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.     

Maintenance intravesical bacillus Calmette‐Guérin instillation for Ta,T1 cancer and carcinoma in situ of the bladder: Randomized controlled trial by the BCG Tokyo Strain Study Group

Objectives: We carried out a prospective, randomized, controlled trial to investigate the efficacy and safety of both induction and maintenance therapy with intravesical instillation of bacillus Calmette‐Guérin (BCG) for high‐risk non‐muscle invasive bladder cancer (NMIBC). Methods: Intravesical instillation of 80 mg Tokyo strain was given to patients with high‐risk NMIBC, including carcinoma in situ (CIS), once weekly for eight consecutive weeks as induction therapy. Patients who achieved complete response (CR) were randomly assigned to either the maintenance group or the observation group. Results: A total of 90 patients were enrolled. After induction therapy, 75% of the patients achieved CR and 53 of them were enrolled in the randomized comparative phase. A total of four maintenance instillations were given. Median follow‐up was 26.5 and 28.7 months after randomization in the maintenance and the observation group, respectively. Although it was not statistically significant, the 2‐year recurrence‐free survival rate in the maintenance group (95.8%) was higher than that in the observation group (74.1%, P = 0.078). Univariate analysis identified maintenance therapy as a significant factor influencing recurrence. During induction therapy, 82.2% of patients experienced urination‐related adverse drug reactions, but most events were not serious. There were fewer adverse drug reactions with maintenance therapy than with induction therapy. Neither induction therapy nor maintenance therapy reduced patients’ quality of life (QOL). Conclusions: These findings show high levels of efficacy and safety of BCG induction treatment for high‐risk NMIBC, and suggest that the number of maintenance instillations could probably be reduced without reducing treatment efficacy or influencing QOL.     

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 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.     

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.     

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.     

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.     

Narrow‐band imaging cystoscopy to evaluate the response to bacille Calmette‐Guérin therapy: preliminary results

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To evaluate whether narrow‐band imaging cystoscopy (NBIC) can identify bladder tumour suspected on follow‐up white‐light cystoscopy (WLC) after intravesical bacille Calmette‐Guérin (BCG) therapy, as BCG causes an intense reaction in the bladder, appearing as red lesions on WLC, which might be residual tumour or BCG‐induced inflammation.

PATIENTS AND METHODS

Sixty‐one patients with high‐risk non‐muscle‐invasive bladder tumours were evaluated 3 months after starting induction BCG therapy. All patients had abnormal erythematous lesions on WLC, suspected to be residual carcinoma in situ. After WLC, they were evaluated by NBIC, urine cytology and biopsy, followed by transurethral resection of all visible lesions.

RESULTS

Of the 61 patients, 22 (36%) had residual tumour. NBIC correctly identified tumour in 21 patients, but another 10 had unnecessary biopsy (NBIC positive, negative biopsy). Only one of 30 patients who had negative NBIC findings had tumour. NBIC outperformed urine cytology in detecting residual tumour after BCG therapy.

CONCLUSION

NBIC appears to better identify patients who have suspected residual tumour on follow‐up WLC at 3 months after BCG therapy.     

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.     

A single‐institution experience with induction and maintenance intravesical docetaxel in the management of non‐muscle‐invasive bladder cancer refractory to bacille Calmette‐Guérin therapy

OBJECTIVE

To analyse the durability of response for patients with non‐muscle‐invasive bladder cancer (NMIBC) refractory to bacille Calmette‐Guérin (BCG) therapy and treated with intravesical docetaxel in a combined induction and maintenance regimen.

PATIENTS AND METHODS

A previous phase I trial showed docetaxel to be safe for intravesical therapy, with no systemic absorption and minimal toxicity after six weekly instillations for patients with BCG‐refractory NMIBC. In that trial, docetaxel gave a 56% complete response (CR) rate at 12 weeks, but the durability was only 22%. Thus a second group of patients was treated with a 6‐week induction and then given monthly maintenance therapy with intravesical docetaxel. Thirteen patients with BCG‐refractory Ta, T1, or Tis transitional cell carcinoma were treated. Induction therapy was administered as six weekly intravesical instillations of 75 mg followed by single‐dose monthly maintenance therapy for nine additional instillations in patients who had a CR. The initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy, and urine cytology. The follow‐up consisted of quarterly cystoscopy with biopsy and cytology, and periodic imaging.

RESULTS

The median follow‐up was 13 months; 10 of 13 patients had a CR after induction, and six have remained disease‐free during the follow‐up. Of those in who the treatment failed, six had transurethral resection of the tumour and one a cystectomy. All 10 initial responders completed at least three instillations of maintenance therapy to date (median nine instillations), of whom six have remained recurrence‐free.

CONCLUSION

Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a selected group of patients with BCG‐refractory NMIBC, and might decrease the overall risk of recurrence in high‐risk NMIBC.