Bacillus Calmette-Guérin Instillation Research Articles

A retrospective study on tolerability and complications of bacillus Calmette-Guérin (BCG) instillations for non-muscle-invasive bladder cancer

Objectives: The objective was to evaluate the tolerability of BCG treatment and to evaluate the effects of interruption on treatment outcomes. The incidence and characteristics of severe complications were observed.Methods: From hospital records, all bladder carcinoma patients treated with BCG instillations in the institution from 2009–2015 were retrospectively identified. The reasons for interruption, treatment outcome, number of instillations, and diagnosis of BCG infection were recorded.Results: Of the 418 patients who started BCG instillation therapy, 176 (42.1%) interrupted BCG treatment. Of those, 23 (5.5%) patients interrupted because of suspected BCG infection. Systemic BCG infection was found in seven (1.7%), and local infection in five (1.2%) patients. Interruption of treatment was due to other adverse effects in 71 patients (17.0%), BCG failure in 46 patients (11.0%), and other reasons in 36 patients (8.6%). Fifty percent of interruptions due to adverse effects occurred within the first 6 months. The probabilities of tumor recurrence (20.0% vs 10.7%, p = 0.014, OR = 2.077, CI95% = 1.149–3.753) and disease progression (5.4% vs 1.2%, p = 0.018, OR = 4.534, CI95% = 1.152–17.840) were higher among patients whose BCG treatment was interrupted.Conclusions: Severe complications were encountered in only <5% of patients. Adverse effects requiring treatment interruption were more likely to happen within the first year of treatment. Interrupting BCG treatment due to adverse effects increased the risk of disease progression and tumor recurrence.

Intravesical Ty21a Vaccine Promotes Dendritic Cells and T Cell-Mediated Tumor Regression in the MB49 Bladder Cancer Model.

Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC). Here, we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor regression toward the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By IHC and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective doses of Ty21a. Flow-cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.

Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer.

Because of its proven efficacy, intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is an important treatment for nonmuscle invasive bladder cancer at high risk of recurrence or progression. However, approximately 8% of patients have to stop BCG instillation as a result of its complications. Complications induced by BCG therapy can have a variety of clinical manifestations. These adverse reactions may occur in conjunction with BCG instillation or may not develop until months or years after BCG cessation. An essential step in the management complications arising from BCG is early establishment of diagnosis, particularly for distant, disseminated, and obscure infections. Therefore we reviewed the literature on the potential complications after intravesical BCG immunotherapy for bladder cancer and provide an overview on the incidence, diagnosis, and treatment modality of genitourinary and systemic BCG-induced complications.

Keynote-676: Phase 3 study of bacillus calmette-guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction.

TPS502 Background: Intravesical instillation of BCG is the standard of care for patients with HR NMIBC. However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for progression, representing a significant unmet need. Programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment may attenuate responses to BCG. KEYNOTE-676 is a randomized, comparator-controlled, phase 3 trial to evaluate the efficacy and safety of the PD-1 inhibitor pembro plus BCG in patients with persistent/recurrent HR NMIBC after BCG therapy. Methods: Adult (≥18 years) patients with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy are eligible. Patients are required to have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks prior to randomization, to have no concurrent extravesical disease, and to have ECOG performance status score 0-2, adequate organ function, and tissue for biomarker analysis. Patients will be randomly assigned 1:1 to continue on BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment will be stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Primary end point is complete response rate in participants with CIS. Secondary end points will include event-free survival, patient-reported outcomes, and safety. Responses will be assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until pathology-confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Recruitment will begin November 2018 and will continue until ~550 patients are enrolled. (NCT03711032). Clinical trial information: NCT03711032.

Association of the commensal urinary microbiome with response to Bacillus Calmette-Guérin (BCG) immunotherapy in nonmuscle invasive bladder cancer.

423 Background: Standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical BCG. Despite its established efficacy, up to 50% of patients may recur. The development of predictive biomarkers for BCG immunotherapy would enhance treatment algorithms and potentially uncover mechanisms of resistance. Recent data have characterized the presence of a commensal urine microbiome, but its role in BCG-treated NMIBC patients remains unexplored. We assessed the composition of the urine microbiome in NMIBC patients and evaluated associations with response to therapy. Methods: Patients with a newly diagnosed bladder tumor were enrolled prior to TURBT on an institutional review board-approved study at a single institution. Adjuvant BCG instillation was administrated to high-risk patients according to the surgical histology. Urine samples for microbiome assessment were collected by catheterization to eliminate urethral contamination before the TURBT and up to 8 additional timepoints. 16S sequencing and analysis was performed on baseline specimens prior to BCG. Results: Among 31 patients enrolled, 10 (32%) recurred and 21 (68%) had no recurrence with a median follow up of 6 months. Median age was 69 years (range 46-87), and 9 (29%) patients were female and 22 patients (71%) were male. The most abundant phyla observed were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. Together these accounted for &gt; 99% of the phyla detected in the cohort. Global analysis of distances by operational taxonomic units (OTUs) indicated a significant difference between patients with and without recurrence (Bonferroni-corrected P = 0.017). The abundance of Proteobacteria was higher in patients with recurrence (P = 0.035), with stronger differences observed for specific classes such as Gammaproteobacteria (P = 0.0025). Firmicutes such as Lactobacillales were more abundant in patients without recurrence (P = 0.049). Conclusions: In this study we detected variation in the composition of the urine microbiome in NMIBC patients, which may predict response to BCG immunotherapy. Further studies to confirm these results are ongoing.

Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG).

350 Background: The PD-1 inhibitor pembro has durable antitumor activity in pts with metastatic urothelial carcinoma. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting pembro may benefit. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study; updated results for pts with carcinoma in situ (CIS) with or without papillary tumor (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts with HR NMIBC or progressive disease during treatment were required to discontinue. Primary end point: complete response rate (CRR); key secondary end points: duration of response and safety. Results: 103 pts (median age 73 years; CIS alone 71.8%; median number of prior BCG instillations 12) have enrolled in cohort A. 3-mo CRR rate was 38.8% (95% CI 29.4%-48.9%) by central assessment. Among 40 pts who achieved CR at 3 mo, 72.5% maintained CR at last follow-up (median 14.0 mo; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ mo). 80.2% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). 10 (25.0%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle invasive or metastatic disease. Treatment-related adverse events (AEs) occurred in 65 (63.1%) pts; most frequent were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.6%) pts; 1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.4%) pts. Conclusions: Pembro had encouraging activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial. Clinical trial information: NCT02625961.

Bladder health in patients treated with BCG instillations for T1G2-G3 bladder cancer – a follow-up five years after the start of treatment

Objective: Investigate symptoms and how they affect daily life in patients with Non-Muscle Invasive Bladder Cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) instillations.Materials and methods: Patients treated with BCG were included. After an initial transurethral resection (TURB) followed by a second-look resection, the patients were given an induction course with BCG for 6 weeks followed by maintenance therapy for 2 years. The patients answered a questionnaire before, during and after the treatment. The questionnaire contained questions about specific symptoms combined with bother questions on how each symptom affected patients’ life.Results: In total, 113 of 116 patients responded to the first questionnaire. Thirty per cent of all patients were bothered by disease-specific symptoms before the start of BCG. Few patients reported fever, haematuria, illness or urinary tract symptoms. No difference in symptoms was found between patients with or without concomitant CIS (carcinoma in situ). Patients younger than 65 years of age reported a greater worry about the symptom burden in the future than those who were older. Patients younger than 65 years reported a decreased level of mental well-being.Conclusion: Patients with bladder cancer T1G2–G3 had disease-specific symptoms present already before the start of the BCG. The burden of symptoms was reduced over time and showed that the bladder might recover. BCG instillations had side-effects that negatively affected the patient’s well-being. It is important to record the patients’ baseline bladder and voiding status before as well as during the BCG-instillation period in order to understand symptoms caused by the treatment.

What to do during Bacillus Calmette-Guérin shortage? Valid strategies based on evidence.

Over the last decade, the world has experienced health-threatening supply shortages of Bacillus Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). We summarize the current literature to assist in treatment decisions in light of suboptimal supply. Currently available data do not support a superiority of one BCG strain over the other. Intravesical chemotherapy seems to provide similar results in term of disease progression but not recurrence in intermediate-risk patients. One trial has shown that a 3-year maintenance course of BCG in high-risk NMIBC has no advantage in term of progression or overall survival in comparison with 1-year maintenance. Synergo radiofrequency-induced hyperthermia is a reliable alternative in intermediate or high-risk NMIBC with at least similar recurrence rates compared with BCG. Patients with intermediate-risk NMIBC can be offered multiple instillations of intravesical chemotherapy for up to 12 months. In high-risk patients and in case of BCG shortage, BCG instillations can be terminated when the patient has completed 1 year of maintenance. Mitomycin C is an alternative in lowest risk high-risk (G3Ta) NMIBC, whereas patients with pT1/carcinoma in situ can be offered Synergo with mitomycin C when radical cystectomy is not feasible. Immediate radical cystectomy should always be considered in highest risk NMIBC after weighing up benefit to risk.

Intravesical Radiofrequency-Induced Chemohyperthermia for Carcinoma in Situ of the Urinary Bladder: A Retrospective Multicentre Study.

Objective:To examine the effect of intravesical radiofrequency-induced chemohyperthermia (RF-CHT) in carcinoma in-situ (CIS) patients overall and split according to previously received therapy.Methods:CIS patients that underwent an induction and maintenance phase of≥6 RF-CHT instillations, and had either pathology or cystoscopy plus cytology available at 6 months of follow-up were retrospectively included. Complete response (CR), recurrences, cystectomy-free rate, overall survival (OS), and adverse events were evaluated. Analysis was performed for overall, bacillus Calmette-Guérin (BCG)-unresponsive, other BCG-treated, and treatment naïve patients.Results:Patients (n = 150) had a mean of 17.5, 9.2, or 0 previous BCG instillations in the BCG-unresponsive (n = 50), other BCG-treated (n = 46, missing n = 4), and treatment naïve groups (n = 47, missing n = 3), respectively. After 6 months, a CR of 46.0%, 71.7%, and 83.0% was found (p < 0.001). Subsequent 2-year recurrence rates were 17.4%, 27.3%, and 12.8%, respectively. The overall cystectomy-free rate and OS at mean follow-up (35.8 months) were 78.5% and 78.0%, respectively. These were 71.4% vs. 84.1% vs. 86.7% (cystectomy-free rate, p = 0.006) and 76.0% vs. 69.6% vs. 87.2% (OS, p = 0.06) for BCG-unresponsive vs. other BCG-treated vs. treatment naïve patients. Progression to muscle-invasive disease was seen in 13.3% of patients. Patients stopped induction or maintenance RF-CHT instillations due to adverse events in respectively 13.4% and 17.8%.Conclusions:Intravesical RF-CHT showed good results in both treatment naïve and BCG-treated CIS patients, avoiding the need for cystectomy in 78.5% of cases for at least 3 years with a modest risk of progression. Thus, RF-CHT proves an alternative to cystectomy in selected high-risk patients.

The Optimal Timing of Restaging Resection before Introduction of Bacillus Calmette-Guerin Immunotherapy in Patients with High-Risk Non-Muscle-Invasive Bladder Cancer

Introduction: The study aimed to analyze the influence of restaging transurethral resection of bladder tumor (reTURB) timing on outcomes in patients receiving Bacillus Calmette-Guerin (BCG) immunotherapy. Material and Methods: This retrospective study enrolled 491 patients with bladder cancer receiving BCG intravesical therapy between 1998 and 2016. All patients were followed up for at least 12 months and received at least 7 BCG instillations. The patients were analyzed in terms of recurrence free, progression free, and cancer specific survival (CSS). Results: Median follow-up was 57 months (12–257 months). The risk for all analyzed clinical events was higher in patients who underwent reTURB after 6 weeks from primary TURB. After the change point of 57 days after primary resection, further delay was not associated with increased risk of recurrence and progression. The time limit for CSS was 76 days. With every 1 more day of time interval between TURB and reTURB, the risk of each clinical event in follow-up increased by 4%. Conclusions: There is no benefit of the reTURB performed after 8 weeks from primary TURB. Optimal timing of reTURB is from 2 to 6 weeks after initial TURB. However, even within this time frame, the sooner the procedure is performed, the risk of recurrence, progression, or cancer-specific death is lower.

Intramuscular Immunization Induces Antigen-specific Antibodies in Urine

Towards the development of vaccines against urinary tract infections (UTI), we determined the ability of intramuscular (i.m.) immunization to result in antigen-specific antibodies in urine. As a model antigen/vaccine, levels of total and vaccine-specific antibodies were determined in urine as a spin-out study of a phase 1 trial. Non–muscle-invasive bladder cancer (NMIBC) patients at different risks of progression, undergoing intravesical bacillus Calmette-Guérin (BCG) immunotherapy or not, received an adjuvanted recombinant protein vaccine that resulted in high titers of vaccine-specific serum immunoglobulin G (IgG) in all patients, regardless of the risk group. Vaccine-specific IgG and immunoglobulin A (IgA) were detected in urine of half of the patients at low risk of progression NMIBC and in all the intermediary/high- (int/high) risk patients. Vaccine-specific IgG titers were correlated to total urinary IgG levels, the latter being higher in the int/high-risk patients. In contrast, vaccine-specific IgA did not correlate to urinary IgA levels. Furthermore, vaccine-specific antibodies were transiently increased by intravesical BCG instillations. Altogether, our data show that a standard i.m. immunization can effectively induce antigen-specific antibodies in urine, which, upon selection of optimal vaccine targets, may provide protection against UTI. Vaccine-specific IgG titers were dependent on conditions affecting total urinary IgG levels, while production of vaccine-specific IgA in situ might independently contribute to protection against infections in the bladder. Patient summaryTowards the development of vaccines able to protect against urinary tract infections, we examined the potential of the intramuscular vaccination using a model antigen. We found two types of specific antibodies in the urine, which together may locally contribute to protection against infections, thus supporting the use of such a standard immunization route.

Conventional and PD-L1-expressing Regulatory T Cells are Enriched During BCG Therapy and may Limit its Efficacy

The regulation of immune responses occurring during Bacillus Calmette-Guerin (BCG) therapy need to be better scrutinized in order to identify new targetable pathways for non-muscle invasive bladder cancer treatment. Immunoregulatory mechanisms have emerged as key players in various cancers. While T lymphocytes are crucial for the control of tumor growth, they often include regulatory subsets known to restrain their anti-tumor activity. In this prospective study, we assessed conventional regulatory T cells (cTregs) and PD-L1-expressing CD4 T cells (PD-L1+ Tregs) levels in blood and urine of urothelial cancer (UCa) patients undergoing BCG treatment. Local cTregs were found at higher frequencies than their counterpart in the periphery and induced by bladder tumor cells in vitro. Interestingly, while circulating PD-L1+ Tregs were hardly detectable in the blood of healthy donors and UCa patients, substantial levels were found in patients’ urine. In vitro experiments suggested that BCG infection of urothelial cells could induce PD-L1+ Tregs, partially via an interferon-β-mediated mechanism. Of note, high level of Tregs in urine was associated with rapid recurrence following BCG therapy. Our findings demonstrate that T lymphocytes recruited during BCG therapy encompass a significant fraction of regulatory cells including a non-classical source of PD-L1 and reinforce treatment strategies combining BCG with PD-1/PD-L1 checkpoint inhibitors as promising approaches for non-muscle invasive bladder cancer. Patient summaryWe investigated the presence of particular immune cell types in the urine of bladder cancer patients undergoing Bacillus Calmette-Guerin (BCG) therapy. We identified a cell type that is strongly enriched in the urine after BCG instillation and that may favor tumor recurrence. This immune subpopulation might be targeted for bladder cancer treatment.

Bacillus Calmette-Guérin may have clinical benefit for glandular or squamous differentiation in non-muscle invasive bladder cancer patients: retrospective multicenter study

To clarify the efficacy of intravesical Bacillus Calmette-Guérin (BCG) instillation for non-muscle invasive bladder (NMIBC) cancer with variant histology, especially glandular differentiation or squamous differentiation. From May 1991 through June 2016, 53 patients were diagnosed retrospectively as having NMIBC with variant histology. Among these patients, 47 NMIBC patients with squamous differentiation or glandular differentiation were analyzed for this study. The median follow-up interval from diagnosis of NMIBC with variant histology was 28.9 months (1.5-168.8). Of these patients, 38 (80.9%) and 9 (19.1%) were diagnosed as having glandular differentiation and squamous differentiation, respectively. Radical cystectomy was conducted for six (12.8%) immediately after the diagnosis of NMIBC with variant histology. Of the 41 patients with bladder preservation, 20 (48.8%), 3 (7.3%), 3 (7.3%) and 15 (36.6%) underwent BCG, THP, MMC and no additional treatment, respectively. There were significant differences between BCG and other treatments or no additional treatment for recurrence (P = 0.034), progression (P = 0.004) and cancer-specific survival (P = 0.014). Overall, our results show that intravesical BCG instillation for variant histology in NMIBC leads to a better prognosis with regard to progression and cause-specific survival than other intravesical treatments or no additional treatment. BCG treatment may also have a clinical benefit for variant histology in non-muscle invasive bladder cancer patients.

Priming with percutaneous bacillus Calmette-Guerin (BCG) prior to intravesical BCG treatment safely improves BCG-specific response in patients with bladder cancer

Abstract Bacillus Calmette-Guérin (BCG) is the gold standard immunologic agent for patients with high-grade non-muscle invasive bladder cancer (NMIBC). Nevertheless, responses to BCG are heterogeneous and limited options exist when BCG therapy fails. Preclinical data in animal models of bladder cancer (BC) suggests that priming with percutaneous BCG vaccine prior to intravesical BCG instillation can enhance BCG-specific immunity and improve outcome. To study the safety, immunogenicity and preliminary efficacy of this approach, we administered percutaneous BCG 21 days prior to intravesical BCG instillation in “prime patients” with NMIBC (n=13) in a prospective single-arm clinical trial. Immune responses and clinical outcomes were monitored and compared to a contemporaneous cohort of “control patients” (n=9) receiving intravesical BCG without prior percutaneous BCG. Priming was well tolerated and no grade ≥3 adverse events were observed. Compared to control, prime patients had improvement in both local and systemic measures of BCG-specific immunity, scored by increased post-BCG urinary IL-8 and IL-17A and increased circulating CD4, CD8, and γδ T cell proliferation and effector function in response to BCG. Furthermore, ex vivo cytotoxicity of circulating NK and γδ T cells against RT4 BC was significantly increased in prime patient after BCG treatment and was mediated in part by NKG2D, suggesting an important role of innate effector immune mechanisms underlying BCG’s antitumor activity. Remarkably, no prime patients progressed whereas 3 out of 9 control patients progressed to muscle-invasive disease and underwent cystectomy. Thus, BCG priming safely enhances BCG-specific immunity and could improve outcome for patients with NMIBC.

Clinical Role of Programmed Cell Death-1 Expression in Patients with Non-muscle-invasive Bladder Cancer Recurring After Initial Bacillus Calmette–Guérin Therapy

The programmed cell death-1 (PD-1) pathway has been suggested to play an important role in tumor immune escape. We evaluated changes in PD-1 expression before and after Bacillus Calmette-Guérin (BCG) therapy and its prognostic significance in non-muscle-invasive bladder cancer (NMIBC) patients. We examined 78 paired tissue samples of NMIBC in tumors just before BCG therapy and BCG-relapsing tumors, defined as recurrence after achieving disease-free status by initial BCG instillations for 6months. We counted PD-1-positive cells, and PD-1 expression was defined as high when the number of PD-1-positive cells was more than 18 under ×200 magnification. The median number of PD-1-positive cells in tumors just before BCG therapy was 3.5, significantly lower than that in BCG-relapsing tumors (17.0, p < 0.001). High PD-1 expression was observed in 20 tumors just before BCG therapy (25.6%) and 36 BCG-relapsing tumors (46.2%). Fifty-two cases (66.6%) showed an increase in the number of PD-1-positive cells in BCG-relapsing tumors. High PD-1 expression in BCG-relapsing tumors was independently associated with subsequent tumor recurrence (p = 0.011) and stage progression (p = 0.033). The 5-year recurrence-free and progression-free survival rates were 40.7 and 74.1% in patients with high PD-1 expression in BCG-relapsing tumors, significantly lower than those in their counterparts (72.9 and 94.1%, respectively). PD-1 was induced by BCG therapy, and its expression in BCG-relapsing tumors may be an important indicator for predicting worse clinical outcomes in NMIBC patients treated with BCG therapy.

Optimizing Diagnosis of Urothelial Bladder Cancer with Blue Light Cystoscopy via Recognition of False-Positive Lesions.

Introduction: Blue light cystoscopy (BLC) using hexaminolevulinate (Cysview®) improves the detection of nonmuscle invasive bladder cancer (NMIBC).1–3 BLC results in lower recurrence rate and a better recurrence-free survival, as well as a progression benefit.4 However, false-positive (FP) fluorescence can occur for various reasons and can vary among different series. Studies have shown that FP rates are not significantly different from white light (WL) cystoscopy. We evaluated different scenarios producing FP in BLC.Methods: Under institutional review board approval, we prospectively enrolled consecutive patients undergoing transurethral resection of bladder lesions into a BLC registry between April 2014 and December 2016. Several cases are highlighted in the video demonstrating cystoscopic view under WL and blue light in specific circumstances increasing the chance of detecting an FP lesion.Results: BLC with Cysview is demonstrated in several challenging cases for the detection of NMIBC. Possible FP scenarios include tangential views of the bladder neck or side walls (1) trigone, trabeculations, or diverticula; (2) in setting of inflammation like cystitis; (3) postintravesical therapy, that is, <6 weeks interval from prior bacillus Calmette-Guérin (BCG); (4) prior resection within 6 weeks; (5) bright tiny spots; and (6) site of ureterectomy/bladder cuff resection, early fading lesions (after irrigation). Unnecessary biopsy of these lesions can be avoided through simple techniques such as changing the angle of the cystoscopic view, several rounds of irrigation, and avoiding BLC too early after BCG instillation or prior resection.Conclusions: Use of BLC with Cysview can help with the detection of NMIBC as well as carcinoma in situ in patients undergoing transurethral resection of bladder tumor for bladder cancer. The reported FP rates of BLC will decrease with experience and recognition of the mentioned scenarios.Prior presentation: None.No competing financial interests exist.Runtime of video: 7 mins 16 secs

PD66-11 HYPERTHERMIC INTRAVESICAL CHEMOTHERAPY FOR BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Non-invasive III1 Apr 2018PD66-11 HYPERTHERMIC INTRAVESICAL CHEMOTHERAPY FOR BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER Joep de Jong, Kees Hendricksen, Marloes Rosier, Joost Boormans, and Hugh Mostafid Joep de JongJoep de Jong More articles by this author , Kees HendricksenKees Hendricksen More articles by this author , Marloes RosierMarloes Rosier More articles by this author , Joost BoormansJoost Boormans More articles by this author , and Hugh MostafidHugh Mostafid More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.3007AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Adjuvant intravesical instillations with bacillus Calmette-Guerin (BCG) is the recommended treatment option for patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC). Despite adequate BCG treatment, a large proportion of patients experiences a recurrence. Although radical cystectomy is the Gold Standard for BCG-unresponsive NMIBC, a number of patients are unfit for or unwilling to consider this option. The optimal therapy in such cases is unknown. The objective of the present study was to assess the efficacy of hyperthermic intravesical chemotherapy (HIVEC®) in BCG-unresponsive intermediate and high-risk NMIBC patients. METHODS From October 2014 to July 2017 NMIBC patients who were defined BCG-unresponsive (recurrence of high-grade disease after having had a minimum of 5/6 induction and 2/3 maintenance BCG instillations) were prospectively included at three academic institutions. All patients were planned to receive HIVEC® treatment, consisting of an induction phase followed by maintenance therapy. Only patients who had a minimum of 5 HIVEC® instillations were included in the present analysis. Patients were followed by cystoscopy and cytology every three months and a CT-scan yearly. The primary outcome was the recurrence-free survival (RFS). The Common Terminology Criteria for Adverse Events (CTCAE) was used to assess side-effects. RESULTS The study population consisted of 59 BCG-unresponsive NMIBC patients (8% intermediate- and 92% high risk) of whom 55 underwent ≥5 HIVEC® treatments. Histology was urothelial carcinoma in all patients and T-stage was pTis in 31, pTa in 10, pT1 in 9, pT1+CIS in 3 and pTa+CIS in two patients. The median age and follow-up was 72 years and 9.0 months [IQR 7.1 - 19.5]. The overall recurrence rate was 58% and the mean RFS was 16.6 months [SE 2.1] (Fig.1). In patients having carcinoma in situ (n= 36), the recurrence rate was also 58% and the mean RFS was 16.2 months [SE 2.8]. Progression occurred in 3 patients and two patients experienced severe side-effects (CTCAE >2). CONCLUSIONS HIVEC® seems a valid treatment option for BCG-unresponsive intermediate- or high-risk NMIBC patients. We report a mean RFS of >1 year, potentially avoiding or postponing the need for radical surgery in these patients. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1234-e1235 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Joep de Jong More articles by this author Kees Hendricksen More articles by this author Marloes Rosier More articles by this author Joost Boormans More articles by this author Hugh Mostafid More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The role of neural precursor cell-expressed developmentally down-regulated protein 9 in predicting bacillus Calmette-Guerin response in nonmuscle invasive bladder cancer

ObjectiveTo report the sensitivity and specificity of neural precursor cell-expressed developmentally down-regulated protein 9 (NEDD9) protein high expression in predicting BCG response and its effect on recurrence or progression free survivals. Patients and methodsBetween May 2014 and April 2017, a prospective cohort study was conducted on 105 patients with intermediate or high-risk nonmuscle invasive bladder cancer. Immunohistochemical staining with mouse monoclonal anti-NEDD9 antibody was done. Examination of the slides was done to detect NEDD9 cytoplasmic expression. Intravesical induction bacillus Calmette-Guerin (BCG) instillation therapy was started for all patients 2 to 4 weeks after endoscopy with once weekly instillation for 6 weeks. Intravesical maintenance BCG instillation was then continued every 3 months for at least 1 year. Follow up with cystoscopy every 3 months for 2 years and every 6 months after that. ResultsThe mean age ± SD of the patients was 57 ± 4.5 years. The median follow-up period was 25 (12–36) months. NEDD9 protein was highly expressed in 61 (58.1%) patients, whereas low expression was in 44 (41.9%) patients. Sensitivity and specificity of NEDD9 high expression in predicting recurrence were 83.6% and 64.2%, respectively. Its sensitivity and specificity in predicting progression to muscle invasion or distant metastases were 91.3% and 51.2%, respectively. Its sensitivity and specificity in predicting complete response to BCG therapy were 84.1% and 80.9%. Kaplan-Meier test showed highly significant difference (P<0.0001) in survival without recurrence or progression between patients showing high expression and those showing low expression. ConclusionNEDD9 protein tissue marker could be used as a predictive marker for BCG response in nonmuscle invasive bladder cancer with reasonable sensitivity and specificity.

Prevention of topic toxicity of BCG with single-dose prulifloxacin. Preliminary results of a randomized pilot study

Toxicity is a major problem for patients undergoing intravesical therapy with Bacillus Calmette-Guérin (BCG) for the conservative management of intermediate or high-risk non-muscle invasive bladder cancer (NMI-BC). A prospective pilot trial was designed to evaluate the adoption of a single dose of prulifloxacin to prevent the toxicity of BCG. Treatment tolerability and its possible influence on BCG efficacy have been analyzed. The study was designed to evaluate the action of prulifloxacin in patients with intermediate or high-risk NMI-BC, undergoing 6-week induction cycle of BCG. Main exclusion criteria were previous intravesical therapy, urinary infection and any other factor that could influence tolerability to BCG intravesical immunotherapy. The patients were randomized to receive BCG alone versus BCG plus prulifloxacin. BCG toxicity and local tolerability were evaluated by self-administered EORTC QLQ-BLS24 questionnaire, and BCG adverse events (AEs) were classified according a four-class classification. The toxicity and tolerability evaluations were performed at baseline, one week after every instillation and one week and one month after the last instillation. Cystoscopy and cytology were performed 3-monthly. Recurrence and progression were recorded. The study included 43 patients receiving 258 instillations of BCG. The patients were randomized to receive BCG alone (Arm A: 132 instillations in 22 patients) versus BCG plus prulifloxacin given as a single oral dose (600 mg) 6 hours after the instillation. An advantage in favor of prulifloxacin prophylaxis emerged, according to EORTC QLQ-BLS24, in overall incidence of nocturnal micturitions (56% vs 28.6%; p=0.001), insomnia (40% vs 14.3%; p=0.002), urgency (70% vs 42.6%; p=0.05), incontinence (44% vs 12.7%; p=0.01) and bothersome events due to intravesical therapy (84% vs 63.5%; p=0.02). Systemic class IIB and III adverse events occurred in only 14.2% and 3.5% of the patients, respectively. No class IV AE was detected. Due to the low incidence no statistically significant difference was evident between the two arms (p=0.6). Three patients of Arm B and 1 patient of Arm A interrupted the treatment, after the 3rd - 4th instillation. Anti-tuberculosis therapy war required for 3 months in only one patient. Three and 2 instillations were postponed for one-(two) week(s) in Arm B and Arm A, respectively. Prulifloxacin, generally well tolerated, was withdrawn in one patient due to skin allergic reaction. Recurrence rate at a mean follow-up of 12 months did not significantly differ between the two arms. Prulifloxacin decreases the incidence of local symptoms and improves the compliance to BCG intravesical therapy. Due to the low number of events, no evidence emerges in our study about its capability of preventing severe systemic toxicity, although it has proved effective in reducing local symptoms.

Optimal duration and dosage of BCG intravesical immunotherapy: A free final time optimal control approach

In this paper, we propose a free final time optimal control approach applied to 4 ordinary differential equations which describe the tumor‐immune interactions after the injection of the bacillus Calmette‐Guérin (BCG) in the bladder of a hypothetical patient. The main goal of this optimal control strategy is to find the optimal dosage amount needed in each instillation of BCG for stimulating the immune‐system and then killing superficial bladder tumors and to determine the optimal duration of treatment, adequate for stopping the intravesical therapy with lesser side‐effects. For this, we introduce into the model of interest, a control function which represents the dose of BCG immunotherapy procedure and we formulate a minimization problem where the final time is considered free (nonfixed). The characterization of the sought optimal control noted u∗ is derived based on Pontryagin's maximum principle, while the formulation of the sought optimal final time noted is based on formulae of sensitivity which are obtained conditions from the derivative of the objective function with respect to . We investigate the resolution of the free final time optimal control problem in 3 possible cases: (a) when is quadratic in the final gain function, (b) when the final gain function does not depend on , and (c) when is linear in the final gain function. Finally, we obtain the sought optimal dose of BCG, and we conclude that in case (a), we obtain an optimal duration which is more beneficial regarding the activation of immune cells while cases (b) and (c) both provide an optimal duration which is more adequate for the minimization of the tumoral population.