World Journal of Urology (2021) 39:3337–3344 https://doi.org/10.1007/s00345-021-03653-1 ORIGINAL ARTICLE Association of patients’ sex with treatment outcomes after intravesical bacillus Calmette–Guérin immunotherapy for T1G3/HG bladder cancer David D’Andrea1 · Francesco Soria2 · Anne J. Grotenhuis3 · Eugene K. Cha4,5 · Nuria Malats6 · Savino Di Stasi7 · Steven Joniau8 · Tommaso Cai9 · Bas W. G. van Rhijn10 · Jaques Irani11 · Jeffrey Karnes12 · John Varkarakis13 · Jack Baniel14 · Joan Palou15 · Marek Babjuk16 · Martin Spahn17 · Peter Ardelt18 · Renzo Colombo19 · Vincenzo Serretta20 · Guido Dalbagni5 · Paolo Gontero2 · Riccardo Bartoletti21 · Stephane Larré22 · Per‑Uno Malmstrom23 · Richard Sylvester24 · Shahrokh F. Shariat1,4,5,25,26,27,28 Received: 14 November 2020 / Accepted: 28 February 2021 / Published online: 13 March 2021 © The Author(s) 2021 Abstract Purpose To investigate the association of patients’ sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette–Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC). Materials and methods We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients’ sex with HG- recurrence and disease progression. Results A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01–1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92–1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients’ sex was not associated with recurrence (HR 0.99, 95%CI 0.80–1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78–1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78–1.60, p = 0.55). Conclusion Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response. Keywords Bladder cancer · BCG · Response · Age · Progression · Recurrence Introduction Identifying the patients who are most likely to recur or pro- gress during or after adjuvant BCG would be highly valuable Standard treatment of high-risk non-muscle-invasive blad- in the clinical decision-making process and patient counsel- der cancer (NMIBC) is complete transurethral resection ling. These patients could be offered alternative treatment (TURB) followed by adjuvant intravesical immunotherapy strategies such as early/immediate radical cystectomy [3]. with bacillus Calmette–Guérin (BCG) [1, 2]. Despite ade- To address this unmet need, an effort has been put into the quate treatment, around 40% of patients with T1 urinary development of prognostic models and risk stratification bladder cancer (UBC) will experience disease recurrence tools such as those from the European Organization for and around 20% disease progression, respectively [2–4]. Research and Treatment of Cancer (EORTC) and the Club Urológico Español de Tratamiento Oncológico (CUETO) [5, 6]. However, the performance of these models is still * David D’Andrea dd.dandrea@gmail.com under debate, in part because they do not take in account the heterogeneous genomic landscape and mutational burden Extended author information available on the last page of the article 13 Vol.:(0123456789) 3338 World Journal of Urology (2021) 39:3337–3344 of the disease [7], or other adverse pathologic features such Outcome measurement as lympho-vascular invasion and variant histology [8–12]. Moreover, sex-based differences in biology, epidemiology, The primary endpoint was the association of patients’ sex and outcomes of UBC are well documented in muscle-inva- with disease recurrence, during BCG therapy or after com- sive UBC [13, 14]. However, the association of patients’ sex pletion of BCG therapy. The secondary endpoint was the with treatment outcome to BCG therapy is still controversial association of patients’ sex with disease progression to [5, 7, 15, 16] and has so far been implemented only in the MIBC. CUETO risk tables [5]. The “time to event” was calculated as the time between To fill this gap in knowledge, we investigated the impact first pT1G3/HG diagnosis and a histopathological confirmed of sex on clinical outcomes of patients treated with TURB recurrence or progression with TURB. Patients who did not and BCG for T1 G3/high-grade (HG) UBC. develop a recurrence during the follow-up were censored at their last follow-up visit. Methods Statistical analyses Study population Statistical analyses were performed in different steps. First, to account for missing baseline data that were assumed to We analyzed the data of 2635 patients treated with adjuvant be missing at random, we performed multiple imputations intravesical BCG for T1 UBC between 1984 and 2019 within by using chained equations. Thirty imputed data sets were a multicenter collaboration including 25 centers across generated using predictive mean matching for numeric vari- Europe and the United States of America. ables, logistic regression for binary variables, and Bayesian polytomous regression for factor variables. Second, we used inverse probability weighting (IPW) to reduce the bias of TURB and adjuvant BCG instillations unweighted estimators and adjust for covariates imbalance between males and females. The variables used to estimate A second look TURB was performed at the physician’s dis- the inverse probability weights were age, smoking status, cretion based on pathologic and intraoperative findings. All exposure to chemical compounds, previous low-grade UBC, surgical specimens were processed according to standard previous intravesical therapy, presence of detrusor muscle in pathologic procedures and staged according to the TNM the TURB specimen, G3 grade, multifocal T1 UBC, tumor classification. Tumor grade was assigned according to the size > 3 cm, concomitant CIS, second look TURB, number 1973 and/or 2004 World Health Organization system. of BCG induction cycles and number of BCG maintenance Metastatic disease and concomitant upper urinary-tract cycles. Post-weighting balance in covariates was evaluated urothelial carcinoma were excluded using radiological by using standardized mean differences (supplementary fig- imaging. ure S1). Third, unweighted and IPW-adjusted univariable Due to the retrospective nature of the study, the indica- Cox proportional hazard regression analyses were used to tion and duration for adjuvant BCG therapy were given at estimate the hazard ratios (HR) with their 95% confidence the physician’s discretion. An adequate BCG treatment was intervals (CI) for the association of patients’ sex with recur- defined as the administration of at least five of six doses of rence and disease progression. Fourth, we estimated recur- an initial induction course plus at least two of three doses of rence and disease progression rates between groups using maintenance therapy or the administration of at least five of cumulative incidence curves. six doses of an initial induction course plus at least two of Finally, we performed subgroups analyses in the weighted six doses of a second induction course [17]. population using IPW-adjusted Cox proportional hazard regression analyses investigating the association of sex with Follow‑up disease recurrence, HG-recurrence, and disease progression in patients adequately treated with BCG. Outcome estimates Due to the retrospective nature of the study, follow-up was were graphically visualized using cumulative incidence not standardized but rather performed according to institu- curves. tional standards and based on guidelines at the time and at Statistical significance was considered at p < 0.05. All the physician’s discretion. tests were performed with R (R Foundation for Statistical Computing, v3.5.1). 13 World Journal of Urology (2021) 39:3337–3344 3339 Table 1  Baseline characteristics of 2635 patients treated with transurethral resection of the bladder (TURB) and adjuvant intravesical bacillus Calmette–Guérin (BCG) for pT1G3/HG urinary bladder cancer (UBC) in unweighted and weighted study population after multiple imputation Unweighted Weighted Male Female p SMD Male Female p SMD n 2170 465 2634.6 2638.8 Age, median (IQR) 68 (60–74) 69 (61–76) < 0.01 0.11 68 (61–74) 68 (59–75) 0.56 0.08 Smoking status, n (%) Never 523 (24.1) 244 (52.5) < 0.01 0.62 766.5 (29.1) 766.2 (29.0) 0.95 0.02 Former 955 (44.0) 115 (24.7) 1070.0 (40.6) 1091.6 (41.4) Current 692 (31.9) 106 (22.8) 798.1 (30.3) 781.1 (29.6) Exposure to chemical compounds, n (%) No 1977 (91.1) 453 (97.4) < 0.01 0.27 2429.6 (92.2) 2443.7 (92.6) 0.87 0.01 Yes 193 (8.9) 12 (2.6) 204.9 (7.8) 195.2 (7.4) Previous LG UBC, n (%) No 1928 (88.8) 416 (89.5) 0.76 0.02 2343.8 (89.0) 2347.1 (88.9) 0.99 < 0.01 Yes 242 (11.2) 49 (10.5) 290.7 (11.0) 291.7 (11.1) Previous intravesical therapy, n (%) No 2053 (94.6) 445 (95.7) 0.40 0.05 2497.2 (94.8) 2495.6 (94.6) 0.88 0.01 Yes 117 (5.4) 20 (4.3) 137.3 (5.2) 143.2 (5.4) Detrusor muscle in the TURB specimen, n (%) No 369 (17.0) 99 (21.3) 0.03 0.11 466.1 (17.7) 455.4 (17.3) 0.84 0.01 Yes 1801 (83.0) 366 (78.7) 2168.5 (82.3) 2183.5 (82.7) Grade G3 (WHO 1973), n (%) No 134 (6.2) 32 (6.9) 0.64 0.03 167.8 (6.4) 208.5 (7.9) 0.34 0.06 Yes 2036 (93.8) 433 (93.1) 2466.8 (93.6) 2430.3 (92.1) High grade (WHO 2004), n (%) 1586 (100.0) 354 (100.0) NA NA 1938.1 (100.0) 1996.6 (100.0) NA NA Multifocal pT1 UBC, n (%) No 1425 (65.7) 305 (65.6) 1.00 < 0.01 1731.4 (65.7) 1765.0 (66.9) 0.67 0.02 Yes 745 (34.3) 160 (34.4) 903.2 (34.3) 873.9 (33.1) Tumor size > 3 cm, n (%) No 1439 (66.3) 296 (63.7) 0.30 0.06 1734.5 (65.8) 1717.2 (65.1) 0.79 0.02 Yes 731 (33.7) 169 (36.3) 900.1 (34.2) 921.6 (34.9) Concomitant CIS, n (%) No 1602 (73.8) 358 (77.0) 0.17 0.07 1960.3 (74.4) 1964.1 (74.4) 0.99 < 0.01 Yes 568 (26.2) 107 (23.0) 674.3 (25.6) 674.7 (25.6) Invasion of the prostatic urethra, n (%) No 2058 (94.8) – NA NA 2501.1 (94.9) – NA NA Yes 112 (5.2) – 133.5 (5.1) – Second look TURB, n (%) No 1272 (58.6) 258 (55.5) 0.23 0.06 1532.1 (58.2) 1562.2 (59.2) 0.72 0.02 Yes 898 (41.4) 207 (44.5) 1102.5 (41.8) 1076.6 (40.8) Induction BCG instillations, median (IQR) 6 (6–6) 6 (6–6) 0.05 0.10 6 (6–6) 6 (6–6) 0.43 0.01 Maintenance BCG instillations, median (IQR) 9 (5–11) 9 (6–10) 0.62 0.02 9 (5–10) 9 (6–10) 0.72 < 0.01 IQR  interquartile range, LG  low-grade, CIS  carcinoma in situ, SMD  standardized mean difference Results comparisons showed that both groups differed significantly with respect to age, smoking status, exposure to chemical A total of 2170 (82%) males and 465 (18%) females were compounds and detrusor muscle in the TURB specimen. available for analysis. Unweighted and weighted clinico- Overall, 64% of patients without muscle at first TURB pathologic features of the patients, stratified by sex, are underwent a second look TURB and 37% of patients with shown in Table 1. Standardized differences of unweighted muscle at first TURB underwent a second look TURB. 13 3340 World Journal of Urology (2021) 39:3337–3344 After IPW adjustment, all relevant standardized differ- unweighted univariable Cox regression analyses, patients’ ences were less than 10%, which indicated that clinico- sex was not associated with disease recurrence (crude HR pathologic features between groups were subsequently 1.01, 95%CI 0.81–1.26, p = 0.91), HG-recurrence (crude comparable. HR 1.02, 95%CI 0.79–1.31, p = 0.87) or disease progres- The median follow-up for alive patients in the cohort was sion (crude HR 1.10, 95%CI 0.77–1.58, p = 0.60). On IPW- 50 months (IQR 26–88). Within this period, 1090 (50%) adjusted Cox regression analyses, patients’ sex was not asso- males and 244 (52%) females experienced a recurrence, and ciated with disease recurrence (HR 0.99, 95%CI 0.80–1.24, 391 (18%) males and 104 (22%) females experienced a dis- p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78–1.29, ease progression. On unweighted univariable Cox regression p = 0.99) or disease progression (HR 1.12, 95%CI 0.78–1.60, analyses, female sex was associated with disease progression p = 0.55) (Fig. 2). (crude HR 1.24, 95%CI 1.001–1.54, p = 0.04) but not with recurrence (crude HR 1.07, 95%CI 0.93–1.23, p = 0.34). On IPW-adjusted univariable Cox regression analyses, female sex was also associated with disease progression (HR 1.25, Discussion 95%CI 1.01–1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92–1.22, p = 0.41) (Fig. 1). In a retrospective analysis of a large multicenter interna- Overall, 544 patients, 436 (20%) males and 108 (23%) tional dataset of patients treated with TURB and adjuvant females, were treated with radical cystectomy for BCG intravesical BCG for T1G3/HG UBC, we found an associa- failure. Data on pathologic T-stage were available for 506 tion of female sex with disease progression. However, this patients. Within this group, 146 (36%) males and 34 (34%) difference disappeared in patients adequately treated with females had non-organ confined disease (pT3/pT4 and/or BCG. positive nodal stage, p = 0.65). The difference in incidence and oncologic outcomes of A total of 1056 patients, 871/2170 males (40%) and UBC has been widely reported in the literature14. These 185/465 females (40%), were treated with adequate BCG. Of dissimilarities have been partially explained by the activity these, 52% (454) of the males and 54% (99) of the females of the sex steroid hormone pathways, differences in the qual- had recurrences, 38% (328) of the males and 40% (74) of ity of treatment, and sex-specific differences in immunity the females had HG-recurrence and 17% (151) of the males [18–21]. However, results across studies are controversial and 20% (37) of the females had disease progression. On and are mainly related to muscle-invasive UBC. A B Fig. 1  Cumulative incidence curves for the association of patients’ and adjuvant intravesical bacillus Calmette–Guérin (BCG) for T1G3/ sex with time to disease recurrence (a) and progression in 2635 HG urinary bladder cancer patients treated with transurethral resection of the bladder (TURB) 13 World Journal of Urology (2021) 39:3337–3344 3341 A B C Fig. 2  Cumulative incidence curves for the association of patients’ thral resection of the bladder (TURB) and adequate adjuvant intraves- sex with time to disease recurrence (a) high-grade (HG) recurrence ical bacillus Calmette–Guérin (BCG) for T1G3/HG urinary bladder (b) and disease progression (c) in 1056 patients treated with transure- cancer In NMIBC, the bulk of the evidence presented by the cur- series of 1021 patients treated with TURB and induction rent literature questions the prognostic value and differential BCG, authors did not find an association of patients’ sex response to BCG between males and females. with disease recurrence or progression [25]. However, in The CUETO and the 2016 updated EORTC risk tables are this series, only 40% of the patients included had a T1 UBC. the two most used prognostic tools in clinical decision mak- We expanded upon these limitations by investigating the ing for patients with UCB treated with BCG [5, 6]. Because association of patients’ sex in a large multicenter dataset of patients’ sex was found to be associated with disease recur- T1 UBC. To the best of our knowledge, this is the largest rence in the CUETO data, sex has been implemented in their series representing real-world clinical data. Moreover, our model. Neither the CUETO nor the EORTC studies found an analyses adjusted relevant prognostic variables, which were association between patient’s sex and disease progression. not reported in other studies. The association of patients’ sex with oncologic outcomes Another major limitation of the previously mentioned of T1 UBC has been investigated in several other retrospec- retrospective series is the administration of intravesical tives series, with similar results. BCG therapy restricted to the induction course. Indeed, In a retrospective series of 146 patients and in a subgroup the efficacy of the treatment, particularly in patients with analysis of 234 out of 916 patients treated with TURB and high-risk, is dependent on the maintenance schedule [26, adjuvant intravesical BCG, female sex was not found to be 27]. We added detail on these shortcomings by investigating an independent predictor of disease recurrence and progres- the association of patients’ sex with oncologic outcomes in sion [15, 16]. patients adequately treated with BCG [17]. In this subgroup, There are several factors that should be considered when the association of patients’ sex with disease progression contextualizing our study with these results. In the study by could no longer be observed. This generates the hypothesis Palou et al. [15], patients were treated with TURB, which that an adequate BCG treatment might equalize the effect of was clinically judged complete by the surgeon, and did not patients’ sex on therapy response. However, the number of undergo a second look TURB. Also in the study by Kluth patients in this subgroup might have been too small to detect et al. [16], data on second look TURB were not available. a statistically significant difference. Despite the presence of detrusor muscle in all the specimens, Our study is not devoid of limitations, which are mainly which is considered a surrogate marker for the quality of the inherent to its retrospective design. During the large time resection [22, 23], the residual disease could not be ruled span of study treatment modalities such as endoscopic image out. Complete resection is essential for the optimal outcomes enhancement [28], changes in local clinical practices at each as it impacts prognosis and adjuvant therapy response in site and imaging modalities used for surveillance may have patients with NMIBC [24]. changed significantly. We had no information on the BCG Both series could be biased by the relatively small number strain used. However, there is no evidence on the differen- of patients and events. In a larger single-center retrospective tial effectiveness of one strain compared to another [29, 30], 13 3342 World Journal of Urology (2021) 39:3337–3344 passaging and sub-culturing over the years may have changed Funding Open access funding provided by Medical University of the virulence of mycobacteria and immunological response in Vienna. the host [31]. We had histopathology information at disease recurrence only for the first recurrence. Therefore, we could Compliance with ethical standards not assess whether the patient developed an HG-recurrence Conflicts of interest All authors declare that they have no conflict of after a first low grade recurrence. Finally, we acknowledge interest for this manuscript. the limitation of a missing central pathology review and the lack of information on histologic variants and lymphovascu- Research involving human participants and/or animals This retrospec- lar invasion. Moreover, histopathological examination was tive study was conducted on already available data. performed according to institutional standards at each center, Informed consent Not necessary as this is a retrospective analysis. which could have led to heterogeneous results. Despite all these limitations, our study has relevant clini- Open Access This article is licensed under a Creative Commons Attri- cal implications. Given the current world-wide BCG short- bution 4.0 International License, which permits use, sharing, adapta- age, accurate selection of patients who are more likely to tion, distribution and reproduction in any medium or format, as long respond to the therapy is of paramount importance to avoid as you give appropriate credit to the original author(s) and the source, overtreatment, reduce complications, and drug wastage. We provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are analyzed a cohort of NMIBC patients treated with BCG with included in the article’s Creative Commons licence, unless indicated the highest risk of disease recurrence and progression and otherwise in a credit line to the material. If material is not included in found an association of female sex with disease progression. the article’s Creative Commons licence and your intended use is not This evidence may help physicians during patient counsel- permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a ling regarding adjuvant therapies or early cystectomy and copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. follow-up scheduling. References Conclusion 1. Chang SS, Boorjian SA, Chou R et al (2016) Diagnosis and treat- Our analysis generates the hypothesis of differential onco- ment of non-muscle invasive bladder cancer: AUA/SUO guide- line. J Urol 196:1021–1029. https://​doi.​org/​10.​1016/j.​juro.​2016.​ logic outcomes in female compared to male patients if not 06.​049 adequately treated with BCG for T1G3/HG UBC. Further 2. 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Transl Androl Urol 8:85–93. https://​doi.​org/​10.​21037/​tau.​ Eur Urol Focus. https://​doi.​org/​10.​1016/j.​euf.​2019.​06.​001 2018.​08.​19 20. Godoy G, Gakis G, Smith CL, Fahmy O (2016) Effects of andro- gen and estrogen receptor signaling pathways on bladder cancer Publisher’s Note Springer Nature remains neutral with regard to initiation and progression. Bladder Cancer 2:127–137. https://d​ oi.​ jurisdictional claims in published maps and institutional affiliations. org/​10.​3233/​blc-​160052 21. Koti M, Ingersoll MA, Gupta S et al (2020) Sex differences in bladder cancer immunobiology and outcomes: a collaborative 13 3344 World Journal of Urology (2021) 39:3337–3344 Authors and Affiliations David D’Andrea1 · Francesco Soria2 · Anne J. Grotenhuis3 · Eugene K. Cha4,5 · Nuria Malats6 · Savino Di Stasi7 · Steven Joniau8 · Tommaso Cai9 · Bas W. G. van Rhijn10 · Jaques Irani11 · Jeffrey Karnes12 · John Varkarakis13 · Jack Baniel14 · Joan Palou15 · Marek Babjuk16 · Martin Spahn17 · Peter Ardelt18 · Renzo Colombo19 · Vincenzo Serretta20 · Guido Dalbagni5 · Paolo Gontero2 · Riccardo Bartoletti21 · Stephane Larré22 · Per‑Uno Malmstrom23 · Richard Sylvester24 · Shahrokh F. Shariat1,4,5,25,26,27,28 1 15 Department of Urology, Comprehensive Cancer Center, Department of Urology, Fundacio Puigvert, University Medical University of Vienna, Vienna, Austria of Barcelona, Barcelona, Spain 2 16 Division of Urology, University of the Studies of Turin, Department of Urology, Motol Hospital, University of Praha, AOU Città Della Salute e Della Scienza di Torino, Presidio Prague, Czech Republic Molinette, Turin, Italy 17 Department of Urology, University Hospital of Wuerzburg, 3 Department of Urology, Radboud University Nijmegen Wuertzburg, Germany Medical Centre, Nijmegen, The Netherlands 18 Department of Urology, Universitätsklinik Freiburg, 4 Department of Urology, Weill Medical College of Cornell, Freiburg, Germany University, New York, NY, USA 19 Departement of Urology, Università Vita Salute, Ospedale 5 Department of Urology, Memorial Sloan Kettering Cancer S. Raffaele, Milan, Italy Center, New York, NY, USA 20 Department of Surgical, Oncological and Stomatological 6 Genetic and Molecular Epidemiology Group, Spanish Sciences, University of Palermo, Palermo, Italy National Cancer Research Centre (CNIO), Madrid, Spain 21 Department of Translational Research and New 7 Department of Urology, Policlinico Tor Vergata-University Technologies, University of Pisa, Pisa, Italy of Rome, Rome, Italy 22 Department of Urology, CHU de Reims, Reims, France 8 Oncologic and Reconstructive Urology, Department 23 Department of Urology, Academic Hospital, Uppsala of Urology, University Hospitals Leuven, Leuven, Belgium University, Uppsala, Sweden 9 Department of Urology, Santa Chiara Hospital, Trento, Italy 24 European Association of Urology Non-Muscle Invasive 10 Department of Surgical Oncology (Urology), Netherlands Bladder Cancer Guidelines Panel, Brussels, Belgium Cancer Institute-Antoni Van Leeuwenhoek Hospital, 25 Department of Urology, Second Faculty of Medicine, Charles Amsterdam, The Netherlands University, Prague, Czech Republic 11 Department of Urology, Centre Hospitalier Universitaire La 26 Institute for Urology and Reproductive Health, Milétrie, University of Poitiers, Poitiers, France I.M. Sechenov First Moscow State Medical University, 12 Department of Urology, Mayo Clinic, Rochester, MN, USA Moscow, Russia 13 27 Department of Urology, Sismanoglio Hospital, University Department of Urology, University of Jordan, Amman, of Athens, Athens, Greece Jordan 14 28 Department of Urology, Rabin Medical Centre, Tel Aviv, European Association of Urology Research Foundation, Israel Arnhem, The Netherlands 13