Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin

PURPOSE: We prospectively examined the incidence of recurrence and progression in patients with stage pT1, grade 3 carcinoma of the bladder following complete transurethral resection of the bladder tumor and adjuvant immunotherapy with bacillus Calmette-Guerin (BCG). MATERIALS AND METHODS: Between July 1987 and March 1999, 123 patients presenting to our clinic with superficial urothelial carcinoma (stage pT1, grades 1 to 3) received adjuvant intravesical immunotherapy with BCG after histologically confirmed complete transurethral tumor resection. Disease was stage pT1, grade 3 in 44 patients (36%). Median followup was 28 months (mean 43, range 5 to 141). RESULTS: Of the patients 36 (82%) with bladder preservation remained tumor-free during followup after 1 or 2 cycles of BCG. Superficial tumor recurred in 5 patients (11%) and muscle invasive progression was noted in 7 (16%). Radical cystectomy was performed in 4 cases (9%). Of the patients 5 (11%) died of cancer. Tumor-free survival for all patients was 89% (39 of 44). CONCLUSIONS: Adjuvant immunotherapy with BCG after complete transurethral resection of bladder tumor represents a highly effective primary treatment of stage pT1, grade 3 carcinoma of the bladder. Immediate radical cystectomy does not appear necessary.     

T2a transitional cell carcinoma of the bladder: long-term experience with intravesical immunoprophylaxis with bacillus Calmette-Guerin

PURPOSE: In this prospective study we evaluate the effect of combined transurethral resection of early muscle invasive bladder cancer and immunotherapy with bacillus Calmette-Guerin (BCG) in patients unfit for radical cystectomy or refusing more aggressive therapies. MATERIALS AND METHODS: A total of 22 patients with a mean age 73.6 years were included in the study. Inclusion criteria were histologically proven muscle invasive transitional cell carcinoma of the bladder with a tumor-free second resection and negative staging examinations in patients unfit for radical cystectomy or refusing more aggressive therapies. All patients received 6 weekly instillations of 120 mg. BCG starting 14 to 21 days after the last transurethral resection of the tumor. Followup at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Every 6 months computerized tomography of the abdomen and bone scans were performed. RESULTS: The overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94%. One muscle invasive recurrence was noted at 69 months, which was again treated with the same regimen but ultimately led to radical cystectomy 21 months later. One patient died of progressive recurrence in the upper urinary tract. The 5-year recurrence-free survival rate was 46.5%. The only severe complication was BCG pneumonitis. CONCLUSIONS: The data show encouraging results for transurethral resection of bladder tumor with intravesical BCG therapy in select patients with T2a bladder cancer who are not candidates for radical cystectomy.     

Two courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder

Bacillus Calmette-Guerin intravesical immunotherapy is becoming the adjunctive treatment of choice for patients with recurrent superficial transitional cell carcinoma of the bladder. The recurrence rates following bacillus Calmette-Guerin therapy reported to date vary widely but generally they fall within the 20 per cent range. The results of retreatment of bacillus Calmette-Guerin failures with a second 6-week course of intravesical bacillus Calmette-Guerin have not been reported previously. We report the response rates of 61 patients treated with a single 6-week course of intravesical bacillus Calmette-Guerin, and 25 patients who failed to respond to the initial course and were treated with a second 6-week course. Intravesical bacillus Calmette-Guerin therapy (120 mg. Pasteur strain) was administered weekly for 6 weeks. No intradermal injections of bacillus Calmette-Guerin were given. Patients were followed with urinary cytology and bladder biopsy every 3 months. Patients with tumor at followup were treated with a second 6-week course of intravesical bacillus Calmette-Guerin. Of 19 patients with carcinoma in situ 8 (42 per cent) responded to the initial course of bacillus Calmette-Guerin, while 5 of 9 (56 per cent) became free of tumor after the second course, for a cumulative response rate of 68 per cent (mean followup 13.5 +/- 2.1 months). Of 13 patients treated for residual papillary tumors 6 (46 per cent) responded to the initial course of bacillus Calmette-Guerin and 3 of 7 (43 per cent) to the subsequent course, providing a cumulative response rate of 69 per cent (mean followup 14.8 +/- 2.8 months). Of 29 patients treated for prophylaxis against tumor recurrence 20 (69 per cent) remained free of tumor after a single 6-week course, while 6 of 9 (67 per cent) were free of tumor after the second treatment course. A 90 per cent cumulative response rate was observed in the prophylaxis category (mean followup 12.8 +/- 1.3 months). Over-all 48 of 61 patients (79 per cent) were observed to respond when all 3 categories and both treatment courses were considered. Individually, the response rate for each 6-week treatment course was 56 per cent (34 of 61 and 14 of 25, respectively). Toxicity for each treatment course was well tolerated and consisted of dysuria/frequency, hematuria and a flu-like syndrome. Toxicity was progressively more severe with prolonged treatment. Retreatment with a second course of bacillus Calmette-Guerin is warranted for patients failing the initial treatment course.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intravesical bacillus Calmette-Guerin therapy for in situ transitional cell carcinoma involving the prostatic urethra

A total of 23 patients presenting with multifocal superficial bladder cancer and concomitant in situ transitional cell carcinoma of the prostatic urethra (mucosal in 19 and ductal in 4) underwent transurethral resection and intravesical bacillus Calmette-Guerin therapy. Median followup was 51.6 months (range 6 to 105 months). Of the 23 patients 13 (48 per cent) had a complete response with a median followup of 43.7 months without recurrence. Progression of some type (local, muscle invasion or metastasis) occurred in 10 patients (44 per cent); none occurred in the prostatic urethra. Median interval free of progression was 55.7 months; 7 of 10 patients required cystectomy for progression or refractory disease in the bladder (prostate negative for transitional cell carcinoma). A trial of complete transurethral resection plus intravesical bacillus Calmette-Guerin is a viable alternative to immediate radical cystectomy for patients with mucosal and/or ductal involvement of the prostatic urethra with in situ transitional cell carcinoma.     

Intravesical bacillus Calmette-Guerin in the treatment of superficial transitional cell carcinoma of the bladder

Pasteur strain bacillus Calmette-Guerin was used to treat 145 patients with superficial transitional cell carcinoma of the bladder: 47 had established residual disease (therapeutic group) and 130 received prophylactic/adjuvant therapy (including 32 who had a complete response in the therapeutic group and then were placed into the prophylactic group). Among the patients in the therapeutic group a complete response rate of 68 per cent (32 of 47 patients, 95 per cent confidence limits 55 to 81 per cent) was achieved. Of those in the prophylactic/adjuvant group 85 per cent (111 of 130 patients, 95 per cent confidence limits 73 to 91 per cent) remain free of disease. The median followup for the therapeutic group was 17 months (range 3 to 49 months). In the prophylactic/adjuvant therapy group the followup was greater than 3 years in 7 per cent, 2 to 3 years in 23 per cent, 1 to 2 years in 29 per cent and up to 1 year in 41 per cent (median 18 months). Our study confirms that Pasteur strain bacillus Calmette-Guerin is safe and efficacious in the treatment and prevention of recurrent superficial bladder carcinoma.     

Efficacy of intravesical bacillus Calmette-Guerin for carcinoma in situ of bladder

Three months after an initial 6-week course ofintravesical bacillus Calmette-Guerin (BCG) given between January 1990 and March 2005, 94 (90%) out of 104 patients with carcinoma in situ (CIS) of the bladder achieved a complete response (CR). The 5- and 10-year recurrence-free rates were 67 and 60%, respectively (median follow-up 42 months). Three months after a second course ofintravesical BCG given to 23 patients who failed the initial induction course for CIS was evaluated. Of these, 96% achieved a CR, and the 5- and 10-year recurrence-free rates were 56 and 28%,respectively (median follow-up 23 months). Only one patient who received a second course of BCG therapy showed disease progression. Two of the 4 patients with BCG-refractory CIS of the bladder achieved CR after intravesical gemcitabine therapy and maintained a tumor-free status beyond 6 months. Five of the 16 patients showing disease progression had upper urinary tract cancer, 4 had recurrent or muscle invasive bladder cancer, 6 had prostatic involvement of CIS, and one patient had urethral recurrence. Three of the 16 patients died. Bladder preservation was achieved in 97 of the 104 patients, although 7 patients ultimately underwent radical cystectomy and urinary diversion for aggressive disease. In conclusion, some patients may be managed safely by repeated endoscopic resection and intravesical therapy with cystectomy postponed until objective evidence of progression exists.     

The limits of bacillus Calmette-Guerin for carcinoma in situ of the bladder

PURPOSE: Historically carcinoma in situ of the bladder has been treated with radical cystectomy based on the aggressive and potentially invasive nature of this disease. The introduction in the late 1970s of intravesical bacillus Calmette-Guerin (BCG) has made this therapy the gold standard in the management of carcinoma in situ. Cases that are refractory or resistant to BCG therapy are a management dilemma with various available treatment options. MATERIALS AND METHODS: A comprehensive literature review of the current management of carcinoma in situ of the bladder was performed using MEDLINE, a review of current urology journals and abstracts from recent urology meetings. Data focused on BCG resistant carcinoma in situ of the bladder and current approaches in use for refractory disease. RESULTS: Complete and durable response rates have been reported in more than 70% of patients with carcinoma in situ who are treated with intravesical BCG. To our knowledge the optimal therapeutic regimen has not been established, although extended periods of treatment beyond the originally described 6-week course have not been shown to improve complete response rates. Prolonged administration of BCG is associated with adverse side effects. Various prognostic indicators of recurrence and progression exist that may identify a subset of cases unlikely to respond favorably to a conservative approach, including carcinoma in situ with associated stage T1 bladder lesions, diffuse and multifocal carcinoma in situ, multiple recurrences with intravesical therapy and extravesical involvement. Current molecular markers may also predict the response of carcinoma in situ to therapy. Treatment options available for BCG refractory carcinoma in situ of the bladder include intravesical chemotherapy, combined immuno-chemotherapy and radical cystectomy. Intravesical valrubicin and oral bropirimine have been shown to induce a complete response rate of 21% to 50%, although data on long-term followup are forthcoming. Radical cystectomy remains effective therapy for aggressive carcinoma in situ of the bladder. CONCLUSIONS: The current management of carcinoma in situ of the bladder is ill defined due to the variable natural history and unpredictable response of this disease to therapy. Controversy exists as to the optimal treatment of carcinoma in situ of the bladder since different forms of carcinoma in situ may exist that complicate therapeutic decisions for appropriate therapy. Some tumor characteristics are associated with more aggressive behavior and may be predictive of treatment outcome.     

Intravesical bacillus Calmette-Guerin therapy for stage T1 grade 3 transitional cell carcinoma of the bladder: recurrence,progression and survival in a study of 57 patients

PURPOSE: Stage T1 grade 3 transitional cell carcinoma of the bladder is associated with a high risk of tumor recurrence and progression. We report our experience with stage T1 grade 3 bladder tumors treated with bacillus Calmette-Guerin (BCG) therapy in the last 10 years. MATERIALS AND METHODS: We analyzed the outcome in 57 consecutive patients treated with intravesical BCG for stage T1 grade 3 bladder cancer between 1991 and 2001. After initial transurethral resection all patients received a 6-week course of BCG therapy consisting of 1 instillation weekly. All patients underwent systematic biopsies at the end of the first BCG course. Patients with negative biopsies received maintenance BCG therapy, consisting of intravesical instillations each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months after the first course. Patients with residual tumor received a second course of 6 weekly instillations. Time to tumor recurrence and progression, and the rate of patient survival were retrospectively analyzed. RESULTS: Median followup was 53 months (range 9 to 110). Minimum followup was 2 years in 36 cases (63.2%) and 5 years in 28 (49.1%). After the first BCG course 50 patients (87.7%) had no residual disease, while 7 (12.3%) had residual tumor. The recurrence and progression rates were 42.1% and 22.8%, respectively. The rate of delayed cystectomy was 14%. The rate of disease specific survival was 87.7%. CONCLUSIONS: Our study confirms that BCG therapy is effective conservative treatment for patients with stage T1 grade 3 bladder tumors.     

Squamous cell carcinoma of the urinary bladder after intravesical bacillus Calmette-Guerin therapy for carcinoma in situ: a case report

A 88-year-old woman presented with bladder tamponade caused by gross hematuria. She had received 2 courses of bacillus-Calmette-Guerin (BCG) intravesical instillation therapy 4 months previously because of the bladder tumor with carcinoma in situ (CIS). Imaging studies and cystoscopy showed a bladder tumor invading into perivesical fat. She underwent total cystectomy and bilateral ureterocutaneostomy on May 27, 2002. Histopathologically, the tumor consisted of squamous cell carcinoma and transitional cell carcinoma.     

Bacillus Calmette-Guerin for superficial transitional cell carcinoma of the bladder

Pasteur strain bacillus Calmette-Guerin was used to treat superficial transitional cell carcinoma of the bladder in 28 patients. Patients selected for treatment had an incomplete resection, positive selected site biopsies and/or post-resection positive cytology findings. Complete response required negative histology and cytology findings at cystoscopic followup 4 to 8 weeks after completion of treatment. Of the patients 20 (71 per cent) demonstrated a complete response, including all 6 with carcinoma in situ. Results converted to negative in 16 of 17 patients with positive urine cytology findings and 4 with positive prostatic urethral biopsies. Of the responders 8 had received prior treatment with thiotepa. The treatment regimen of 120 mg. Pasteur strain bacillus Calmette-Guerin weekly for 6 weeks was well tolerated. It was necessary to limit the number of treatments to 5 because of local irritative effects in only 3 patients. No chronic bladder disability has been noted during followup of 3 to 30 months. This experience supports the efficacy of bacillus Calmette-Guerin as a cost-effective, well tolerated treatment modality for patients with superficial transitional cell carcinoma of the bladder.     

Prophylactic maltose tetrapalmitate and bacillus Calmette-Guerin immunotherapy of recurrent superficial bladder tumors: preliminary report

We divided randomly into 3 groups 47 patients with recurrent superficial transitional cell carcinoma of the bladder: group 1-15 controls who underwent transurethral resection only, group 2-17 patients who underwent transurethral resection and bacillus Calmette-Guerin therapy, and group 3-15 patients treated by transurethral resection and maltose tetrapalmitate. Mean followup was 22.93 months for the controls, 28.0 months for group 2 and 24.4 months for group 3. The recurrence rate per 100 patient-months was 11.34 in the controls, 7.4 in group 2 and 7.19 in group 3, and the recurrence index per month was 0.113, 0.070 and 0.072, respectively. The recurrence rate and recurrence index per month were significantly decreased in the treated groups compared to the controls (p less than 0.005). There was no significant difference between the bacillus Calmette-Guerin and maltose tetrapalmitate groups. Invasive carcinoma developed in 60 per cent of the controls, 29.4 per cent of group 2 and 20 per cent of group 3. Invasive carcinoma required cystectomy or definitive radiotherapy. Bacillus Calmette-Guerin caused irritation of the bladder mucosa, while maltose tetrapalmitate did not have any side effects.     

Sequential bacillus Calmette-Guerin and epirubicin versus bacillus Calmette-Guerin alone for superficial bladder tumors: a randomized prospective study.

PURPOSE: This study was designed to find a new therapeutic modality that may have the same efficacy and lower toxicity than bacillus Calmette-Guerin (BCG) for the treatment of superficial transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Between January 1993 and July 1997 a prospective randomized trial was conducted on 139 patients with stages pTa and pT1 bladder transitional cell carcinoma to compare the prophylactic efficacy and toxicity of sequential BCG and epirubicin (group 1) versus BCG alone (group 2). Group 1 comprised 69 patients who received alternating doses of 150 mg. BCG and 50 mg. epirubicin (1 drug at a time), while 70 patients in group 2 received 150 mg. BCG at each instillation. Treatment was continued for 6 weeks followed by 10 monthly instillations. RESULTS: Therapy was discontinued permanently in 3 group 1 and 12 group 2 patients due to severe side effects, and they were excluded from the study. Among the 124 evaluable patients (96 men and 28 women, mean age 58.2 years) mean followup was 30.4 months (range 12 to 50). Recurrence and progression rates were statistically comparable in both groups. Interval to first recurrence with or without progression was longer in group 1 than in group 2 (log rank p = 0.05). Toxicity and complications were significantly lower with sequential treatment than with BCG alone at rates of 27.3% (18 patients) and 70.7% (41), respectively (p = 0.001). CONCLUSIONS: Sequential BCG and epirubicin are comparable to BCG alone in efficacy and superior in terms of toxicity.     

Sequential immunocytological evaluation of murine transitional cell carcinoma during intralesional bacillus Calmette-Guerin and interleukin-2 immunotherapy.

The antitumor effect of intralesionally administered recombinant interleukin-2 was highly effective (90% complete response) in murine bladder cancer. We postulated that interleukin-2 may be integral to the Bacillus Calmette-Guerin-induced antitumor response in human bladder cancer. Flow cytometric evaluation of the tumor infiltrates was compared before and after intralesional treatment of an established, untreated murine bladder tumor model with recombinant interleukin-2, Bacillus Calmette-Guerin or saline. Large increases in the number of tumor infiltrating immune cells occurred between the day of randomization and the second day (one day after the first treatment) in all three groups. However, since tumor volume was reduced by treatment, the ratios of the immune cells to tumor volume was increased. The ratios of T(helper), T(cytotoxic)/suppressor cells, macrophages, and natural killer cells to tumor volume were 1.5 to 3.4 times higher in the interleukin-2 and Bacillus Calmette-Guerin groups in comparison to the saline group. The ratio of T(helper)/T(cytotoxic)/suppressor cells however, remained approximately the same despite treatment. Over the next 22 days all subpopulations of tumor infiltrating immune cells decreased in number and frequency to less than measurable levels. The similar modulation of infiltrating immune cell subpopulations by Bacillus Calmette-Guerin and interleukin-2 may indicate that the production of interleukin-2 is part of the tumor modulating mechanism of Bacillus Calmette-Guerin.     

The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ

Intravesical instillations of Tice strain bacillus Calmette-Guerin were given to 33 patients with biopsy proved carcinoma in situ. An induction phase consisting of 12 weekly instillations was followed by a maintenance phase of instillations bimonthly for 3 months and then monthly for 18 months. A total of 6 patients did not complete the induction phase because of adverse reactions but 4 were rendered free of tumor and have had no recurrence. Of the remaining 27 patients 18 became free of tumor after 12 weeks of therapy (3 had recurrences during the maintenance period), 6 after 18 weeks (with 1 recurrence) and 3 after 24 weeks. Thus, 31 of 33 patients (94 per cent) were rendered free of carcinoma in situ. There were 4 recurrences in these patients (13 per cent). The 27 patients who have remained free of disease have been followed for 1.75 to 8.5 years, with an average of 5.25 years. Side effects, principally bladder irritability, were a problem early in the study. With the use of isoniazid, nonsteroidal anti-inflammatory agents and bladder antispasmodics, the treatment has been safe and tolerated well. The study indicates that bacillus Calmette-Guerin is effective in eliminating carcinoma in situ in most patients, although prolonged treatment may be necessary. Maintenance therapy appears to be of value in reducing the incidence of recurrent tumor.     

Maintenance intravesical bacillus calmette-guerin for superficial transitional cell carcinoma of bladder. A retrospective study

Eighteen patients with recurrent and/or multifocal superficial transitional cell carcinoma of the bladder who were rendered tumor-free by transurethral resection and were then treated with either a single or second six-week course of induction Bacillus Calmette-Guerin (BCG) therapy, followed by maintenance therapy, were retrospectively reviewed. A 73 percent complete response rate was achieved in those patients treated prophylactically, while a 70 percent complete response rate was observed in patients treated for carcinoma in situ (CIS) with an average follow-up of twenty-nine months. Maintenance therapy may be warranted in those patients able to tolerate it without significant side effects.     

Outcomes after intravesical bacillus Calmette-Guerin are not affected by substaging of high grade T1 transitional cell carcinoma

PURPOSE: Substaging of T1 bladder tumors into T1a and T1b based on invasion of the tumor superficial to and beyond the muscularis mucosa has been assigned prognostic significance. We determined whether outcomes after intravesical bacillus Calmette-Guerin (BCG) differ between stage T1a and T1b subcategories. MATERIALS AND METHODS: Retrospective pathological evaluation of the initial transurethral resection specimens of stage T1 bladder tumors was performed by 2 pathologists. Grade 1, 2 or 3 and stage T1a or T1b were assigned to each case. Followup was from the date of transurethral resection to date of death or the last visit. Kaplan-Meier probability and log rank test were used to evaluate recurrence and progression. RESULTS: Substaging was performed in 49 of the 55 patients (89%) with stage T1 disease. Disease was stage T1a in 32 (65%), stage T1b in 17 (35%), grade 3 in 45 (92%) and grade 2 in 4 (8%) cases. Maximum followup was 147 months (median 71) and 28 cases had a minimum of 5 years of followup. Recurrence was noted in 33 cases (67.3%), including 22 stage T1a (69%) and 11 stage T1b (65%), at a median followup of 11.3 and 8.6 months, respectively. Progression to a higher stage of disease was recorded in 12 cases (24.4%), including 7 (22%) stage T1a and 5 (29%) stage T1b, at a median followup of 108 and 120 months, respectively. The difference between T1a and T1b subcategories was not statistically significant in regard to recurrence-free (p = 0.7203) and progression-free (p = 0.574) outcomes. CONCLUSIONS: Substaging of T1 tumors did not affect response to BCG in regard to recurrence or progression. Therefore, intravesical BCG is effective for stages T1a and T1b disease.     

The significance of bacillus Calmette-Guerin in the therapy of carcinoma in situ of the bladder

We treated ten patients with carcinoma in situ of the bladder (primary type, 6 and secondary type, 4) by intravesical bacillus Calmette-Guerin therapy. All patients received 8 weekly instillation, and among them 3 patients were followed by additional instillation monthly for 7 months. Complete regression (negative biopsies and cytology study) was observed after 8 weekly instillation in all patients. To elucidate the mechanism of action of BCG on carcinoma in situ, the biopsied specimens after BCG instillation were examined light and electronmicroscopically. It was speculated that BCG might act on cancer cells in two ways: one was sloughing and denudation of the cancer cells by acute tuberculous cystitis, and the other was a role of the macrophages through immune reaction. In our study, the toxicity and complications seemed to be much severer than previously reported. Vesicoureteral reflux was observed in 6 patients. Decreased bladder capacity noted in all patients, among them radical cystectomy and colocystoplasty were performed in 2 patients under the diagnosis of bladder contracture. Although complete regression was observed in all patients after 8 weekly BCG instillation, the duration being free from cancer cells was variable. And we also discussed on the additional therapy in such patients in the literature.