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.     

Analysis of factors predicting intravesical recurrence of superficial transitional cell carcinoma of the bladder without concomitant carcinoma in situ

BACKGROUND: The objective of this study was to investigate risk factors for intravesical recurrence in patients with superficial bladder cancer without concomitant carcinoma in situ (CIS). METHODS: In this series, we analyzed data from patients with newly diagnosed superficial Ta or T1 transitional cell carcinoma (TCC) of the bladder without concomitant CIS who underwent complete transurethral resection (TUR) without any adjuvant intravesical instillation therapies. Multivariate analysis was used to determine significant risk factors affecting intravesical recurrence after TUR. Differences in clinicopathological features between primary and recurrent tumors were also characterized. RESULTS: Among 341 patients undergoing TUR of Ta or T1 bladder cancer, 187 diagnosed as having concomitant CIS and/or treated with adjuvant intravesical therapy were excluded, and the remaining 154 were evaluated. Intravesical recurrence was detected in 64 of the 154 patients, showing a 5-year recurrence-free survival rate of 58.3%. Among several factors examined, only tumor size was significantly associated with intravesical recurrence. Multivariate analysis identified tumor size as an independent predictor for intravesical recurrence irrespective of other parameters including age, gender, multiplicity, growth pattern, grade and stage. Recurrent tumors were significantly smaller and of a lower grade and lower stage than primary tumors, despite the absence of differences in growth pattern and the multiplicity between them. CONCLUSIONS: These findings suggest that primary tumor size could be used as a potential risk factor for predicting intravesical recurrence following TUR of superficial TCC of the bladder without concomitant CIS, and that the pathological characteristics of recurrent tumors are more favorable than those of primary tumors.     

Clinical outcome of conservative therapy for stage T1, grade 3 transitional cell carcinoma of the bladder

BACKGROUND: The objective of this study was to retrospectively investigate the effectiveness of transurethral resection of bladder tumor (TURBT) and intravesical instillation therapy for stage T1, grade 3 (T1G3) transitional cell carcinoma (TCC) of the urinary bladder. METHODS: Between January 1995 and December 1997, 97 patients with T1G3 TCC of the urinary bladder were treated by TURBT and adjuvant intravesical instillation with bacillus Calmette-Guérin (BCG) or other anticancer agents. The recurrence-free survival rates were evaluated according to several clinicopathological factors. The cases that progressed to muscle invasive disease were also analysed. RESULTS: In this series, the median follow-up period was 25 months (range, 5- 41) after the initial TURBT. Intravesical recurrence was noted in 44 patients (45%), and the 1, 2, and 3 year recurrence-free survival rates were 72%, 58%, and 42%, respectively. Multivariate analyses revealed that the risk of intravesical recurrence was significantly higher for patients who did not receive BCG therapy, irrespective of age, gender, tumor size, multiplicity, pathological stage, concomitant carcinoma in situ, and lymphovascular involvement. Moreover, after a median of 10 months, disease progression occurred in seven patients (7%), of which only one patient was treated by BCG therapy after initial TURBT. CONCLUSION: These findings suggest that intravesical instillation with BCG combined with TURBT is an effective conservative treatment for T1G3 TCC of the bladder. Patients with negative prognostic factors should be treated by BCG rather than other anticancer agents after TURBT.     

Results of Transurethral Resection Plus Adjuvant Intravesical Chemotherapy for Superficial Bladder Cancer

Background : We analyzed the results of conservative therapy for superficial bladder cancer to determine the risk factors for recurrence and progression.
Methods : Between May 1984 and February 1997, 111 patients with primary superficial bladder cancer were treated by a transurethral resection with or without intravesical instillation of chemotherapy, or for patients with concomitant carcinoma in situ (CIS), bacillus Calmette-Guerin. We examined the relationship between tumor stage, grade, incidence of concomitant CIS and recurrence-free survival according to pathologic findings and the drugs instilled.
Results : The incidence of concomitant CIS in pTI, grade 3 tumors was significantly higher than that in pTa, grade 1 tumors (42% vs. 3%, P= 0.006). The 5-year recurrence-free survival rate of all patients was 73%. There was no significant difference in recurrence-free survival and pathologic stage, tumor grade, presence of concomitant CIS, or drugs used for instillation. However, the recurrence-free survival in patients with 5 tumors was significantly lower than in patients with less than 5 tumors. Of the 111 patients, only 3 patients demonstrated disease progression and underwent a radical cystectomy, while 1 patient with a pTI b, grade 3 tumor developed a tumor in the ureter. No patient died of bladder cancer.
Conclusion : Our results indicate that the prognosis of superficial bladder cancer patients with a high-stage, high-grade (pTI, grade 3) tumor is favorable when treated by a transurethral resection and intravesical instillation. Bacillus Calmette-Guerin therapy is useful to prevent the recurrence of tumors with concomitant CIS.     

Prognostic factors for survival and bladder recurrence in transitional cell carcinoma of the upper urinary tract

BACKGROUND: Prognostic factors for survival in transitional cell carcinoma of the upper urinary tract have been extensively evaluated, but detailed analyses of patterns of bladder recurrence after surgery have been rare. METHODS: The outcome and tumor recurrence of 93 patients with transitional cell carcinoma of the upper urinary tract surgically treated between 1975 and 1999 were reviewed, retrospectively. Disease-specific survival by pathologic stage and grade were analyzed by the Kaplan-Meier METHOD: Prognostic factors for survival and bladder recurrence were examined by univariate and multivariate analysis. RESULTS: The 5-year disease-specific survival rates of the patients with pTa, T1 and T2 were 92.9%, 100% and 88.9%, respectively. However, that of the pT3 patients was 61.9% and the median survival of the pT4 cases was only 7 months. Bladder recurrence was seen in 40 cases and recurrences occurred within 1 year in 32 of these patients. The stage and grade of metachronous bladder tumors usually resembled those of primary tumors, but invasive recurrences were seen in 19% of recurrent cases with primary pTa, pT1 tumors. The significant prognostic factor for survival was pathologic stage (pT3, pT4), but no significant variables were detected for bladder recurrence by multivariate analysis. CONCLUSIONS: The prognosis of pT3, pT4 patients is poor and effective systemic adjuvant therapy is necessary. Invasive bladder recurrence occurred in 19% of patients with superficial primary tumors. As no significant prognostic variables for bladder recurrence were identified, careful follow up for bladder recurrence is important even if the primary tumors are non-invasive.     

The relation of mutant p53 accumulation in transitional cell carcinoma of bladder with pathological stage,grade, recurrence and survival

In this study prognostic significance and clinical value of mutant p53 gene in bladder transitional cell tumors is investigated.In our clinic, between 1997–2000, transurethral resection was performed in 48 cases, 3 females (6%) and 45 males (94%) with the diagnosis of primary bladder tumor, age ranges between 30–81 years old (average 58.9 ± 9.9).The patients whose pathology results were transitional cell carcinoma weregathered into two groups as p53 positive and p53 negative byimmunuhistochemical study. These cases who were followed 1–36 monthswere compared to each other for pathologic state, tumor grade, recurrenceand survival.It's found out that mutant p53 accumulation is related to high grade andpathologic stage tumors. But it's concluded that p53 positivity doesn'teffect recurrence and survival rates.     

5-aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer

OBJECTIVE: To assess the influence of 5-aminolaevulinic acid-induced fluorescence cystoscopy (FC) during transurethral resection (TUR) on the recurrence rate and the length of tumour-free interval in stage Ta/T1 transitional cell carcinoma (TCC) of the urinary bladder. PATIENTS AND METHODS: In all, 122 patients with primary or recurrent stage Ta/T1 bladder TCC treated with TUR were enrolled in a prospective randomized study. In group A the TUR was performed with standard white-light endoscopy, and in group B with FC. The patients were followed using standard cystoscopy and urinary cytology. The recurrence-free interval was evaluated in whole groups, for single and multiple, and for primary and recurrent tumours separately. RESULTS: At the time of the first cystoscopy (10-15 weeks after TUR) tumour recurrence was detected in 23 of 62 patients (37%) in group A, but only in five of 60 patients (8%) in group B. The recurrence-free survival rates in group A were 39% and 28% after 12 and 24 months, compared to 66% and 40% respectively in group B (P = 0.008, log-rank test). In separate analyses, the recurrence-free survival rates were significantly higher using FC in multiple (P = 0.001) and in recurrent (P = 0.02) tumours. In solitary and primary tumours the median time to recurrence was also longer in group B, but the difference was not statistically significant. CONCLUSION: 5-aminolaevulinic acid-induced FC during TUR reduces the recurrence rate in stage Ta/T1 bladder TCC. The most significant benefit is in patients with multiple and recurrent tumours.     

Recurrence, progression and success in stage Ta grade 3 bladder tumors treated with low dose bacillus Calmette-Guerin instillations

PURPOSE: Bacillus Calmette-Guerin (BCG) therapy is considered to be an effective prophylactic and therapeutic agent for high risk superficial transitional cell carcinoma of the bladder. Nevertheless, in a select uncommon population of stage Ta grade 3 superficial lamina-free tumors the results of this treatment have not yet been well established. We evaluated recurrence and progression rates, and the success of BCG therapy in a population with stage Ta grade 3 transitional cell carcinoma of the bladder. MATERIALS AND METHODS: Of the 605 patients treated at our institution from 1982 to 1996 for the histopathological diagnosis of primary bladder cancer 32 (5.3%) with stage Ta grade 3 noninvasive primary bladder tumor were treated with intravesical instillations of 75 mg. Pasteur strain BCG in 50 ml. saline weekly for 6 weeks. At a followup of 2 to 13 years (mean 58.4 months) patients were evaluated with urinary cytology, cystoscopy, transurethral resection and random mucosal biopsies. Recurrence, grade and stage progression, death and causality were analyzed. RESULTS: Of the 32 patients 9 (28%) responded positively to BCG without recurrence, while disease recurred as stage Ta in 8 (25%) and T1 in 7 (22%), and progressed to muscle layer infiltration in 8 (25%). Four patients (12%) died of bladder cancer. The number of tumors at primary resection, gross examination, the mitotic index or an association with carcinoma in situ did not appear to be predictive factors of progression to muscle invasion. Urine cytology (I to II versus III to IV) appeared to correlate highly with progression and BCG response (p<0.001) with excellent sensitivity (1) but low specificity (0.67). CONCLUSIONS: Our study demonstrates the high progression potential of stage Ta grade 3 tumors, since nearly 50% recurred and 25% progressed to invasive disease. These results may be closely compared with the results of previous trials of stage T1 grade 3 disease. We suggest that recurrence should be detected at an early stage using long-term followup with strict observance of the surveillance protocols during a minimum 5-year tumor-free period.     

The role of bcl-2, p53, and ki-67 index in predicting tumor recurrence for low grade superficial transitional cell bladder carcinoma

PURPOSE: We assess the prognostic significance of bcl-2 expression, p53 mutation and ki-67 index for low grade, superficial transitional cell bladder carcinoma. MATERIALS AND METHODS: The medical records of 93 cases of primary, low grade (24 G1, 69 G2), superficial (70 pTa, 23 pT1) transitional cell carcinoma of the bladder were reviewed. Association of bcl-2, p53 and ki-67 index immunoreactivity with tumor grade and stage was examined. Prognostic significance of tumor grade, pathological stage, bcl-2 expression, p53 mutation and ki-67 index in predicting tumor recurrence was assessed. RESULTS: Of the tumors 60 (70%) had p53 mutation and 9 (10.5%) expressed bcl-2. These 2 markers did not relate to tumor grade or pathological stage. Median ki-67 index was 10.9% and positively correlated with tumor grade. Recurrence was noted in 34.9% of patients with a median followup of 26 months (range 1 to 84). The ki-67 index was the only significant prognostic indicator in univariate and multivariate analyses. This marker can further distinguish grade 2 tumors with a favorable prognosis from those with an unfavorable outcome. CONCLUSIONS: The ki-67 labeling index is an independent predictor of tumor recurrence for patients with primary superficial, low grade bladder cancers.     

A clinical study of recurrence and progression of grade 3 superficial bladder tumor]

Forty-one patients who had grade 3, superficial, transitional cell carcinoma of the bladder were treated with transurethral resection of bladder tumor between January, 1986 and April, 1998. The clinicopathological studies were conducted on intravesical recurrence, disease progression, and prognosis using multivariate analyses. Intravesical recurrence was found in 18 patients (43.9%), and the recurrence-free rate was 77.0% for 1 year. The 3- and 5-year recurrence-free rates were 57.7% and 38.5% for patients with stage pTa disease, and 36.3% and 36.3% for patients with stawe pT1-disease. There was a significant difference between the recurrence-free rates in the patients with stage pTa disease and those with stage pT1 disease (p < 0.01). Disease progression was observed after a mean period of 14.2 months after treatment in 6 patients (14.6%) with pT1 tumors. Three of these patients died of cancer. In the multivariate analyses with clinical and pathological factors, bladder irritability, urine cytology after initial treatment, and tumor multiplicity were the factors contributing to a high risk for recurrence. Intravesical instillation with Calmette-Guerin bacillus was found to prevent recurrence. These results suggest that radical surgery should be performed in a timely manner in patients with G3-stage pT1 tumors because they have a higher risk of recurrence and progression as compared to patients with G3-stage pTa tumors.     

Stage T1, grade 3 transitional cell carcinoma of the bladder: an unfavorable tumor?

Transurethral resection only was performed in 172 patients with initial stage Ta, T1 transitional cell carcinoma of the bladder. Additional treatment during the course of disease was given to 9 patients with carcinoma in situ and to 8 patients with tumor progression. The mean followup was 106 months. The 10-year survival rates were 95 per cent for patients with stage Ta, grade 1 disease, 89 per cent for stage Ta, grade 2, 84 per cent for stage Ta, grade 3, 78 per cent for stage T1, grade 2 and 50 per cent for stage T1, grade 3. The percentage of first tumor recurrence at the same site increased with tumor grade (stage T1, grade 3 was 74 per cent). The recurrence rate in stage T1, grade 3 tumors (4.08) differed significantly from the other groups of superficial tumors. The tumor progression rate for stage T1, grade 3 tumors (32.5 per cent) was significantly higher as well. The characteristics of stage T1, grade 3 tumors with and without progression were different in regard to multiplicity, recurrence rate, mean interval to recurrence and type of tumor invasion. Of the 13 patients who died of progressive neoplastic disease 11 presented initially with stage T1, grade 3 tumors. When these results are considered it is obvious that a patient with a stage T1, grade 3 tumor deserves additional therapy, such as chemotherapy, immunotherapy or phototherapy.     

P16 immunoreactivity is an independent predictor of tumor progression in minimally invasive urothelial bladder carcinoma

OBJECTIVE: To evaluate the prognostic impact of p16 immunoreactivity in minimally invasive transitional cell bladder carcinomas (stage T1). METHODS: Multi-tissue-arrays containing 73 samples of T1 bladder carcinomas were stained immunohistochemically for p16. Additionally, p53 and Ki-67 antigen expression were examined. A multivariate analysis including other prognostically relevant factors like tumor grade and sub-stage was performed. RESULTS: Loss of p16 expression occurred in 54% of cases and was significantly associated with reduced progression-free (p=0.018 by univariate analysis), but not with recurrence-free survival (p=0.341). Median Ki-67 antigen and p53 index were 51% (range, 1-93%) and 10% (range, 0-100%), respectively. Both indices correlated significantly (p=0.041 and p=0.024, respectively) with recurrence-free, but not with progression-free survival. Also tumor grade was significantly associated with tumor recurrence (p=0.006). By multivariate analysis, tumor grade (p=0.008) was identified as an independent predictor of tumor recurrence, whereas p16 expression (p=0.009) was identified as an independent predictor of tumor progression. CONCLUSION: According to our data, there is a significant correlation between loss of p16 expression and tumor progression in patients with minimally-invasive bladder cancer. Immunohistochemical p16 staining may therefore represent a useful tool of providing additional information on the clinical outcome of these patients.     

Decreased expression of KAI1 metastasis suppressor gene is a recurrence predictor in primary pTa and pT1 urothelial bladder carcinoma

OBJECTIVE: To examine the expression of the KAI1 metastasis suppressor gene and to evaluate its relationship with tumor recurrence in primary pTa and pT1 urothelial bladder carcinoma. METHODS: Samples were obtained from 87 patients after transurethral resection (TUR). Tumor stage and grade were reviewed in 33 patients with pTa and in 54 patients with pT1, with a mean follow-up time of 47.4 +/- 30.1 months. The KAI1 protein immunohistochemical assay was performed. Prognosis was analyzed using the Kaplan-Meier method and Cox's proportional hazards model. Correlation between KAI1 expression and recurrence according to each clinicopathological factor was comparatively evaluated using the chi-squared test. RESULTS: Decreased expression of KAI1 protein failed to reach statistical significance for stage (P = 0.25) or morphology of tumor stem (P = 0.19), but it was significantly related to tumor size (P = 0.016). The recurrence-free 5-year survival rates of the group with decreased KAI1 expression was 69.7%, which was significantly higher than the 22.2% for the KAI1-positive group (P < 0.0001). In univariate and multivariate analyses, decreased expression of KAI1 protein, stage pT1, tumor size >3 cm and sessile tumors were independent prognosis factors of recurrence. Despite the lower recurrence rate expected by considering only the clinicopathological factors, decreased KAI1 expression was able to identify the group with a high risk of recurrence. CONCLUSIONS: Downregulated KAI1 expression in bladder tumors tends to relate to stage and morphology of the tumor stem and was significantly correlated to tumor size. Decreased expression of KAI1 was associated with the degree of invasiveness and progression of the cancer and was an independent prognostic factor of recurrence in primary pTa and pT1 urothelial bladder carcinoma.     

Immunohistochemical study of p53 and Ki-67 overexpression in grade 3 superficial bladder tumor in relationship to tumor recurrence and prognosis]

PURPOSE: The major drawback of the current treatment for superficial bladder tumor is the high rate of recurrence. Especially, the tumor with grade 3 component has a tendency to recur and progress in stage. However, we have difficulty in predicting tumor recurrence and stage progression accurately by conventional clinicopathological factors. We evaluated the efficacy of p53 and Ki-67 overexpression as a predictor of recurrence or prognosis in patients with superficial bladder tumor of grade 3. MATERIALS AND METHODS: Samples were obtained from 41 patients with superficial transitional cell carcinoma of the bladder of grade 3 who were treated by transurethral resection (TUR). The immunohistochemical study was performed using the antibodies against the p53 protein and Ki-67 antigen on formalin-fixed, paraffinembedded tissue specimens from initial tumors. We evaluated the correlation between these results and several clinicopathological factors. RESULTS: The p53 index and the Ki-67 index in pTa, pT1a and pT1b tumors were 26.4 +/- 30.1%, 28.6 +/- 30.0%, and 34.6 +/- 32.6% (p53) and 20.5 +/- 22.5%, 20.0 +/- 29.3%, and 29.2 +/- 28.4% (Ki-67). There was no significant difference between the each index and tumor stage. Eighteen cases (43.9%) had intravesical recurrence. The p53 index of the initial tumor from the tumor free cases (n = 23), recurrent cases without stage progression (n = 12), and stage progression cases (n = 6) were 19.7 +/- 28.2%, 42.0 +/- 28.7%, and 42.5 +/- 32.0%. Between the recurrence-free cases and the recurrent cases without progression, the p53 index of the initial tumor had statistical significance (p < 0.05). The Ki-67 index was shown to be the same pattern as the p53 index, but there was not statistical significance. Four of patients with stage progression had tumor progression within six months. Three of the patients with tumors with stage progression died of the cancer. In multivariate analysis, tumor multiplicity (p = 0.01), BCG intravesical instillation (p = 0.04), p53 index (p = 0.01) and Ki-67 index (p = 0.02) were the positive risk factors for tumor recurrence, but only the p53 index was the positive risk factor for prognosis fo the patients (p = 0.03). CONCLUSION: These results suggest that the immunohistochemical study of p53 overexpression is a useful predictor for tumor recurrence and prognosis in patients with superficial bladder tumor with grade 3.     

Prognostic factors in patients with primary transitional cell carcinoma of the upper urinary tract

A total of 50 patients with primary transitional cell carcinoma of the upper urinary tract underwent deoxyribonucleic acid ploidy characterization by flow cytometric analysis of paraffin embedded specimens. The primary tumor was diploid in 29 patients (58%) and aneuploid in 21 (42%). Aneuploidy was identified more frequently in grade 3 than in grades 1 and 2 neoplasms (p = 0.001). Additionally, grade 3 neoplasms occurred more often with invasive (stages T2 to T3) compared to superficial (stages TA, TIS and T1) tumors (p = 0.002). However, deoxyribonucleic acid ploidy was not significantly associated with tumor stage. Among the 49 patients treated by a definitive operation the median survival free of disease and median over-all survival were 33.7 and more than 120 months, respectively. Variables examined included deoxyribonucleic acid ploidy, tumor grade, tumor stage, primary tumor site and type of operation. In the univariate analysis deoxyribonucleic acid ploidy was the only significant predictor of survival free of disease (p = 0.04). Aneuploid tumors had a median survival free of disease of 19 versus 59 months for diploid tumors. However, in the multivariate analysis of factors affecting survival free of disease, the type of operation performed was the only significant variable. Patients undergoing nephroureterectomy with en bloc bladder cuff excision had a favorable survival free of disease (p = 0.04). Tumor stage was the only significant factor associated with over-all survival in univariate and multivariate analyses (p = 0.02 and 0.005, respectively). Patients with superficial tumors had a median survival of more than 120 versus 72 months for patients with invasive tumors. The data suggest that deoxyribonucleic acid ploidy may be a useful parameter to identify risk groups and plan the management of patients with primary transitional cell carcinoma of the upper urinary tract.     

Prognostic significance of bladder tumor history and tumor location in upper tract transitional cell carcinoma

PURPOSE: We studied prognostic factors for 5-year disease specific and recurrence-free survival in patients treated for upper urinary tract transitional cell carcinoma. MATERIALS AND METHODS: Since July 1987, 72 patients with a mean age of 58.9 years have undergone nephroureterectomy with bladder cuff excision. Median followup was 62.2 months (range 6 to 192). Patient age, sex, detection duration and mode, bladder tumor history, smoking habit, stone disease history, and tumor stage, grade and location were evaluated as prognostic factors. RESULTS: Overall 5-year disease specific and recurrence-free survival rates were 74.9% and 67.8%, respectively. Univariate analysis revealed anemia, positive bladder tumor history, T stage, grade and tumor location in the upper tract as significant prognostic factors. On multivariate analysis T stage, grade and tumor location in the urothelium were the only significant variables for the 5-year disease specific and recurrence-free survival rates. CONCLUSIONS: High tumor stage and grade, and ureteral location were significantly associated with worse disease specific and recurrence-free survival in patients with upper urinary tract transitional cell carcinoma. Our results may help define the patient groups that need adjuvant therapy and they may form a basis for further controlled studies.     

Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study

PURPOSE: Bacillus Calmette-Guerin (BCG) immunotherapy has been widely accepted as the optimal treatment for carcinoma in situ and high grade superficial transitional cell carcinoma. However, controversy remains regarding the role of maintenance therapy, and its long-term effect on recurrence and progression. MATERIALS AND METHODS: All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical and percutaneous Connaught BCG. Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm). Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy. The 384 eligible patients who were disease-free at randomization constitute the primary intent to treat analytic group because they could be followed for disease recurrence. All patients were followed for adverse effects of treatment, recurrence, disease worsening and survival. RESULTS: No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months (95% confidence interval 25.1 to 56.8) in the no maintenance and 76.8 months (64.3 to 93.2) in the maintenance arm (log rank p<0.0001). Estimated median time for worsening-free survival, defined as no evidence of progression including pathological stage T2 disease or greater, or the use of cystectomy, systemic chemotherapy or radiation therapy, was 111.5 months in the no maintenance and not estimable in the maintenance arm (log rank p = 0.04). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm. CONCLUSIONS: Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival.     

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.     

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.     

Clinical study of grade 3, superficial transitional cell carcinoma of the urinary bladder]

PURPOSE: To evaluate the treatment of grade 3 superficial (stage pTa and pT 1) transitional cell carcinoma (T.C.C.) of the urinary bladder, retrospective analysis was performed with special reference to tumor prognostic factors. MATERIALS AND METHODS: From July 1971 to september 1995, 51 cases with grade 3 superficial T.C.C. of the urinary bladder were treated. The survival rates and prognostic factors of these patient were analyzed. RESULTS: Five year survival rate of grade 3, superficial tumors was 92.3% and showed significantly better prognosis compared to patients with pT 2 and pT 3 tumors of grade 3 (p < 0.001). As a initial treatments, transurethral resection (TUR) was conducted in 45 patients (88%). Intravesical recurrence was observed in 20 of 45 patients (44%) and 12 of 20 patients (60%) were recurred within 1 year. Non-recurrent rates of the patients treated with TUR were 69.6% at 1 year, 58.8% at 3 year, 49.7% at 5 year, respectively. No significant differences were noted regarding factors of tumor size, figures and a number of tumor. Of the 51 patients, 10 (19.6%) progressed beyond stage T 2 and 6 died with the disease. Survival rates at 10 years follow up in patients with non-papillary and papillary tumor were 57.1% and 97.8%, respectively. CONCLUSION: These results suggested that TUR should be performed as a initial treatment for the patients with grade 3 superficial T.C.C. of the urinary bladder. However, non-papillary tumors should be considered of more intensive treatment like as radical cystectomy, adjuvant chemotherapy or irradiation.