggested as a novel approach for thromboprophylaxis in gynecological cancer patients treated with ISBT.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eThe limitations of this study include its single-center retrospective design. Thus, further studies with multicenter prospective designs are needed to establish the efficacy of screening and thromboprophylaxis for VTE during ISBT.\u003c/p\u003e \u003cp\u003eDD levels should be closely measured before and after ISBT to detect the incidence or worsening of VTE for patients diagnosed with DVT before ISBT. The Caprini score may be useful to evaluate the risks for the incidence or worsening of VTE induced by prolonged bed rest during ISBT.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003evenous thromboembolism (VTE), D-dimer (DD), pulmonary embolism (PE), Interstitial brachytherapy (ISBT), local control (LC), high dose rate (HDR), Venous ultrasound imaging (VUI), deep vein thrombosis (DVT), activated partial thromboplastin time (aPTT), external beam radiotherapy (EBRT), midline block (MB), high-risk clinical target volume (HRCTV), concurrent chemotherapy with radiotherapy (CCRT), organ at risk (OAR), external beam radiotherapy (EBRT)\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis retrospective study was approved by the institutional review board of Tsukuba University and was conducted according to the tenets of the 1975 Declaration of Helsinki. The need for informed consent was waived owing to the retrospective nature of the study.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable (our manuscript did not contain any individual person\u0026rsquo;s data in any form).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets supporting the conclusions of this article are available upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCompeting interests:\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eNot Applicable\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthor\u0026rsquo;s Contributions\u003c/h2\u003e\n\u003cp\u003eKNM, TT, OK, AA, and KN: Conceptualization, Methodology, Formal Analysis, Investigation\u003c/p\u003e\n\u003cp\u003eTS and TO: Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eKK, TS, and HS: Writing \u0026ndash; Review \u0026amp; Editing\u003c/p\u003e\n\u003cp\u003eKNM: Validation, Supervision, Project administration\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eThis research was supported by the University of Tsukuba.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSatoh T, Matsumoto K, Tanaka YO, Akiyama A, Nakao S, Sakurai M, et al. Incidence of venous thromboembolism before treatment in cervical cancer and the impact of management on venous thromboembolism after commencement of treatment. Thromb Res. 2013;131:127-32.\u003c/li\u003e\n\u003cli\u003eSatoh T, Matsumoto K, Uno K, Sakurai M, Okada S, Onuki M, et al. Silent venous thromboembolism before treatment in endometrial cancer and the risk factors. Br J Cancer. 2008;99:1034-9.\u003c/li\u003e\n\u003cli\u003eSatoh T, Oki A, Uno K, Sakurai M, Ochi H, Okada S, et al. High incidence of silent venous thromboembolism before treatment in ovarian cancer. Br J Cancer. 2007;97:1053-7.\u003c/li\u003e\n\u003cli\u003eGould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(Suppl 2):e227S-77S.\u003c/li\u003e\n\u003cli\u003eHarrison KA, Haire WD, Pappas AA, Purnell GL, Palmer S, Holdeman KP, et al. Plasma D-dimer: a useful tool for evaluation suspected pulmonary embolus. J Nucl Med. 1993;34:896-8.\u003c/li\u003e\n\u003cli\u003eWells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Eng J Med. 2003;349:1227-35.\u003c/li\u003e\n\u003cli\u003eGeerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell C, et al. Prevention of venous thromboembolism: the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(Suppl 3):338S-400S.\u003c/li\u003e\n\u003cli\u003eRogers SO Jr, Kilaru RK, Hosokawa P, Henderson WG, Zinner MJ, Khuri SF. Multivariable predictors of postoperative venous thromboembolic events after general and vascular surgery: results from the patient safety in surgery study. J Am Coll Surg. 2007;204:1211-21.\u003c/li\u003e\n\u003cli\u003eCaprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon. 2005;51:70-8.\u003c/li\u003e\n\u003cli\u003eMendez LC, Weiss Y, D\u0026rsquo;Souza D, Ravi A, Barbera L, Leung E. Three-dimensional-guided perineal-based interstitial brachytherapy in cervical cancer: A systematic review of technique, local control, and toxicities. Radiother Oncol. 2017;123:312-8.\u003c/li\u003e\n\u003cli\u003eDale RG. The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy. Br J Radiol. 1985;58:515-28.\u003c/li\u003e\n\u003cli\u003eGuyatt GH, Norris SL, Schulman S, Hirsh J, Eckman MH, Akl EA, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl 2):53S-70S.\u003c/li\u003e\n\u003cli\u003eBahl V, Hu HM, Henke PK, Wakefield TW, Campbell Jr DA, Caprini JA. A validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg. 2010;251:344-50.\u003c/li\u003e\n\u003cli\u003eCollins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trial in general, orthopedic, and urologic surgery. N Eng J Med. 1988;318:1162-73.\u003c/li\u003e\n\u003cli\u003eCollen JF, Jackson JL, Shorr AF, Moores LK. Prevention of venous thromboembolism in neurosurgery: a metaanalysis. Chest 2008;134:237-49.\u003c/li\u003e\n\u003cli\u003ePezzuoli G, Neri Serneri GG, Settembrini P, Coggi G, Olivari N, Buzzetti G, et al. Prophylaxis of fatal pulmonary embolism in general surgery using low-molecular weight heparin Cy 216: a multicenter, double-blind, randomized, controlled, clinical trial versus placebo (STEP). STEP-Study Group. Int Surg. 1989;74:205-10.\u003c/li\u003e\n\u003cli\u003eLyman GH, Khorana AA, Kuderer NM, Bohlke K, Lee AYY, Arcelus JI, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2189-204.\u003c/li\u003e\n\u003cli\u003eWhite RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90:446-55.\u003c/li\u003e\n\u003cli\u003eAlcalay A, Wun T, Khatri V, Chew HK, Harvey D, Zhou H, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol\u003cem\u003e.\u003c/em\u003e 2006;24:1112-8.\u003c/li\u003e\n\u003cli\u003eClarke-Pearson DL, Synan IS, Coleman RE, Hinshaw W, Creasman WT. The natural history of postoperative venous thromboli in gynecologic oncology: a prospective study of 382 patients. Am J Obstet Gynecol. 1984;148:1051-4.\u003c/li\u003e\n\u003cli\u003eAgnelli G, Bolis G, Capussotti L, carpa RM, Tonelli F, Bonizzoni E, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg. 2006;243:89-95.\u003c/li\u003e\n\u003cli\u003eSpyropoulos AC, Hussein M, Lin J, Battleman D. Rates of venous thromboembolism occurrence in medical patients among the insured population. Thromb Haemost. 2009;102:951-7.\u003c/li\u003e\n\u003cli\u003eTasaka N, Minaguchi T, Hosokawa Y, Takao W, Itagaki H, Nishida K, et al. Prevalence of venous thromboembolism at pretreatment screening and associated risk factors in 2086 patients with gynecological cancer. J Obstet Gynaecol Res. 2020;46:765-73.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gynecological cancer, image-guided adaptive brachytherapy, interstitial brachytherapy, venous thromboembolism, deep vein thrombosis","lastPublishedDoi":"10.21203/rs.3.rs-138401/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-138401/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground:\u003c/em\u003e Screening and management of venous thromboembolism (VTE) after surgery is important in preventing sublethal VTE. However, the risk factors for VTE during interstitial brachytherapy (ISBT) remain unknown, and appropriate screening and management strategies are yet to be established. This study therefore aimed to evaluate the risk factors for VTE resulting from requisite bed rest during ISBT for gynecologic cancers.\u003c/p\u003e\u003cp\u003e\u003cem\u003eMethods:\u003c/em\u003e We retrospectively analyzed 47 patients. For patients without definitive preceding radiotherapy, whole pelvic irradiation (30-50 Gy) followed by ISBT of 12-30 Gy/2-5 fx/1-3 days was administered to CTV D90. For patients with preceding radiotherapy, 36-42 Gy/6-7 fx/3-4 days was delivered by ISBT alone. D-dimer (DD) was measured at initial presentation, 1 week before ISBT, pre-ISBT, on the day of, and the day following needle removal. Patients were divided into three groups according to the risk of VTE and were managed accordingly. Group 1: DD was not detected (negative) before ISBT. Group 2: VTE was not detected on venous ultrasound imaging, although DD was positive before ISBT. Group 3: VTE was detected (positive) before ISBT. An intermittent pneumatic compression device was used during ISBT; for this, patients without VTE before ISBT required to remain in the supine position. Heparin or oral anticoagulants were administered to patients with VTE before ISBT.\u003c/p\u003e\u003cp\u003e\u003cem\u003eResults:\u003c/em\u003e Overall, the median values of DD pre-ISBT, on the day of, and on the day following needle removal were 1.0 (0.4-5.8), 1.1 (0.5-88.9), and 1.5 (0.7-40.6) μg/mL, respectively. After ISBT, no patients had deep vein thrombosis (DVT) in groups 1 and 2. In group 3, 7 of 14 patients experienced worsening of VTE but remained asymptomatic. In univariate analysis, DVT diagnosed before ISBT, Caprini score ≥5, and difference in DD values between pre-ISBT and the day of or the day following needle removal ≥1 were associated with the incidence or worsening of VTE.\u003c/p\u003e\u003cp\u003e\u003cem\u003eConclusion:\u003c/em\u003e DD should be measured before and after ISBT to detect the incidence or worsening of VTE in patients with DVT. The Caprini score may help in the prediction of VTE during or after ISBT.\u003c/p\u003e","manuscriptTitle":"Risk Factors for Venous Thromboembolism Induced by Prolonged Bed Rest during Interstitial Brachytherapy for Gynecological Cancer: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-01-05 16:50:36","doi":"10.21203/rs.3.rs-138401/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-05-29T07:00:00+00:00","index":0,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-04-11T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-01-26T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-01-25T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-12-29T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-12-29T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-12-28T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-12-28T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e2464b7-3452-4473-b2a2-ed94ec1cf145","owner":[],"postedDate":"January 5th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":1706604,"name":"Oncology"},{"id":1706605,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-06-11T16:19:00+00:00","versionOfRecord":[],"versionCreatedAt":"2021-01-05 16:50:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-138401","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-138401","identity":"rs-138401","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}