Abstract
Objective
Intravesical BCG treatment is the most frequently preferred adjuvant treatment option with its effective results in non-muscle invasive bladder tumors. Despite effective results, systemic and local side effects can be observed and can be one of the main reasons for treatment discontinuation. In this study we aimed to identify clinical factors predicting BCG-related side effects during intravesical BCG therapy in patients with non-muscle invasive bladder cancer.
Methods
Demographic and clinical data of patients who received intravesical adjuvant BCG therapy for non-muscle invasive bladder tumor were obtained from patient records. Data on side effects following intravesical BCG therapy and clinical approaches were collected. After creating the patient sample, binary logistic regression analysis was performed to identify parameters and independent risk factors predicting BCG-related side effects, and to evaluate data related to the clinical management of BCG-related side effects.
Results
Among the 276 patients included in the study, 23(8.3%) developed BCG-related local and systemic side effects. The mean IPSS(13.5 ± 2.9 vs. 17.6 ± 1.7) and mean tumor size(2.5 ± 0.9 vs. 3.6 ± 1.0 cm)were significantly higher in the group with BCG-related side effects(p < 0.001). The rate of CIS was significantly higher in the group with BCG-related side effects(21.7% vs. 3.9%,p = 0.004). Local side effects included cystitis symptoms in 18(78.2%) patients and epididymo-orchitis in 2(8.6%) patients. Systemic side effects included malaise and fever below 38.5 °C in 4(17.3%) patients, and fever above 38.5 °C lasting longer than 48 h in 2(8.6%) patients. Logistic regression analysis identified IPSS, tumor size, and the presence of CIS as independent risk factors.
Conclusion
High IPSS, large tumor size, and the presence of CIS were significant predictors of side effects during intravesical BCG therapy. Clinicians can ensure more effective use of BCG by preventing treatment discontinuation through approaches such as the use of quinolones and dose reduction in patients with these factors.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12894-025-01734-6.
Keywords: Intravesical BCG therapy, Non-Muscle invasive bladder Cancer, BCG-Related side effects, Independent risk factors
Introduction
Intravesical BCG (Bacillus Calmette-Guérin) therapy is an effective method used as adjuvant treatment for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) and is recommended in current guidelines [1]. While other adjuvant treatment options, such as intravesical chemotherapeutics like epirubicin and mitomycin C, as well as combined use with interferon, are available for NMIBC, meta-analyses have shown that recurrence and progression is lower in patients who have taken intravesical BCG therapy [2–4].
Intravesical BCG therapy’s prominent effect mechanism involves the interaction of the attenuated Mycobacterium bovis strain with the urothelium and fibronectin, leading to humoral immunity that stimulates cytotoxic T cells, thereby targeting tumor cells by the immune system [5]. Typically, intravesical BCG therapy is administered with an induction phase of 1 dose weekly for 6 weeks, followed by a maintenance phase of 1 dose weekly for 3 weeks at the 3rd, 6th, and 12th months over a period of 1 or 3 years [6]. BCG-related side effects are generally observed in less than 5% of cases, with infectious complications being the most common [7]. Infectious complications can be successfully managed with antibiotic therapy and supportive treatment; however, this process can rarely lead to systemic responses such as sepsis [8].
Another risk posed by side effects related to intravesical BCG is the potential discontinuation or incompletion of treatment [9]. Consequently, the inability to provide adjuvant therapy poses a potential risk for tumor recurrence and progression. Patients generally experience symptoms within the first year of treatment, leading to discontinuation [9]. Additionally, findings suggest that elderly patients are able to continue intravesical BCG therapy with fewer side effects [10].
Based on these frequently observed clinical complications that can lead to treatment discontinuation, our study aims to evaluate the associated risk factors in patients who develop side effects following intravesical BCG therapy.
Materials and methods
Patients
The study commenced after obtaining approval from the local ethics committee (Approval No: BAEK 2024/04–90). After receiving approval from the ethics committee, patients diagnosed with NMIBC and treated with intravesical BCG instillation in our urology clinic from January 1, 2014, to December 30, 2023, were included in the study. Patients diagnosed with muscle-invasive bladder tumor, upper urinary tract urothelial cancer, those in the EAU NMIBC low-risk group, those with a history of intravesical chemotherapy, those with positive urine culture before BCG, and those whose medical records were inaccessible were excluded from the study. IPSS, total PSA and prostate volume were obtained from all male patients and 17 patients without these data were excluded from the study.
Clinical management
Patients diagnosed with primary bladder tumors undergo TUR-B, and intravesical BCG therapy is initiated for intermediate and high-risk NMIBC cases based on EAU NMIBC risk classification following pathology results [11]. Intravesical BCG therapy is planned with a 6-week induction BCG treatment, followed by 3-week intravesical BCG treatments at 3, 6, 12, 18, 24, 30, and 36 months. First intravesical BCG administratition was started at least two weeks after last TUR-B. An urine culture is taken before each BCG dose, and appropriate antibiotic therapy is administered in case of infection. Before intravesical BCG treatment, patients are informed about BCG-related side effects according to the EAU guideline and if occurs hospital admission is recommended. Patients who develop cystitis related to intravesical BCG are recorded in the hospital’s record system upon the relevant application and hospitalized if necessary. Patients who didn’t develop BCG-related side effects or didn’t apply to the hospital are questioned about side effects when they came for the next BCG dose and are recorded in the hospital record system. BCG-related side effects were classified as local and systemic, according to EAU 2024 guidelines. Patients with lower urinary tract symptoms such as dysuria, urgency, hematuria, and pollakiuria without bacterial growth in urine culture, as well as those developing epididymo-orchitis and granulomatous prostatitis, were identified as having local side effects, whereas fever above > 38.5 °C and over 48 h, malaise accompanied by arthralgia, allergic rashes, and sepsis were considered systemic side effects [1].
Data collection
After applying the inclusion and exclusion criteria, demographic and clinical data obtained prior to TUR-B were recorded from the hospital management system. These data included age, gender, BMI, smoking status, preoperative complete blood count, serum creatinine levels, total PSA (for male patients), International Prostate Symptom Score (IPSS) (for male patients), and prostate volume (for male patients). Data on tumor location, size (of the largest lesion), and operation duration were obtained from operation notes. Tumor diameter was measured intraoperatively using the tip of the TUR loop. Pathological data, including tumor T stage, grade, and accompanying carcinoma in situ (CIS), were collected. Additionally, BCG-related side effects, the time of side effects, treatment and follow-up period, and data of patients whose treatment had to be terminated were recorded.
Statistical analysis
Data were analyzed using SPSS, version 22.0. Categorical variables were reported as numbers and percentages, while continuous variables were expressed as means and standard deviations. The normality of continuous variable distributions was assessed with the Kolmogorov-Smirnov test. For comparing the means of two independent groups with normal distributions, the Student’s t-test was used. For groups that did not follow a normal distribution, the Mann-Whitney U test was applied. The percentages of categorical variables were compared using Pearson’s chi-square test and Fisher’s exact test. Univariable and multivariable logistic regression analyses were performed to identify factors predictive of BCG-related side effects. A p-value of less than 0.05 was considered statistically significant.
Results
A total of 276 patients who received intravesical BCG therapy were included in the study. Among these, 23 patients (8.3%) developed BCG-related local and systemic side effects. The mean age for the groups with and without BCG-related side effects was 59.8 ± 6.5 years and 57.5 ± 6.3 years (p > 0.05). When comparing demographic and clinical parameters, gender, BMI, smoking history, WBC count, HGB level, PLT count, creatinine, PSA levels, and prostate volume were similar between the groups (p > 0.05). The mean IPSS was significantly higher in the group with BCG-related side effects (13.5 ± 2.9 vs. 17.6 ± 1.7, p < 0.001). Timing of first BCG dose were similar for each groups (17.4 ± 2.1 vs. 18.0 ± 1.9, p > 0.05).
When comparing intraoperative findings and pathological results between the groups, tumor size and operation time were significantly higher in the group with BCG-related side effects (p < 0.001). Tumor localization and tumor T classification were similar for both groups (p > 0.05). The rate of CIS in the group with BCG-related side effects was significantly higher at 21.7% compared to 3.9% (p = 0.004), and the rate of low-grade tumors was 56.5% compared to 30.4% (p = 0.011). The clinical characteristics and their comparison between groups are presented in Table 1.
Table 1.
Comparison of demographic and clinic variables between BCG related side effects observed and non-observed group
| Variables | None BCG side effects | BCG side effects | P value |
|---|---|---|---|
| Number of patients, n(%) | 253 (91.7) | 23 (8.3) | |
| Gender, n(%) | 1.000& | ||
|
Male Female |
232 (91.6) 21 (8.4) |
22 (95.7) 1 (4.3) |
|
| Mean age ± SD, (yrs) | 57.5 ± 6.3 | 59.8 ± 6.5 | 0.822** |
| Smoking, n(%) | 0.274# | ||
|
Yes No |
140 (55.3) 113 (44.7) |
10 (43.5) 13 (56.5) |
|
| Mean BMI ± SD, kg/m2 | 22.9 ± 2.09 | 23.7 ± 2.92 | 0.100** |
| Mean WBC count ± SD, µ/L | 8.47 ± 2.11 | 8.35 ± 2.04 | 0.753** |
| Mean HGB level ± SD, g/dl | 15.3 ± 1.7 | 15.5 ± 1.0 | 0.784** |
| Mean PLT count ± SD, 103 µ/L | 281.9 ± 65.4 | 278.9 ± 67.9 | 0.831* |
| Mean creatinine value ± SD, mg/dL | 0.89 ± 0.31 | 0.90 ± 0.20 | 0.793* |
| Mean PSA ± SD, ng/ml | 1.3 ± 0.9 | 1.3 ± 0.6 | 0.286** |
| Mean prostat volume ± SD, ml | 63.9 ± 17.3 | 69.4 ± 25.6 | 0.413** |
| Mean IPSS ± SD | 13.5 ± 2.9 | 17.6 ± 1.7 | < 0.001** |
| Mean tumor diameter ± SD, cm | 2.5 ± 0.9 | 3.6 ± 1.0 | < 0.001** |
| Tumor localization, n(%) | 0.251& | ||
|
Trigon (1) Right bladder wall (2) Left bladder wall (3) Upper wall (4) Posterior wall (5) |
66 (26.1) 65 (25.7) 46 (18.2) 38 (15.0) 38 (15.0) |
11 (47.8) 6 (26.1) 3 (13.0) 2 (8.7) 1 (4.3) |
1 vs. 2 0.266 1 vs. 3 0.155 1 vs. 4 0.130 1 vs. 5 0.058 2 vs. 3 0.736 2 vs. 4 0.709 2 vs. 5 0.418 3 vs. 4 1.000 3 vs. 5 0.626 4 vs. 5 1.000 |
| T stage, n(%) | 0.584# | ||
|
Ta T1 |
114 (45.1) 139 (54.9) |
9 (39.1) 14 (60.9) |
|
| Second TUR-B | 0.852# | ||
|
Yes No |
154 (60.8) 99 (39.2) |
15 (65.2) 8 (34.8) |
|
| Carcinoma in situ, n(%) | 0.004& | ||
|
Yes With T1 With Ta No |
10 (3.9) 8 (80.0) 2 (20.0) 243 (96.1) |
5 (21.7) 5 (100.0) 0 (0.0) 18 (78.3) |
|
| Tumors’ WHO grade, n(%) | 0.011# | ||
|
Low grade High grade |
77 (30.4) 176 (69.6) |
13 (56.5) 10 (43.5) |
|
| Mean operation time ± SD, min. | 34.9 ± 18.6 | 45.5 ± 12.2 | 0.003** |
| Timing of first BCG ± SD, days | 17.4 ± 2.1 | 18.0 ± 1.9 | 0.153* |
*Independent sample t test
**Mann whitney U test
#Pearson chisquare test
&Fisher’s exact test
SD, standart deviation; BCG, Bacillus calmette guerin; SD, standart deviation; BMI, body mass index; WBC, white blood cell; HGB, Hemoglobine; PLT, platelet; PSA, Prostate specific antigen; IPSS, International prostatic symptom score
Statistically significant values shown as bold
BCG-related side effects included cystitis symptoms in 18 (78.2%) patients, epididymo-orchitis in 2 (8.6%) patients as local side effects, malaise and fever below 38.5 °C in 4 (17.3%) patients, and fever above 38.5 °C lasting longer than 48 h in 2 (8.6%) patients as systemic side effects. Twelve patients with local side effects had positive urine cultures. Two of the patients with systemic side effects had positive urine cultures. Side effects were observed during the induction phase of BCG therapy in 15 patients, within the first year in 5 patients, and after the first year in 6 patients. One patient discontinued treatment due to BCG-related cystitis symptoms, 2 patients due to epididymo-orchitis, and 2 patients due to fever lasting longer than 48 h. One of these patients developed a contracted bladder despite treatment, and radical cystectomy was planned. The clinical characteristics, treatment protocols, and follow-up data of patients with BCG-related side effects are summarized in Table 2.
Table 2.
BCG-related side effects, clinical management and follow-up characteristics
| BCG-related side effects | N (%) | Time of symptoms | Clinical management and treatment | Follow-up |
|---|---|---|---|---|
| Local | 20 (86.9) | |||
| Symptoms of cystitis | 18 (78.2) |
Induction period: 12 (66.6) Induction-1 year: 5 (27.7) Over 1 year: 1 (5.5) |
BCG treatment postponed. Urine culture performed. 11 patients’ urine cultures were positive. Quinolon and NSAİD were started. | 17 patient continues ıntravesical BCG treatment. 1 patient developed contracted bladder and underwent radical cystectomy. |
| Epididimo-orchitis | 2 (8.6) | Over 1 year: 2 (100.0) | BCG treatment stopped. Urine culture performed. 1 patient’s urine culture was positive. Quinolon and NSAİD were started. | Intravesical therapy was stopped. |
| Systemic | 6 (26.0) | |||
| Fever > 38.5 °C for > 48 h | 2 (8.6) | Induction period: 2 (100) | BCG treatment stopped. Urine culture, Chest X-ray and blood tests performed. 2 patients’ urine culture were positive. Meropenem was started with the recommendation of the infectious diseases specialist. | Intravesical therapy was stopped. |
| Malasia with fever < 38.5 °C for < 48 h | 4 (17.3) |
Induction period:1 (25.0) Over 1 year: 3 (75.0) |
BCG treatment postponed. Urine culture performed. NSAİD started. | Intravesical therapy continues. |
Univariate binary logistic regression analysis was conducted to assess the parameters predicting BCG-related side effects. In the univariate analysis, IPSS, tumor size, the presence of CIS, and WHO bladder tumor grade (LG, HG) were identified as significant predictive factors. Due to the small number of female patients, they were excluded from the multivariate analysis, which identified IPSS, tumor size, and the existence of CIS as independent risk factors for predicting BCG-related side effects (p < 0.05). Table 3 shows the results of binary logistic regression analysis.
Table 3.
To predict BCG related side effects, univariable and multivariable binary logistic regression analysis were performed
| Variable | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p value | OR | 95% CI | p value | |
| Age(yr) | 1.006 | 0.724-1.104 | 0.683 | |||
| Gender | 0.581 | 0.072-4.383 | 0.581 | |||
| BMI(kg/m2) | 1.005 | 0.374-2.702 | 0.992 | |||
| Smoking(mm) | 0.484 | 0.193-1.216 | 0.123 | |||
| WBC count(µ/L) | 1.003 | 0.796-1.263 | 0.981 | |||
| HGB level(g/dl) | 1.083 | 0.812-1.445 | 0.586 | |||
| PLT count(103 µ/L) | 1.000 | 0.993-1.006 | 0.903 | |||
| Creatinine value(mg/dL) | 1.064 | 0.099-5.047 | 0.730 | |||
| PSA value(ng/ml) | 0.700 | 0.518-1.554 | 0.898 | |||
| Prostate volume(ml) | 1.018 | 0.995-1.042 | 0.119 | |||
| IPSS | 1.359 | 1.197–1.542 | < 0.001 | 1.269 | 1.110–1.451 | < 0.001 |
| Tumor diameter(cm) | 2.708 | 1.709–4.291 | < 0.001 | 2.666 | 1.561–4.553 | < 0.001 |
| TNM classification(Ta-T1) | 1.377 | 0.544-3.476 | 0.495 | |||
| Carcinoma in situ | 6.500 | 1.982–21.320 | 0.002 | 5.271 | 1.165–23.839 | 0.031 |
| WHO grade (LG-HG) | 0.337 | 0.141–0.801 | 0.014 | 1.667 | 0.181-1.442 | 0.205 |
| Operation time(min.) | 1.023 | 0.994-1.047 | 0.057 | |||
| Timing of first BCG (days) | 1.012 | 0.802-1.119 | 0.672 | |||
OR, odds ratio; CI, confidence interval; BMI, body mass index; WBC, white blood cell; HGB, hemoglobine level; PLT, platelet count; PSA, prostate specific antigen; IPSS, International prostatic symptom score; LG, Low grade; HG, High grade; WHO, world health organization
Statistically significant values shown as bold
Discussion
Intravesical BCG therapy is a treatment modality recommended in the EAU 2024 guidelines, having been shown to be most effective treatment option in reducing both recurrence and progression in intermediate- and high-risk NMIBC [12]. However, this treatment modality carries the risk of local inflammatory reactions and even severe systemic infections, which can be life-threatening [13]. While the precise rate of side effects from intravesical BCG therapy is not thoroughly documented, the EAU 2024 guidelines suggest that severe adverse effects are reported in less than 5% of patients. In a cohort study conducted by Larsen et al., involving 15 years of patient data, the incidence of BCG-related side effects was reported to be 1%, with 78.4% of these being local genitourinary system-related [8]. Brausi et al. reported cystitis symptoms as the most common side effect, observed in 35% of cases following intravesical BCG therapy [9]. In our sample, the incidence of BCG-related side effects was 8.3%, with cystitis symptoms being the most frequently observed side effect, similar to other studies. Larsen et al.‘s retrospective cohort study only screened patients with ICD (International Statistical Classification of Diseases and Related Health Problems) codes, while Brausi et al. conducted a prospective multicenter study. The different designs of these studies and the varying rates of BCG-related side effects observed in our sample can be attributed to the differences in study designs.
Deterioration in bladder function following TUR-B, may be confused with BCG toxicity. Lower urinary tract symptoms are frequently observed after TUR-B, particularly following deep resections involving large areas. Reduced bladder capacity and impaired contractility are expected outcomes in such cases. Although this raises the question of whether lower urinary tract symptoms in symptomatic patients are related to BCG or TUR-B, the absence of large-based tumor resections in our sample that could have caused bladder dysfunction, along with symptom improvement after treatment, supported the evaluation of patients in terms of BCG toxicity. The lack of standardized definitions based on duration and symptoms in evaluating BCG toxicity highlights the necessity of further investigation and underscores the need for a classification system in this regard.
The most significant factor that puts clinicians in a dilemma regarding the application of intravesical BCG is the potential for serious systemic side effects. Systemic side effects can manifest in various clinical presentations, including malaise, fever, arthralgia, allergic reactions, and BCG sepsis, requiring long-term treatment [14]. Although the incidence of BCG-related sepsis is less than 1%, its potential to cause mortality has driven clinicians to seek preventive approaches [15]. The most commonly implemented protocol is to complete the treatment regimen with a one-third dose, which has been shown in literature studies to reduce BCG toxicity while preventing recurrence and progression similarly to the full-dose regimen [16–18]. However, the EORTC study suggests that dose reduction does not decrease toxicity and increases the risk of recurrence, particularly in the one-year treatment group [19]. Another approach involves the use of quinolone antibiotics in conjunction with intravesical BCG, which has been reported to reduce side effects, although it is not yet a standardized routine clinical prophylaxis [20]. Therefore, dose reduction or the addition of quinolones in patients at high risk for BCG-related side effects could be alternative approaches for clinicians.
Although there are limited studies investigating risk factors for BCG toxicity, age has been examined in a study by Oddens et al., which reported that 16.4% of patients over 75 years of age discontinued treatment due to BCG toxicity compared to 21.9% of those aged 60 and below [10]. In a study by Brausi et al. comparing BCG administration regimens, no significant findings were detected regarding BCG toxicity among groups based on dose and timing of administration [9]. In this study, side effects leading to discontinuation of treatment were predominantly observed in the first year. Similarly, in our study, intravesical BCG-related side effects were most frequently observed during the induction period of BCG therapy. Supporting the literature, fewer side effects were encountered after the first year of intravesical BCG therapy [21].
In the cohort analysis by Larsen et al., male gender was identified as a risk factor for BCG-related side effects, while age and comorbidity burden were not [8]. In our sample, gender was not a statistically significant factor for BCG-related side effects, which could be due to the limited number of female bladder cancer cases.
The IPSS, a widely used tool for evaluating benign prostatic hyperplasia (BPH), helps assess the severity of lower urinary tract symptoms and the effectiveness of BPH management [22]. Given that advanced age and male gender are risk factors for bladder cancer, BPH and LUTS are often encountered comorbidities in this patient group. Consequently, IPSS, which had not been previously evaluated as a parameter according to our literature review, emerged as an independent risk factor for the development of BCG-related side effects in male patients in our study.
Tumor diameter and the existence of CIS are crucial parameters for classifying patients with non-muscle invasive bladder cancer (NMIBC) into intermediate- and high-risk categories, as they indicate the extent and aggressiveness of the disease within the bladder and significantly influence treatment decisions [1]. We hypothesize that in patients with larger tumor sizes and CIS, the larger resected bladder mucosa area may increase the contact of intravesical BCG with the systemic circulation, potentially leading to more frequent side effects.
Despite the findings presented in our study, there are limitations. The small number of female cases limited the ability to evaluate gender as a significant factor. Due to the retrospective design, the timing of the first BCG dose was not available for all patients, and the small sample size is a primary limitation. Despite these limitations, our study contributes to current research on BCG toxicity, suggesting that parameters such as IPSS, tumor size, and the presence of CIS, which we identified as risk factors, should be considered by clinicians. In patients at high risk for BCG-related side effects, dose reduction or the addition of quinolone prophylaxis may help reduce the risk of BCG toxicity and provide valuable guidance to clinicians.
Conclusions
Intravesical BCG therapy, especially during the first year of treatment, is associated with BCG-related side effects. Independent risk factors for predicting these side effects include a high IPSS, larger tumor size, and accompanying CIS. Evaluating these factors in high-risk patients can help clinicians take preventive measures, such as the use of quinolones or dose reduction, without compromising the effectiveness of BCG therapy. Additional researches with larger sample sizes is necessary to validate these findings and develop more detailed guidelines for managing BCG toxicity.
Electronic supplementary material
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Abbreviations
- BCG
Bacillus Calmette Guerin
- NMIBC
Non-muscle invasive bladder cancer
- EAU
European Association of Urology
- TUR-B
Transurethral resection-bladder
- BMI
Body mass index
- PSA
Prostate specific antigen
- IPSS
International prostatic symptom score
- CIS
Carcinoma in situ
- SPSS
Statistical Package for the Social Sciences
- WBC
White Blood Cell
- HGB
Hemoglobine
- PLT
Platelet
- LG
Low grade
- HG
High grade
- ICD
International Statistical Classification of Diseases and Related Health Problems
- EORTC
European Organisation For Research And Treatment Of Cancer
- LUTS
Lower Urinary Tract Symptoms
Author contributions
TA, FC and AEC designed the study protocol. SOD and MA collected the data and did the statystical analysis. IK and AU revised the manuscript. All authors wrote and revised the main text.
Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was approved by the University of Health Sciences, Erzurum Medicine Faculty Scientific Research Ethics Committee. This study was conducted in accordance with the Declaration of Helsinki.
Consent for publication
Written informed consent was taken from all participants to participate in the study.
Clinical trial number
BAEK 2024/04–90.
Conflict of interest
All authors declare no potential conflict of interest with this publication.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6.
- 2.Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 2004;93(4):485–90. [DOI] [PubMed] [Google Scholar]
- 3.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-Guérin, and bacillus Calmette-Guérin plus Isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Böhle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol. 2003;169(1):90–5. [DOI] [PubMed] [Google Scholar]
- 5.Rousseau M, O’brien CJ, Antequera E, Zdimerova H, Cansever D, Canton T et al. Identification of sex differences in tumor-specific T cell infiltration in bladder tumor-bearing mice treated with BCG immunotherapy. 2020;6(4):507–24.
- 6.Grimm MO, van der Heijden AG, Colombel M, Muilwijk T, Martínez-Piñeiro L, Babjuk MM, et al. Treatment of High-grade Non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: results of the European association of urology research foundation randomised phase III clinical trial NIMBUS. Eur Urol. 2020;78(5):690–8. [DOI] [PubMed] [Google Scholar]
- 7.van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European organisation for research and treatment of Cancer Genito-Urinary group phase III trial. Eur Urol. 2003;44(4):429–34. [DOI] [PubMed] [Google Scholar]
- 8.Larsen ES, Nordholm AC, Lillebaek T, Holden IK, Johansen IS. The epidemiology of Bacille Calmette-Guérin infections after bladder instillation from 2002 through 2017: a nationwide retrospective cohort study. BJU Int. 2019;124(6):910–6. [DOI] [PubMed] [Google Scholar]
- 9.Brausi M, Oddens J, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG. Eur Urol. 2014;65(1):69–76. [DOI] [PubMed] [Google Scholar]
- 10.Oddens JR, Sylvester RJ, Brausi MA, Kirkels WJ, van de Beek C, van Andel G, et al. Increasing age is not associated with toxicity leading to discontinuation of treatment in patients with urothelial non-muscle-invasive bladder cancer randomised to receive 3 years of maintenance Bacille Calmette-Guérin: results from European organisation for research and treatment of Cancer Genito-Urinary group study 30911. BJU Int. 2016;118(3):423–8. [DOI] [PubMed] [Google Scholar]
- 11.Sylvester RJ, Rodríguez O, Hernández V, Turturica D, Bauerová L, Bruins HM, et al. European association of urology (EAU) prognostic factor risk groups for Non-muscle-invasive bladder Cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: an update from the EAU NMIBC guidelines panel. Eur Urol. 2021;79(4):480–8. [DOI] [PubMed] [Google Scholar]
- 12.Lobo N, Hensley PJ, Bree KK, Nogueras-Gonzalez GM, Navai N, Dinney CP, et al. Updated European association of urology (EAU) prognostic factor risk groups overestimate the risk of progression in patients with Non-muscle-invasive bladder Cancer treated with Bacillus Calmette-Guérin. Eur Urol Oncol. 2022;5(1):84–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Maintenance bacillus calmette-guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized southwest oncology group study, et al. J Urol. 2000;163(4):1124–9. [PubMed] [Google Scholar]
- 14.Witjes JA, Palou J, Soloway M, Lamm D, Brausi M, Spermon JR, et al. Clinical practice recommendations for the prevention and management of intravesical Therapy–Associated adverse events. Eur Urol Supplements. 2008;7(10):667–74. [Google Scholar]
- 15.Serretta V. BCG and bladder cancer. Forty-eight years after Morales report. Urologia. 2024:3915603241252909. [DOI] [PubMed]
- 16.Martínez-Piñeiro JA, Flores N, Isorna S, Solsona E, Sebastián JL, Pertusa C, et al. Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose of intravesical Bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int. 2002;89(7):671–80. [DOI] [PubMed] [Google Scholar]
- 17.Inman BA, Re. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol. 2006;175(5):1960. author reply– 1. [DOI] [PubMed] [Google Scholar]
- 18.Ojea A, Nogueira JL, Solsona E, Flores N, Gómez JM, Molina JR, et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol. 2007;52(5):1398–406. [DOI] [PubMed] [Google Scholar]
- 19.Oddens J, Brausi M, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63(3):462–72. [DOI] [PubMed] [Google Scholar]
- 20.Damiano R, De Sio M, Quarto G, Di Lorenzo G, Perdonà S, Palumbo IM, et al. Short-term administration of Prulifloxacin in patients with nonmuscle-invasive bladder cancer: an effective option for the prevention of bacillus Calmette-Guérin-induced toxicity? BJU Int. 2009;104(5):633–9. [DOI] [PubMed] [Google Scholar]
- 21.van der Meijden APM, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European organisation for research and treatment of Cancer Genito-Urinary group phase III trial. Eur Urol. 2003;44(4):429–34. [DOI] [PubMed] [Google Scholar]
- 22.Lee H, So S, Cho MC, Cho SY, Paick JS, Oh SJ. Clinical outcomes of holmium laser enucleation of the prostate: A large prospective registry-based patient cohort study under regular follow-up protocol. Invest Clin Urol. 2024;65(4):361–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.