Efficacy of bacillus Calmette‐Guérin in the treatment of superficial bladder cancer: The impact of previous intravesical treatment

Objective: To clinically evaluate the role of intravesical bacillus Calmette‐Guérin (BCG) in the management of superficial bladder cancer, focusing on dose, age, high grade/stage, and pretreatment episodes with other therapies in long‐term follow‐up patients. Methods: A total of 213 patients with superficial (Ta‐T1) transitional cell carcinoma of the bladder received 6–8 weekly instillations of 40, 60 or 80 mg of Tokyo strain BCG. Further 6–8 monthly applications were given in some cases. Results: Recurrence‐free and progression‐free survival rates were compared with reference to dose, age, previous treatment, grade, stage, and high risk categories. Overall recurrence‐free rates for 3, 5, and 10 years were 70.8%, 67.1%, and 57.6%, with progression‐free survival rates of 94.5%, 93.6%, 90.6%, respectively. In univariate analyses, younger cases demonstrated higher recurrence‐free survival rates, but without statistical significance (P = 0.1229). Recurrence‐free rates were significantly higher for cases without previous intravesical treatment (P = 0.0010). There was no significant BCG dose‐dependence. High grade and high stage patients were confirmed as having higher recurrence and progression rates. Conclusions: Intravesical instillation of BCG is the most effective in the long term when chosen as the initial prophylactic therapy for the prevention of recurrence in superficial bladder cancer.     

Intravesical bacillus Calmette–Guérin instillation in non‐muscle‐invasive bladder cancer: A review

Intravesical bacillus Calmette–Guérin has been the standard of care for high‐risk non‐muscle‐invasive bladder cancer for 40 years. It remains one of the most successful immunotherapies ever used. Bacillus Calmette–Guérin shows superior efficacy to alternative intravesical treatments, and has an established role in reducing both recurrence and progression in non‐muscle‐invasive bladder cancer. It remains relatively safe, and has acceptable tolerability of both local and systemic side‐effects. The present review provides insights into the role of bacillus Calmette–Guérin compared with alternative treatments both in primary and refractory settings.     

Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette‐Guérin

Study Type – Diagnosis (case series) Level of Evidence 4

OBJECTIVE

To determine if hexylaminolaevulinate fluorescence cystoscopy (HAL‐FC) has the potential to improve the diagnosis of bladder cancer in patients who have been treated with bacille Calmette‐Guérin (BCG).

PATIENTS AND METHODS

Patients scheduled for rigid cystoscopy after BCG therapy were recruited prospectively between April 2005 and February 2006. Patients received HAL (Hexvix^TM, PhotoCure ASA, Oslo, Norway) and the D‐light system (Storz, Tuttlingen, Germany) was used to detect fluorescence. The bladder was mapped and biopsies taken under white light and then using HAL‐FC. The main outcome was the frequency and nature of additional pathology detected by HAL‐FC. Twenty‐seven patients (21 men and six women; median age 70 years, range 49–82) underwent 32 HAL‐FC.

RESULTS

Recurrent bladder cancer was detected in 11 of the 32 (34%) examinations. HAL‐FC detected additional pathology in five of the 27 (19%) patients. In two of these cases the additional pathology was clinically significant (one pT4G3 intraprostatic transitional cell carcinoma and one intravesical pT1G2 + carcinoma in situ), whereas in three cases the pathology was hyperplasia/dysplasia. Overall, the false‐positive biopsy rate with HAL‐FC was 63%. In the presence of positive voided urine cytology six of eight patients had recurrent bladder tumour and the false‐positive biopsy rate was only 34%. Urine cytology was positive in four of five of the patients in whom additional pathology was detected by HAL‐FC.

CONCLUSIONS

Clinically significant occult pathology can be detected using HAL‐FC after BCG therapy, but in <10% of cases. The rate of false‐positive biopsies is high but in our hands appears to be lower than with white‐light guided biopsies after BCG. Our pragmatic approach is to use HAL‐FC after BCG when clinical suspicion is high, and when the preoperative voided urine cytology is positive.     

Bacillus Calmette–Guérin treatment of non‐muscle invasive bladder cancer

Bacillus Calmette–Guérin (BCG) has been used in the intravesical treatment of non‐muscle invasive bladder cancer (NMIBC) for nearly 35 years; however, its use is still subject to controversy. The objective of this paper is to review the role of BCG in the treatment of patients with NMIBC. Clinical trials, meta‐analyses and guidelines related to the administration, safety and efficacy of intravesical BCG were reviewed. Intravesical BCG is more effective than intravesical chemotherapy in decreasing the risk of recurrence and progression to muscle invasive disease; however, it is associated with more local and systemic side‐effects. It is the gold standard in patients at high risk of progression. Maintenance BCG is required in order to achieve the best therapeutic results; however, the optimal dose, induction and maintenance schedules, and duration of treatment are unknown and might be different for each patient. Patients failing BCG treatment have a poor prognosis, and cystectomy is then the recommended treatment. Patients at low risk of recurrence and progression should not receive BCG, because of its side effects. Intermediate‐risk patients might be treated with either intravesical chemotherapy or BCG; however, for patients at high risk of progression, BCG is recognized as the treatment of choice. Further research is urgently needed to identify markers associated with BCG failure and to develop effective alternatives to cystectomy in patients failing BCG.     

Clinical outcomes of bacillus Calmette-Guérin instillation therapy for carcinoma in situ of urinary bladder

Objectives:   We analyzed the clinical outcomes of instillation therapy with Bacillus Calmette-Guerin (BCG) to treat carcinoma in situ (CIS) and searched for prognostic factors that could predict disease progression.
Methods:   Between January 1995 and January 2001, 185 patients (male, 155; female, 30) diagnosed with bladder CIS underwent weekly BCG instillations (80 mg of Tokyo 172 strain) for eight weeks. Primary, concomitant, and secondary CIS was found in 62 (33.5%), 60 (32.4%) and 63 (34.1%), patients, respectively. Seventy-five (40.5%) and 64 (34.6%) patients had limited and extensive CIS, respectively. The median follow up period was 37.5 months (range 4–95 months).
Results:   The overall complete response rate was 86.5%. The five-year progression-free survival rate was 78.5%. Several factors, such as age (<60 or ≥60 years), gender, previous transurethral resection, type of CIS, and CIS extension (three or more positive sites out of four to six biopsy sites was defined as extensive), were examined by multivariate analysis to predict progression. The extension of CIS was the only independent prognostic factor. The five-year recurrence-free rate of complete responders ( n  = 160) was 66.0%. Radical cystectomy was performed in 10 patients (6.3%) during follow up incomplete responders, of whom seven had invasive bladder cancer. Extravesical involvement was identified in 30 patients (16.2%) among whom, 21 (11.3%) had upper urinary tract recurrence and nine (4.9%) had prostatic involvement.
Conclusion:   Therapy with BCG is effective against CIS, the extent of which might be a prognostic factor. Disease progression including extravesical involvement should be carefully monitored over the long-term after BCG therapy.     

Adverse drug reactions of intravesical bacillus Calmette–Guérin instillation and risk factors of the development of adverse drug reactions in superficial cancer and carcinoma in situ of the bladder

BACKGROUND: We examined the incidence and severity of adverse drug reactions following intravesical bacillus Calmette-Guerin (BCG) instillation for superficial bladder cancer including carcinoma in situ. We investigated the relationship between adverse drug reactions and patient background to clarify risk factors for the development of adverse drug reactions. METHODS: A total of 123 patients who underwent intravesical BCG instillation for treatment and prophylaxis between April 1997 and June 2000 were included in this study. Adverse drug reactions were divided into local and systemic categories and the severity of reactions was classified according to the presence or absence of postponement or discontinuation of instillation, with or without treatment for the reaction itself. RESULTS: Of 123 patients, 95.9% showed adverse drug effects and 50.4% needed some sort of treatment. Discontinuation of instillation due to adverse drug reactions was observed in nine patients. Regarding the necessity of treatment for adverse drug effects, the purpose of instillation and BCG dose were independent significant factors on multivariate analysis. CONCLUSION: Although there was a high rate of adverse drug reactions after intravesical BCG instillation, the rate of discontinuation of instillation was not high and serious adverse reactions were rare. The scale of the present study was small, but these results suggest that BCG instillation was well tolerated. When instillation is being performed for the purpose of treatment, and the BCG dose is 80 mg, greater attention might be needed to monitor for the development of adverse drug effects.     

Bacillus Calmette–Guérin strain differences as the basis for immunotherapies against bladder cancer

In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette–Guérin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non‐muscle‐invasive bladder cancer. Bacillus Calmette–Guérin is a family of vaccines derived in 1921 by the in vitro attenuation of Mycobacterium bovis. Subsequently, bacillus Calmette–Guérin seed lots were spread around the world, and both phenotypic and genotypic differences among the strains have been compiled. In recent genomic comparisons, the evolution of the different bacillus Calmette–Guérin substrains has begun to emerge. However, some of these genetic alterations in bacillus Calmette–Guérin strains have yet to be shown to affect the therapeutic effects and/or adverse effects. There are thus ongoing research efforts to assess the effects of these genetic alterations on the properties of bacillus Calmette–Guérin strains, with the ultimate goal of identifying an ideal bacillus Calmette–Guérin strain for treatment of non‐muscle‐invasive bladder cancer and providing clues for the improvement of bacillus Calmette–Guérin strains. The present review provides a history of bacillus Calmette–Guérin immunotherapy, and discusses the genetic differences among bacillus Calmette–Guérin strains, the different clinical outcomes afforded by bacillus Calmette–Guérin strains and possible future developments.     

Association of tumour necrosis factor‐α gene (T‐1031C,C‐863A,and C‐857T) polymorphisms with bladder cancer susceptibility and outcome after bacille Calmette‐Guérin immunotherapy

OBJECTIVE

To investigate the association of tumour necrosis factor‐α gene (TNF‐α) polymorphisms T‐1031C, C‐863A, and C‐857T with bladder cancer risk and recurrence after bacille Calmette‐Guérin (BCG) immunotherapy, as TNF‐α regulates inflammatory process influencing bladder cancer susceptibility and outcome of BCG immunotherapy.

PATIENTS AND METHODS

In all, 220 patients with bladder cancer and 206 controls were recruited. Genotyping was done using allele specific‐polymerase chain reaction.

RESULTS

A T‐1031C, CC genotype and haplotype ?1031C/?863C/?857T showed enhanced susceptibility to bladder cancer, with an odds ratio (OR) of 2.23 and 95% confidence interval (CI) of 1.17–4.26; and an OR of 6.05 and 95%CI of 2.46–14.90, respectively. A T‐1031C, CC genotype had a reduced risk of recurrence after BCG treatment (hazard ratio 0.38, 95%CI 0.14–0.98).

CONCLUSION

The present data suggests that T‐1031C (CC) genotype and C/C/T haplotype may confer risk for bladder cancer, moreover T‐1031C (CC) decreased the risk of recurrence after BCG immunotherapy.     

Bacillus Calmette–Guérin treatment of urothelial carcinoma arising in the ileal neobladder after radical cystectomy

In January 2005, a 66‐year‐old man underwent radical cystectomy and ileal neobladder reconstruction for invasive bladder cancer. A total of 3 years after the cystectomy, left‐side ureteral cancer was diagnosed, and a nephroureterectomy was carried out in May 2008. In October 2011, he complained of asymptomatic macroscopic hematuria. We detected multiple papillary pedunculated and broad‐based tumors in the left side and the dome of the neobladder. The patient underwent transurethral resection of the bladder tumor, and a pathological diagnosis of high‐grade pTa urothelial carcinoma was made. A total of 4 months later, tumors recurred in the right side and anterior wall of the neobladder. We carried out transurethral resection of the bladder tumor again; the pathological diagnosis was high‐grade pTa urothelial carcinoma with carcinoma in situ. Bacillus Calmette–Guérin instillation was carried out seven times into the neobladder, without any severe side‐effects. Tumor recurrence was not observed up to 8 months after bacillus Calmette–Guérin treatment.     

Reduced bladder cancer recurrence rate with cardioprotective aspirin after intravesical bacille Calmette‐Guérin

OBJECTIVE

To evaluate the recurrence‐free survival (RFS) rate of patients taking cardioprotective aspirin after intravesical bacille Calmette‐Guérin (BCG) for high‐grade noninvasive urothelial carcinoma of the bladder, as preventing the recurrence of superficial bladder cancer might decrease patient morbidity and mortality from this disease, and nonsteroidal anti‐inflammatory agents (NSAIDs) have shown promise in preclinical prevention through inhibition of the prostaglandin pathway and other mechanisms.

PATIENTS AND METHODS

In all, 43 patients with carcinoma in situ (CIS) and/or high‐grade papillary bladder cancer were treated with intravesical BCG. Patients were stratified according to whether they took cardioprotective aspirin after treatment, and Kaplan‐Meier curves of RFS were compared by log‐rank analysis. Multivariable analysis was used for potentially confounding factors, including maintenance BCG, the presence of CIS, and smoking status.

RESULTS

Of patients taking cardioprotective aspirin, the 5‐year RFS rate was 64.3%, compared with 26.9% for patients not taking aspirin, with a significantly higher RFS by univariable log rank analysis (P = 0.03). Even after adjusting for the other factors by multivariable analysis, aspirin seems to affect recurrence (hazard ratio 0.179, P = 0.001). Maintenance BCG (hazard ratio 0.233, P = 0.02) and smoking history (hazard ratio 3.199, P = 0.05) also significantly affected recurrence.

CONCLUSION

There was a significantly higher RFS rate in patients taking cardioprotective aspirin after intravesical BCG therapy for bladder cancer. The results of this study support the further investigation of aspirin and other NSAIDs as preventive agents in patients being treated for superficial bladder cancer.