Intravesical bacillus Calmette-Guérin (Tokyo 172 strain) therapy for carcinoma in situ of the bladder

To evaluate the clinical response to intravesical instillation therapy with bacillus Calmette-Guérin (BCG) Tokyo 172 strain for carcinoma in situ (CIS) of the bladder and subsequent patient prognosis, we reviewed data for 30 patients treated between 1985 and 1994. Median follow-up was 56 months. The CIS cases comprised two groups: primary (19 patients) and subsequent to development of a gross neoplasm (11 patients). Either 40 mg (n=20) or 80 mg (n=10) doses of BCG were instilled weekly for 8 weeks. This intravesical therapy resulted in apparent eradication of tumour cells in 25 of the 30 patients for a complete response (CR) rate of 83%, with no difference found between primary and secondary groups. Tumours later recurred in 6 of the 25 patients (24%) and disease progression was found in only 3 (12%). In contrast, progression occurred in 3 of 5 patients (60%) for which a complete response was not achieved with intravesical BCG therapy. The difference between these two groups was significant (p=0.04). Total cystectomy was performed in 2 of 25 CR patients (8%) first and in 4 of the 5 unresponsive (80%), the statistical difference being highly significant (p=0.003). The 5-year survival rate was 96% for the study subjects as a whole. In conclusion, CIS unresponsive to BCG therapy should be treated with immediate total cystectomy while cases demonstrating a complete response should be followed up for a long period.     

Intravesical instillation of bacillus Calmette-Guerin for superficial bladder carcinoma: study on significance of additional maintenance instillations of bacillus Calmette-Guerin

The efficacy of maintenance bacillus Calmette-Guerin (BCG) instillations for superficial bladder tumors was studied by prospective randomized trial. From June 1985 to October 1988, 42 newly diagnosed patients with superficial bladder carcinoma (pTa or pT1) were treated by transurethral tumor resection and subsequent five daily instillations of mitomycin C. Then they were divided into non-maintenance group (22 patients) and maintenance group (20 patients) by randomization. The patients received six weekly instillations of 80 mg of BCG. Tokyo strain (Japan BCG manufacturing Co., Tokyo, Japan), suspended in 40 ml of physiological saline, and the patients in the maintenance group received four additional instillations of BCG every three months. We could not complete the six-week course of BCG instillations in three patients due to adverse effects (two in non-maintenance group and one in maintenance group) and we lost six patients from follow-up within one year (one in non-maintenance group and five in maintenance group). The mean follow-up period of the remaining 33 patients was 28.1 months. Of these 33 patients, six patients had been found to have recurrent tumors, and the over-all three-year non-recurrence rate was 82%. Before employing BCG, when we used only mitomycin C after TUR-Bt, the three year non-recurrence rate was 58%. This indicates prophylactic effect of BCG instillations. The stage of the initial tumor of the six recurrent cases were all pT1b. The non-recurrence rate of the patients with pT1b tumor was significantly lower than that of the patients with pTa and pT1a tumor. However, multiplicity and grade of tumors did not affect the non-recurrence rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analyses of the effects of intravesical Bacillus Calmette-Guerin (Tokyo 172 strain) therapy of superficial bladder cancer

In this paper, we summarize the results of a multicentric controlled study of induction treatment with intravesical BCG in patients with superficial bladder cancer (Ta, T1) or CIS. The BCG Tokyo 172 strain (Japan BCG K.K.) was given for 8 weeks, as a rule, in a dose of either 80 mg or 120 mg in 40 ml of saline instilled into the bladder. Sixty-six (90.5%) of the 73 patients registered in the study were evaluable for response. High response rates were obtained in the patients with Ta or T1 tumors, irrespective of the treatment dose; 65.4% CR, 27.3% PR and 7.3% NC for all. The number of CIS patients is too small to draw any conclusions, but 54.5% CR, 36.4% PR and 9.1% NC were obtained. Several factors were evaluated in relation to the tumor ablative effects. The CR rate was significantly higher for tumors less than 1 cm in size compared with tumors 1-3 or larger in size, although the response rates, including CR and PR, were very similar irrespective of the size. Other factors did not contribute to provoke a significant difference. Japanese elder people show a high positive rate of PPD reaction. Thus, in our study, 78% of the patients showed positive PPD reaction. In this situation, no significant relation between PPD reaction and BCG efficacy was obtained. In addition, OKT8, OKT7, OKT4, OKT4/OKT8 ratio, Leu7, ADCC activity and NK activity did not show any correlation with tumor ablative effect of BCG.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recurrence of Primary Superficial Bladder Cancer Treated with Prophylactic Intravesical Tokyo 172 Bacillus Calmette-Guerin: A Long-Term Follow-up

Background Long-term results after transurethral resection (TUR) and prophylactic intravesical Tokyo 172 bacillus Calmette-Guerin (BCG) therapy for primary superficial bladder cancer were analyzed by multivariate analysis, and factors affecting the recurrence of bladder tumors after this therapy were examined.
Methods One-hundred and forty-one consecutive patients with primary superficial bladder cancer who consulted the Department of Urology at Wakayama Medical College and affiliated hospitals between May 1985 and May 1990 were studied. Tokyo strain BCG was given intravesically (80 mg in 40mL saline) weekly for 6 weeks.
Results The 5-year cumulative recurrence-free rate by the Kaplan-Meier method was 0.702 in 141 patients with primary superficial bladder cancer. The 5-year recurrence-free function using the proportional hazard model was 0.743. Using the Cox proportional hazard model, variables that significantly contributed to recurrence after intravesical BCG included female sex, tumor size less than 1 cm in diameter, and T1 tumor stage. Patient age, tumor type, multiplicity, tumor grade, and concomitant carcinoma in situ did not contribute to recurrence.
Conclusion Long-term results showed that prophylactic intravesical Tokyo strain BCG after TUR for primary superficial bladder cancer is also effective in preventing the recurrence of bladder cancer, and the biologic behavior of superficial bladder cancer other than stage T1 tumor may be altered after intravesical BCG.     

Ablative and prophylactic effects of BCG Tokyo 172 strain for intravesical treatment in patients with superficial bladder cancer and carcinoma in situ of the bladder. Bladder cancer BCG Study Group]

We investigated the effects of intravesical instillation of BCG Tokyo 172 strain on patients with superficial bladder cancer and CIS of the bladder for tumor ablation and prophylaxis. This is the first controlled multicenter study for governmental approval of BCG Tokyo 172 strain for the treatment of superficial bladder cancer and CIS of the bladder. One hundred-fifty-seven patients (125 with Ta or T1, and 32 with CIS) were treated by 80 mg of BCG diluted in 40 ml of saline, once a week for 8 weeks. The dose and interval adopted in this multicenter study was determined by the previous Phase II study conducted by the same Study Group. Out of 125 superficial tumor Ta, T1, 83 (66.4%) showed complete disappearance of the tumor (CR) and 26 (20.8%) partial disappearance (PR), and out of 32 CIS, 27 (84.4%) showed CR and 2 (6.3%) PR. Among those patients showing CR, and PR who were treated with additional TUR-Bt, 98 patients were randomised for a controlled study of prophylactic BCG instillation. Prophylactic treatment consisted of 40 mg of BCG diluted in 40 ml of saline, monthly for 12 months. Forty-two patients were assigned to the treatment group, whereas the remaining 56 to the control group without any prophylactic instillation. Three cases showed tumor recurrence during the prophylactic phase. Twenty-five cases could not be treated for the whole course of prophylactic instillation mainly due to bladder irritable symptoms. Recurrent free curves were compared till 1050 days after the initiation of the study. However, there was no significant difference between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravesical bacillus Calmette-Guerin instillation therapy for carcinoma in situ of the urinary bladder and prediction of effects by urinary cytologic examination

PURPOSE: We investigated the effects of intravesical BCG instillations for carcinoma in situ (CIS) of the urinary bladder. And we have retrospectively analyzed the prediction of effects by fresh urinary cytologic examinations before instillation. MATERIAL AND METHODS: 33 patients were treated for bladder CIS (1991-1997) with a median follow-up of 30 months (range from 9 to 90 months). The patients (27 males and 6 females) ranged in age from 46 to 91 (average 71 years) and received 6 to 12 weekly BCG Tokyo 172 strain 80 mg instillations. They were divided into 3 groups based on tumor history: primary (9), secondary (15), concurrent (9). The prediction of effects were analyzed by scoring fresh urinary cytologic examinations before instillation. RESULTS: 22 cases (67%) were responded and they have remained free of disease for follow-up period. The statistic evaluation proved to show the significance between the effects of treatment and the sum of scoring (cellular appearance and existence of large nuclear cells). CONCLUSION: We confirmed the effects of this treatment. The prediction of effect of this treatment seemed to be indicative by fresh urinary cytologic examinations before instillation, especially cellular appearance and existence of large nuclear cells.     

Intravesical BCG as a treatment for superficial and in situ transitional cell carcinoma of the bladder

Intravesical BCG is already established as effective therapy in the management of superficial bladder cancer. However, varying results have been obtained with different BCG strains; these are ascribed to variations in their immunogenicity. The locally available BCG strain which contains approximately 1.2 x 10(9) colony-forming units per 120 mg was used for intravesical instillation in 27 patients with recurrent superficial transitional cancer of the bladder. Ten of the 13 patients who received BCG prophylactically to reduce or stop recurrencies completed therapy and 7 (70%) were in remission after 1 or 2 courses with a mean follow-up of 2 years. Fourteen patients received BCG therapeutically for in situ carcinoma. Thirteen of these patients completed therapy and 9 (69%) responded favourably after 1 or 2 courses of BCG for a mean follow-up period of 23 months. Adverse effects of the treatment were mild and well tolerated except in a patient who received radiotherapy. Although 21 patients experienced irritable bladder symptoms only 1 discontinued treatment as a direct result. The only other patient in whom treatment had to be stopped, developed severe polyarthritis after 3 instillations. A statistically significant reduction in the number of recurrences (P less than 0.001) was experienced by the patients who received BCG prophylactically. Although this is a very limited study, the locally available BCG strain exhibited therapeutic activity. It is cost-effective and warrants further study.     

Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term results of EORTC GU Group phase II protocol 30861

OBJECTIVES: This phase II study was designed to assess the response rate, side effects and long-term efficacy of BCG in the treatment of carcinoma in situ (Cis) of the urinary bladder. METHODS: 103 eligible patients with Cis were treated with 6 consecutive weekly intravesical instillations of 120 mg BCG-Connaught. In case of no response, a second 6-week course was given. RESULTS: A complete response (CR) was observed in 77 of the 103 eligible patients (75%) and 93 evaluable patients (83%). In 6 of 10 patients the CR was induced by a second cycle of 6 weekly instillations. After a median follow-up of 7.6 years, 39 of the 77 CR patients (50%) are still alive and have retained their bladder, 31 (40%) without tumor recurrence. Another 7 patients underwent cystectomy and are still alive while 16 (20%) have died due to bladder cancer. Ten patients stopped treatment due to toxicity. In 2 patients, cystectomy was done because of severe cystitis and reduced bladder capacity. Drug cystitis, bacterial cystitis and fever occurred in 45, 15 and 15% of the patients, respectively. Severe drug cystitis was noted in 3 out of 10 patients receiving more than 6 instillations, necessitating cystectomy in 1 case. CONCLUSION: Intravesical short-term BCG is an effective treatment modality in Cis, yielding a high CR rate. This therapy may however be suboptimal in some patients as the 5-year disease-free rate in complete responders drops to 60%. Still, this is an acceptable result for patients in whom cystectomy would otherwise be performed in virtually all cases.     

Intravesical bacillus Calmette-Guerin (BCG) in the treatment of superficial bladder cancer. Prospective randomized study for prophylactic effect

We report the results of prospective randomized study which was designed to evaluate prophylactic effects of intravesical bacillus Calmette-Guerin (BCG) in the treatment of superficial transitional cell carcinoma of the bladder. A total of 44 cases who had no previous treatment of bladder cancer were randomly assigned to BCG or control groups after TUR. BCG group (23 cases) received intravesical instillation of 80 mg BCG (Tokyo strain) at one week intervals for 6 weeks, at two week intervals for 12 weeks, and at one month intervals for 20 months. In BCG groups, 3 cases had recurrence at 6 months and 1 case at 9 months, while the other 19 cases had no recurrent disease for 3 to 34 months (average 20.3 months) of follow-up. Control group (21 cases) had no further treatment after TUR. In control group, recurrence was seen at 3 months in 3 cases, at 6 months in 5 cases, at 9 months in 2 cases, at 12 months in 3 cases and at 21 months in 1 case. Only 7 cases in the control group were free of recurrence for 8 to 45 months (average 32.3 months) of follow-up. One and two year-recurrence rates in BCG group (18.4%, 18.4%) was significantly (p less than 0.01) lower than those in control group (63.2%, 68.9%). Among the complications of intravesical BCG were cystitis (76.2%), low grade fever (13.0%), and several days' persistent gross hematuria (13.0%). Most of these signs were self-limited and only in 2 cases instillation of BCG was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study on prophylactic intravesical instillation of bacillus Calmette-Guerin (BCG) and adriamycin for superficial bladder cancers

In this study we evaluated 77 patients with superficial bladder cancer who were treated with either intravesical bacillus Calmette-Guerin (BCG) (44 patients) or doxorubicin hydrochloride (Adriamycin, ADR) (33 patients) for prophylaxis of tumor recurrence after transurethral resection. The estimated actuarial probability of non-recurrence rate at three years for the BCG group was 73.0%, and the actuarial non-recurrence rate for the ADR group was 27.3%; a statistically significant difference (p = 0.0013). A comparison between the two groups was also made according to the patient's background, including whether the tumor was initial or recurrent, solitary or multiple, and the tumor grade. In all areas of the study, except for grade-1 tumors, the BCG group was significantly superior to the ADR group. The efficacy of BCG therapy as a result of different BCG treatment protocol was evaluated for six weekly instillations 1) without further maintenance instillation, 2) followed by 12 months of maintenance, and 3) followed by more than 18 months of maintenance. Long-term maintenance BCG instillation group (more than 18 months) showed the most favorable results, however, the differences were not statistically significant. These results indicate that intravesical BCG instillation was significantly superior to ADR in the prevention of bladder cancer recurrence and that six weekly intravesical BCG instillations may provide adequate prophylactic effects against recurrence of superficial bladder cancers.     

Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results

We treated 40 patients with superficial bladder cancer via intravesical bacillus Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual carcinoma or 3) flat carcinoma in situ. A single course of intravesical bacillus Calmette-Guerin therapy was successful in 6 of 11 patients (55 per cent) treated for residual carcinoma and 6 of 12 (50 per cent) treated for carcinoma in situ. Of 17 patients receiving a single course of bacillus Calmette-Guerin for prophylaxis 11 remained free of tumor during short-term followup. A second course of therapy was administered to failures in each treatment category, which resulted in favorable responses in 5 of 6 patients treated for prophylaxis, 2 of 5 treated for residual tumor and 3 of 6 treated for carcinoma in situ. Over-all complete responses were achieved in 16 of 17 patients (94 per cent) treated for prophylaxis, 8 of 11 (73 per cent) for residual carcinoma and 8 of 12 (66 per cent) for carcinoma in situ, with a mean followup from the final treatment of 9.3, 12.3 and 7.9 months, respectively. Favorable results occurred more frequently among patients who exhibited a granulomatous inflammatory response in the bladder and delayed hypersensitivity skin test response to purified protein derivative. Marked variability in viability of bacillus Calmette-Guerin organisms was observed among different lots of bacillus Calmette-Guerin, and a direct relationship was observed between bacillus Calmette-Guerin vaccine viability and therapeutic efficacy. Most patients who failed initial therapy with a low viability lot of bacillus Calmette-Guerin responded favorably to re-treatment with a higher viability lot. The results suggest that the level of viability of each lot of bacillus Calmette-Guerin vaccine should be verified before clinical use.     

Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study

OBJECTIVES: To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. METHODS: Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. RESULTS: Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p=0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p=0.07), but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. CONCLUSION: One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.     

Equivalent efficacy of mitomycin C plus doxorubicin instillation to bacillus Calmette-Guerin therapy for carcinoma in situ of the bladder

BACKGROUND: To elucidate the most efficient topical therapy for carcinoma in situ of the bladder, the efficacy of intravesical mitomycin C plus doxorubicin therapy was compared with bacillus Calmette-Guerin (BCG) therapy. The clinical behavior of the tumor was analysed according to the histological grade. METHODS: Forty-two patients with carcinoma in situ of the bladder were randomized to intravesical BCG (21 patients) or mitomycin C plus doxorubicin sequential therapy (21 patients) as first line treatment. The non-responders underwent the subsequent instillation of the other intravesical therapy alternately. Of the patients, 27 had grade 2 and 15 had grade 3 cancer. RESULTS: Both topical therapies were equally effective with initial response rates of 86% (18/21) for BCG and 81% (17/21) for mitomycin C plus doxorubicin, irrespective of the tumor grade. Of seven initial non-responders, five patients achieved a complete response by subsequent instillation, resulting in a total response rate of 95%. After a mean follow-up of 47 months, five patients (12%) developed disease progression. The progression rates were not different between the topical therapies, but were significantly higher in grade 3 than in grade 2 cases. CONCLUSION: It appears likely that mitomycin C plus doxorubicin instillation has an equivalent efficacy to BCG as the initial therapy of carcinoma in situ and the combination of them would be the most efficient treatment for the disease. Moreover, histological grading would be clinically useful in defining the tumor characteristics and behavior of carcinoma in situ of the bladder.     

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.     

BCG和IL—2膀胱灌注预防膀胱癌复发的疗效观察

为了解ＢＣＧ与白介素２（ＩＬ２）联合应用膀胱灌注预防膀胱癌术后复发的疗效，将６８例膀胱癌随机分为两组：一组用ＢＣＧ１５０ｍｇ＋ＩＬ２１００００Ｕ，另一组单用ＢＣＧ１５０ｍｇ行膀胱内灌注。随访３～７５个月，平均３９．６个月，无肿瘤复发者ＢＣＧ＋ＩＬ２组３２例（９４％），单用ＢＣＧ组２８例（８２％），两组比较有显著性差异（Ｐ＜０．０１）。结果表明：ＢＣＧ与ＩＬ２联合应用能更有效地防止膀胱癌术后复发。     

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.