Comparison of intravesical instillation of Bacille Calmette-Guérin and epirubicin: a randomized controlled trial

Comparison of intravesical instillation of Bacille Calmette-Guérin and epirubicin: a randomized controlled trial | 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 Comparison of intravesical instillation of Bacille Calmette-Guérin and epirubicin: a randomized controlled trial Yanxiang Shao, Weixiao Yang, Thongher Lia, Xu Hu, Zhen Yang, Shangqing Ren, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-79981/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The optimal regimen of instillation for patients with non-muscle invasive bladder cancer (NMIBC) and the recurrence-related factors are still needed to be clear. Methods The patients underwent transurethral resection of bladder tumor who diagnosed as intermediate or high risk NMIBC were randomized to receive bacillus Calmette–Guérin (BCG) 19, 15 times or epirubicin (EPI) 18 times (2:2:1). The primary end point was disease-free survival (DFS), the secondary end point was progression free survival (PFS). Associations between clinicopathological factors and prognosis were estimated, with accuracy of the prognostic models Spanish Urological Club for Oncological Treatment (CUETO) and European Organization for Research and Treatment of Cancer (EORTC) evaluated. Results A total of 93 patients (BCG19 for 35; BCG15 for 37 and EPI18 for 21) were included, with median follow-up time for 33.46 months. Recurrence and progression occurred in 22 and 8 of patients separately, and significant longer recurrence-free survival was noted in the BCG and primary bladder cancer groups. Higher general complication rate was seen in BCG group compared with EPI groups (83.33% and 61.90%, respectively; P = 0.022), but no grade 3–5 adverse events happened in both groups. Concordance indices for the CUETO and EORTC models were 0.766 and 0.741 for all our series and 0.812 and 0.817 for the BCG subgroup, respectively. Conclusion BCG instillation significantly reduced the rate of recurrence compared with epirubicin in this population. The EORTC and CUETO models exhibited high accuracies for the prediction of BCG treatment failure. Trial registration: This study was approved by Center for Drug Evaluation of National Medical Products Administration (CDENMPA, China) and Ethics Committee of our institute, with the whole process supervised. The registration number in CDE-NMPA was CTR20150840 (website of CDE: http://www.cde.org.cn/ ). Urology & Nephrology bladder cancer bacillus Calmette–Guérin epirubicin recurrence predictive mode Figures Figure 1 Background Approximately 75% of patients with bladder cancer have non-muscle invasive bladder cancer (NMIBC; Ta or T1 disease) at the time of primary diagnosis( 1 ). These patients can be divided into three risk groups (i.e., low, intermediate, and high risk). For intermediate- and high-risk patients, transurethral resection of bladder tumor (TUR-BT) and subsequent intravesical drug instillation are the standard treatments. However, there is currently no conclusion reached regarding treatment with instillation ( 2 ). It has been confirmed that treatment with Bacillus Calmette–Guérin (BCG) following TUR-BT is superior to TUR-BT alone or combined with chemotherapy in Caucasian patients( 3 , 4 ). In addition, maintenance treatment with BCG has been recommended for intermediate- and high-risk patients( 2 ). However, the use of BCG in Chinese patients has been limited by the high rate of intolerance and complications previously reported in clinical practice, and the design of trials of BCG instillation has been suboptimal. Moreover, despite the administration of maintenance therapy with BCG, 32.6% and 13.4% of patients continue to experience recurrence and tumor progression, respectively( 5 ). In this study, we performed a randomized controlled trial to evaluate the efficacy and safety of adjuvant intravesical BCG or epirubicin (EPI) therapy for different regimes; we also estimated the predictive value for prognostic models to evaluate the prognostic factors for NMIBC. Methods Patients and treatment A prospective, randomized, controlled, non-blinded study, conducted at West China Hospital, Sichuan University, compared intravesical BCG and EPI treatment. The study was approved by the ethics committee of the Center for Drug Evaluation of the National Medical Products Administration (China) and Ethics Committee of West China Hospital. The inclusion criteria were: age 20–75 years; TUR-BT with completely tumor resection. BT was completely resected with pathologically proven intermediate or high-risk non-muscle invasive bladder urothelium carcinoma according to the European Association of Urology (EAU) guidelines for risk stratification of NMIBC(2). Exclusion criteria were: a. Eastern Cooperative Oncology Group performance status score >1; b. patients with active tuberculosis or receiving treatment for anti-tuberculous; c. immune deficiency or undergoing immunosuppressive therapy; d. severe complication (e.g., serious cardiovascular and cerebrovascular disease), or presence of other types of cancer; e. previous diagnosis with muscle-invasive bladder cancer; f. patients underwent treatment (e.g., chemotherapy, radiotherapy or immunotherapy) during the previous 4 weeks which may influence the research results; f. serious intraoperative and postoperative complications (e.g., bladder perforation, serious postoperative hematuresis, bladder irritation, etc.); and g. patients not suitable to receive treatment or not able to participate in our trial due to pregnancy, severe disability, serious psychological problems, etc. Post-operative immediate irrigation with EPI 50 mg was performed within 24 h after TUR-BT. After confirming the presence of intermediate- or high-risk NMIBC according to surgical findings and the final pathological report, patients who participated in the study were randomized into three bladder irrigation groups: a. BCG 19 group (BCG 120 mg weekly for six times, followed by biweekly irrigation for three times, and then monthly for 10 times, for a total of 19 irrigations with BCG); b. BCG 15 group (BCG 120 mg weekly for six times, followed by irrigations for the first 3 weeks and at 3, 6, and 12 months after surgery, for a total of 15 irrigations with BCG); and c. EPI 18 group (EPI 50 mg weekly for eight times, followed by monthly irrigation for 10 times, for a total of 18 irrigations). The randomization was performed within 14 days after surgery, at a 2:2:1 ratio (Das for IWRS Version 5.0, BioVoice & BioGuider, Beijing, China). Subsequently, irrigation was initiated on day 14 post operation and the duration of treatment was 1 year. Follow-up and outcomes For intermediate-risk patients, cystoscopy was performed 3 and 6 months after surgery, then biannually until 5 years. For high-risk patients, cystoscopy was performed trimonthly until 2 years after surgery, then biannually until 5 years. Urinalysis was performed prior to each irrigation. Patients were followed up until recurrence, progression, or discontinuation of treatment for any reason. Adverse effects were recorded at each follow-up according to the Common Terminology Criteria for Adverse Events Version 4.0(6). The initiation time was the day TUR-BT was performed. The primary end point was recurrence during follow-up, while the secondary end point was progression to muscle-invasive bladder cancer or therapy-related discontinuation of treatment. Recurrence-free survival (RFS) and progression-free survival (PFS) times were recorded. BCG failure and intolerance were recorded according to the definitions of the EAU (2). Data collection Recorded clinical variants included gender, age and smoking history. Intraoperative recordings included tumor size, site, and number. Tumor histopathological type, T stage (8th American Joint Committee on Cancer TNM classification system)(7), tumor grade (2004 World Health Organization grading system), and carcinoma in situ status. All pathological reports were provided by the Pathology Department of West China Hospital. Statistical methods Differences in survival between two or more subgroups were evaluated using log-rank tests. Univariate and multivariate Cox regression analyses were performed to determine the clinicopathological parameters associated with the recurrence of patients with NMIBC. Patients were stratified using the European Organization for Research and Treatment of Cancer (EORTC) risk tables(8) and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model(5). The predictive ability of these outcome prediction models was evaluated using the concordance index (c-index)(9). Statistical analyses were performed using the SPSS Statistics version 25 (IBM, Armonk, NY, USA) and The R Programming Language 3.5.0 software (The R Foundation, Vienna, Austria). A P-value <0.05 denoted statistical significance. Results Patient baseline data Totally 93 patients were enrolled for analysis (BCG19, BCG15 and EPI 18 groups for 35, 37 and 21 cases respectively, Table 1). The mean age was 62.96 years (standard deviation: 8.16 years), and the median follow-up time was 33.46 months (interquartile range: 18.30–44.80 months). There was no significant difference noted in baseline clinicopathological factors between the BCG and EPI treatment subgroups, except for T stage. Eight patients underwent radical cystectomy after NMIBC. Efficacy and safety for BCG and EPI treatment After follow-up for more than one year, recurrence occurred in 12 BCG treated patients (16.67%), with 9 of them suffered recurrence in the course of BCG irrigation. Progression happened in 6 BCG treated patients (8.33%). Meanwhile, number of recurrence and progression for EPI were 10 (47.61%) and 2 (9.52%) respectively. 6 cases suffered recurrence during EPI therapy (28.57%). RFS was significantly longer in the BCG group (Figure 1, P=0.002), but no significant differences were seen between BCG19 and BCG15 regime subgroups (Figure 1, P=0.975). PFS differences between BCG and EPI therapy could not be evaluated since limited ending events. Side effects were also collected (Table 2). Higher general complication rate was seen in BCG group compared with EPI groups (83.33% and 61.90%, respectively; P=0.022); however, most of complications for BCG group were treatment-free and there were no severe adverse events (grade 3-5) happened for these two treatment groups. Urocystitis was the most frequent complication for intravesical therapy, for which incidences were significant higher in BCG subgroup (75.00% vs 52.38%, P=0.047); fever was a unique complication after BCG therapy (16.67%), but all of them were treatment-free. Hematuresis occurred both after BCG and EPI treatment, with no significant difference demonstrated (43.1% vs 42.9%, P=0.987). There were more patients suffered rare complications such as respiratory infection, hypertension and hyperglycemia after BCG therapy, but difference wasn’t significant (29.17% vs 9.52%, P=0.122). Six patients didn’t complete full cycle of BCG therapy due to intolerance of complications, and all of them happened during the maintenance period (each had 3 patients for BCG 19 and 15 subgroups; five were due to urocystitis and one for hematuriesis); only one patient among them suffered disease recurrence two years after treatment had ended. Influence of clinicopathological factors and treatment methods on recurrence Among the 93 post-TUR-BT patients, the univariate analysis revealed that better survival was observed in those without smoking and previous bladder cancer history, with younger age, low tumor stage and less tumor number (Table 3). However, only prior recurrent history was significantly correlated with poor RFS (P=0.001). Meanwhile, when we considered these in BCG treatment subgroups (n=72), we also found better PFS for male patients and those with well nuclear grade, but weren’t significant; and PFS for those patients with prior recurrence rate less than one per year significant poorer than those with recurrence rate for more than one per year (P=0.033). The EORTC risk tables and CUETO scoring model were used to predict recurrence in patients with postoperative NMIBC. For all 93 cases, the c-index of EORTC and CUETO was 0.766 and 0.741, respectively. These numbers were obviously higher than those of prediction according to tumor stage or grade alone or by EAU risk group stratification (Table 4). Meanwhile, higher predictive accuracy was recorded in the BCG subgroup (0.812 and 0.817, respectively) (Table 4). Discussion Recurrence of NMIBC is affected by numerous factors, including tumor size, number of tumors, prior recurrence rate, T stage, grade, and presence of carcinoma in situ ( 8 ). Patients at high risk of recurrence and progression can be identified through a comprehensive consideration of these factors. In the risk group stratification of EAU, patients with NMIBC are stratified into three risk groups (low, intermediate, and high risk) and different treatment strategies and follow-up measures are recommended( 2 ). However, these strategies are not effective, with 47.8% of patients suffering at least one recurrence( 8 ). Since Morales first reported the irrigation treatment with BCG in bladder cancer( 10 ), the efficacy of this method has been widely demonstrated and became the standard therapy for intermediate- and high-risk NMIBC( 11 ). Lower recurrence rates were observed in BCG-treated patients compared with those who underwent chemotherapy( 3 , 12 ); however, higher complication rates also occurred( 13 ). There is a limited number of studies on the use of BCG in Chinese patients due to the intolerance and contraindications of therapy with BCG. Nonetheless, this was gradually accepted by patients due to the improvement of supporting method. We firstly reported a randomized controlled trial of Chinese patients which compared the efficacy of BCG and EPI on NMIBC. The results suggested that, although six patients showed intolerance to therapy with BCG, this approach has advantages in preventing recurrence, without a significantly higher rate of side effects versus treatment with EPI. Six weeks inductive BCG instillations only are not enough for intermediate and high risk NMIBC treatment, and current evidences support 1–3 years maintenance schedule( 14 ). A recent meta-analysis which included 1951 patients demonstrated that longer-maintenance therapy didn’t increase side effect compared with induction therapy only, and longer maintenance (more than 1 years) wasn’t superior to 1 years maintenance( 15 ). However, the optimal number and frequency of maintenance intravesical therapy is still unknown( 2 ). Since that, we compared two regime of 1 years BCG maintenance therapy, and found that there was no significant difference between BCG 15 and 19 regimes among recurrence and side effects. Even treated with BCG, recurrence continues to occur in many patients treated with BCG; 32.6% as reported by Jesus et al.( 5 ). Even after a full course of maintenance therapy with BCG, 15.7% and 26.3% of patients continue to experience early and late recurrence, respectively( 16 ). Hence, considerable efforts were focused on the prognostic prediction of NMIBC to more rationally stratify patients, and identify those more suitable for individual surveillance and treatment programs. The EORTC scoring system, based on patients who underwent several instillation protocols, is used to predict recurrence and prognosis in patients with NMIBC (c-index of internal validation of 0.66 and 0.75, respectively)( 8 ). Subsequently, the CUETO scoring model was designed to predict prognosis in patients receiving maintenance therapy with BCG (c-index of interval validation of 0.636 and 0.687 for early recurrence and progression, respectively)( 5 ). Compared with risk group stratification, the tumor recurrence status (an important prognostic factor) was included in the CUETO and EORTC. Furthermore, in our study, these two models exhibited significantly better differentiations than risk group stratification, especially in BCG-treated patients, suggesting that CUETO and EORTC may be more suitable for the prediction and stratification of patients with NMIBC. There are limitations for our study. For one thing, the sample size is relatively small for further subgroup analysis; for another, the follow-up time is short so that the secondary end point of progression could not be evaluated since limited positive events occurred. However, since all patients had completed more than 1 year’s follow-up with complications recorded in detail, present results can well reflect the feasibility of BCG instillations in Asian NMIBC populations. Conclusion Maintenance treatment with BCG demonstrated better control of recurrence in Chinese patients with NMIBC after TUR-BT versus intravesical therapy with EPI. Prior recurrence status is an important prognostic factor for recurrence, while the EORTC and CUETO prognostic models exhibited higher prediction accuracy for recurrence than tumor stage, grade, or risk group stratification. Abbreviations NMIBC: non-muscle invasive bladder cancer; TUR-BT: transurethral resection of bladder tumor; BCG: Bacillus Calmette–Guérin; EPI: epirubicin; EAU: European Association of Urology; RFS: Recurrence-free survival; PFS: progression-free survival; EORTC: European Organization for Research and Treatment of Cancer; CUETO: Spanish Urological Club for Oncological Treatment. Declarations Ethics approval and consent to participate and publications This study was approved by Center for Drug Evaluation of National Medical Products Administration (CDENMPA, China) and Ethics Committee of our institute, with the whole process supervised. The registration number in CDE-NMPA was CTR20150840 (Registered 21 December 2015, website of CDE: http://www.cde.org.cn/). All the research registration and ethical approval documents were added below. Patients and their authorized family members had been fully informed before follow-up work was performed, with informed consent signed. All procedures adhere to CONSORT guideline. Availability of data and materials The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions. Competing Interests The authors declare that they have no competing interests. Funding This study was supported by the National Natural Science Foundation of China (Reference Number: 81672552) and the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Reference number: ZY2016104). X L was the recipient of these funding. Authors’ contributions X L managed the study. Y S, W Y, T L designed the study, X H, Z Y, S R and K W collected the data. Y S controlled the quality of data and algorithms. W Y, T L analyzed and interpreted the data. J L, W D, S X managed the statistical analysis. S F, Y W prepared the manuscript. Y S, W Y, T L edited the manuscript. X L reviewed the manuscript. All authors read and approved the final manuscript Acknowledgements We would like to thank Ranran Liu, Xue Yao and Xuelin Zhang who helped us to collect and collate data. References Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234-41. Babjuk M, Burger M, Comperat EM, Gontero P, Mostafid AH, Palou J, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol. 2019;76(5):639-57. Sylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais Da Silva F, Powell PH, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73. Pan J, Liu M, Zhou X. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with non-muscle invasive bladder cancer? An update and cumulative meta-analysis. Front Med. 2014;8(2):241-9. Fernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Pineiro L, Gonzalez M, et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J Urol. 2009;182(5):2195-203. SERVICES USDOHAH. Common Terminology Criteria for Adverse Events (CTCAE). USA: National Institutes of Health; 2010. Bernard H. Bochner DEH, Jason A. Efstathiou, Badrinath Konety, Cheryl T. Lee, Jam es M. M cKiernan, Elizabeth R. Plimack, Víctor E. Reuter, Sríkala Srídhar, Raghunandan Vikram, and Walter M. Stadler. AJCC Cancer Staging Manual 8th Edition - Urinary Bladder. 2017. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466-5; discussion 75-7. Harrell FE, Jr., Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361-87. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-3. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-9. Shang PF, Kwong J, Wang ZP, Tian J, Jiang L, Yang K, et al. Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2011(5):CD006885. Jarvinen R, Kaasinen E, Sankila A, Rintala E, FinnBladder G. Long-term efficacy of maintenance bacillus Calmette-Guerin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol. 2009;56(2):260-5. Sylvester RJ. Maintenance Bacillus Calmette-Guerin Therapy: The Search for the Optimum Treatment Schedule Continues. Eur Urol. 2015;68(2):263-4; discussion 5-6. Huang Z, Liu H, Wang Y, Zhang C, Xu T. Determining optimal maintenance schedules for adjuvant intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Curr Med Res Opin. 2017;33(8):1379-87. Cambier S, Sylvester RJ, Collette L, Gontero P, Brausi MA, van Andel G, et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guerin. Eur Urol. 2016;69(1):60-9. Tables Table 1. Clinicopathological data of patients with NMIBC Clinicopathological variants BCG group (n=72) EPI group (n=21) Total (n=93) P-value Gender 0.390 Male 57 19 76 Female 15 2 17 Preoperative age (years) 0.930 ≤60 24 8 32 60–70 34 10 44 >70 14 3 17 Smoking history 0.089 No 43 8 51 Yes 29 13 42 Prior recurrence rate 0.232 Primary 44 13 57 Recurrent, ≤1 rec/yr 18 2 20 Recurrent, >1 rec/yr 10 6 16 T category 0.002 Ta 51 21 72 T1 21 0 21 Grade 0.331 Low grade 32 12 44 High grade 40 9 49 Tumor size 0.465 3 23 8 31 Risk stage 0.453 Intermediate risk 27 10 37 High risk 45 11 56 Recurrence 0.006 No 60 11 71 Yes 12 10 22 EORTC risk tables 0.218 1–4 28 5 33 5–9 39 16 55 10-17 5 0 5 CUETO scoring model 0.962 0-4 21 7 28 5-6 26 8 35 7-9 20 5 25 10-16 5 1 6 NMIBC: non-muscle invasive bladder cancer; n: number of patients; yr: year; No: number; Recurrent, ≤1 rec/yr: prior recurrence rate of less than one per year; Recurrent, >1 rec/yr: prior recurrence rate of more than one per year; EORTC: European Organization for Research and Treatment of Cancer; CUETO: Spanish Urological Club for Oncological Treatment. Table 2. Complications for intravesical therapy. Complication BCG19 n (%) BCG15 n (%) EPI18 n (%) P value BCG19 vs 15 P value BCG vs EPI Urocystitis 27(73.0%) 27(77.1%) 11(52.4%) 0.683 0.047 Hematuresis 17(48.6%) 14(37.8%) 9(42.9%) 0.358 0.987 Fever 5(14.3%) 7(18.9%) 0(0.0%) 0.598 0.062 Others 9(24.3%) 12(34.3%) 2(9.5%) 0.353 0.122 CTCAE grade Grade1 29(82.9%) 24(64.9%) 13(61.9%) - - Grade2 2(5.7%) 6(16.2%) 0(0.0%) - - Grade3-5 0(0.0%) 0(0.0%) 0(0.0%) - - Total adverse events 31(88.6%) 30(81.1%) 13(61.9%) 0.226 0.022 BCG: Bacillus Calmette–Guérin; EPI: epirubicin; n: number, CTCAE: Common Terminology Criteria for Adverse Events; Others: rare complications including respiratory infection, hypertension and hyperglycemia. Table 3. Univariate analysis of the NMIBC cohort and BCG subgroup Clinical pathological data Total patients (n=93) BCG subgroup (n=72) P-value Hazard ratio (95% CI) P-value Hazard ratio (95% CI) Males a 0.538 1.466 (0.434–4.958) 0.718 0.786 (0.213–2.905) 60–70 years b 0.255 0.592 (0.240–1.459) 0.546 0.682 (0.197–2.360) >70 years c 0.310 0.512 (0.140–1.865) 0.647 0.682 (0.132–3.514) Smoking history d 0.071 2.226 (0.933–5.314) 0.473 1.514 (0.488–4.695) Recurrent e 0.001 9.781 (3.281–29.164) 0.003 21.864 (2.818–169.651) Recurrent, ≤1 rec/yr f 0.062 3.282 (0.944–11.412) 0.033 10.827 (1.209–96.991) Recurrent, >1 rec/yr g 0.001 15.121 (5.297–43.167) 0.001 53.346 (6.522–436.343) T1 h 0.892 1.072 (0.394–2.915) 0.246 1.972 (0.626–6.215) High grade i 0.920 0.958 (0.415–2.212) 0.359 1.754 (0.528–5.825) Tumor size ≥3 cm j 0.009 0.266 (0.098–0.722) 0.068 0.193 (0.042–0.884) No. tumors >3 k 0.344 1.509 (0.644–3.540) 0.397 1.644 (0.520–5.197) High-risk tumor stage l 0.504 1.345 (0.564–3.210) 0.108 3.482 (0.762–15.912) BCG 15 group m 0.956 0.969 (0.312–3.005) 0.975 1.018 (0.328–3.158) EPI 18 group n 0.019 3.378 (1.225–9.313) - - a : compared with females; b and c : compared with age ≤60 years; d : compared with non-smokers; e , f , and g : compared with incipient patients; h : compared with Ta; i : compared with low grade; j : compared with tumor size <3 cm; k : compared with number of tumors ≤3; l : compared with intermediate-risk patients; m : compared with the BCG 19 group; n : compared with the BCG cohort. NMIBC: non-muscle invasive bladder cancer; BCG: Bacillus Calmette–Guérin; CI: confidence interval.; Recurrent, ≤1 rec/yr: prior recurrence rate of less than one per year; Recurrent, >1 rec/yr: prior recurrence rate of more than one per year. Table 4. Predictive value of prognostic models Prognostic grading systems Total NMIBC cohort BCG subgroup c-index (95% CI) c-index (95% CI) T stage 0.526 (0.514–0.538) 0.592 (0.575–0.609) Nuclear grade 0.534 (0.521–0.547) 0.590 (0.575–0.605) Risk group stratification 0.572 (0.561–0.583) 0.635 (0.623–0.647) CUETO scoring model 0.766 (0.753–0.779) 0.812 (0.800–0.827) EORTC risk table 0.741 (0.729–0.753) 0.817 (0.805–0.829) NMIBC: non-muscle invasive bladder cancer; BCG: Bacillus Calmette–Guérin; CI: confidence interval; c-index: concordance index; EORTC: European Organization for Research and Treatment of Cancer; CUETO: Spanish Urological Club for Oncological Treatment. 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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-79981","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":4164529,"identity":"e4f80998-eac9-48c1-8b80-c2830143ad7e","order_by":0,"name":"Yanxiang Shao","email":"","orcid":"","institution":"Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yanxiang","middleName":"","lastName":"Shao","suffix":""},{"id":4164530,"identity":"c2b0c29d-f5bc-4b0e-a2ec-83f5ec464ef1","order_by":1,"name":"Weixiao Yang","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weixiao","middleName":"","lastName":"Yang","suffix":""},{"id":4164531,"identity":"2d5ba077-0798-474c-8c15-931ba8f540e6","order_by":2,"name":"Thongher Lia","email":"","orcid":"","institution":"West China Hospital Sichuan Universty","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thongher","middleName":"","lastName":"Lia","suffix":""},{"id":4164532,"identity":"8121804a-2a1c-47bd-9f19-49223436246a","order_by":3,"name":"Xu Hu","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Hu","suffix":""},{"id":4164533,"identity":"72281bb7-c55e-4048-8ac0-b7de188f4b88","order_by":4,"name":"Zhen Yang","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Yang","suffix":""},{"id":4164534,"identity":"dac89a0f-c24b-4918-9727-6e4d1055ac27","order_by":5,"name":"Shangqing Ren","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shangqing","middleName":"","lastName":"Ren","suffix":""},{"id":4164535,"identity":"c37d1534-746d-4156-83be-f4f62272fd4e","order_by":6,"name":"Kan Wu","email":"","orcid":"","institution":"Sichuan University West China Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kan","middleName":"","lastName":"Wu","suffix":""},{"id":4164536,"identity":"7f156be8-abd9-449d-b5bc-0c81afdfce96","order_by":7,"name":"Jianbang Liu","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianbang","middleName":"","lastName":"Liu","suffix":""},{"id":4164537,"identity":"2646baa5-1567-40df-9d9e-e71336e3066a","order_by":8,"name":"Weichao Dou","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weichao","middleName":"","lastName":"Dou","suffix":""},{"id":4164538,"identity":"fdfb370e-10b4-4a28-90d9-11e221821240","order_by":9,"name":"Sanchao Xiong","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sanchao","middleName":"","lastName":"Xiong","suffix":""},{"id":4164539,"identity":"cef641f8-c7af-42a8-bf7d-84b78f65563e","order_by":10,"name":"Shuyang Feng","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shuyang","middleName":"","lastName":"Feng","suffix":""},{"id":4164540,"identity":"568ff359-3096-4958-b7e5-a26bed84b82c","order_by":11,"name":"Yaohui Wang","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yaohui","middleName":"","lastName":"Wang","suffix":""},{"id":4164541,"identity":"c0151df7-3528-4bba-87c6-33989b299530","order_by":12,"name":"Yang Liu","email":"","orcid":"","institution":"West China Hospital Sichuan University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Liu","suffix":""},{"id":4164542,"identity":"58dda5b5-ba87-441b-9b90-fa41362a18bb","order_by":13,"name":"Xiang Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIie3Qv2oCMRzA8Z/8ILeE3ppwcs/wK4Grkz6LuIbiVBTBCrf6AO2LZO7hcMuJq6On4FZQkOJo4uZyubFgvkNIIB/yByAU+o+hG8YiHZTL+5q/tCMkFFQVwI8lrN1RBMPFVt8JeAmVeKwv1FOd79/icNb9LgOs99sGInP2prokUkzeR1SYkb0YU0o3kBghS4R9C0t0JgqDlnA7byAMoz9HhktZOfLpJzHyTJ4s+RLckZWfyJx/JO6TiWtFa1Nyhp630KY08jqZpxRVr7upmQ3iKK8PTcSF/HHp2e7qXFtsCoVCoSfuBo/1PDVYpHD7AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-8471-0015","institution":"Sichuan University West China Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2020-09-18 10:11:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-79981/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-79981/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":3352373,"identity":"a6d220b6-516a-45f1-a6a6-6dd070d2655e","added_by":"auto","created_at":"2020-11-03 15:19:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":620828,"visible":true,"origin":"","legend":"Comparison of recurrence-free survival for different intravesical instillation groups (A) Comparison of RFS between BCG and epirubicin groups. (B) Comparison of RFS between different BCG regime subgroups. RFS: recurrence-free survival; NMIBC: non-muscle invasive bladder cancer; BCG 19: BCG 19 times group; BCG 15: BCG 15 times group; EPI 18: epirubicin 18 times group.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-79981/v1/66b6a865c0dfef07401af2c6.jpg"},{"id":13608899,"identity":"d9314ebd-9b5d-4eb4-8237-4d5782e78405","added_by":"auto","created_at":"2021-09-17 06:18:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":539196,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-79981/v1/71821a66-a4ee-4c03-a7e4-2fd3550f6219.pdf"},{"id":3352374,"identity":"0085348f-b8ed-48e9-bd9e-a8b4779adf67","added_by":"auto","created_at":"2020-11-03 15:19:52","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":222720,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-79981/v1/afca5ce86588d88cddd28c99.doc"},{"id":3352375,"identity":"e10c4e28-b646-4dbc-aadd-19f0b305f016","added_by":"auto","created_at":"2020-11-03 15:19:52","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":56832,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010FlowDiagram.doc","url":"https://assets-eu.researchsquare.com/files/rs-79981/v1/65c29214c1b6090713626c06.doc"}],"financialInterests":"","formattedTitle":"Comparison of intravesical instillation of Bacille Calmette-Guérin and epirubicin: a randomized controlled trial","fulltext":[{"header":"Background","content":" \u003cp\u003eApproximately 75% of patients with bladder cancer have non-muscle invasive bladder cancer (NMIBC; Ta or T1 disease) at the time of primary diagnosis(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). These patients can be divided into three risk groups (i.e., low, intermediate, and high risk). For intermediate- and high-risk patients, transurethral resection of bladder tumor (TUR-BT) and subsequent intravesical drug instillation are the standard treatments. However, there is currently no conclusion reached regarding treatment with instillation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt has been confirmed that treatment with Bacillus Calmette\u0026ndash;Gu\u0026eacute;rin (BCG) following TUR-BT is superior to TUR-BT alone or combined with chemotherapy in Caucasian patients(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In addition, maintenance treatment with BCG has been recommended for intermediate- and high-risk patients(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, the use of BCG in Chinese patients has been limited by the high rate of intolerance and complications previously reported in clinical practice, and the design of trials of BCG instillation has been suboptimal. Moreover, despite the administration of maintenance therapy with BCG, 32.6% and 13.4% of patients continue to experience recurrence and tumor progression, respectively(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this study, we performed a randomized controlled trial to evaluate the efficacy and safety of adjuvant intravesical BCG or epirubicin (EPI) therapy for different regimes; we also estimated the predictive value for prognostic models to evaluate the prognostic factors for NMIBC.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients and treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA prospective, randomized, controlled, non-blinded study, conducted at West China Hospital, Sichuan University, compared intravesical BCG and EPI treatment. The study was approved by the ethics committee of the Center for Drug Evaluation of the National Medical Products Administration (China) and Ethics Committee of West China Hospital.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were: age 20\u0026ndash;75 years; TUR-BT with completely tumor resection. BT was completely resected with pathologically proven intermediate or high-risk non-muscle invasive bladder urothelium carcinoma according to the European Association of Urology (EAU) guidelines for risk stratification of NMIBC(2).\u003c/p\u003e\n\u003cp\u003eExclusion criteria were: a. Eastern Cooperative Oncology Group performance status score \u0026gt;1; b. patients with active tuberculosis or receiving treatment for anti-tuberculous; c. immune deficiency or undergoing immunosuppressive therapy; d. severe complication (e.g., serious cardiovascular and cerebrovascular disease), or presence of other types of cancer; e. previous diagnosis with muscle-invasive bladder cancer; f. patients underwent treatment (e.g., chemotherapy, radiotherapy or immunotherapy) during the previous 4 weeks which may influence the research results; f. serious intraoperative and postoperative complications (e.g., bladder perforation, serious postoperative hematuresis, bladder irritation, etc.); and g. patients not suitable to receive treatment or not able to participate in our trial due to pregnancy, severe disability, serious psychological problems, etc.\u003c/p\u003e\n\u003cp\u003ePost-operative immediate irrigation with EPI 50 mg was performed within 24 h after TUR-BT. After confirming the presence of intermediate- or high-risk NMIBC according to surgical findings and the final pathological report, patients who participated in the study were randomized into three bladder irrigation groups: a. BCG 19 group (BCG 120 mg weekly for six times, followed by biweekly irrigation for three times, and then monthly for 10 times, for a total of 19 irrigations with BCG); b. BCG 15 group (BCG 120 mg weekly for six times, followed by irrigations for the first 3 weeks and at 3, 6, and 12 months after surgery, for a total of 15 irrigations with BCG); and c. EPI 18 group (EPI 50 mg weekly for eight times, followed by monthly irrigation for 10 times, for a total of 18 irrigations). The randomization was performed within 14 days after surgery, at a 2:2:1 ratio (Das for IWRS Version 5.0, BioVoice \u0026amp; BioGuider, Beijing, China). Subsequently, irrigation was initiated on day 14 post operation and the duration of treatment was 1 year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up and outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor intermediate-risk patients, cystoscopy was performed 3 and 6 months after surgery, then biannually until 5 years. For high-risk patients, cystoscopy was performed trimonthly until 2 years after surgery, then biannually until 5 years. Urinalysis was performed prior to each irrigation. Patients were followed up until recurrence, progression, or discontinuation of treatment for any reason. Adverse effects were recorded at each follow-up according to the Common Terminology Criteria for Adverse Events Version 4.0(6).\u003c/p\u003e\n\u003cp\u003eThe initiation time was the day TUR-BT was performed. The primary end point was recurrence during follow-up, while the secondary end point was progression to muscle-invasive bladder cancer or therapy-related discontinuation of treatment. Recurrence-free survival (RFS) and progression-free survival (PFS) times were recorded. BCG failure and intolerance were recorded according to the definitions of the EAU (2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecorded clinical variants included gender, age and smoking history. Intraoperative recordings included tumor size, site, and number. Tumor histopathological type, T stage (8th American Joint Committee on Cancer TNM classification system)(7), tumor grade (2004 World Health Organization grading system), and carcinoma in situ status. All pathological reports were provided by the Pathology Department of West China Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDifferences in survival between two or more subgroups were evaluated using log-rank tests. Univariate and multivariate Cox regression analyses were performed to determine the clinicopathological parameters associated with the recurrence of patients with NMIBC. Patients were stratified using the European Organization for Research and Treatment of Cancer (EORTC) risk tables(8) and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model(5). The predictive ability of these outcome prediction models was evaluated using the concordance index (c-index)(9).\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using the SPSS Statistics version 25 (IBM, Armonk, NY, USA) and The R Programming Language 3.5.0 software (The R Foundation, Vienna, Austria). A P-value \u0026lt;0.05 denoted statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient baseline data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotally 93 patients were enrolled for analysis (BCG19, BCG15 and EPI 18 groups for 35, 37 and 21 cases respectively, Table 1). The mean age was 62.96 years (standard deviation: 8.16 years), and the median follow-up time was 33.46 months (interquartile range: 18.30\u0026ndash;44.80 months). There was no significant difference noted in baseline clinicopathological factors between the BCG and EPI treatment subgroups, except for T stage. Eight patients underwent radical cystectomy after NMIBC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy and safety for BCG and EPI treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter follow-up for more than one year, recurrence occurred in 12 BCG treated patients (16.67%), with 9 of them suffered recurrence in the course of BCG irrigation. Progression happened in 6 BCG treated patients (8.33%). Meanwhile, number of recurrence and progression for EPI were 10 (47.61%) and 2 (9.52%) respectively. 6 cases suffered recurrence during EPI therapy (28.57%). RFS was significantly longer in the BCG group (Figure 1, P=0.002), but no significant differences were seen between BCG19 and BCG15 regime subgroups (Figure 1, P=0.975). PFS differences between BCG and EPI therapy could not be evaluated since limited ending events.\u003c/p\u003e\n\u003cp\u003eSide effects were also collected (Table 2). Higher general complication rate was seen in BCG group compared with EPI groups (83.33% and 61.90%, respectively; P=0.022); however, most of complications for BCG group were treatment-free and there were no severe adverse events (grade 3-5) happened for these two treatment groups. Urocystitis was the most frequent complication for intravesical therapy, for which incidences were significant higher in BCG subgroup (75.00% vs 52.38%, P=0.047); fever was a unique complication after BCG therapy (16.67%), but all of them were treatment-free. Hematuresis occurred both after BCG and EPI treatment, with no significant difference demonstrated (43.1% vs 42.9%, P=0.987). There were more patients suffered rare complications such as respiratory infection, hypertension and hyperglycemia after BCG therapy, but difference wasn\u0026rsquo;t significant (29.17% vs 9.52%, P=0.122). Six patients didn\u0026rsquo;t complete full cycle of BCG therapy due to intolerance of complications, and all of them happened during the maintenance period (each had 3 patients for BCG 19 and 15 subgroups; five were due to urocystitis and one for hematuriesis); only one patient among them suffered disease recurrence two years after treatment had ended.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInfluence of clinicopathological factors and treatment methods on recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 93 post-TUR-BT patients, the univariate analysis revealed that better survival was observed in those without smoking and previous bladder cancer history, with younger age, low tumor stage and less tumor number (Table 3). However, only prior recurrent history was significantly correlated with poor RFS (P=0.001). Meanwhile, when we considered these in BCG treatment subgroups (n=72), we also found better PFS for male patients and those with well nuclear grade, but weren\u0026rsquo;t significant; and PFS for those patients with prior recurrence rate less than one per year significant poorer than those with recurrence rate for more than one per year (P=0.033).\u003c/p\u003e\n\u003cp\u003eThe EORTC risk tables and CUETO scoring model were used to predict recurrence in patients with postoperative NMIBC. For all 93 cases, the c-index of EORTC and CUETO was 0.766 and 0.741, respectively. These numbers were obviously higher than those of prediction according to tumor stage or grade alone or by EAU risk group stratification (Table 4). Meanwhile, higher predictive accuracy was recorded in the BCG subgroup (0.812 and 0.817, respectively) (Table 4).\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eRecurrence of NMIBC is affected by numerous factors, including tumor size, number of tumors, prior recurrence rate, T stage, grade, and presence of carcinoma in situ (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Patients at high risk of recurrence and progression can be identified through a comprehensive consideration of these factors. In the risk group stratification of EAU, patients with NMIBC are stratified into three risk groups (low, intermediate, and high risk) and different treatment strategies and follow-up measures are recommended(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, these strategies are not effective, with 47.8% of patients suffering at least one recurrence(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSince Morales first reported the irrigation treatment with BCG in bladder cancer(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), the efficacy of this method has been widely demonstrated and became the standard therapy for intermediate- and high-risk NMIBC(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Lower recurrence rates were observed in BCG-treated patients compared with those who underwent chemotherapy(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e); however, higher complication rates also occurred(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). There is a limited number of studies on the use of BCG in Chinese patients due to the intolerance and contraindications of therapy with BCG. Nonetheless, this was gradually accepted by patients due to the improvement of supporting method. We firstly reported a randomized controlled trial of Chinese patients which compared the efficacy of BCG and EPI on NMIBC. The results suggested that, although six patients showed intolerance to therapy with BCG, this approach has advantages in preventing recurrence, without a significantly higher rate of side effects versus treatment with EPI.\u003c/p\u003e \u003cp\u003eSix weeks inductive BCG instillations only are not enough for intermediate and high risk NMIBC treatment, and current evidences support 1\u0026ndash;3\u0026nbsp;years maintenance schedule(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A recent meta-analysis which included 1951 patients demonstrated that longer-maintenance therapy didn\u0026rsquo;t increase side effect compared with induction therapy only, and longer maintenance (more than 1\u0026nbsp;years) wasn\u0026rsquo;t superior to 1\u0026nbsp;years maintenance(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, the optimal number and frequency of maintenance intravesical therapy is still unknown(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Since that, we compared two regime of 1\u0026nbsp;years BCG maintenance therapy, and found that there was no significant difference between BCG 15 and 19 regimes among recurrence and side effects.\u003c/p\u003e \u003cp\u003eEven treated with BCG, recurrence continues to occur in many patients treated with BCG; 32.6% as reported by Jesus et al.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Even after a full course of maintenance therapy with BCG, 15.7% and 26.3% of patients continue to experience early and late recurrence, respectively(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Hence, considerable efforts were focused on the prognostic prediction of NMIBC to more rationally stratify patients, and identify those more suitable for individual surveillance and treatment programs. The EORTC scoring system, based on patients who underwent several instillation protocols, is used to predict recurrence and prognosis in patients with NMIBC (c-index of internal validation of 0.66 and 0.75, respectively)(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Subsequently, the CUETO scoring model was designed to predict prognosis in patients receiving maintenance therapy with BCG (c-index of interval validation of 0.636 and 0.687 for early recurrence and progression, respectively)(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Compared with risk group stratification, the tumor recurrence status (an important prognostic factor) was included in the CUETO and EORTC. Furthermore, in our study, these two models exhibited significantly better differentiations than risk group stratification, especially in BCG-treated patients, suggesting that CUETO and EORTC may be more suitable for the prediction and stratification of patients with NMIBC.\u003c/p\u003e \u003cp\u003eThere are limitations for our study. For one thing, the sample size is relatively small for further subgroup analysis; for another, the follow-up time is short so that the secondary end point of progression could not be evaluated since limited positive events occurred. However, since all patients had completed more than 1 year\u0026rsquo;s follow-up with complications recorded in detail, present results can well reflect the feasibility of BCG instillations in Asian NMIBC populations.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eMaintenance treatment with BCG demonstrated better control of recurrence in Chinese patients with NMIBC after TUR-BT versus intravesical therapy with EPI. Prior recurrence status is an important prognostic factor for recurrence, while the EORTC and CUETO prognostic models exhibited higher prediction accuracy for recurrence than tumor stage, grade, or risk group stratification.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eNMIBC: non-muscle invasive bladder cancer; TUR-BT: transurethral resection of bladder tumor; BCG: Bacillus Calmette\u0026ndash;Gu\u0026eacute;rin; EPI: epirubicin; EAU: European Association of Urology; RFS: Recurrence-free survival; PFS: progression-free survival; EORTC: European Organization for Research and Treatment of Cancer; CUETO: Spanish Urological Club for Oncological Treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate and publications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by Center for Drug Evaluation of National Medical Products Administration (CDENMPA, China) and Ethics Committee of our institute, with the whole process supervised. The registration number in CDE-NMPA was CTR20150840 (Registered 21 December 2015,\u0026nbsp;website of CDE: http://www.cde.org.cn/). All the research registration and ethical approval documents were added below. Patients and their authorized family members had been fully informed before follow-up work was performed, with informed consent signed. All procedures adhere to CONSORT guideline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (Reference Number: 81672552) and the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (Reference number: ZY2016104). X L was the recipient of these funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX L managed the study. Y S, W Y, T L designed the study, X H, Z Y, S R and K W collected the data. Y S controlled the quality of data and algorithms. W Y, T L analyzed and interpreted the data. J L, W D, S X managed the statistical analysis. S F, Y W prepared the manuscript. Y S, W Y, T L edited the manuscript. X L reviewed the manuscript. All authors read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Ranran Liu, Xue Yao and Xuelin Zhang who helped us to collect and collate data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBurger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234-41.\u003c/li\u003e\n\u003cli\u003eBabjuk M, Burger M, Comperat EM, Gontero P, Mostafid AH, Palou J, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol. 2019;76(5):639-57.\u003c/li\u003e\n\u003cli\u003eSylvester RJ, Brausi MA, Kirkels WJ, Hoeltl W, Calais Da Silva F, Powell PH, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.\u003c/li\u003e\n\u003cli\u003ePan J, Liu M, Zhou X. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with non-muscle invasive bladder cancer? An update and cumulative meta-analysis. Front Med. 2014;8(2):241-9.\u003c/li\u003e\n\u003cli\u003eFernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Pineiro L, Gonzalez M, et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J Urol. 2009;182(5):2195-203.\u003c/li\u003e\n\u003cli\u003eSERVICES USDOHAH. Common Terminology Criteria for Adverse Events (CTCAE). USA: National Institutes of Health; 2010.\u003c/li\u003e\n\u003cli\u003eBernard H. Bochner DEH, Jason A. Efstathiou, Badrinath Konety, Cheryl T. Lee, Jam es M. M cKiernan, Elizabeth R. Plimack, V\u0026iacute;ctor E. Reuter, Sr\u0026iacute;kala Sr\u0026iacute;dhar, Raghunandan Vikram, and Walter M. Stadler. AJCC Cancer Staging Manual 8th Edition - Urinary Bladder. 2017.\u003c/li\u003e\n\u003cli\u003eSylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466-5; discussion 75-7.\u003c/li\u003e\n\u003cli\u003eHarrell FE, Jr., Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361-87.\u003c/li\u003e\n\u003cli\u003eMorales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-3.\u003c/li\u003e\n\u003cli\u003eChang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-9.\u003c/li\u003e\n\u003cli\u003eShang PF, Kwong J, Wang ZP, Tian J, Jiang L, Yang K, et al. Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2011(5):CD006885.\u003c/li\u003e\n\u003cli\u003eJarvinen R, Kaasinen E, Sankila A, Rintala E, FinnBladder G. Long-term efficacy of maintenance bacillus Calmette-Guerin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol. 2009;56(2):260-5.\u003c/li\u003e\n\u003cli\u003eSylvester RJ. Maintenance Bacillus Calmette-Guerin Therapy: The Search for the Optimum Treatment Schedule Continues. Eur Urol. 2015;68(2):263-4; discussion 5-6.\u003c/li\u003e\n\u003cli\u003eHuang Z, Liu H, Wang Y, Zhang C, Xu T. Determining optimal maintenance schedules for adjuvant intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Curr Med Res Opin. 2017;33(8):1379-87.\u003c/li\u003e\n\u003cli\u003eCambier S, Sylvester RJ, Collette L, Gontero P, Brausi MA, van Andel G, et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guerin. Eur Urol. 2016;69(1):60-9.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. \u003c/strong\u003eClinicopathological data of patients with NMIBC\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eClinicopathological variants\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eBCG group (n=72)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eEPI group (n=21)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eTotal (n=93)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.390\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003ePreoperative age (years)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.930\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026le;60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e60\u0026ndash;70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026gt;70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eSmoking history\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.089\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003ePrior recurrence rate\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.232\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003ePrimary\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eRecurrent, \u0026le;1 rec/yr\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eRecurrent, \u0026gt;1 rec/yr\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eT category\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eTa\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e72\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eT1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eGrade\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.331\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eLow grade\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eHigh grade\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eTumor size\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.465\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026lt;3 cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026ge;3 cm\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eNo. tumors\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.793\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026le;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e62\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026gt;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eRisk stage\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.453\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eIntermediate risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e37\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eHigh risk\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eRecurrence\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.006\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eEORTC risk tables\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.218\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e1\u0026ndash;4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e33\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e5\u0026ndash;9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e10-17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eCUETO scoring model\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.962\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e0-4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e5-6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e7-9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e10-16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNMIBC: non-muscle invasive bladder cancer; n: number of patients; yr: year; No: number; Recurrent, \u0026le;1 rec/yr: prior recurrence rate of less than one per year; Recurrent, \u0026gt;1 rec/yr: prior recurrence rate of more than one per year; EORTC: European Organization for Research and Treatment of Cancer; CUETO: Spanish Urological Club for Oncological Treatment.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Complications for intravesical therapy.\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eComplication\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eBCG19\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eBCG15\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eEPI18\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCG19 vs 15\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBCG vs EPI\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eUrocystitis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e27(73.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e27(77.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e11(52.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.683\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.047\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eHematuresis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e17(48.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e14(37.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e9(42.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.358\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.987\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eFever\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e5(14.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e7(18.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0(0.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.598\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.062\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eOthers\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e9(24.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e12(34.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e2(9.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.353\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.122\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eCTCAE grade\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eGrade1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e29(82.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e24(64.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13(61.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eGrade2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e2(5.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e6(16.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0(0.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003eGrade3-5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0(0.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0(0.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0(0.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eTotal adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e31(88.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e30(81.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e13(61.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.226\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.022\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBCG: Bacillus Calmette\u0026ndash;Gu\u0026eacute;rin; EPI: epirubicin; n: number, CTCAE: Common Terminology Criteria for Adverse Events; Others: rare complications including respiratory infection, hypertension and hyperglycemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. \u003c/strong\u003eUnivariate analysis of the NMIBC cohort and BCG subgroup\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eClinical pathological data\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal patients (n=93)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\"\u003e\n\u003cp\u003e\u003cstrong\u003eBCG subgroup (n=72)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003eHazard ratio (95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eMales\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.538\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.466 (0.434\u0026ndash;4.958)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.718\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.786 (0.213\u0026ndash;2.905)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003e60\u0026ndash;70 years\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.255\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.592 (0.240\u0026ndash;1.459)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.546\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.682 (0.197\u0026ndash;2.360)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026gt;70 years\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.310\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.512 (0.140\u0026ndash;1.865)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.647\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.682 (0.132\u0026ndash;3.514)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eSmoking history\u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.071\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e2.226 (0.933\u0026ndash;5.314)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.473\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.514 (0.488\u0026ndash;4.695)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eRecurrent\u003csup\u003ee\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e9.781 (3.281\u0026ndash;29.164)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.003\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e21.864 (2.818\u0026ndash;169.651)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eRecurrent, \u0026le;1 rec/yr\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ef\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.062\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e3.282 (0.944\u0026ndash;11.412)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.033\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e10.827 (1.209\u0026ndash;96.991)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eRecurrent, \u0026gt;1 rec/yr\u003csup\u003eg\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e15.121 (5.297\u0026ndash;43.167)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e53.346 (6.522\u0026ndash;436.343)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eT1\u003csup\u003eh\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.892\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.072 (0.394\u0026ndash;2.915)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.246\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.972 (0.626\u0026ndash;6.215)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eHigh grade\u003csup\u003ei\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.920\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.958 (0.415\u0026ndash;2.212)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.359\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.754 (0.528\u0026ndash;5.825)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eTumor size \u0026ge;3 cm\u003csup\u003ej\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.266 (0.098\u0026ndash;0.722)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.068\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.193 (0.042\u0026ndash;0.884)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eNo. tumors \u0026gt;3\u003csup\u003ek\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.344\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.509 (0.644\u0026ndash;3.540)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.397\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.644 (0.520\u0026ndash;5.197)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eHigh-risk tumor stage\u003csup\u003el\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.504\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.345 (0.564\u0026ndash;3.210)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.108\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e3.482 (0.762\u0026ndash;15.912)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eBCG 15 group\u003csup\u003em\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.956\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.969 (0.312\u0026ndash;3.005)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.975\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e1.018 (0.328\u0026ndash;3.158)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eEPI 18 group\u003csup\u003en\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.019\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e3.378 (1.225\u0026ndash;9.313)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e: compared with females; \u003csup\u003eb\u003c/sup\u003e and \u003csup\u003ec\u003c/sup\u003e: compared with age \u0026le;60 years; \u003csup\u003ed\u003c/sup\u003e: compared with non-smokers; \u003csup\u003ee\u003c/sup\u003e, \u003csup\u003ef\u003c/sup\u003e, and \u003csup\u003eg\u003c/sup\u003e: compared with incipient patients; \u003csup\u003eh\u003c/sup\u003e: compared with Ta; \u003csup\u003ei\u003c/sup\u003e: compared with low grade; \u003csup\u003ej\u003c/sup\u003e: compared with tumor size \u0026lt;3 cm; \u003csup\u003ek\u003c/sup\u003e: compared with number of tumors \u0026le;3; \u003csup\u003el\u003c/sup\u003e: compared with intermediate-risk patients; \u003csup\u003em\u003c/sup\u003e: compared with the BCG 19 group; \u003csup\u003en\u003c/sup\u003e: compared with the BCG cohort.\u003c/p\u003e\n\u003cp\u003eNMIBC: non-muscle invasive bladder cancer; BCG: Bacillus Calmette\u0026ndash;Gu\u0026eacute;rin; CI: confidence interval.; Recurrent, \u0026le;1 rec/yr: prior recurrence rate of less than one per year; Recurrent, \u0026gt;1 rec/yr: prior recurrence rate of more than one per year.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. \u003c/strong\u003ePredictive value of prognostic models\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic grading systems\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal NMIBC cohort\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\"\u003e\n\u003cp\u003e\u003cstrong\u003eBCG subgroup\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003ec-index\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003ec-index\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eT stage\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.526\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.514\u0026ndash;0.538)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.592\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.575\u0026ndash;0.609)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eNuclear grade\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.534\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.521\u0026ndash;0.547)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.590\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.575\u0026ndash;0.605)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eRisk group stratification\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.572\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.561\u0026ndash;0.583)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.635\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.623\u0026ndash;0.647)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eCUETO scoring model\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.766\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.753\u0026ndash;0.779)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.812\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.800\u0026ndash;0.827)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd\u003e\n\u003cp\u003e\u003cstrong\u003eEORTC risk table\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.741\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.729\u0026ndash;0.753)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e0.817\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd\u003e\n\u003cp\u003e(0.805\u0026ndash;0.829)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNMIBC: non-muscle invasive bladder cancer; BCG: Bacillus Calmette\u0026ndash;Gu\u0026eacute;rin; CI: confidence interval; c-index: concordance index; EORTC: European Organization for Research and Treatment of Cancer; CUETO: Spanish Urological Club for Oncological Treatment.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"bladder cancer, bacillus Calmette–Guérin, epirubicin, recurrence, predictive mode","lastPublishedDoi":"10.21203/rs.3.rs-79981/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-79981/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe optimal regimen of instillation for patients with non-muscle invasive bladder cancer (NMIBC) and the recurrence-related factors are still needed to be clear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe patients underwent transurethral resection of bladder tumor who diagnosed as intermediate or high risk NMIBC were randomized to receive bacillus Calmette\u0026ndash;Gu\u0026eacute;rin (BCG) 19, 15 times or epirubicin (EPI) 18 times (2:2:1). The primary end point was disease-free survival (DFS), the secondary end point was progression free survival (PFS). Associations between clinicopathological factors and prognosis were estimated, with accuracy of the prognostic models Spanish Urological Club for Oncological Treatment (CUETO) and European Organization for Research and Treatment of Cancer (EORTC) evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 93 patients (BCG19 for 35; BCG15 for 37 and EPI18 for 21) were included, with median follow-up time for 33.46 months. Recurrence and progression occurred in 22 and 8 of patients separately, and significant longer recurrence-free survival was noted in the BCG and primary bladder cancer groups. Higher general complication rate was seen in BCG group compared with EPI groups (83.33% and 61.90%, respectively; P\u0026thinsp;=\u0026thinsp;0.022), but no grade 3\u0026ndash;5 adverse events happened in both groups. Concordance indices for the CUETO and EORTC models were 0.766 and 0.741 for all our series and 0.812 and 0.817 for the BCG subgroup, respectively.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBCG instillation significantly reduced the rate of recurrence compared with epirubicin in this population. The EORTC and CUETO models exhibited high accuracies for the prediction of BCG treatment failure.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eThis study was approved by Center for Drug Evaluation of National Medical Products Administration (CDENMPA, China) and Ethics Committee of our institute, with the whole process supervised. The registration number in CDE-NMPA was CTR20150840 (website of CDE: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.cde.org.cn/\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e","manuscriptTitle":"Comparison of intravesical instillation of Bacille Calmette-Guérin and epirubicin: a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-11-03 15:16:46","doi":"10.21203/rs.3.rs-79981/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"490dbf9e-78bb-40c2-a5cc-a7d6e67e51e5","owner":[],"postedDate":"November 3rd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":962562,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2021-01-03T15:09:55+00:00","versionOfRecord":[],"versionCreatedAt":"2020-11-03 15:16:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-79981","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-79981","identity":"rs-79981","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}