Radiation-associated Second Primary Cancers After Iodine-125 Low-Dose-Rate Brachytherapy for Localized Prostate Cancer

Radiation-associated Second Primary Cancers After Iodine-125 Low-Dose-Rate Brachytherapy for Localized Prostate Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Radiation-associated Second Primary Cancers After Iodine-125 Low-Dose-Rate Brachytherapy for Localized Prostate Cancer Kojiro Niwa, Koji Iinuma, Masahiro Nakano, Masayuki Tomioka, Masaya Ito, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8657808/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Mar, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Low-dose-rate brachytherapy with iodine-125 (LDR-BT) is an established curative radiation treatment modality for localized prostate cancer (PCa). This study aimed to evaluate the long-term incidence of radiation- associated secondary primary cancer (RASPC) after LDR-BT in Japanese patients with localized PCa and identify predictive factors associated with RASPC. Methods and materials: We retrospectively reviewed the clinical records of 478 consecutive patients with localized PCa who underwent LDR-BT at the Gifu University Hospital. This study’s primary endpoint was RASPC incidence, including bladder and rectal/anal cancers. The secondary endpoint was the identification of risk factors for LDR-BT that predicted RASPC development. Results After a median follow-up period of 105 months, RASPC developed in 13 patients (2.7%). Bladder cancer and rectal/anal canal cancer were observed in seven (1.5%) and six (1.3%) patients, respectively. Multivariate analysis showed that a biologically effective dose (BED) ≥ 197 Gy was associated with increased risk of RASPC (hazard ratio 4.145; 95% confidence interval 1.108–15.498; p = 0.035). Conclusions RASPC incidence after LDR-BT was relatively low; BED ≥ 197 Gy was identified as an independent significant predictor for developing RASPC. Adequate tumor control can be achieved through appropriate radiation dose administration; carefully planned long-term follow-up may be beneficial for RASPC early detection. Prostate cancer Low-dose-rate brachytherapy Radiation-associated second primary cancer Biologically effective dose Late toxicity Figures Figure 1 Figure 2 Figure 3 Introduction Prostate cancer (PCa) is one of the most common malignancies among men worldwide and in Japan [ 1 , 2 ]. Definitive treatment modalities for localized PCa, including active surveillance, surgical intervention, and radiation therapy (RT), have demonstrated favorable oncological outcomes worldwide [ 2 ]. The low-dose-rate brachytherapy with iodine-125 (LDR-BT), which is used in combination with or without external beam radiation therapy (EBRT), is one of the most effective treatment modalities for RT [ 3 ]. LDR-BT generally yields favorable oncological outcomes [ 4 – 6 ]. Previous studies from our institution demonstrated excellent long-term oncological outcomes after LDR-BT [ 4 – 6 ]. A median follow-up period of 90.0 months revealed a 10-year biochemical recurrence (BCR)-free rate of 95.3% [ 6 ]. Notably, the 10-year BCR-free rate maintained a high level of 93.4% among patients with PCa categorized as high-risk according to the D'Amico classification [ 6 , 7 ]. Although LDR-BT is an effective treatment for long-term cancer control, there are still significant treatment-related toxicities, including radiation-related late complications involving the genitourinary and gastrointestinal organs, including radiation-associated secondary primary cancers (RASPC). RASPC is generally defined as occurring > five years after receiving RT [ 10 – 12 ]. This critical complication should be considered when selecting the most effective treatment for localized PCa. Conversely, the occurrence of late complications, including RASPC, in patients with PCa who underwent RT, particularly LDR-BT, followed by long-term observation, remains limited. Therefore, this study aimed to evaluate the long-term incidence of RASPC after LDR-BT for localized PCa in Japanese patients. Additionally, an analysis was conducted to determine predictive factors associated with RASPC occurrence. Materials and methods Patients We retrospectively reviewed the clinical records of 478 consecutive patients with PCa who underwent LDR-BT at the Gifu University Hospital between August 2004 and December 2019. Patients with localized PCa, without lymph node or distant metastases, were enrolled according to the 2016 American Joint Committee on Cancer Staging Manual [ 13 ]. Patients were divided into risk categories according to the National Comprehensive Cancer Network (NCCN) classification [ 14 ]. The following clinical data were collected from the enrolled patients: age, body mass index (BMI), initial serum prostate-specific antigen (PSA) level, clinical T stage, biopsy Gleason grade [ 15 ], NCCN risk classification, prostate volume (PV) at LDR-BT, presence or absence of androgen deprivation therapy (ADT), and follow-up duration. Colonoscopies were performed before LDR-BT in all patients who had not undergone this examination within the previous two years, in accordance with the protocol initiated in April 2010 [ 16 ]. Patients with lymph node involvement, distant metastasis, a history of transurethral resection of the prostate, or a maximum urinary flow rate < 10 mL/s on uroflowmetry were excluded from the study. Due to the retrospective nature of this study, informed consent was waived, according to the Japanese Ethical Guidelines. An opt-out approach was implemented, thereby giving patients the opportunity to decline participation. This study was reviewed and approved by the Institutional Review Board of Gifu University (approval number: 29–106). Although smoking history was not systematically documented for the entire cohort, detailed smoking status was meticulously reviewed for all patients who developed bladder cancer, based on medical records. Treatment of LDR-BT As previously documented, this report details the treatment procedures for LDR-BT at our institution [ 8 , 9 , 17 ]. Patients with low-risk PCa and a PV > 50 mL received neoadjuvant ADT for at least 3 months before LDR-BT. Patients diagnosed with intermediate-risk PCa were administered ADT for 9 months, followed by LDR-BT with or without EBRT. Patients with high- or very high-risk PCa underwent LDR-BT combined with EBRT and ADT for 24 months. During the administration of EBRT, the radiation field was confined to the prostate and seminal vesicles. Patients were implanted with loose 125I radioactive seeds (Oncoseed, Nippon Medi-Physics, Tokyo, Japan) by the Mick Applicator (Mick Radio-Nuclear Instruments, Bronx, NY, USA) or the ProLink® (Cincinnati, OH, USA) delivery system (C. R. Bard, Inc., Murray Hill, NJ, USA) under real-time confirmation by transrectal ultrasound transperineally into the prostate [ 18 ]. A prescribed minimum peripheral dose of 145 Gy was used for LDR-BT monotherapy, and 104 Gy was used when combined with EBRT. When EBRT was used, a total dose of 40 Gy in 2-Gy fractions was delivered to the prostate and seminal vesicles within 1 month after LDR-BT. In all cases, a modified peripheral loading technique was applied after preplanning the seed implantation [ 19 ]. Therapeutic planning and post-implant dosimetric evaluations were performed using the updated American Association of Physicists in Medicine Task Group 43 for-malism and Variseed version 7.1 (Varian Medical Systems, Palo Alto, CA, USA). Subsequent dosimetric evaluations were conducted using both computed tomography (CT) and magnetic resonance imaging (MRI) modalities, with assessments performed one month after LDR-BT [ 20 ]. The dosimetric parameters that were the focus of this study included the minimum dose received by 90% of the prostate gland (D90), biologically effective dose (BED), minimum percentage of the dose received by 30% of the urethra (UD30), and the rectal volume receiving 100% of the prescribed dose (RV100). The BED was calculated using an alpha/beta ratio of 2. All patients were monitored with follow-up examinations at 3–6 months intervals for 5 years, followed by biennial checkups. The follow-up process included interval history, physical examination, and PSA measurement. Furthermore, MRI scans were obtained 3, 5, and 10 years after LDR-BT. Patients presenting with gross or microscopic hematuria underwent a series of diagnostic procedures, including urinalysis, urinary cytology, and cystoscopy. Patients presenting with bloody stool or other lower gastrointestinal symptoms underwent colonoscopy. These examinations resulted in a diagnosis of RASPC. The follow-up period was defined as the time interval between the completion of RT and the most recent follow-up visit or date of death. BCR definition was established in accordance with the Radiation Therapy Oncology Group-Phoenix classification, which sets the threshold for the PSA nadir at 2 ng/mL [ 21 ]. RASPC RASPC was defined as an in-field second primary cancer that developed at least 5 years after LDR-BT, including bladder, urethral, rectal, and anal canal cancers [ 11 , 12 , 22 ]. The definition of RASPC utilized in this study was employed to identify secondary cancers that developed within the radiation field after a sufficient latency period. However, it is important to note that this does not imply that all malignant tumors occurring within the radiation field are attributable to radiation exposure, nor can they be clearly distinguished from age-related cancers. RASPC was defined exclusively in cases in which the diagnosis was subsequently confirmed by biopsy or surgical pathology. Statistical analysis The primary endpoint of the study was RASPC incidence, including bladder and rectal/anal cancers. The secondary endpoint was the identification of risk factors for LDR-BT that predicted the RASPC development. Additionally, the incidences of bladder and rectal/anal canal cancers were analyzed. The chi-square test was used to evaluate differences between categorical variables, and the Mann–Whitney U test was used for continuous variables. The incidence rates of RASPC, bladder cancer, and anal canal cancer were evaluated using cumulative incidence proportions, and differences according to clinical variables were assessed using the chi-square test. The Kaplan–Meier method was used to estimate overall survival (OS) and BCR. Cox proportional hazard models were used to assess the relationship between potential predictors of RASPC. To assess the robustness of the association between BED and RASPC, given the limited number of RASPC cases in the primary Cox proportional hazards model, a sensitivity analysis was conducted using a reduced model containing only age and BED. Death was treated as a competing event, and the cumulative incidence function was estimated. The optimal cut-off values for age, BMI, and BED were determined using receiver operating characteristic curve analysis [ 23 ]. The data were analyzed using software JMP 14 (SAS Institute Inc., Cary, NC, USA). All statistical analyses were two-sided, and p < 0.05 was considered statistically significant. Results Patient characteristics Baseline patient characteristics are summarized in Table 1 . The median age, BMI, and PSA level of the entire cohort were 66.0 years (interquartile range [IQR]: 62.0–71.0), 23.5 kg/m² (IQR: 21.9–25.3), and 6.5 ng/mL (IQR: 5.1–9.1), respectively. According to the NCCN risk classification, 154 patients were classified as low risk, 126 as favorable intermediate risk, 137 as unfavorable intermediate risk, 54 as high risk, and seven as very high risk. The median BED, UD30, and RV100 were determined to be 194.8 Gy (IQR: 179.1–208.8), 191.2 Gy (IQR: 159.5–218.3), and 0.3% (IQR: 0.1–0.7), respectively. The median follow-up period was 105.0 months (IQR: 71.0–134.0). The median overall survival (OS) was found to be 242.0 months. The median BCR-free survival was not reached; however, the 10-year BCR-free survival rate was 94.9%. Notably, only one patient died of PCa. Table 1 Patient characteristics and postdosimetric parameters. LDR-BT only (n = 276) LDR-BT + EBRT (n = 202) p Age (year, median, IQR) 66.0 (62.0–70.0) 67.0 (63.0–71.0) 0.124 BMI (kg/m 2 , median, IQR) 23.4 (21.8–25.2) 23.7 (22.0-25.5) 0.348 PSA (ng/mL, median, IQR) 6.0 (4.9–7.7) 8.3 (5.7–11.7) < 0.001 Clinical T stage (number, %) T1c 185 (67.0) 67 (33.2) < 0.001 T2a 75 (27.2) 57 (28.2) T2b 7 (2.5) 23 (11.4) T2c 8 (2.9) 43 (21.3) T3a 0 12 (5.9) T3b 1 (0.4) 0 Gleason Group Grade (number, %) 1 175 (63.4) 20 (9.9) < 0.001 2 95 (34.4) 76 (37.6) 3 5 (1.8) 61 (30.2) 4 1 (0.4) 28 (13.9) 5 0 17 (8.4) NCCN risk classification (number, %) Low risk 154 (55.8) 0 < 0.001 Favorable-intermediate risk 85 (30.8) 41 (20.3) Unfavorable-intermediate risk 34 (12.3) 103 (51.0) High risk 3 (1.1) 51 (25.3) Very high risk 0 7 (3.4) Neoadjuvant ADT (number, %) 196 (71.0) 169 (83.7) 0.002 Prostate volume at LDR-BT (mL, median, IQR) 25.1 (19.2–31.0) 20.9 (16.8–27.2) < 0.001 Postdosimetric parameters %D90 (%) 119.5 (111.4-126.3) 119.8 (111.2-128.2) 0.888 Prostate D90 (Gy) 173.1 (161.4–183.0) 124.6 (115.8-133.3) < 0.001 BED (Gy) 183.6 (170.6-194.8) 208.2 (200.5-215.7) < 0.001 % UD30 (Gy) 211.0 (194.3–2313) 154.1 (141.3-176.6) < 0.001 Rectum V100 (%) 0.3 (0.1–0.8) 0.3 (0-0.7) 0.429 Follow-up period (month, median, IQR) 103.0 (72.0-132.0) 110.0 (68.5-137.5) 0.652 Proportion of patients with RASPC Thirteen patients (2.7%) had RASPC. The median time to development of RASPC was 103.5 months (IQR: 71.0–132.0), and the 10-year incidence rate was 1.3% (Fig. 1 ). Seven cases of bladder cancer (1.5%) and six cases of rectal/anal canal cancer (1.3%) were documented. The median time to development was 103.5 months (IQR: 71.0–132.3) for bladder cancer and 105.0 months (IQR: 71.0–133.3) for rectal/anal canal cancer. The 10-year incidence rates of bladder and rectal/anal canal cancers were 1.3% and 0%, respectively (Fig. 2 ). Of the patients studied, one died from bladder cancer and the other from rectal cancer. Among the seven patients who developed bladder cancer, three had a history of smoking, three were non-smokers, and smoking status was unknown in one patient. Predictive factors of RASPC The 10-year cumulative incidence of RASPC tended to be higher in patients with BED ≥ 197 Gy than in those with BED < 197 Gy, and the 15-year cumulative incidence of RASPC was significantly higher in patients with BED ≥ 197 Gy than in those with BED < 197 Gy. ( p = 0.033; Fig. 3 ). The 10-year and 15-year cumulative incidence rates of RASPC were 0.7% and 1.5% in the LDR-BT monotherapy group, and 1.5% and 3.0% in the combination LDR-BT and EBRT group ( p = 0.654 and p = 0.335, respectively). Although a slightly higher tendency for RASPC incidence was observed in the combined LDR-BT and EBRT group, no significant difference was found. When patients were stratified by RV100 (< 0.64 mL vs. ≥0.64 mL), the 10-year cumulative incidence of RASPC was 0.9% in the < 0.64 mL group and 1.5% in the ≥ 0.64 mL group ( p = 0.626). The 15-year cumulative incidence rates were 1.8% and 2.9%, respectively ( p = 0.481). After thorough analysis, no substantial discrepancy in RASPC occurrence was noted between the two groups. The associations between RASPC and clinical covariates are presented in Table 2 . In an exploratory multivariable Cox regression model including age, BMI, NCCN risk category, neoadjuvant ADT, and BED, BED ≥ 197 Gy was associated with an increased risk of RASPC (hazard ratio [HR] 4.145; 95% confidence interval [CI] 1.108–15.498; p = 0.035; Table 2 ). In sensitivity analyses using a reduced multivariable model including only age and BED, BED ≥ 197 Gy remained significantly associated with RASPC (HR 3.842, 95% CI 1.050–14.062, p = 0.042). In the model, BED was represented as a continuous variable with adjustment for age. The analysis revealed that BED exhibited no statistically significant association with RASPC (HR per 10 Gy in-crease: 1.028, 95% CI 0.820–1.288). Table 2 Predictive factors of radiation-induced second primary cancers in patients with localized prostate cancer who underwent Iodine-125 low-dose-rate brachytherapy: results of multivariate analysis. Multivariate analysis Number HR 95%CI p Age (year) < 69 296 1 (ref.) - 0.386 ≥ 69 182 0.506 0.109–2.358 BMI (kg/m 2 ) < 26.0 397 1 (ref.) - 0.465 ≥ 26.0 81 0.465 0.059–3.628 NCCN risk classification Low + Intermediate risk 417 1 (ref.) - 0.995 Poor risk 61 0.993 0.120–8.239 Neoadjuvant ADT No 113 1 (ref.) - 0.138 Yes 365 0.399 0.119–1.342 BED (Gy) < 197.0 251 1 (ref.) - 0.035 ≥ 197.0 227 4.145 1.108–15.498 Discussion RASPC has been reported in numerous cases of malignant neoplasms treated with RT, including breast, oral, and cervical cancers, and lymphoma [ 24 – 26 ]. Radiation-induced DNA damage and long-term genomic instability are considered key mechanisms underlying RASPC development [ 27 , 28 ]. The latency period for RASPC is generally considered to range from several years to decades, thereby underscoring the significance of prolonged follow-up in patients with cancer who have undergone RT therapy. Prolonged survival after definitive RT highlights the clinical importance of evaluating long-term RASPC risk. Table 3 summarizes previous studies on LDR-BT with or without EBRT for PCa. The median follow-up period in these studies ranged from 69.6 to 165.6 months, with the reported incidence rates of RASPC ranging from 1.0 to 4.3% [ 29 – 34 , 36 ]. A previous study examining the incidence of RASPC after LDR-BT in 897 Japanese patients found RASPC in 1.3% of the patients during a median follow-up period of 85.2 months [ 33 ]. Regarding the prevalence of various diseases, bladder cancer was observed in 1.0% of patients, while rectal cancer was identified in 0.3% [ 33 ]. A study examining the risk of bladder cancer development in 1,162 Japanese patients treated with LDR-BT alone or in combination with EBRT reported a bladder cancer incidence of 3.0% at a median follow-up period of 124.8 months [ 35 ]. In this study, the incidence of RASPC was 2.7% over a median follow-up period of 105.0 months. The incidence rates of bladder cancer and rectal/anal canal cancer were 1.5% and 1.3%, respectively. In our cohort, which has been followed for approximately 10 years, the incident rate of RASPC was consistent with that reported in previous studies that had comparable follow-up periods. However, the cumulative incidence of RASPC may increase significantly with longer follow-up periods. Previous studies with long-term follow-up have demonstrated a time-dependent increase in RASPC incidence [ 32 , 36 ]. In these cohorts, the incidence of RASPC in the same patient population increased from 2.1% at a median follow-up of 69.6 months to approximately 7% after more than 14 years of follow-up. The present study indicates that the majority of RASPC cases occurred more than five years after LDR-BT, suggesting that longer-term, systematic follow-up is crucial. Specifically, the implementation of more frequent monitoring, including urine tests, fecal occult blood tests, and colonoscopies, between five and ten years after LDR-BT administration may lead to the early detection of RASPC. Table 3 Previous reports on the development of radiation-induced second primary cancers in patients with localized prostate cancer who underwent Iodine-125 low-dose-rate brachytherapy. Author (Year) Patients (Number) Treatment (Number) Follow-up period (Month, median) Incident rate (Number, %) Secondary cancer site (Number) Liauw SL, et al. (2006) [ 30 ] 348 LDR-BT alone: 125 LDR-BT + EBRT: 223 126.0 15 (4.3) Bladder: 1 Colorectal: 3 Prostatic urethra: 1 Musunuru H, et al. (2006) [ 31 ] 1805 LDR-BT alone: 1805 96.0 13 (1.0) Bladder: 10 Rectal: 3 Hinnen KA, et al. (2011) [ 31 ] 1187 LDR-BT alone: 1187 85.2 26 (2.2) Bladder: 9 Rectal: 17 Hamilton SN, et al. (2014) [ 33 ] 2418 LDR-BT alone: 2418 69.6 51 (2.1) Bladder: 32 Rectal: 19 Nakai Y, et al. (2016) [ 34 ] 897 LDR-BT alone: 507 LDR-BT + EBRT: 390 85.2 12 (1.3) Bladder: 9 Rectal: 3 Cosset JM, et al. (2017) [ 35 ] 675 LDR-BT alone: 675 132.0 14 (2.1) Bladder: 9 Rectal: 5 Ozawa et al. (2022) [ 36 ] 1162 LDR-BT alone: 607 LDR-BT + EBRT: 555 124.8 - Bladder: 27 St-Laurent MP, et al. (2024) [ 37 ] 2378 LDR-BT: 2378 165.6 15 years: 7.0% Bladder: 107 Rectal: 51 Present study 478 LDR-BT alone: 276 LDR-BT + EBRT: 202 105.0 13 (2.8) Bladder: 7 Rectal: 6 The relationship between LDR-BT and the risk of developing RASPC remains controversial. RASPC development after LDR-BT for PCa is associated with several risk factors, including advanced age, history of smoking, and the use of combination therapy involving EBRT [ 32 , 37 , 38 ]. Smoking is recognized as a well-established risk factor for developing bladder cancer [ 39 , 40 ]. The present study indicates that both smokers and non-smokers developed bladder cancer subsequent to LDR-BT, thereby suggesting that radiation therapy may have influenced the subsequent carcinogenesis. However, smoking history was not documented for the entire cohort, which prevented its inclusion as a covariate in multivariate analysis and left unaccounted for potential bias. According to the findings of several single-center studies, RASPC incidence with LDR-BT is comparable to that of radical prostatectomy (RP) [ 31 , 41 ]. Similarly, studies examining the risk of bladder cancer development found no significant differences between patients who received LDR-BT and non-RT for PCa [ 42 , 43 ]. These reports suggest that LDR-BT alone may not increase the long-term risk of secondary primary malignancies. Conversely, St-Laurent et al. [ 36 ] demonstrated that patients with PCa undergoing LDR-BT exhibited a significantly higher risk of RASPC compared with RP (HR 1.81, 95% CI 1.45–2.26, p < 0.001). Furthermore, epidemiological data indicated an elevated prevalence of bladder and rectal cancer in patients diagnosed with PCa after LDR-BT [ 44 ]. In this study, high-dose exposure, specifically BED ≥ 197 Gy, was identified as an independent predictor of RASPC development. Radiotherapy as a definitive treatment has been shown to increase the likelihood of secondary malignancies irrespective of the primary tumor type [ 45 , 46 ]. Inskip et al. [ 46 ] demonstrated a clear dose-response relationship between radiation exposure and the development of new primary solid cancers [ 45 ]. Specifically, elevated radiation doses have been demonstrated to markedly increase the likelihood of developing secondary malignant neoplasms irrespective of the primary cancer type [ 45 ]. Similarly, another study evaluated the correlation between therapeutic radiation and the likelihood of secondary malignancies in multiple organs [ 46 ]. This analysis revealed that radiation dosage plays a pivotal role in carcinogenesis irrespective of the specific tumor type [ 46 ]. However, the importance of increasing the BED to achieve favorable oncological outcomes after LDR-BT for localized PCa has been well-documented [ 47 , 48 ]. The variability in the study results may be attributed to various factors, including treatment-related conditions, follow-up periods, patient backgrounds, dosimetric parameters, and monitoring intensity. Patients who have undergone high-dose LDR-BT require meticulous and prolonged follow-up to ensure optimal outcomes and mitigate potential complications. The achievement of a BED exceeding 197 Gy with LDR-BT monotherapy alone is a rare achievement, and the administration of additional EBRT is common in most cases. However, no statistically significant difference was observed between the LDR-BT monotherapy group and the LDR-BT + EBRT combination group at either the 10-year or 15-year follow-up points. These findings suggest that while adding EBRT may increase the radiation dose to pelvic tissues, the risk of developing RASPC is not solely attributable to the additional EBRT irradiation. Conversely, the development of bladder or anorectal cancer is anticipated to occur at a certain rate in elderly men, regardless of their history with radiation therapy. Therefore, a critical aspect of interpreting these findings is recognizing that the RASPC observed in this cohort cannot be attributed exclusively to radiation exposure. This study has several limitations. First, it was a retrospective, single-center analysis, which may limit generalizability. Second, the number of radiation-associated second primary cancer events was small, and multivariable analyses should therefore be interpreted as exploratory. Third, smoking history, an important risk factor for bladder cancer, was not systematically available for the entire cohort and could not be included in multivariable analyses. Fourth, detailed dose–volume analyses of organs at risk were not performed and may provide additional insights in future studies. Finally, the absence of a non-irradiated control group or age-matched general population data precluded direct estimation of excess radiation-attributable risk. Conclusions In this long-term retrospective analysis of Japanese patients with localized PCa treated with LDR-BT with or without EBRT, RASPC incidence was found to be low. However, BED ≥ 197 Gy emerged as an independent predictor of RASPC, suggesting that higher radiation doses, while essential for optimal tumor control, may be associated with an increased risk of RASPC. These findings emphasize the critical need for meticulous and sustained post-treatment monitoring, particularly in patients undergoing high-dose LDR-BT. Early detection and timely intervention for RASPC may help maintain favorable long-term oncological outcomes and minimize the potential impact of RASPC on patient prognosis. Declarations Conflict of interest statement The authors declare no conflicts of interest. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgements Not applicable. References International Agency for Research on Cancer Cancer Today. 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Radiat Oncol J 36(2):85–94 Travis LB, Demark W, Allan JM et al (2013) Aetiology, genetics and prevention of secondary neo-plasms in adult cancer survivors. Nat Rev Clin Oncol 10(5):289–301 Liauw SL, Sylvester JE, Morris CG et al (2006) Second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up. Int J Radiat Oncol Biol Phys 66(3):669–673 Musunuru H, Mason M, Murray L et al (2014) Second primary cancers occurring after I-125 brachytherapy as monotherapy for early prostate cancer. Clin Oncol (R Coll Radiol) 26(4):210–215 Hinnen KA, van Schaapveld M M, et al (2011) Prostate brachytherapy and second primary cancer risk: a competitive risk analysis. J Clin Oncol 29(34):4510–4515 Hamilton SN, Tyldesley S, Hamm J et al (2014) Incidence of second malignancies in prostate cancer patients treated with low-dose-rate brachytherapy and radical prostatectomy. Int J Radiat Oncol Biol Phys 90(4):934–941 Nakai Y, Tanaka N, Asakawa I et al (2022) Late genitourinary and gastrointestinal toxicity and radiation-induced second primary cancers in patients treated with low-dose-rate brachytherapy. Brachytherapy 21(5):626–634 Cosset JM, Belin L, Wakil G et al (2017) Second malignancies after permanent implant prostate cancer brachytherapy: A single-institution study of 675 patients treated between 1999 and 2003. Cancer Radiother 21(3):210–215 Ozawa Y, Yagi Y, Nakamura K et al (2022) Secondary bladder cancer during long-term follow-up after iodine-125 permanent seed implantation for localized prostate cancer. Brachytherapy 21(4):451–459 St-Laurent MP, Acland G, Hamilton SN et al (2024) Long-Term Second Malignancies in Prostate Cancer Patients Treated With Low-Dose-Rate Brachytherapy and Radical Prostatectomy. J Urol 212(1):63–73 Fernandez Ots A, Browne L, Chin YS et al (2016) The risk of second malignancies after 125I prostate brachytherapy as monotherapy in a single Australian institution. Brachytherapy 15(6):752–759 Boorjian S, Cowan JE, Konety BR et al (2007) Cancer of the Prostate Strategic Urologic Research Endeavor Investigators. Bladder cancer incidence and risk factors in men with prostate cancer: results from Cancer of the Prostate Strategic Urologic Research Endeavor. J Urol 177(3):883–887 Masaoka H, Matsuo K, Oze I et al (2023) Cigarette Smoking, Smoking Cessation, and Bladder Cancer Risk: A Pooled Analysis of 10 Cohort Studies in Japan. J Epidemiol 33(11):582–588 Yu Q, Li B, Lin H et al (2025) Smoking-related bladder cancer burden from 1990 to 2021: An age-period-cohort analysis of the global burden of disease study. Tob Induc Dis 23 Huang J, Kestin LL, Ye H et al (2011) Analysis of second malignancies after modern radio-therapy versus prostatectomy for localized prostate cancer. Radiother Oncol 98(1):81–86 Moon K, Stukenborg GJ, Keim J et al (2006) Cancer incidence after localized therapy for prostate cancer. Cancer 107(5):991–998 Abdel-Wahab M, Reis IM, Hamilton K (2008) Second primary cancer after radiotherapy for prostate cancer–a seer analysis of brachytherapy versus external beam radiotherapy. Int J Radiat Oncol Biol Phys 72(1):58–68 Nieder AM, Porter MP, Soloway MS (2008) Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180(5):2005–2009 Inskip PD, Sigurdson AJ, Veiga L et al (2016) Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects. Int J Radiat Oncol Biol Phys 94(4):800–807 Kamran SC, Berrington de Gonzalez A, Ng A et al (2016) Therapeutic radiation and the potential risk of second malignancies. Cancer 122(12):1809–1821 Stock RG, Stone NN (2002) Importance of post-implant dosimetry in permanent prostate brachytherapy. Eur Urol 41(4):434–439 Okamoto K, Wada A, Kohno N (2017) High biologically effective dose radiation therapy using brachytherapy in combination with external beam radiotherapy for high-risk prostate cancer. J Contemp Brachytherapy 9(1):1–6 Cite Share Download PDF Status: Published Journal Publication published 29 Mar, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 16 Feb, 2026 Reviewers agreed at journal 27 Jan, 2026 Reviewers invited by journal 27 Jan, 2026 Editor assigned by journal 21 Jan, 2026 First submitted to journal 20 Jan, 2026 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. 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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-8657808","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":580920510,"identity":"3e1559aa-5098-4cdb-ae4a-808f62741e69","order_by":0,"name":"Kojiro Niwa","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Kojiro","middleName":"","lastName":"Niwa","suffix":""},{"id":580920511,"identity":"901c9de9-0dc8-46e0-92e8-58f8fe851e79","order_by":1,"name":"Koji Iinuma","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-0362-8624","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":true,"prefix":"","firstName":"Koji","middleName":"","lastName":"Iinuma","suffix":""},{"id":580920512,"identity":"69a22c09-01b6-4f26-b522-1622abd598a2","order_by":2,"name":"Masahiro Nakano","email":"","orcid":"","institution":"Gifu Prefecture: Gifu-ken","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Nakano","suffix":""},{"id":580920513,"identity":"c93b02ff-3771-4d14-8c5b-029008b05ff1","order_by":3,"name":"Masayuki Tomioka","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Tomioka","suffix":""},{"id":580920514,"identity":"e9d3fd73-96f7-4242-a1d7-5255869d0465","order_by":4,"name":"Masaya Ito","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Masaya","middleName":"","lastName":"Ito","suffix":""},{"id":580920515,"identity":"ac8817c6-0674-4e2b-bbca-546285a2f241","order_by":5,"name":"Takayuki Mori","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Mori","suffix":""},{"id":580920516,"identity":"ac6e7062-57dc-45f1-9a61-1174639f0009","order_by":6,"name":"Kota Kawase","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Kota","middleName":"","lastName":"Kawase","suffix":""},{"id":580920517,"identity":"f71fe8e4-dbfc-48ed-9007-3982ec8694f7","order_by":7,"name":"Tomoki Taniguchi","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Tomoki","middleName":"","lastName":"Taniguchi","suffix":""},{"id":580920518,"identity":"4d0ef89a-37af-4742-ba58-f4f6125d4a5d","order_by":8,"name":"Yuki Tobisawa","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Tobisawa","suffix":""},{"id":580920519,"identity":"eea0dbf9-b6a7-433a-9717-4781670dfde3","order_by":9,"name":"Keita Nakane","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Nakane","suffix":""},{"id":580920520,"identity":"5c7b2d0d-d747-4abd-bd1e-562c13b0122b","order_by":10,"name":"Masayuki Matsuo","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Masayuki","middleName":"","lastName":"Matsuo","suffix":""},{"id":580920521,"identity":"f4d4f9b8-121e-49b3-80a5-adb9d785f76b","order_by":11,"name":"Takuya Koie","email":"","orcid":"","institution":"Gifu University School of Medicine Graduate School of Medicine: Gifu Daigaku Igakubu Daigakuin Igakukei Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Koie","suffix":""}],"badges":[],"createdAt":"2026-01-21 09:36:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8657808/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8657808/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-026-03020-3","type":"published","date":"2026-03-29T16:09:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":101365811,"identity":"a97e6ef8-75dd-4001-b2de-27645ee503c9","added_by":"auto","created_at":"2026-01-29 00:58:35","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":67467,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of radiation- associated second primary cancers (RASPC) after iodine-125 low-dose-rate brachytherapy. The 10-year and 15-year cumulative incidences of RASPC were 1.3% and 2.1%, respectively.\u003c/p\u003e","description":"","filename":"Figure12025.11.30.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8657808/v1/97265987d3fb1e99b80b4a96.jpg"},{"id":101398526,"identity":"17bf15e1-5005-4b1c-894e-1a4906eb64af","added_by":"auto","created_at":"2026-01-29 09:42:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":158222,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of bladder and rectal/anal canal cancers following iodine-125 low-dose-rate brachytherapy. (a) Cumulative incidence of bladder cancer. The 10-year and 15-year cumulative incidences of bladder cancer were 1.3% and 1.3%, respectively. (b) Cumulative incidence of rectal and anal canal cancers. The 10-year and 15-year cumulative incidences of rectal/anal canal cancers were 0% and 0.8%, respectively.\u003c/p\u003e","description":"","filename":"Figure2a2025.11.30.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8657808/v1/df095c39e3099b1968810cc4.jpg"},{"id":101365813,"identity":"e262bcc4-75c1-4fe3-9a0f-5e80c6c2bb7f","added_by":"auto","created_at":"2026-01-29 00:58:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":101587,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of radiation- associated second primary cancers (RASPC) stratified by biologically effective dose (BED). The 15-year cumulative incidence was significantly higher in patients with BED ≥197 Gy than in those with BED \u0026lt;197 Gy (\u003cem\u003ep\u003c/em\u003e = 0.033).\u003c/p\u003e","description":"","filename":"Figure32025.11.30.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8657808/v1/f86676cbcbb347c9cb09d3a0.jpg"},{"id":105755643,"identity":"8948bfa8-fd42-4469-b541-401c9712a351","added_by":"auto","created_at":"2026-03-30 16:28:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1107466,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8657808/v1/7da77df3-def8-44de-8a56-14d5cadf5372.pdf"}],"financialInterests":"","formattedTitle":"Radiation-associated Second Primary Cancers After Iodine-125 Low-Dose-Rate Brachytherapy for Localized Prostate Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer (PCa) is one of the most common malignancies among men worldwide and in Japan [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Definitive treatment modalities for localized PCa, including active surveillance, surgical intervention, and radiation therapy (RT), have demonstrated favorable oncological outcomes worldwide [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe low-dose-rate brachytherapy with iodine-125 (LDR-BT), which is used in combination with or without external beam radiation therapy (EBRT), is one of the most effective treatment modalities for RT [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. LDR-BT generally yields favorable oncological outcomes [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Previous studies from our institution demonstrated excellent long-term oncological outcomes after LDR-BT [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A median follow-up period of 90.0 months revealed a 10-year biochemical recurrence (BCR)-free rate of 95.3% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, the 10-year BCR-free rate maintained a high level of 93.4% among patients with PCa categorized as high-risk according to the D'Amico classification [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although LDR-BT is an effective treatment for long-term cancer control, there are still significant treatment-related toxicities, including radiation-related late complications involving the genitourinary and gastrointestinal organs, including radiation-associated secondary primary cancers (RASPC). RASPC is generally defined as occurring\u0026thinsp;\u0026gt;\u0026thinsp;five years after receiving RT [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. This critical complication should be considered when selecting the most effective treatment for localized PCa. Conversely, the occurrence of late complications, including RASPC, in patients with PCa who underwent RT, particularly LDR-BT, followed by long-term observation, remains limited.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to evaluate the long-term incidence of RASPC after LDR-BT for localized PCa in Japanese patients. Additionally, an analysis was conducted to determine predictive factors associated with RASPC occurrence.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe retrospectively reviewed the clinical records of 478 consecutive patients with PCa who underwent LDR-BT at the Gifu University Hospital between August 2004 and December 2019. Patients with localized PCa, without lymph node or distant metastases, were enrolled according to the 2016 American Joint Committee on Cancer Staging Manual [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Patients were divided into risk categories according to the National Comprehensive Cancer Network (NCCN) classification [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The following clinical data were collected from the enrolled patients: age, body mass index (BMI), initial serum prostate-specific antigen (PSA) level, clinical T stage, biopsy Gleason grade [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], NCCN risk classification, prostate volume (PV) at LDR-BT, presence or absence of androgen deprivation therapy (ADT), and follow-up duration. Colonoscopies were performed before LDR-BT in all patients who had not undergone this examination within the previous two years, in accordance with the protocol initiated in April 2010 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Patients with lymph node involvement, distant metastasis, a history of transurethral resection of the prostate, or a maximum urinary flow rate\u0026thinsp;\u0026lt;\u0026thinsp;10 mL/s on uroflowmetry were excluded from the study.\u003c/p\u003e \u003cp\u003e Due to the retrospective nature of this study, informed consent was waived, according to the Japanese Ethical Guidelines. An opt-out approach was implemented, thereby giving patients the opportunity to decline participation. This study was reviewed and approved by the Institutional Review Board of Gifu University (approval number: 29\u0026ndash;106).\u003c/p\u003e \u003cp\u003eAlthough smoking history was not systematically documented for the entire cohort, detailed smoking status was meticulously reviewed for all patients who developed bladder cancer, based on medical records.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment of LDR-BT\u003c/h3\u003e\n\u003cp\u003eAs previously documented, this report details the treatment procedures for LDR-BT at our institution [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Patients with low-risk PCa and a PV\u0026thinsp;\u0026gt;\u0026thinsp;50 mL received neoadjuvant ADT for at least 3 months before LDR-BT. Patients diagnosed with intermediate-risk PCa were administered ADT for 9 months, followed by LDR-BT with or without EBRT. Patients with high- or very high-risk PCa underwent LDR-BT combined with EBRT and ADT for 24 months. During the administration of EBRT, the radiation field was confined to the prostate and seminal vesicles.\u003c/p\u003e \u003cp\u003ePatients were implanted with loose 125I radioactive seeds (Oncoseed, Nippon Medi-Physics, Tokyo, Japan) by the Mick Applicator (Mick Radio-Nuclear Instruments, Bronx, NY, USA) or the ProLink\u0026reg; (Cincinnati, OH, USA) delivery system (C. R. Bard, Inc., Murray Hill, NJ, USA) under real-time confirmation by transrectal ultrasound transperineally into the prostate [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A prescribed minimum peripheral dose of 145 Gy was used for LDR-BT monotherapy, and 104 Gy was used when combined with EBRT. When EBRT was used, a total dose of 40 Gy in 2-Gy fractions was delivered to the prostate and seminal vesicles within 1 month after LDR-BT. In all cases, a modified peripheral loading technique was applied after preplanning the seed implantation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherapeutic planning and post-implant dosimetric evaluations were performed using the updated American Association of Physicists in Medicine Task Group 43 for-malism and Variseed version 7.1 (Varian Medical Systems, Palo Alto, CA, USA). Subsequent dosimetric evaluations were conducted using both computed tomography (CT) and magnetic resonance imaging (MRI) modalities, with assessments performed one month after LDR-BT [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The dosimetric parameters that were the focus of this study included the minimum dose received by 90% of the prostate gland (D90), biologically effective dose (BED), minimum percentage of the dose received by 30% of the urethra (UD30), and the rectal volume receiving 100% of the prescribed dose (RV100). The BED was calculated using an alpha/beta ratio of 2.\u003c/p\u003e \u003cp\u003eAll patients were monitored with follow-up examinations at 3\u0026ndash;6 months intervals for 5 years, followed by biennial checkups. The follow-up process included interval history, physical examination, and PSA measurement. Furthermore, MRI scans were obtained 3, 5, and 10 years after LDR-BT. Patients presenting with gross or microscopic hematuria underwent a series of diagnostic procedures, including urinalysis, urinary cytology, and cystoscopy. Patients presenting with bloody stool or other lower gastrointestinal symptoms underwent colonoscopy. These examinations resulted in a diagnosis of RASPC. The follow-up period was defined as the time interval between the completion of RT and the most recent follow-up visit or date of death. BCR definition was established in accordance with the Radiation Therapy Oncology Group-Phoenix classification, which sets the threshold for the PSA nadir at 2 ng/mL [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eRASPC\u003c/h3\u003e\n\u003cp\u003eRASPC was defined as an in-field second primary cancer that developed at least 5 years after LDR-BT, including bladder, urethral, rectal, and anal canal cancers [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The definition of RASPC utilized in this study was employed to identify secondary cancers that developed within the radiation field after a sufficient latency period. However, it is important to note that this does not imply that all malignant tumors occurring within the radiation field are attributable to radiation exposure, nor can they be clearly distinguished from age-related cancers. RASPC was defined exclusively in cases in which the diagnosis was subsequently confirmed by biopsy or surgical pathology.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe primary endpoint of the study was RASPC incidence, including bladder and rectal/anal cancers. The secondary endpoint was the identification of risk factors for LDR-BT that predicted the RASPC development. Additionally, the incidences of bladder and rectal/anal canal cancers were analyzed. The chi-square test was used to evaluate differences between categorical variables, and the Mann\u0026ndash;Whitney U test was used for continuous variables. The incidence rates of RASPC, bladder cancer, and anal canal cancer were evaluated using cumulative incidence proportions, and differences according to clinical variables were assessed using the chi-square test. The Kaplan\u0026ndash;Meier method was used to estimate overall survival (OS) and BCR. Cox proportional hazard models were used to assess the relationship between potential predictors of RASPC. To assess the robustness of the association between BED and RASPC, given the limited number of RASPC cases in the primary Cox proportional hazards model, a sensitivity analysis was conducted using a reduced model containing only age and BED. Death was treated as a competing event, and the cumulative incidence function was estimated. The optimal cut-off values for age, BMI, and BED were determined using receiver operating characteristic curve analysis [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The data were analyzed using software JMP 14 (SAS Institute Inc., Cary, NC, USA). All statistical analyses were two-sided, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eBaseline patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age, BMI, and PSA level of the entire cohort were 66.0 years (interquartile range [IQR]: 62.0\u0026ndash;71.0), 23.5 kg/m\u0026sup2; (IQR: 21.9\u0026ndash;25.3), and 6.5 ng/mL (IQR: 5.1\u0026ndash;9.1), respectively. According to the NCCN risk classification, 154 patients were classified as low risk, 126 as favorable intermediate risk, 137 as unfavorable intermediate risk, 54 as high risk, and seven as very high risk. The median BED, UD30, and RV100 were determined to be 194.8 Gy (IQR: 179.1\u0026ndash;208.8), 191.2 Gy (IQR: 159.5\u0026ndash;218.3), and 0.3% (IQR: 0.1\u0026ndash;0.7), respectively. The median follow-up period was 105.0 months (IQR: 71.0\u0026ndash;134.0). The median overall survival (OS) was found to be 242.0 months. The median BCR-free survival was not reached; however, the 10-year BCR-free survival rate was 94.9%. Notably, only one patient died of PCa.\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 characteristics and postdosimetric parameters.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLDR-BT only\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;276)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT\u0026thinsp;+\u0026thinsp;EBRT\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;202)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year, median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.0 (62.0\u0026ndash;70.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.0 (63.0\u0026ndash;71.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.124\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e, median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.4 (21.8\u0026ndash;25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.7 (22.0-25.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.348\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSA (ng/mL, median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0 (4.9\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3 (5.7\u0026ndash;11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical T stage (number, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e185 (67.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (33.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (28.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (21.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGleason Group Grade\u003c/p\u003e \u003cp\u003e(number, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e175 (63.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95 (34.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (37.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (30.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (13.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (8.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNCCN risk classification\u003c/p\u003e \u003cp\u003e(number, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFavorable-intermediate risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (20.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnfavorable-intermediate risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e103 (51.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (25.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVery high risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoadjuvant ADT\u003c/p\u003e \u003cp\u003e(number, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e196 (71.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e169 (83.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstate volume at LDR-BT\u003c/p\u003e \u003cp\u003e(mL, median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.1 (19.2\u0026ndash;31.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.9 (16.8\u0026ndash;27.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostdosimetric parameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%D90 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119.5 (111.4-126.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119.8 (111.2-128.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.888\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstate D90 (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e173.1 (161.4\u0026ndash;183.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.6 (115.8-133.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e183.6 (170.6-194.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e208.2 (200.5-215.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e% UD30 (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e211.0 (194.3\u0026ndash;2313)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e154.1 (141.3-176.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRectum V100 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3 (0.1\u0026ndash;0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3 (0-0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.429\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up period\u003c/p\u003e \u003cp\u003e(month, median, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103.0 (72.0-132.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e110.0 (68.5-137.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.652\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProportion of patients with RASPC\u003c/h3\u003e\n\u003cp\u003eThirteen patients (2.7%) had RASPC. The median time to development of RASPC was 103.5 months (IQR: 71.0\u0026ndash;132.0), and the 10-year incidence rate was 1.3% (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Seven cases of bladder cancer (1.5%) and six cases of rectal/anal canal cancer (1.3%) were documented. The median time to development was 103.5 months (IQR: 71.0\u0026ndash;132.3) for bladder cancer and 105.0 months (IQR: 71.0\u0026ndash;133.3) for rectal/anal canal cancer. The 10-year incidence rates of bladder and rectal/anal canal cancers were 1.3% and 0%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Of the patients studied, one died from bladder cancer and the other from rectal cancer. Among the seven patients who developed bladder cancer, three had a history of smoking, three were non-smokers, and smoking status was unknown in one patient.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePredictive factors of RASPC\u003c/h3\u003e\n\u003cp\u003eThe 10-year cumulative incidence of RASPC tended to be higher in patients with BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy than in those with BED\u0026thinsp;\u0026lt;\u0026thinsp;197 Gy, and the 15-year cumulative incidence of RASPC was significantly higher in patients with BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy than in those with BED\u0026thinsp;\u0026lt;\u0026thinsp;197 Gy. (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The 10-year and 15-year cumulative incidence rates of RASPC were 0.7% and 1.5% in the LDR-BT monotherapy group, and 1.5% and 3.0% in the combination LDR-BT and EBRT group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.654 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.335, respectively). Although a slightly higher tendency for RASPC incidence was observed in the combined LDR-BT and EBRT group, no significant difference was found. When patients were stratified by RV100 (\u0026lt;\u0026thinsp;0.64 mL vs. \u0026ge;0.64 mL), the 10-year cumulative incidence of RASPC was 0.9% in the \u0026lt;\u0026thinsp;0.64 mL group and 1.5% in the \u0026ge;\u0026thinsp;0.64 mL group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.626). The 15-year cumulative incidence rates were 1.8% and 2.9%, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.481). After thorough analysis, no substantial discrepancy in RASPC occurrence was noted between the two groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe associations between RASPC and clinical covariates are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In an exploratory multivariable Cox regression model including age, BMI, NCCN risk category, neoadjuvant ADT, and BED, BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy was associated with an increased risk of RASPC (hazard ratio [HR] 4.145; 95% confidence interval [CI] 1.108\u0026ndash;15.498; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In sensitivity analyses using a reduced multivariable model including only age and BED, BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy remained significantly associated with RASPC (HR 3.842, 95% CI 1.050\u0026ndash;14.062, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042). In the model, BED was represented as a continuous variable with adjustment for age. The analysis revealed that BED exhibited no statistically significant association with RASPC (HR per 10 Gy in-crease: 1.028, 95% CI 0.820\u0026ndash;1.288).\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\u003ePredictive factors of radiation-induced second primary cancers in patients with localized prostate cancer who underwent Iodine-125 low-dose-rate brachytherapy: results of multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003e\u0026lt;\u0026thinsp;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.386\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.109\u0026ndash;2.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003e\u0026lt;\u0026thinsp;26.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.465\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;26.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.465\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.059\u0026ndash;3.628\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNCCN risk classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eLow\u0026thinsp;+\u0026thinsp;Intermediate risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e417\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.995\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.120\u0026ndash;8.239\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeoadjuvant ADT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.138\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.399\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.119\u0026ndash;1.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\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\u003e\u0026lt;\u0026thinsp;197.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;197.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.108\u0026ndash;15.498\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRASPC has been reported in numerous cases of malignant neoplasms treated with RT, including breast, oral, and cervical cancers, and lymphoma [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Radiation-induced DNA damage and long-term genomic instability are considered key mechanisms underlying RASPC development [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The latency period for RASPC is generally considered to range from several years to decades, thereby underscoring the significance of prolonged follow-up in patients with cancer who have undergone RT therapy. Prolonged survival after definitive RT highlights the clinical importance of evaluating long-term RASPC risk.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes previous studies on LDR-BT with or without EBRT for PCa. The median follow-up period in these studies ranged from 69.6 to 165.6 months, with the reported incidence rates of RASPC ranging from 1.0 to 4.3% [\u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. A previous study examining the incidence of RASPC after LDR-BT in 897 Japanese patients found RASPC in 1.3% of the patients during a median follow-up period of 85.2 months [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Regarding the prevalence of various diseases, bladder cancer was observed in 1.0% of patients, while rectal cancer was identified in 0.3% [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. A study examining the risk of bladder cancer development in 1,162 Japanese patients treated with LDR-BT alone or in combination with EBRT reported a bladder cancer incidence of 3.0% at a median follow-up period of 124.8 months [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In this study, the incidence of RASPC was 2.7% over a median follow-up period of 105.0 months. The incidence rates of bladder cancer and rectal/anal canal cancer were 1.5% and 1.3%, respectively. In our cohort, which has been followed for approximately 10 years, the incident rate of RASPC was consistent with that reported in previous studies that had comparable follow-up periods. However, the cumulative incidence of RASPC may increase significantly with longer follow-up periods. Previous studies with long-term follow-up have demonstrated a time-dependent increase in RASPC incidence [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In these cohorts, the incidence of RASPC in the same patient population increased from 2.1% at a median follow-up of 69.6 months to approximately 7% after more than 14 years of follow-up. The present study indicates that the majority of RASPC cases occurred more than five years after LDR-BT, suggesting that longer-term, systematic follow-up is crucial. Specifically, the implementation of more frequent monitoring, including urine tests, fecal occult blood tests, and colonoscopies, between five and ten years after LDR-BT administration may lead to the early detection of RASPC.\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\u003ePrevious reports on the development of radiation-induced second primary cancers in patients with localized prostate cancer who underwent Iodine-125 low-dose-rate brachytherapy.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003cp\u003e(Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003cp\u003e(Number)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003cp\u003e(Number)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFollow-up period\u003c/p\u003e \u003cp\u003e(Month, median)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncident rate\u003c/p\u003e \u003cp\u003e(Number, %)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSecondary cancer site\u003c/p\u003e \u003cp\u003e(Number)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiauw SL, et al.\u003c/p\u003e \u003cp\u003e(2006) [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 125\u003c/p\u003e \u003cp\u003eLDR-BT\u0026thinsp;+\u0026thinsp;EBRT: 223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e126.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 1\u003c/p\u003e \u003cp\u003eColorectal: 3\u003c/p\u003e \u003cp\u003eProstatic urethra: 1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMusunuru H, et al.\u003c/p\u003e \u003cp\u003e(2006) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 1805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e96.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 10\u003c/p\u003e \u003cp\u003eRectal: 3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHinnen KA, et al.\u003c/p\u003e \u003cp\u003e(2011) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 1187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e85.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 9\u003c/p\u003e \u003cp\u003eRectal: 17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHamilton SN, et al.\u003c/p\u003e \u003cp\u003e(2014) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 2418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 32\u003c/p\u003e \u003cp\u003eRectal: 19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNakai Y, et al.\u003c/p\u003e \u003cp\u003e(2016) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e897\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 507\u003c/p\u003e \u003cp\u003eLDR-BT\u0026thinsp;+\u0026thinsp;EBRT: 390\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e85.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 9\u003c/p\u003e \u003cp\u003eRectal: 3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCosset JM, et al.\u003c/p\u003e \u003cp\u003e(2017) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e675\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 675\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e132.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 9\u003c/p\u003e \u003cp\u003eRectal: 5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOzawa et al.\u003c/p\u003e \u003cp\u003e(2022) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 607\u003c/p\u003e \u003cp\u003eLDR-BT\u0026thinsp;+\u0026thinsp;EBRT: 555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e124.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSt-Laurent MP, et al. (2024) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT: 2378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e165.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 years: 7.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 107\u003c/p\u003e \u003cp\u003eRectal: 51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e478\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLDR-BT alone: 276\u003c/p\u003e \u003cp\u003eLDR-BT\u0026thinsp;+\u0026thinsp;EBRT: 202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e105.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBladder: 7\u003c/p\u003e \u003cp\u003eRectal: 6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe relationship between LDR-BT and the risk of developing RASPC remains controversial. RASPC development after LDR-BT for PCa is associated with several risk factors, including advanced age, history of smoking, and the use of combination therapy involving EBRT [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Smoking is recognized as a well-established risk factor for developing bladder cancer [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The present study indicates that both smokers and non-smokers developed bladder cancer subsequent to LDR-BT, thereby suggesting that radiation therapy may have influenced the subsequent carcinogenesis. However, smoking history was not documented for the entire cohort, which prevented its inclusion as a covariate in multivariate analysis and left unaccounted for potential bias. According to the findings of several single-center studies, RASPC incidence with LDR-BT is comparable to that of radical prostatectomy (RP) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Similarly, studies examining the risk of bladder cancer development found no significant differences between patients who received LDR-BT and non-RT for PCa [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. These reports suggest that LDR-BT alone may not increase the long-term risk of secondary primary malignancies. Conversely, St-Laurent et al. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] demonstrated that patients with PCa undergoing LDR-BT exhibited a significantly higher risk of RASPC compared with RP (HR 1.81, 95% CI 1.45\u0026ndash;2.26, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, epidemiological data indicated an elevated prevalence of bladder and rectal cancer in patients diagnosed with PCa after LDR-BT [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In this study, high-dose exposure, specifically BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy, was identified as an independent predictor of RASPC development. Radiotherapy as a definitive treatment has been shown to increase the likelihood of secondary malignancies irrespective of the primary tumor type [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Inskip et al. [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] demonstrated a clear dose-response relationship between radiation exposure and the development of new primary solid cancers [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Specifically, elevated radiation doses have been demonstrated to markedly increase the likelihood of developing secondary malignant neoplasms irrespective of the primary cancer type [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Similarly, another study evaluated the correlation between therapeutic radiation and the likelihood of secondary malignancies in multiple organs [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. This analysis revealed that radiation dosage plays a pivotal role in carcinogenesis irrespective of the specific tumor type [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. However, the importance of increasing the BED to achieve favorable oncological outcomes after LDR-BT for localized PCa has been well-documented [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The variability in the study results may be attributed to various factors, including treatment-related conditions, follow-up periods, patient backgrounds, dosimetric parameters, and monitoring intensity. Patients who have undergone high-dose LDR-BT require meticulous and prolonged follow-up to ensure optimal outcomes and mitigate potential complications. The achievement of a BED exceeding 197 Gy with LDR-BT monotherapy alone is a rare achievement, and the administration of additional EBRT is common in most cases. However, no statistically significant difference was observed between the LDR-BT monotherapy group and the LDR-BT\u0026thinsp;+\u0026thinsp;EBRT combination group at either the 10-year or 15-year follow-up points. These findings suggest that while adding EBRT may increase the radiation dose to pelvic tissues, the risk of developing RASPC is not solely attributable to the additional EBRT irradiation. Conversely, the development of bladder or anorectal cancer is anticipated to occur at a certain rate in elderly men, regardless of their history with radiation therapy. Therefore, a critical aspect of interpreting these findings is recognizing that the RASPC observed in this cohort cannot be attributed exclusively to radiation exposure.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it was a retrospective, single-center analysis, which may limit generalizability. Second, the number of radiation-associated second primary cancer events was small, and multivariable analyses should therefore be interpreted as exploratory. Third, smoking history, an important risk factor for bladder cancer, was not systematically available for the entire cohort and could not be included in multivariable analyses. Fourth, detailed dose\u0026ndash;volume analyses of organs at risk were not performed and may provide additional insights in future studies. Finally, the absence of a non-irradiated control group or age-matched general population data precluded direct estimation of excess radiation-attributable risk.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this long-term retrospective analysis of Japanese patients with localized PCa treated with LDR-BT with or without EBRT, RASPC incidence was found to be low. However, BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy emerged as an independent predictor of RASPC, suggesting that higher radiation doses, while essential for optimal tumor control, may be associated with an increased risk of RASPC. These findings emphasize the critical need for meticulous and sustained post-treatment monitoring, particularly in patients undergoing high-dose LDR-BT. Early detection and timely intervention for RASPC may help maintain favorable long-term oncological outcomes and minimize the potential impact of RASPC on patient prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest statement\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eInternational Agency for Research on Cancer Cancer Today. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gco.iarc.fr/today/en/dataviz/pie?mode=cancer\u0026amp;group_populations=1\u0026amp;sexes=1\u003c/span\u003e\u003cspan address=\"https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer\u0026amp;group_populations=1\u0026amp;sexes=1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Accessed November 25, 2025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Cancer Center Japan, Cancer Information Service (2025) Cancer statistics in Japan: Prostate cancer. 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J Contemp Brachytherapy 9(1):1\u0026ndash;6\u003c/span\u003e\u003c/li\u003e\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":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Prostate cancer, Low-dose-rate brachytherapy, Radiation-associated second primary cancer, Biologically effective dose, Late toxicity","lastPublishedDoi":"10.21203/rs.3.rs-8657808/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8657808/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e Low-dose-rate brachytherapy with iodine-125 (LDR-BT) is an established curative radiation treatment modality for localized prostate cancer (PCa). This study aimed to evaluate the long-term incidence of radiation- associated secondary primary cancer (RASPC) after LDR-BT in Japanese patients with localized PCa and identify predictive factors associated with RASPC.\u003c/p\u003e\u003ch2\u003eMethods and materials:\u003c/h2\u003e \u003cp\u003eWe retrospectively reviewed the clinical records of 478 consecutive patients with localized PCa who underwent LDR-BT at the Gifu University Hospital. This study\u0026rsquo;s primary endpoint was RASPC incidence, including bladder and rectal/anal cancers. The secondary endpoint was the identification of risk factors for LDR-BT that predicted RASPC development.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAfter a median follow-up period of 105 months, RASPC developed in 13 patients (2.7%). Bladder cancer and rectal/anal canal cancer were observed in seven (1.5%) and six (1.3%) patients, respectively. Multivariate analysis showed that a biologically effective dose (BED)\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy was associated with increased risk of RASPC (hazard ratio 4.145; 95% confidence interval 1.108\u0026ndash;15.498; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eRASPC incidence after LDR-BT was relatively low; BED\u0026thinsp;\u0026ge;\u0026thinsp;197 Gy was identified as an independent significant predictor for developing RASPC. Adequate tumor control can be achieved through appropriate radiation dose administration; carefully planned long-term follow-up may be beneficial for RASPC early detection.\u003c/p\u003e","manuscriptTitle":"Radiation-associated Second Primary Cancers After Iodine-125 Low-Dose-Rate Brachytherapy for Localized Prostate Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 00:58:30","doi":"10.21203/rs.3.rs-8657808/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-02-16T20:14:54+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-01-27T06:30:51+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-27T06:29:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-21T13:54:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2026-01-21T04:23:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a716221a-62a4-425e-a463-39535fa77388","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:25:29+00:00","versionOfRecord":{"articleIdentity":"rs-8657808","link":"https://doi.org/10.1007/s10147-026-03020-3","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2026-03-29 16:09:06","publishedOnDateReadable":"March 29th, 2026"},"versionCreatedAt":"2026-01-29 00:58:30","video":"","vorDoi":"10.1007/s10147-026-03020-3","vorDoiUrl":"https://doi.org/10.1007/s10147-026-03020-3","workflowStages":[]},"version":"v1","identity":"rs-8657808","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8657808","identity":"rs-8657808","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}