Bacillus Calmette-Guérin Instillation Research Articles

Cumulative incidence of and risk factors for BCG infection after adjuvant BCG instillations.

To investigate the cumulative incidence proportion of disseminated or local Bacillus Calmette-Guérin (BCG) infections after adjuvant BCG instillations in patients with non-muscle-invasive bladder cancer (NMIBC). We analysed the timing and occurrence of BCG infections and absolute and relative risk in relation to patient characteristics available in the Swedish nationwide database 'BladderBaSe 2.0'. The cumulative incidence proportion of a BCG infection was indicated by a reported diagnosis of tuberculosis (TB) in the patient registry or filing a prescription for tuberculostatic drugs. The cumulative incidence proportion was 1.1% at the 5-year follow-up in 5033 patients exposed to adjuvant BCG instillations. The incidence rate was highest during the first 2 years after start of BCG instillations. Women had a lower risk than men (hazard ratio 0.23, 95% confidence interval 0.07-0.74). Age and calendar time at diagnosis, comorbidity, tumour risk group, previous medication with corticosteroids, immunosuppressive drugs, or time between transurethral resection of the bladder tumour and commencing the adjuvant BCG instillation were not associated with risk. These data further supports that the overall risk of a BCG infection after BCG-instillation treatment for NMIBC is low. The great majority of infections occur in the first 2 years, calling for an awareness of the diverse symptoms of BCG infection during this period. We provide evidence for male sex as a risk factor; however, the statistical precision is low and with a risk of selection bias, making it difficult to rule out the other suggested risk factors without further studies with different approaches.

Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin (BCG) with or without pembrolizumab for high-risk (HR) non–muscle-invasive bladder cancer (NMIBC) that persists/recurs after BCG induction.

TPS722 Background: Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032 .

BCG immunotherapy promotes tumor-derived T-cell activation through the FLT3/FLT3LG pathway in bladder cancer.

Bladder instillation therapy is a common treatment for superficial or nonmuscle invasive bladder cancer. After surgery or reresection, chemotherapy drugs (epirubicin) or medications such as Bacillus Calmette-Guérin (BCG) are used for bladder instillation therapy, which can reduce the risk of bladder cancer recurrence and progression. However, the specific mechanism by which BCG stimulates the antitumor response has not been thoroughly elucidated. Additionally, although BCG immunotherapy is effective, it is difficult to predict which patients will have a positive response. In this study, we explored the BCG-induced immune response and found that high levels of Fms-related receptor tyrosine kinase 3 ligand (FLT3LG) were expressed after BCG treatment. This FLT3LG can directly act on CD8+ T cells and promote their proliferation and activation. The use of FLT3 inhibitors can neutralize the antitumor effects of BCG. In vitro experiments showed that FLT3LG can synergize with T-cell receptor activators to promote the activation of tumor-derived T cells. This study partially elucidates the mechanism of CD8+ T-cell activation in BCG immunotherapy and provides a theoretical basis for optimizing BCG instillation therapy in bladder cancer.

Comparative Analysis of Very Reduced vs Full Dose BCG Treatment for High-Risk Non-Muscle Invasive Bladder Cancer: A Contemporary Experience from Chile

BACKGROUND: Adjuvant bacillus Calmette-Guérin (BCG) is recommended for high-risk (HR) non-muscle invasive bladder cancer (NMIBC), but BCG shortages have led to exploration of reduced-dose regimens and shortened maintenance durations out of necessity, with limited data on treatment efficacy in Latin America. OBJECTIVE: Oncological outcomes of HR-NMIBC patients treated with reduced (RD,1/4th dose) vs full dose (FD) BCG instillations of Danish Strain 1331 BCG. METHODS: We performed a retrospective study of HR-NMIBC patients treated with BCG between 2003 and 2022 at our center in Santiago Chile. We stratified patients according to either RD (1/4th dose) or FD BCG. Univariate and multivariable Cox regression models were used to predict recurrence. Kaplan-Meier method was used to calculate survival estimates. RESULTS: Of a total of 200 patients, 116 (58%) had RD and 84 (42%) FD BCG. Median follow-up was 57 months (IQR: 29–100). Patients who received FD BCG had a lower risk of recurrence (HR: 0.41, 95% CI 0.22–0.74) and high-grade (HG)-recurrence (HR: 0.30, 95% CI 0.15–0.61; p = 0.001). More patients in the RD vs FD group progressed to MIBC (10/84 vs 2/116; p = 0.18). Additionally, patients were less likely to stop BCG treatment in the RD group compared to the FD group due to toxicity (5% vs 11%, p = 0.14). CONCLUSIONS: A 1/4th dose of Danish Strain 1331 BCG treatment was associated with worse recurrence free rate and HG-recurrence rate in our cohort. Patients with RD had lower discontinuation treatment rates due to a reduced toxicity profile. These findings would suggest that RD BCG would compromise oncological outcomes in HR-NMIBC patients.

Comparison of hyperthermic intravesical chemotherapy and Bacillus Calmette-Guerin therapy in high-risk non-muscle invasive bladder cancer: a matched-pair analysis.

To compare adjuvant hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C and standard Bacillus Calmette-Guerin (BCG) therapy in terms of oncological outcomes and adverse events in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). The data of patients with high-risk papillary NMIBC treated with adjuvant intravesical BCG instillations or HIVEC in our institution between June 2017 and August 2022 were analyzed retrospectively. Twenty-four patients who received HIVEC were matched 1:1 with patients receiving BCG therapy based on tumor characteristics (tumor stage and grade), age, gender, smoking status, and the number of tumors (single or multiple). HIVEC and standard BCG treatments were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and adverse events. Forty-eight patients (24 in the BCG group and 24 in the HIVEC group) were included in the study. The median follow-up times of the BCG and HIVEC groups were 32 [interquartile range (IQR): 28.0-47.8] and 28 (IQR: 16.7-41.8) months, respectively (p = 0.11). There was no significant difference between the groups in terms of the 24-month RFS (BCG 83% vs HIVEC 88%, p = 0.64) and the 24-month PFS (BCG 100% vs HIVEC 94%, p = 0.61). Regarding the safety profile, at least one adverse event occurred in 13 (54%) of the patients in the BCG group and 12 (50.0%) of those in the HIVEC group (p = 0.77). This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC.

Quality of Life in Patients with High-grade Non-muscle-invasive Bladder Cancer Undergoing Standard Versus Reduced Frequency of Bacillus Calmette-Guérin Instillations: The EAU-RF NIMBUS Trial.

Adverse events induced by intravesical bacillus Calmette-Guérin (BCG) to treat high-grade non-muscle-invasive bladder cancer (NMIBC) often lead to treatment discontinuation. The EAU-RF NIMBUS trial found a reduced number of standard-dose BCG instillations to be inferior with the standard regimen. Nonetheless, it remains important to evaluate whether patients in the reduced BCG treatment arm had better quality of life (QoL) due to a possible reduction in toxicity or burden. To evaluate whether patients in the EAU-RF NIMBUS trial experienced better QoL after a reduced BCG instillation frequency. A total of 359 patients from 51 European sites were randomized to one of two treatment arms between December 2013 and July 2019. The standard frequency arm (n=182) was 6 weeks of BCG induction followed by 3 weeks of maintenance at months 3, 6, and 12. The reduced frequency arm (n=177) was BCG induction at weeks 1, 2, and 6, followed by maintenance instillations at weeks 1 and 3 of months 3, 6, and 12. Analyses were performed using an intention-to-treat analysis and a per-protocol analysis. QoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 version 3.0 (QLQ-C30 v.03) prior to the first and last instillations of each BCG cycle. Group differences were determined using linear regression corrected for QoL at baseline. Differences in QoL over time were tested for significance using a linear mixed model. Side effects were recorded by the treating physician using a standardized form. Chi-square tests were used to compare the side-effect frequency between the arms. There were no significant differences in the means of each QoL scale between the two arms. There were also no significant changes over time in all QoL domains for both arms. However, differences in the incidence of general malaise at T1 (before the last induction instillation), frequency, urgency, and dysuria at T7 (before the last maintenance instillation) were detected in favor of the reduced frequency arm. Reducing the BCG instillation frequency does not improve the QoL in NMIBC patients despite lower storage symptoms. In this study, we evaluated whether a reduction in the number of received bacillus Calmette-Guérin instillations led to better quality of life in patients with high-grade non-muscle-invasive bladder cancer. We found no difference in the quality of life between the standard and the reduced bacillus Calmette-Guérin instillation frequency. We conclude that reducing the number of instillations does not lead to better quality of life in patients with high-grade non-muscle-invasive bladder cancer.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Phase I/II randomized clinical trial of in-clinic acupuncture prior to BCG in patients with high-risk non-muscle invasive bladder cancer.

4590 Background: Acupuncture can reduce pain and urinary urgency and frequency. Treatment-related dose-limiting dysuria and irritative bladder symptoms are common in patients receiving intravesical Bacillus Calmette-Guerin (BCG) for the treatment of non muscle-invasive bladder cancer (NMIBC). We evaluated the feasibility, safety, and tolerability of weekly in-clinic pre-procedure acupuncture among patients receiving induction BCG. Methods: Patients with high-risk NMIBC undergoing induction BCG were randomized 2:1 to a standardized acupuncture protocol (Acu) or an attention waitlist control. Acu patients received acupuncture prior to each of 6 weekly BCG instillations. Feasibility was assessed via recruitment, retention, and intervention adherence. Acupuncture safety and tolerability were assessed via physician-reported CTCAE v5.0 and adverse events (AEs). Secondary endpoints included BCG treatment adherence, patient-reported BCG-related toxicity, and bladder cancer-specific and generic quality of life (QOL), assessed with the EORTC-QLQ-NMIBC-24 and -C30 surveys. Subjective assessments of acupuncture acceptability were assessed through patient exit surveys. Results: Between 1/21 and 7/22, 43 patients were randomized to Acu (n=28) vs. Control (n=15). Median age was 70.3 years and 76% were male. Week 7 follow-up surveys were completed by 93% of patients; 6 patients withdrew early due to disease progression, refractory gross hematuria, or for patient preference. Acupuncture was successfully delivered prior to each BCG treatment in Acu patients with no acupuncture-related AEs or interruptions to induction BCG. BCG-attributed AEs were reported by 91% Acu and 100% Control patients, including pain (28% vs. 43%, respectively, p=0.34) and urinary symptoms (62% vs. 79%, respectively, p=0.31). Comparing Acu with Controls, change in QOL over the study period demonstrated greater improvements in median urinary symptoms (9.5, IQR 0.0-19.0 vs. 0.0, IQR -14.3-7.1, p=0.02) and a trend towards improvement in median pain scores (16.7, IQR 0.0-16.7 vs. 8.3, IQR 0.0-33.3 p=0.68) among patients in the Acu arm. 96% of Acu patients reported that acupuncture was “very/extremely helpful” and 91% would recommend acupuncture to other patients. Conclusions: Acupuncture prior to induction BCG treatments is feasible and safe. In this Phase I/II trial, we observed reductions in pain and a trend towards improved urinary function scores over successive treatments among patients undergoing in-clinic pre-BCG instillation acupuncture. Patients receiving acupuncture reported high degrees of satisfaction with treatments. Future larger randomized controlled trials are needed to further characterize the efficacy of acupuncture with respect to pain, urinary symptoms and impact on QOL, and continuation of maintenance therapy during BCG treatment. Clinical trial information: NCT04496219 .

Topical instillation of BCG immunotherapy for biopsy-proven primary upper urinary tract carcinoma in situ: A single institution series and systematic review.

Primary upper tract carcinoma in situ (UTcis) is a rare disease whose diagnosis and natural history are poorly understood. Radical nephroureterectomy is the standard of care but in imperatives or selected cases, topical instillations of Bacillus Calmette-Guérin (BCG) may represent a good alternative. The aim of this study was to report the histologic response to BCG instillations for the treatment of biopsy-proven UTcis and to systematically assess the current evidence on topical BCG instillation for the treatment of UTcis. This is a retrospective analysis of patients with biopsy-proven UTcis treated with BCG instillation between 1995 and 2020 in an expert center. The initial diagnosis was performed by a standardized random biopsy scheme during ureterorenoscopy (URS) in patients with positive cytology but negative CT and bladder biopsies. BCG course consisted of 6 weekly instillation of 81 mg Immucyst (Sanofi Pasteur MSD AG, Baar, Switzerland). Administration techniques were single-J, double-J and nephrostomy tube. The primary outcome was the rate of complete histological response at the 3-month 2nd-look-URS. Kaplan-Meier analysis curves assessed recurrence- and progression-free survival. A total of 22 patients (23 renal units) were included. Twenty-one (91.3%) patients completed the planned 6-week instillation cycle. Only one major complication was recorded (renal tuberculosis). Twenty patients had a 3-month 2nd-look-URS, with a complete histological response achieved in 17/20 cases (85%). After a median time of follow-up of 40 months (30-62), 8/20 patients harbored disease recurrence, including 5 cases of disease progression (≥pT2). The main limitations are the retrospective and non-comparative design of the study. Our systematic review (CRD42022324876) identified 15 studies (289 renal units). UTcis suffers from the lack of a standardized definition, and considerable heterogeneity has been found in making the diagnosis and assessing the response to treatment. Our study is the first to propose a histological diagnosis of UTcis as well as a histological re-evaluation of the response to treatment. Topical instillations of BCG appear to be a promising alternative, avoiding radical treatment in the majority of cases.

Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Abstract 2127: TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation

Abstract Introduction: Bacillus Calmette-Guérin (BCG) is the standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) following transurethral resection. However, patients often have heterogeneous responses. Even among those who initially respond well to BCG, 10-20% relapse. Identification of reliable biomarkers predicting the efficacy of BCG remains an unmet need. En bloc resection is a novel technique representing a substantial advancement in the surgical management of NMIBC. We sought to investigate genomic and tumor microenvironmental (TME) profiles in NMIBC and explore potential predictive markers for BCG treatment following en-block resection. Methods: A total of 40 patients with high-risk NMIBC (cTis-T1N0M0) were retrospectively enrolled who underwent en bloc resection followed by BCG instillation. Surgical samples were subjected to NGS sequencing using a 520-gene panel (Burning Rock Biotech, Guangzhou) and multiplex immunofluorescence (mIF) assay. Results: The cohort had a median age of 63 years, and 80% were male. After a median follow-up of 21.8 months, 19/40 patients relapsed with a one-year relapse-free survival (RFS) rate of 57.5%. All tumors were microsatellite stable and showed a median TMB of 7.98muts/Mb. Genomic profiling revealed a high prevalence of alterations in TERT (55%), KDM6A (32.5%), KMT2D (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%), KMT2C (25%), and ARID1A (20%). TME analysis showed higher proportions of M1 macrophages and CD56 dim NK cells in the tumoral compartment and more intense infiltration of CD8+ T cells, exhausted CD8+T, CD56 bright NK cells, and M2 macrophages in the stromal compartment. Multivariate analysis identified TERT C228T mutation (HR=3.28 [95%CI:1.225-8.79], p=0.0181) and alteration in KDM6A (HR=2.94 [95%CI:1.040-8.29], p=0.042) as two independent factors associated with inferior RFS. Patients with concomitant TERT C228T and KDM6A alteration had the shortest RFS (median RFS:5.83months) compared with those who were free of (median RFS: NR) or harbored either one of the two alterations (median RFS:9.13months) (p=0.0022). We also found that tumoral infiltration of CD8+T cells was positively associated with RFS (HR=0.29 [95%CI:0.097-0.885], p=0.0208). Conclusion: The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment. Our findings may facilitate the stratification of patients and better guide the clinical decision-making on the management of NMIBC. Citation Format: Qi-Dong Xia, Yao-Bing Chen, Jian-Xuan Sun, Chen-Qian Liu, Jin-Zhou Xu, Zhi-Peng Yao, Ye An, Meng-Yao Xu, Si-Han Zhang, Xing-Yu Zhong, Na Zeng, Si-Yang Ma, Hao-Dong He, Heng-Long Hu, Jia Hu, Yi Lu, Lin Shao, Si-Qi Li, Zheng Liu, Shao-Gang Wang. TERT C228T and KDM6A alterations are potential predictive biomarkers in non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Guérin instillation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2127.

Manejo del carcinoma in situ de tramo urinario superior diagnosticado por biopsia ureteroscópica: ¿es el bacilo de Calmette-Guérin una alternativa a la nefroureterectomía?

IntroductionRadical nephroureterectomy (RNU) still represents the gold standard treatment for upper tract urothelial carcinoma (UTUC); however, since the 1980s attempts have been made to treat upper urinary tract CIS (UT-CIS) conservatively. The aim of this study was to compare the outcome of patients with primary UT-CIS treated in our center by means of RNU vs. bacillus Calmette-Guérin (BCG) instillations. MethodsThis retrospective study included patients with diagnosis of primary UT-CIS between 1990 and 2018. All patients had histological confirmation of UT-CIS in the absence of other concomitant UTUC. Histological confirmation was obtained by ureteroscopy with multiple biopsies. Patients were treated with RNU, distal ureterectomy, or BCG instillations. Clinicopathological features and outcomes were compared between the RNU and BCG groups. ResultsA total of 28 patients and 29 renal units (RUs) were included. Sixteen (57.1%) patients (17 RUs) received BCG. BCG was administered via a nephrostomy tube in 4 patients, a single-J ureteral stent in 5, and a Double-J stent in 7. Complete response and persistence or recurrence were detected in ten (58.8%) and seven (41.2%) RUs treated with BCG, respectively. Eight (27.6%) RUs underwent RNU, with contralateral recurrence detected in four (50%), and 4 (13.8%) RUs underwent distal ureterectomy. No differences were found in recurrence-free survival (p=0.841) and cancer-specific survival (p=0.77) between the RNU and BCG groups. ConclusionsAlthough RNU remains the gold standard treatment for UT-CIS, our results confirm that BCG instillations are also effective. Histological confirmation of UT-CIS is mandatory before any treatment.

MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023MP08-18 ASYMPTOMATIC BACTERIURIA DOES NOT INCREASE THE RISK OF INFECTIVE COMPLICATIONS IN PATIENTS WITH NON-MUSCLE-INVASIVE BLADDER CANCER UNDERGOING INTRAVESICAL BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY Antti Nummi, Pertti Nurminen, Olli Kesti, Mikael Högerman, Otto Ettala, Peter Boström, Antti Kaipia, Jukka Sairanen, and Riikka Järvinen Antti NummiAntti Nummi More articles by this author , Pertti NurminenPertti Nurminen More articles by this author , Olli KestiOlli Kesti More articles by this author , Mikael HögermanMikael Högerman More articles by this author , Otto EttalaOtto Ettala More articles by this author , Peter BoströmPeter Boström More articles by this author , Antti KaipiaAntti Kaipia More articles by this author , Jukka SairanenJukka Sairanen More articles by this author , and Riikka JärvinenRiikka Järvinen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003223.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Asymptomatic bacteriuria (ABU) is common in patients with non-muscle-invasive bladder cancer (NMIBC). Even though ABU is not considered as an absolute contraindication for bacillus Calmette-Guérin (BCG) administration, many urologists prefer sterile urine or use prophylactic antibiotics prior BCG instillation, aiming to prevent acute urinary tract infection (UTI), bacterial sepsis and BCG infection. However, the use of antibiotics may potentially lead to multidrug-resistant bacterial strains, while the clinical benefit is not clear. The aim of this study was to determine whether ABU increases the risk of infective complications and whether it is justified to screen asymptomatic patients for bacteriuria before BCG instillations. METHODS: We analyzed retrospectively patients who received ≥1 BCG instillations as treatment of NMIBC in our institutions during 2009-2018. Patients had submitted urine specimen 1-7 days prior every BCG instillation. Urine cultures were recorded as no growth or the presence of bacteriuria. ABU was classified as having any positive urine culture but no dysuria or fever. Antibiotic prophylaxis prior BCG administration was recorded. Our primary endpoints were admission to hospital because of UTI, BCG toxicity and BCG infections within 2 weeks of BCG instillation. RESULTS: We analyzed 802 patients and 12 882 BCG instillations. ABU was recorded with 2 200 (17%) instillations. Antibiotics were used in 519 (21%) instillations in bacteriuria group. Hospital admission was recorded after 8 (0.3%) and 37 (0.4%) instillations in the bacteriuria and in the no growth group, respectively (p=0.9). There was no significant difference in hospital admissions between the groups with or without antibiotic prophylaxis (p=0.4). CONCLUSIONS: BCG instillation with ABU is safe and does not increase the risk of developing a symptomatic UTI or severe BCG complications. By consequence, our results do not support routine screening of asymptomatic patients for bacteriuria prior intravesical BCG treatment. Antibiotic prophylaxis should only be used with consideration. Symptomatic UTI remains contraindication for BCG instillation. Source of Funding: Finnish Association of Urology © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e101 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Antti Nummi More articles by this author Pertti Nurminen More articles by this author Olli Kesti More articles by this author Mikael Högerman More articles by this author Otto Ettala More articles by this author Peter Boström More articles by this author Antti Kaipia More articles by this author Jukka Sairanen More articles by this author Riikka Järvinen More articles by this author Expand All Advertisement PDF downloadLoading ...

MP63-19 ADEQUATE VS INADEQUATE BCG INTRAVESICAL THERAPY IN INTERMEDIATE AND HIGH RISK NMIBC: TOTAL NUMBER OF INSTILLATIONS IS WHAT REALLY MATTERS

You have accessJournal of UrologyCME1 Apr 2023MP63-19 ADEQUATE VS INADEQUATE BCG INTRAVESICAL THERAPY IN INTERMEDIATE AND HIGH RISK NMIBC: TOTAL NUMBER OF INSTILLATIONS IS WHAT REALLY MATTERS Mario DE Angelis, Francesco Pellegrino, Mattia Longoni, Pietro Scilipoti, Chiara Re, Alessandro Bertini, Umberto Capitanio, Andrea Salonia, Giorgio Gandaglia, Riccardo Leni, Francesco Montorsi, Alberto Briganti, and Marco Moschini Mario DE AngelisMario DE Angelis More articles by this author , Francesco PellegrinoFrancesco Pellegrino More articles by this author , Mattia LongoniMattia Longoni More articles by this author , Pietro ScilipotiPietro Scilipoti More articles by this author , Chiara ReChiara Re More articles by this author , Alessandro BertiniAlessandro Bertini More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Riccardo LeniRiccardo Leni More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , and Marco MoschiniMarco Moschini More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) is currently recommended by EAU guidelines for proper treatment of patients with intermediate (IR) and high risk (HR) non-muscle invasive bladder cancer (NMIBC). We aimed to verify if complete adherence to BCG therapy relates to better oncological outcomes in terms of risk of recurrence and progression METHODS: We retrospectively identified 250 patients who underwent transurethral resection of bladder cancer between 2012 and 2022 at a tertiary referral centre. All these patients were diagnosed with IR or HR NMIBC and treated with BCG according to EAU guidelines. We evaluated if intravesical treatment was adequate, defined as at least 1 year of maintenance in IR patients and 3 years in HR patients. Multivariable analyses (MVA) tested the impact of number of instillations and therapy adequateness on recurrence and progression. Recurrence and progression were compared with the Kaplan-Meier (KM) analysis according to intravesical therapy adequateness RESULTS: 45 patients (18%) received adequate intravesical therapy according to their class of risk. Patients with adequate treatment received about triple the amount of instillations compared with inadequately treated ones (21 vs 9). Median FU was 42 months. In this period, 75 patients showed disease recurrence, 62 of which were treated inadequately (83%). Similarly, 93% of progressions concerned patients treated inadequately. At MVA, both total number of instillations and proper treatment were related with disease progression (HR 0.92, p=0.015 vs HR 0.22, p=0.041). Conversely, recurrence was only associated with total number of instillation (HR 0.95, p=0.019). KM analysis shows how at 2 years follow-up, progression free survival was higher in patients who received adequate treatment compared with those treat inadequately (96%vs 83%) CONCLUSIONS: A more intense BCG instillation regime is associated with lower risk of recurrence and progression of bladder cancer. In particular, a higher amount of instillations seems to be more related with tumor recurrence and progression. These results confirm the hypothesis that too often real life differ from guidelines, resulting in an actual undertreatment of these patients and the consequent worsening of the disease. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e879 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mario DE Angelis More articles by this author Francesco Pellegrino More articles by this author Mattia Longoni More articles by this author Pietro Scilipoti More articles by this author Chiara Re More articles by this author Alessandro Bertini More articles by this author Umberto Capitanio More articles by this author Andrea Salonia More articles by this author Giorgio Gandaglia More articles by this author Riccardo Leni More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Marco Moschini More articles by this author Expand All Advertisement PDF downloadLoading ...

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

Peritoneal and pulmonary tuberculosis following intravesical administration of Bacillus Calmette-Guérin for bladder cancer.

We report a rare case of peritoneal and pulmonary tuberculosis after intravesical instillation of Bacillus Calmette-Guérin (BCG). A 76-year-old man diagnosed as high-grade urothelial carcinoma (UC) with carcinoma in situ (CIS) was treated with intravesical BCG instillation and transurethral resection of bladder tumor (TUR-BT). Three months later, TUR-BT for recurrent tumors and multiple site biopsy of bladder mucosa were performed. During TUR-BT, near perforation in the posterior wall was observed, and was disappeared after observation with urethral catheterization for 1 week. Two weeks later, he was admitted with a complaint of abdominal distention, and a computed tomography (CT) showed ascites. One week later, CT showed pleural effusion and worsening of ascites. Drainage of pleural effusion and ascites puncture was performed, and elevated adenosine deaminase (ADA) and lymphocytes count were subsequently found. In laparoscopic examination, numerous white nodules were observed in the peritoneum and omentum, and Langhans giant cells were pathologically identified in biopsy specimens. Mycobacterium culture confirmed Mycobacterium tuberculosis complex. The patient was then diagnosed with pulmonary and peritoneal tuberculosis. Anti-tuberculous agents consisting of isoniazid (INH), rifampicin (RFP), and ethambutol (EB) were administered. Six months later, a CT scan showed no evidence of pleural effusion or ascites. There has been no recurrence of either urothelial cancer or tuberculosis during follow-up for 2 years.

Bladder Preservation With Transurethral Tumor Resection and Intravesical BCG Instillation in Superficial Muscle-Invasive Bladder Cancer: A 10-Year Follow-up

Purpose: The aim of this study was to evaluate the 10-year oncological outcomes of bladder preservation with transurethral resection of bladder tumor (TURBT) and intravesical bacillus Calmette-Guérin (BCG) instillation in selected patients with superficial muscle-invasive bladder cancer (MIBC).Materials and Methods: Patients diagnosed with superficial MIBC (stage T2a) by TURBT between 2001 and 2009 were included. Cystectomy-free survival, recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Cox regression analysis was used to identify predictors of each type of survival.Results: Of 145 patients, 135 underwent bladder preservation and 10 underwent immediate radical cystectomy (RC). Among the latter, 9 patients showed downstaging. During a median follow-up of 132 months (interquartile range, 96–161 months), 13 patients underwent RC, with a 10-year cystectomy-free survival rate of 83.9%. Seventy patients (48.3%) had recurrence, and the 10-year RFS rate was 48.9%. Progression occurred in 12 patients (8.3%), with a 10-year PFS rate of 90.1%. Death occurred only in patients who exhibited progression; 5 patients (3.4%) died of bladder cancer, and the 10-year CSS rate was 96.5%. Tumors greater than 3 cm were associated with RC, and a high tumor grade predicted recurrence. RC was related to progression and cancer-specific mortality.Conclusions: Although high-grade tumors require careful follow-up, bladder preservation with TURBT and intravesical BCG instillation can enable the successful management of selected patients with stage T2a MIBC less than 3 cm, without carcinoma in situ or tumor-associated hydronephrosis, in a nonmetastatic setting.

Intravesical instillation of bacillus Calmette-Guerin for non-muscle invasive bladder cancer: outcomes of 421 patients in a single center

To assess the therapeutic effect and adverse effect of intravesical instillation of bacillus Calmette-Guerin (BCG) for treatment of non-muscle invasive bladder cancer (NMIBC) and analyze the independent predictors of patient survival. We retrospectively collected the clinical data from 421 patients (mean age 61.79±11.51 years) with NMIBC, who received intravesical instillation of BCG after surgery in Sun Yat-sen University Cancer Center from September, 2015 to September, 2021. Recurrence-free survival (RFS), progression-free survival (PFS), and disease specific survival (DSS) of the patients were analyzed, and the adverse effects were assessed using Common Terminology Criteria for Adverse Events 5.0. Kaplan-Meier analysis, univariate and multivariate COX regression analyses were used to identify the independent predictors of the patients' survival outcomes. The median follow-up of the patients was 17 months, during which 88 (20.9%) patients experienced recurrence (median time to recurrence of 10 months, range 3-58 months); 40 (9.5%) patients showed tumor progression (median time to progression of 18 months, range 3-50 months); and 14 (3.3%) patients died (median survival time of 30 months, range 8-52 months). Adverse events of grade 1, 2, and 3 occurred in 69, 110, and 23 of the patients, respectively. Survival analysis indicated that an age below 67.5 years (P=0.013), first tumor onset (P < 0.001), solitary tumor (P= 0.010), time to recurrence over one year (P=0.042), low levels of neutrophils (P=0.005), monocytes (P=0.005) and neutrophil/lymphocyte ratio (NLR; P=0.014), and cytokeratin 19 fragment 21-1 (CyFra21-1; P=0.002) were all associated with a higher PFS rate. Multivariate COX analysis suggested that the time of tumor recurrence (P=0.007, HR=2.669, 95% CI: 1.316-5.414), monocyte counts (P=0.015, HR=0.376, 95% CI: 0.171-0.829), and serum CyFra21-1 level (P=0.002, HR=0.312, 95% CI: 0.151-0.647) were independent predictors of RFS; primary tumor or tumor relapse (P=0.003, HR=0.301, 95% CI: 0.138-0.660), neutrophil counts (P=0.028, HR=0.302, 95% CI: 0.103-0.882), and CyFra21-1 level (P=0.029, HR=0.358, 95% CI: 0.142-0.903) were independent predictors of PFS following BCG instillation. Intravesical instillation of BCG is effective for treatment of intermediate or high-risk NMIBC, and the adverse effects are tolerable in most cases. The time of tumor recurrence, monocyte counts, and serum CyFra21-1 level are independent predictors of RFS, and primary tumor or tumor relapse, neutrophil counts, and CyFra21-1 level are independent predictors of PFS.

Time to event following bacillus Calmette-Guerin therapy initiation in Medicare beneficiaries with intermediate- to high-risk non-muscle invasive bladder cancer, 2010-2019.

473 Background: For patients with intermediate- to high-risk non-muscle invasive bladder cancer (NMIBC), standard of care includes transurethral resection (TURBT) followed by induction and maintenance intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). This study describes characteristics and clinical outcomes of Medicare beneficiaries newly diagnosed with NMIBC who initiated BCG therapy following TURBT. Methods: Retrospective cohort study using Centers for Medicare and Medicaid-sourced Medicare Fee-for-Service medical/pharmacy claims (100% sample). Patient selection criteria: ≥1 bladder cancer diagnosis 2010-2019, no prior radiotherapy, systemic therapy, cystectomy, or metastasis in 6 months post-diagnosis, continuously enrolled in Medicare ≥12 months pre- and post-index (or death). Index date = date of first BCG instillation. A literature-based definition for adequate maintenance BCG defined adequate (≥7 instillations of BCG within 274 days of BCG initiation) and inadequate (remainder) BCG therapy for patient stratification. Events: time to BCG discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis. Provider access to BCG (due to supply shortage), patient tolerability, and NMIBC risk status are not captured in claims data. Results: Of 46,052 BCG-treated patients eligible for analysis, 19,859 (43.1%) received adequate BCG therapy. The two cohorts had similar baseline characteristics (Table) and median duration of follow up (46 months). Median (interquartile range [IQR]) time from NMIBC diagnosis to BCG initiation was 2.8 (8.2) months for adequate, 3.7 (14.4) months for inadequate BCG. Time from BCG initiation to discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis are reported in the table. Conclusions: Between 2010 and 2019, 57% of Medicare patients initiating BCG following diagnosis of NMIBC and TURBT may not have received adequate BCG therapy. Patients with inadequate BCG therapy had numerically shorter time to radical cystectomy, systemic therapy, radiation, and metastasis than those with adequate BCG therapy. Characteristics &amp; Outcomes by Cohort. [Table: see text]

Replacement Instead of Discontinuation of Bacillus Calmette-Guérin Instillation in Non-Muscle-Invasive Bladder Cancer

To evaluate the efficacy of intravesical chemotherapy replacement in patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), who underwent bacillus Calmette-Guérin (BCG) instillation but discontinued due to global shortages or toxicity of BCG. This retrospective study included patients with intermediate- and high-risk NMIBC who received BCG intravesical instillation. Those who discontinued the treatment were divided into the pure BCG group and chemotherapy replacement group. Comparisons between these groups were performed. The primary endpoint was bladder recurrence-free survival (RFS). A total of 480 patients were included. Baseline characteristics were similar between groups, but the total instillation times were higher in the chemotherapy replacement group than in the pure BCG group (n = 14.9 vs. 10.5). The chemotherapy replacement group had a better three-year RFS (p = 0.022). On multivariate analysis, the pure BCG group had significantly increased all-time and 3-year recurrences (hazard ratio 2.015 and 2.148) compared to the chemotherapy replacement group. Chemotherapy replacement has a better three-year RFS than no instillation in patients with intermediate- and high-risk NMIBC who received BCG instillation but facing treatment stoppage.