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.     

Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette-Guérin immunotherapy

AIM: In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. METHODS: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12. RESULTS: After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. CONCLUSIONS: We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.     

Transient anuria requiring nephrostomy after intravesical bacillus Calmette-Guérin instillations for superficial bladder cancer

A 76-year-old man received intravesical bacillus Calmette-Guérin (BCG) instillations for recurrent superficial bladder cancer. He had undergone right nephroureterectomy for right renal pelvic cancer 9 months previously. He presented with anuria and left hydronephrosis after the fourth instillation, with serum creatinine increasing up to 15.7 mg/dL. Percutaneous nephrostomy was indwelled, and antegrade pyelography showed left vesicoureteral obstruction. There was no sign of recurrent bladder cancer or ureteral cancer. He started spontaneous voiding on day 4 and the nephrostomy was removed on day 8. Most of the side-effects of intravesical BCG therapy are minor, and major adverse reactions are rare. Life-threatening ureteral obstruction would be a rare complication of BCG immunotherapy. Although BCG intravesical instillation after nephroureterectomy is a common practice, special care should be taken of renal function in patients with unilateral kidney during BCG therapy.     

Treatment of carcinoma in situ with intravesical bacillus Calmette-Guerin without maintenance

PURPOSE: Data concerning the relative efficacy of intravesical bacillus Calmette-Guerin (BCG) on subgroups of carcinoma in situ of the bladder are limited. We report the outcome of primary carcinoma in situ and carcinoma in situ associated with Ta or T1 transitional cell carcinoma of the bladder treated with BCG. MATERIALS AND METHODS: Between 1987 and 1997, 135 patients (median age 70 years) with biopsy proven bladder carcinoma in situ underwent a standard course of 6 BCG instillations. Patients were divided into group 1-23 patients with primary carcinoma in situ, group 2-37 with carcinoma in situ associated with Ta transitional cell carcinoma and group 3-75 with carcinoma in situ associated with T1 transitional cell carcinoma. RESULTS: Median followup was 41 months. For groups 1 to 3, complete response rates at 3 months were 74% (17 of 23 cases), 70% (26 of 37) and 75% (56 of 75), respectively. The overall progression rates at 5 years were 20% (3 of 15 cases), 18% (4 of 22) and 49% (25 of 51). Cancer specific survival rates were 83% (10 of 12 patients), 86% (12 of 14) and 59% (17 of 29), and the numbers of patients alive with the bladder intact were 60% (9 of 15), 58% (11 of 19) and 30% (12 of 40). Patients in group 3 treated with BCG had progression significantly earlier than those in groups 1 and 2 (log-rank test p = 0.013). A complete response to BCG in group 3 patients significantly delayed time to progression (Cox regression p = 0.001) but did not reduce death from transitional cell carcinoma. Indeed, only 38% (8 of 21) of complete responders were alive with the bladder intact at 5 years. CONCLUSIONS: A single course of BCG is remarkably effective for primary carcinoma in situ and carcinoma in situ associated with Ta transitional cell carcinoma but is suboptimal in patients with carcinoma in situ associated with T1 transitional cell carcinoma. Better outcomes in each of the 3 groups may have occurred with maintenance BCG.     

Sufficient prophylactic efficacy with minor adverse effects by intravesical instillation of low-dose bacillus Calmette-Guérin for superficial bladder cancer recurrence

BACKGROUND: Intravesical instillation of bacillus Calmette-Guérin (BCG) is the most efficient strategy for prophylaxis of superficial bladder cancer recurrence. Adverse effects of BCG are major obstacles, but the reduction of BCG dose could minimize these effects. The efficacy and adverse effects of half-dose (40 mg) BCG, Tokyo 172 strain, were prospectively evaluated. METHODS: A total of 93 patients with superficial bladder cancer (pTa or pT1) were sequentially assigned to receive either 40 or 80 mg of BCG after transurethral resection. BCG was administered weekly for 6 weeks postoperatively. Eighty patients observed longer than 12 months after BCG therapy (41, 40 mg group; 39, 80 mg group) were analyzed. RESULTS: BCG therapy course was completed in 71 patients. Tumor recurrence was recognized in 11 of 40 patients in the 40 mg group and in 5 of 31 patients in the 80 mg group. There was no significant difference in tumor recurrence rate between the two groups (P = 0.547). BCG therapy was withdrawn in 1 patient in the 40 mg group and in 8 patients in the 80 mg-group because of BCG-related adverse effects. The morbidity of BCG-related toxicity was significantly higher in the 80 mg group. CONCLUSION: Half-dose of BCG Tokyo 172 strain had a similar efficacy and its toxicity was significantly lower compared to the standard dose. Thus, half-dose of this strain might be suitable, at least for initial BCG therapy, for the prophylaxis of bladder cancer recurrence. Further study would be necessary to clarify the efficacy of low-dose instillation in high-risk patients.     

Tubercular prostatic abscess as a complication of intravesical bacillus Calmette–Guérin immunotherapy

We report a case of tubercular prostatic abscess in a patient who had undergone intravesical bacillus Calmette-Guérin immunotherapy for bladder carcinoma in situ. The abscess required surgical drainage and antituberculous 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.     

Local Toxicity Patterns Associated with lntravesical bacillus Calmette-Guérin: A Southwest Oncology Group Study

Background: While the efficacy of bacillus Calmette-Cuérin (BCG) immunotherapy has been demonstrated, the relative benefit, given a seemingly high incidence and severity of toxicities, remains an issue. Adequate understanding and management of toxicities can maximize the safety of the treatment and enable the administration of required doses of BCC intravesical therapy.
Methods: All week-to-week symptoms recorded for the 143 immunotherapy-naive participants assigned to the BCG arm of SWOG-8216, BCG vs. Doxorubicin in Superficial Bladder Cancer were analyzed in order to document the pattern of toxicities in the first six week induction course of intravesical BCC treatments. The statistical analysis consisted of fitting logistic regression models to these data for the probability of irritative bladder symptoms (16s).
Results: In the optimal model, the probability of IBS depends only on whether there was IBS associated with the previous treatment, and not on which treatment. The estimated probability of having IBS when there were no 16s associated with the previous instillation is 0.136, whereas the estimated probability of having IBS when there was IBS associated with the previous instillation is 0.689.
Conclusions: Irritative bladder symptoms are unlikely in the week after the first intravesical BCG treatment. Once a patient experiences IBS, he or she is more likely to have IBS with the next and subsequent treatments. Clinicians can use the findings of this analysis when informing their patients about the treatment course and when making decisions about continuing treatments.     

Surface antigen expression on bladder tumor cells induced by bacillus Calmette-Guérin (BCG): A role of BCG internalization into tumor cells

BACKGROUND: The antitumor mechanisms of bacillus Calmette-Guérin (BCG) against bladder cancer is still unclear. We previously reported that BCG was internalized by and survived within murine bladder tumor cells (MBT-2) for at least 40 days. In the present study, we investigated the effect of BCG on the surface antigen expression of bladder tumor cells and the characteristics of these cells as antigen-presenting cells in vitro. METHODS: Surface antigen (major histocompatibility complex (MHC) Class II, CD1, CD80 and intercellular adhesion molecule-1 (ICAM-1)) expression on BCG-treated murine (MBT-2) and human (T-24, J82) bladder tumor cells were analyzed using flow cytometry. The production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) from murine lymphocytes sensitized with BCG or BCG-treated tumor cells were also investigated. RESULTS: The expressions of MHC Class II, CD1, CD80 and ICAM-1 were augmented in all of the bladder tumor cell lines used; however, they were augmented to varying degrees among the cell lines that were treated with live BCG. Heat-killed BCG had little or no effect. When murine lymph node cells sensitized with BCG or BCG-treated MBT-2 cells were cocultured with BCG-treated MBT-2 cells, significant amounts of IL-2 and IFN-gamma were produced in the culture medium. CONCLUSIONS: BCG induced the augmented expression of surface antigens, such as MHC Class II, CD1, CD80 and ICAM-1, of bladder tumor cells. Furthermore, BCG-treated MBT-2 cells could stimulate BCG-sensitized lymphocytes to produce IL-2 and IFN-gamma. These results strongly suggest that bladder tumor cells gained the characteristics and functions of antigen-presenting cells (APC).     

Immunohistochemical Study of Tumor-Infiltrating Lymphocytes Before and After Intravesical Bacillus Calmette-Guérin Treatment for Superficial Bladder Cancer

¹Department of Urology, Juntendo University School of Medicine, Tokyo Japan
Background This study investigated changes in the phenotypic characteristics of tumor-infiltrating lymphocytes during intravesical bacillus Calmette-Guérin (BCC) treatment using an immunohistochemical technique.
Methods A total of 16 patients with superficial bladder cancer underwent intravesical BCG treatment for therapeutic purposes. Tissue specimens were obtained from these patients before and after BCG treatment by cold cup biopsies.
Results The numbers of CD3⁺ cells, CD4⁺ cells, CD8⁺ cells, and CD19⁺ cells significantly increased after treatment compared with numbers before treatment (P <0.01). Although γ/δT cells were not observed before treatment, they appeared after treatment in 6 patients- In all these patients, the tumors disappeared or their size was reduced by more than 50%, and none of the tumors recurred. The induction of CD25⁺ cells after treatment was seen in 11 of the 16 patients.
Conclusions γ/δT cells may play an important role in the immune response of the host to the tumor in intravesical BCG treatment (although this correlation was statistically insignificant).     

Long-term outcome of upper urinary tract carcinoma in situ: Effectiveness of nephroureterectomy versus bacillus Calmette-Guérin therapy

BACKGROUND: We examined the long-term outcome and compared the usefulness of nephroureterectomy with that of bacillus Calmette-Guérin (BCG) therapy for the management of upper urinary tract carcinoma in situ (CIS). METHODS: We retrospectively reviewed the post-treatment course of 17 patients with CIS of the upper urinary tract who had undergone either a nephroureterectomy (group A, n = 6) or BCG therapy (group B, n = 11) at our institute. RESULTS: Median follow up was 58.3 months (range 1-120 months). Four of the six patients in group A (67%) had no recurrence and remained cystoscopically, cytologically and radiographically free of disease. The cytology became negative after an 8-week course in nine of the eleven patients in group B (82%; eight of ten units, 77%). Two of the nine patients showed recurrence after BCG therapy. One patient died of respiratory failure caused by a side-effect of BCG, which was interstitial pneumonia. There was no significant difference in either the 5-year recurrence-free survival or the 5-year cancer-specific survival between groups A and B. CONCLUSIONS: BCG therapy for CIS of the upper urinary tract is as effective as nephroureterectomy in long-term outcome, although it has some dangerous aspects. Further experience with treatment of CIS of the upper urinary tract is required.     

Experience with intravesical bacillus Calmette-Guèrin therapy of superficial bladder tumors

Between March, 1978, and July, 1981, 86 patients with polychronotopic superficial papillary bladder tumors and concurrent carcinoma in situ were randomized to receive either transurethral resection alone (43) or TUR plus BCG (43). The results indicate that BCG is not only active in preventing recurrences of new tumors but also effective for the diffuse, flat carcinoma in situ.     

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.     

Immunological protection induced by bacillus Calmette–Guérin treatment in a murine bladder tumor model

BACKGROUND: It has been previously reported that MBT-2 tumor growth is completely inhibited when mice are inoculated with bacillus Calmette-Guérin (BCG). In this study it was examined whether or not vaccination with a mixture of BCG and MBT-2 cells also induces immunological protection against murine bladder tumors. METHODS: Seven hundred thousand MBT-2 cells and 1 mg of BCG (Tokyo 172 strain) per mouse were injected subcutaneously into female C3H/HeN mice. Four and eight weeks after vaccination with this mixture, animals were reinoculated with MBT-2 cells alone or MBT-2 cells cocultured with BCG. RESULTS: Animals vaccinated with a mixture of BCG and MBT-2 cells showed MBT-2 tumor growth but completely rejected the MBT-2 cells cocultured with BCG. MBT-2 cells cocultured with BCG developed into tumors when they were inoculated into the control animals. Splenocytes prepared from vaccinated animals showed specific cytocidal activity against MBT-2 cells precultured with BCG. CONCLUSIONS: The results suggest that a mixture of BCG and MBT-2 cells induces antitumor immunological protection against BCG- or MBT-2-associated antigens presented on MBT-2 cells precultured with BCG.     

Effects of isoniazid (INH) on the BCG-induced local immune response after intravesical BCG therapy for superficial bladder cancer

Because recent investigations showed that the use of isoniazid (INH) severely impaired the local immune reaction to intravesical bacillus Calmette-Guérin (BCG) in the bladder of guinea pigs, in this study the effect of INH in man has been investigated. Patients were treated with BCG with or without oral INH. The concentration of free INH in most urine samples of patients treated with BCG/INH was much higher (mean 38.0±60.9 g INH/ml) than the minimal inhibitory concentration (MIC; 0.1 g INH/ml), suggesting at least a bacteriostatic potential of the INH present. However, in vitro studies showed that these urinary concentrations of INH did not kill BCG organisms effectively, even at a concentration of 150 g/ml for 24h. After the fifth and sixth BCG instillations a significant increase in the concentration of cytokines (IL2, IL6, IL8 and TNFa), IgG and IgA antibodies to BCG and the number of leukocytes in urine was observed. The leukocytes mainly consisted of granulocytes, besides monocytes/macrophages and, in lower amounts, T- and B-lymphocytes and natural killer (NK) cells. The absolute number of granulocytes and the concentration of IgG antibodies after BCG instillation were significantly suppressed by INH, whereas INH appeared to have no effect on the urinary cytokine and IgA antibody concentrations or the total number and phenotype of the leukocytes present. In conclusion, the results of this study indicate that INH does not impair the local immunological stimulation after BCG instillation in man as severely as was observed in the guinea pig and it may be expected that INH does not impair the antitumor efficacy of BCG.     

Immunohistochemical evaluation of p53, proliferating cell nuclear antigen (PCNA) and bcl-2 expression during bacillus calmette-guerin (BCG) intravesical instillation therapy for superficial bladder cancers

Bacillus Calmette-Guerin (BCG) immunotherapy for superficial bladder cancer is now widespread, but non-effective cases are not uncommon and it has yet to be clarified why this is the case. In an attempt to cast light on this problem, we evaluated differences between effective and non-effective cases immunohistochemically using p53, proliferating cell nuclear antigen (PCNA), and bcl-2 antibodies. Between March 1988 and March 1996 a total of 79 superficial bladder cancer patients were treated with BCG intravesical instillation therapy after transurethral resection of bladder tumor (TUR-Bt). Of these, 19 demonstrated recurrence after the initial treatment. From the 60 remaining patients without recurrence, we randomly chose 19 additional cases and evaluated both series for p53, PCNA and bcl-2 immunohistochemical staining using formalin-fixed, paraffin-embedded tissues. For the recurrent cases, material taken prior and subsequent to BCG therapy was available for 17 of the 19 patients. Positive staining for p53 was noted for 42.1% (8/19) of both recurrent and non-recurrent cases, without any difference between the two. The rates for PCNA and bcl-2 were 52.6% (10/19) and 47.4% (9/19) in recurrent, and 36.8% (7/19) and 78.9% (15/19) in non-recurrent cases, respectively. Thus, there was a significant difference for lower incidences of bcl-2 in recurrent cases (P=0.044). Values for p53 and bcl-2 were respectively 47.1% (8/17) and 41.2% (7/17) pre-treatment, and 52.9% (9/17) and 35.3% (6/17) post-treatment in the recurrence group. In contrast to the similarity in these results, PCNA positive cases were 52.9% (9/17) pre-treatment and 17.6% (3/17) post-treatment. These data suggest that there are differences between BCG-sensitive and BCG-resistant bladder cancers in terms of bcl-2 expression. Received: 25 August 1997 / Accepted: 5 February 1998