Smoke load prognostic impact on bacillus Calmette–Guérin (BCG) treated non-muscle invasive bladder cancer

International Urology and Nephrology - Smoking habit is the major risk factor for bladder cancer (BC), related to about 50% of these tumors; however, the tobacco dose–effect impact on BC...     

Role of immunotherapy in bacillus Calmette–Guérin-unresponsive non–muscle invasive bladder cancer

Intravesical instillation of live attenuated bacillus Calmette–Guérin (BCG) is the gold standard for patients with intermediate- and high-risk non–muscle-invasive bladder cancer (NMIBC). BCG-failures include a heterogenous population of patients who share a designation of disease recurrence or progression following BCG and include patients with complete unresponsiveness to BCG, patients who respond initially but develop relapse and, in some cases, patients who are intolerant to BCG due to side effects. Given the efficacy and relatively rapid approval of several monoclonal antibodies against PD-L1 or PD-1 for advanced and metastatic bladder cancer, the role of these checkpoint inhibitors in BCG-relapsing disease at various disease stages is under consideration. Data supporting a role for immune checkpoint inhibitors is largely theoretical with limited supportive data from animal models and from clinical evidence of increased PD-L1 expression in BCG-unresponsive tumors. Current trials in BCG-unresponsive disease are underway and expected to provide insight regarding these concepts.     

Can random bladder biopsies be eliminated after bacillus Calmette–Guérin therapy against carcinoma in situ?

Purpose

Intravesical bacillus Calmette–Guérin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy.

Methods

We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6–8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens.

Results

According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p?=?0.116, and p?<?0.001, respectively). The sensitivity (Sen.), specificity (Spe.), positive predictive value (PPV), and negative predictive value (NPV) of voiding cytology were 50%, 68%, 39%, and 77%, respectively. The values for cystoscopy findings were as follows: Sen.: 87%, Spe.: 57%, PPV: 46%, and NPV: 91%. The values for their combination (having either of them) were as follows: Sen.: 100%, Spe.: 44%, PPV: 43%, and NPV: 100%.

Conclusion

RBB after BCG therapy for patients with negative voiding cytology and negative cystoscopy may be omitted because their risk of BCG-unresponsive disease is significantly low (NPV: 100%).

     

Maintenance bacillus Calmette–Guérin therapy prolongs recurrence-free survival in non-muscle-invasive bladder cancer: A real-world experience

ObjectiveWe studied the benefit of bacillus Calmette–Guérin (BCG) maintenance therapy to determine the ideal maintenance therapy schedule.MethodsWe retrospectively reviewed non-muscle-invasive bladder cancer patients who underwent transurethral resection of bladder tumors and BCG instillation treatment at Chang-Gung Memorial Hospital, Linkou, Taiwan, from January 1997 to December 2009. All patients in the study had non-muscle-invasive urothelial carcinoma of the bladder or carcinoma in situ. We compared the recurrence-free rate of patients who received induction alone and with maintenance BCG therapy sessions. In addition, we analyzed the best number of maintenance therapy sessions that gave the lowest cancer recurrence.ResultsThis study included 427 patients with a mean age of 64 years. The median number of BCG treatments was 11, and the ratio of male to female was 3:1. Receiving an induction dose alone was a significant factor for tumor recurrence with a hazard ratio of 3.77. The recurrent risk rate of patient who received BCG therapy 13–15 times had lower recurrence rate than other groups.ConclusionA maintenance dose gave patients a significant benefit over those who just received induction therapy. BCG maintenance therapy worked best if given 13–15 times in our study.     

Cytological changes induced by intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer

To evaluate cytological changes of urothelial cells with intravesical instillation therapy of the bacillus Calmette-Guérin (BCG), cytological specimens of voided urine from patients with superficial bladder cancer (pTa and pT1) treated with intravesical BCG therapy were examined. The following three groups of patients who had no evidence of recurrence more than 2 years after the treatment were studied: groups 1 and 2, patients who were treated with BCG (n = 22) and epirubicin, a derivative of doxorubicin (n = 22), respectively, for prophylaxis of intravesical recurrence after transurethral resection (TUR); and group 3, patients receiving no intravesical therapy after TUR (n = 12). Sixteen cytological characteristics were studied before and after the treatment in each group. In group 1 patients translucent nuclei and prominent nucleoli, vacuolization of cytoplasm, and eosinophilic cytoplasmic inclusions were frequently observed in urothelial cells as well as an increase in granulocytes, especially within 3 months after BCG instillation therapy. In group 2 patients an increased nuclear/cytoplasmic ratio, hyperchromatic nuclei and prominent nucleoli of urothelial cells were transiently found within 1-2 months after intravesical epirubicin therapy. In group 3, translucent nuclei and prominent nucleoli of urothelial cells were found within 1-2 months after TUR. In conclusion, cytological changes induced by BCG therapy are nonspecific and reactive in nature, different from those due to chemotherapeutic agents and distinguishable from malignant changes of urothelial cells.     

Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer

OBJECTIVES: To examine in a prospective study the incidence of recurrence and progression in patients with Stage T1 bladder carcinoma after complete transurethral resection of the bladder tumor and adjuvant immunotherapy with bacillus Calmette-Guérin (BCG). METHODS: Between July 1987 and April 1999, 126 patients presenting to our clinic with a superficial urothelial carcinoma of the bladder (Stage pT1, grade 1-3) received adjuvant intravesical immunotherapy with BCG after complete transurethral resection of the bladder tumor. In the case of recurrence of superficial tumor (pTa, pT1, or carcinoma in situ), patients received a second cycle of BCG. For muscle-invasive tumor progression (pT2, pT3, or pT4), radical cystectomy was recommended. Six of the patients (5%) presented with Stage pT1,G1 tumor, 74 (59%) with Stage pT1,G2 tumor, and 46 patients (36%) with Stage pT1,G3 tumor. Median follow-up was 53 months (range 3 to 144). RESULTS: One hundred eight patients (86%) remained tumor-free with a retained bladder during the follow-up after one or two 6-week cycles of BCG. Twenty-four patients (19%) had a recurrence of superficial tumor, 13 (10%) had muscle-invasive progression after the first BCG cycle, and an additional 4 (3%) had progression after the second BCG cycle. Six patients (5%) underwent radical cystectomy, and 9 patients (7%) died as a result of tumor progression. The tumor-free survival rate of all patients was 89% (112 of 126). CONCLUSIONS: Adjuvant immunotherapy with BCG after complete transurethral resection of the bladder tumor represents a highly effective primary treatment for Stage T1 carcinoma of the bladder. Even in Stage pT1,G3 tumor, immediate radical cystectomy does not appear necessary.     

Histopathologic and molecular comparative analyses of intravesical Aurora kinase-A inhibitor Alisertib with bacillus Calmette–Guérin on precancerous lesions of bladder in a rat model

Purpose

Recent studies have shown that Aurora-A expression is associated with bladder cancer initiation and progression. In this study, the effects of intravesical Aurora-A inhibitor Alisertib (ALS) and bacillus Calmette–Guérin (BCG) were compared on bladder carcinogenesis.

Methods

Two mg N-Methyl-N-nitrosourea was administered intravesically to forty of Wistar-albino rats every other week for 8 weeks. At week 10, rats were divided into four groups (10/group): No-treatment (vehicle), ALS-alone, BCG-alone, and ALS?+?BCG. The intravesical treatment of ALS, BCG, and ALS plus BCG was performed once a week for 6 weeks. At week 16, bladders were collected for immunohistopathological and Western blot analysis. The cell cycle regulators p53, p21, Aurora-A, phosphorylated Aurora-A (p-Aurora-A), and apoptotic marker cleavage of poly [ADP-ribose] polymerase (c-PARP) were determined by Western blot.

Results

Histopathologically relatively healthy urothelium was observed in ALS?+?BCG group (87.5%) compared to the ALS-alone (50%) and the BCG-alone (50%) groups. The lowest expression of p21 and p53 was detected in the BCG-alone, while the highest level of expression was evident in no-treatment group. The ALS treatment alone caused a slight decrease in Aurora-A while there was a dramatic decrease in p-Aurora-A in comparison to no-treatment group. In overall combined treatment with ALS?+?BCG significantly increased c-PARP compared to all mono-treatments, and decreased all cell cycle parameters compared to no-treatment group.

Conclusions

Although intravesical ALS treatment has similar antiproliferative effects like BCG, ALS?+?BCG combined treatment led to a best histopathologic and apoptotic response. Consequently, BCG combined with Aurora-A inhibition may provide a new intravesical treatment modality in the prevention of bladder carcinogenesis.

     

Increased urinary albumin indicating urothelial leakage following intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer

Summary This study on the increase in albumin in the urine of patients with superficial bladder cancer after intravesical bacillus Calmette-Guérin (BCG) treatment was initiated on the basis of two facts. First, extravasation of serum albumin could be expected as a result of the BCG-induced delayed-type hypersensitivity reaction in the bladder wall. Second, appearance of albumin in the urine was a possibility as cytokines also appear in the urine, although probably after being produced suburothelially by infiltrating leukocytes. Albumin and the cytokines interleukin (IL) 1, IL2, IL6, and tumor necrosis factor alpha (TNF) were determined in urine from 20 patients treated with 6 weekly intravesical BCG instillations, collected prior to each instillation and 2, 4, 6, 8, 12, and 24h thereafter. The mean concentration of albumin in pre-therapy specimens was 112±118 (range 2–432) g albumin/ml urine, approximating 14±14 g/ mol creatinine (creat) (n=15), which was comparable to the mean pre-instillation value of 16±32 g/mol creat (n=96). A significant increase in urinary albumin during the 6 weeks of BCG treatment was observed (P<0.001). However, a large variation existed between individual patients and in some patients no reaction was seen. Maximum albumin concentrations were observed after instillations 3–6. A significant correlation between albumin and concentration of the cytokines IL1, IL2, IL6, and TNF was found (P<0.01), correlation coefficients (r) being 0.56, 0.56, 0.67, and 0.71 (n=418), respectively. During the first 24h after instillation cytokines and albumin peaked in the following order: TNFIL2albuminIL6IL1. TNF peaked most frequently after 2–4h and IL1 after 6h, while IL2, albumin, and IL6 peaked between these time points. In conclusion, the presence of albumin in urine indicates a leakiness of the bladder wall after repeated BCG instillations. Since albumin was shown to be stable in urine and the assay is relatively simple and cheap, it may be performed in most hospitals. This will allow largescale investigations of the correlation between elevation of urinary albumin and (tumor) response on BCG therapy.     

Upper tract urothelial carcinoma following intravesical bacillus Calmette-Guérin therapy for nonmuscle-invasive bladder cancer: Results from a multi-institutional retrospective study

Objectives

The aim of this study was to clarify the prognostic indicators for upper tract urothelial carcinoma (UTUC) following intravesical bacillus Calmette-Guérin (BCG) therapy for nonmuscle-invasive bladder cancer (NMIBC).

Urinary fibronectin levels in patients treated with intravesical bacillus Calmette-Guérin for superficial bladder cancer

Intravesical bacillus Calmette-Guérin (BCG) has been shown to be an effective treatment for superficial transitional cell carcinoma (TCC) of the bladder, but the precise mechanism of action of BCG remains poorly understood. Fibronectin (FN), an important component of the extracellular matrix, has been found to play a role in BCG therapy. Some studies have shown that the soluble form of FN can compete efficiently with the matrix form of binding to the specific receptors on the bacteria and could consequently diminish the effect of BCG treatment. To evaluate a possible correlation between the urinary levels of FN and the efficacy of BCG therapy, we determined prospectively the urinary FN levels in 38 patients with TCC of the bladder and in 25 control subjects without malignancy matched for age and sex. All TCC patients were treated with transurethral tumor resection plus 6 weekly intravesical BCG instillations. After an average follow-up of 30 months, 8 patients (21.1%) had recurrent tumors, while 30 (78.9%) were free of tumor after intravesical BCG therapy. Urinary levels of FN in cancer patients have been shown to be significantly higher than controls (p < 0.001). These elevated levels were not decreased significantly after the operation (p > 0. 05). It was also found that the mean urinary FN levels were not statistically significant between patients with recurrence and complete remission. The data suggest that BCG-bladder tumor cell binding is not influenced by soluble fibronectin and urinary FN may not be a ideal marker for selecting patients to BCG therapy.     

Analysis of sex-based differences to Bacillus Calmette-Guérin for non-muscle invasive bladder cancer

Objective: To evaluate whether differences exist between men and women in response to intravesical BCG treatments. The incidence of urothelial carcinoma of the bladder is lower in women but they tend to present with more aggressive and advanced disease. Some prior studies also suggest there are sex-based differences in response to treatment for non-muscle invasive bladder tumors.Methods: In this retrospective study, we reviewed all consecutive patients who received BCG at the CHU de Québec – Laval University from 2009–2019. Men and women were treated with intravesical BCG therapy following pathologic confirmation of urothelial carcinoma. Outcomes evaluated include recurrence, progression, and treatment tolerability. Recurrence was defined as a pathology confirmed cancer whereas progression was the new development of high-grade (recurrence) pathology or an increase of stage. Tolerability was defined according to the proportion of prescribed BCG received. All clinical details were obtained through review of the medical records, collaborated by pharmacy records for BCG administration. Competing-risk analysis was used to compare outcomes.Results: Among 613 patients who received BCG at our institution between 2009–2019, 472 (77.0%) were men and 141 (23.0%) were women. The recurrence rate was not different between sexes, with a 5-year recurrence risk of 52% (95% CI: 36.93–65.4) among women compared to 57.5% (CI 95%: 51.9–62.6) among men. The overall non-progression rate at 1,3 and 5 years was 97.3% (95% CI: 95.6%–98.3%), 93.6% (95% CI: 91.2%–95.4%), and 91.7% (95% CI: 88.4%–94.1%), respectively. The completion of ≥5 induction BCG instillations and maintenance BCG use was similar in both genders.Conclusions: We report a contemporary NMIBC cohort treated with BCG and find no clear evidence for sex-based differences in response to BCG treatment in regard of progression, recurrence, and tolerability.     

A case of tuberculous epididymitis after Bacillus Calmette-Guérin intravesical instillation therapy for bladder cancer

A 65-year-old male had undergone transurethral resection of bladder tumor (TUR-Bt) four times for recurrent bladder cancer, and each histopathological examination revealed non-invasive urothelial carcinoma, pTa, G2. To prevent further recurrence, he received eight weekly intravesical instillations of Bacillus Calmette-Guérin (BCG). Four months after the BCG therapy, he underwent cystoscopy. One week after the cystoscopy, he developed a painful and swollen left scrotum. Treatment with levofloxacin for acute epididymitis reduced the scrotal pain initially, but the pain increased and 3 months later, a fistula with suppurative discharge appeared at the bottom of the scrotum. A smear of the discharge revealed Gaffky 2, and a culture showed tubercle bacillus. Incisional drainage of the abscess and anti-tuberculosis chemotherapy for 2 months to treat tuberculous epididymitis was not completely effective. We performed a left orchiectomy with resection of the infected scrotal skin. Histopathological examination showed tuberculous epididymitis consisting of a caseating granuloma with epithelioid cells and Langhans giant cells. He received anti-tuberculosis chemotherapy for 4 months postoperatively and had no sign of recurrence 1 year postoperatively.     

Evaluation of multiple recurrence events in superficial bladder cancer patients treated with intravesical bacillus Calmette-Guérin therapy using the Andersen-Gill's model

To evaluate factors affecting recurrenceafter intravesical bacillus Calmette-Guérin(BCG) therapy (Tokyo 172 strain), we revieweddata for 101 patients with superficial bladdercancer (pTa [n = 80] and pT1 [n = 21]) treatedbetween 1985 and 1999. The median follow-upperiod was 58.9 months. Factors affecting thefirst tumour recurrence were evaluated usingCox's proportional hazards model and thoseaffecting multiple recurrence withAndersen-Gill's model. The 5-yearrecurrence-free rate was 63% for all 101patients. The recurrence frequency, defined astimes per 100 patient-months of follow-up,greatly decreased from 7.3 ± 9.6 (SD) beforethe instillation to 2.6 ± 5.6 after thetherapy (p < 0.0001). Patients with pT1tumours tended to have earlier recurrence thanthose with pTa tumours (p = 0.06). Multivariateanalysis using Cox's proportional hazards modelrevealed that a history of bladder cancer andpathological stage were independent factorsaffecting the first tumour recurrence after theBCG therapy. When multiple endpoints ofrecurrence were evaluated using theAndersen-Gill's model, number of tumours aswell as a history of bladder cancer andpathological stage demonstrated significantlinks to tumour recurrence after the BCGtherapy. The 5-year progression-free and 5-yearsurvival rates were 89.3% and 85.3% for allthe 101 patients, respectively. Becauseintravesical recurrence may involve multipleevents during the clinical course of patientswith bladder cancer, the Andersen-Gill's modelappears useful for evaluation of riskfactors.     

Isolated renal tuberculosis following intravesical Bacillus Calmette-Guérin therapy for bladder cancer

We present a case of isolated renal tuberculosis following bacillus Calmette-Guérin (BCG) therapy for bladder cancer. In the presurgical radiographic examination, we suspected an atypical renal cell carcinoma. According to the diagnosis of renal cell carcinoma, we performed a radical nephrectomy. The histological findings were tuberculosis-specific inflammatory changes and the patient received an antituberculous multiple drug therapy for a year. It is concluded that we should pay attention to the possibility of a renal tuberculosis granuloma in any patient who presented with subacute formed renal masses following BCG treatment before deciding on the strategy of the treatment of the renal masses, especially in patients who had received such a treatment which induced an immunocompromised state.