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.     

Multivariate analysis of the prognostic factors of primary superficial bladder cancer

PURPOSE: We evaluate the prognostic factors of recurrence, progression and disease specific mortality in patients with primary superficial Ta and T1 transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We studied a cohort of 1,529 patients with primary superficial transitional cell carcinoma of the bladder treated with transurethral resection and random bladder biopsies. Mean followup was 4.2 years. Statistical analysis was performed using the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model with stepwise forward selection. All p values were 2-sided, with odds ratios and 95% confidence intervals. RESULTS: Multiple tumors (odds ratio 2), tumor greater than 3 cm. (1.65) and carcinoma in situ (1.6) increased, whereas intravesical bacillus Calmette-Guerin (BCG) instillations (0.39) decreased the risk of recurrence. Grade 3 disease (odds ratio 19.9), multiple tumors (1.9), tumor greater than 3 cm. (1.7) and carcinoma in situ (2.1) increased, whereas BCG (0.3) decreased the risk of progression. Grade 3 disease (odds ratio 14) and carcinoma in situ (odds ratio 3) increased the risk of disease specific mortality. CONCLUSIONS: Neither tumor stage nor dysplasia influenced tumor evolution. Multiple tumors, tumor greater than 3 cm. and intravesical BCG instillations were risk factors of recurrence and progression. Carcinoma in situ influenced recurrence, progression and disease specific mortality. Finally, the main predictor of progression and mortality was grade 3 disease.     

A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: is it effective?

Bacillus Calmette-Guerin (BCG) intravesical therapy represents a major advance in the treatment of superficial transitional cell carcinoma of the bladder. To date, however, the optimal treatment schedule must be defined and the toxicity related to the treatment is significant. The preliminary results of a randomized ongoing study performed to evaluate the effectiveness and relative toxicity of a low dose (75 mg.) BCG regimen in the treatment of superficial bladder cancer therapy are reported. A total of 126 patients (70 for prophylaxis of recurrent stages Ta and T1 papillary tumors and 56 for treatment of carcinoma in situ or with microinfiltration of the subepithelial connective tissue) underwent a 6-week course of 75 mg. BCG (Pasteur vaccine). An additional course was given in patients who failed to respond to the induction course. Maintenance therapy was administered in complete responders monthly for 1 year and then quarterly for 1 year. The prophylaxis group (transurethral resection plus BCG) was randomized versus transurethral resection alone (63 patients, control group). A complete response in the prophylaxis, control and therapy groups was observed in 74, 17 and 57% of the patients, respectively, while 4, 17 and 12.5%, respectively, experienced tumor progression. The additional course of therapy increased the response rate. On the contrary, previous unsuccessful intravesical chemotherapy did not affect the response rate. In regard to toxicity, irritative disturbances (27%) and fever (17%) appeared to be significantly decreased compared with the rates reported in the literature. No major complications were experienced. In conclusion, a low dose (75 mg.) Pasteur strain BCG regimen was effective as prophylaxis against recurrent superficial papillary tumors and as treatment of carcinoma in situ or with microinfiltration of the subepithelial connective tissue. Toxicity related to the treatment appeared to be low.     

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.     

A trial of bacillus Calmette-Guérin versus adriamycin in superficial bladder cancer: a South-West Oncology Group Study

One hundred and sixty-one evaluable patients with biopsy-confirmed transitional cell carcinoma of the bladder were studied in a cooperative protocol comparing intravesical BCG and adriamycin. Patients have been followed for 2-25 months (median 15.7 months) with cystoscopy at 3-month intervals, urinary cytology, and bladder biopsy. Sixteen of 88 patients (19%) who received BCG immunotherapy developed tumor recurrence compared with 45 recurrences (54%) in the 83 patients who received adriamycin chemotherapy (p less than 0.001, chi 2). Eighty-nine of the randomized patients had documented carcinoma in situ. The complete response rate in 41 patients with carcinoma in situ who received BCG was 85%, compared with a complete response rate of only 39% in 46 patients who received adriamycin (p less than 0.001, chi 2). These data suggest that BCG immunotherapy is superior to adriamycin chemotherapy in the prevention of recurrent superficial transitional cell carcinoma and the treatment of in situ carcinoma of the urinary bladder.     

Immunotherapy for bladder cancer

The primary role of immunotherapy for bladder cancer is to treat superficial transitional cell carcinomas (ie, carcinoma in situ, Ta, and T1). Immunotherapy in the form of bacille Calmette-Guérin (BCG), interferon, bropirimine, keyhole limpet hemocyanin, and gene therapy is intended to treat existing or residual tumor, to prevent recurrence of tumor, to prevent progression of disease, and to prolong survival of patients. Presently, BCG is commonly used and is the most effective immunotherapeutic agent against superficial transitional cell carcinoma. Data support that BCG has a positive impact on tumor recurrence, disease progression, and survival. Proper attention to maintenance schedules, route of administration, dosing, strains, and viability is essential to obtain the maximum benefits of BCG immunotherapy. This review highlights and summarizes the recent advances concerning immunotherapy, with special emphasis on BCG therapy for transitional cell carcinoma.     

Recurrence and progression in stage T1G3 bladder tumour with intravesical bacille Calmette-Guérin (Danish 1331 strain)

OBJECTIVE: To report recurrence and progression rates in patients with T1G3 superficial bladder carcinoma treated with intravesical bacille Calmette-Guérin (BCG, Danish 1331 strain) after complete transurethral resection. PATIENTS AND METHODS: Data from the records of 111 patients with T1G3 bladder carcinoma treated between January 1991 and December 1999 were analysed for recurrence, progression, salvage therapy and survival. RESULTS: Of the 111 patients with T1G3 bladder tumours, 69 had intravesical BCG therapy, 20 radical cystectomy and 22 only transurethral resection (TUR). Of the 69 patients receiving BCG therapy 37 (54%) had no recurrence, and 24 (35%) had a recurrence that was not muscle-invasive (Ta/T1) and were treated with TUR only. The remaining eight (12%) progressed to muscle invasion and had salvage cystectomy. During the follow-up six patients died, four from disease and three from other causes, while the remaining 63 are alive and well. Of the other 42 patients, 15 are alive after radical cystectomy and 18 after TUR. CONCLUSION: This series further confirms the benefits of intravesical BCG (Danish 1331) in an adjuvant setting; furthermore, this treatment facilitates bladder preservation by reducing recurrences and delaying the progression in many patients.     

Results of adjuvant intravesical Bacillus Calmette-Guérin therapy for grade 3 superficial bladder cancer

To examine the incidence of recurrence, progression and survival in patients with grade 3 superficial bladder cancer after transurethral resection (TUR) and adjuvant intravesical instillation of Bacillus Calmette-Guérin (BCG), we retrospectively studied 39 patients with grade 3 superficial bladder cancer. Nineteen patients with high-grade superficial bladder cancer (pTa, pT1) and 5 patients with grade 3 carcinoma in situ (CIS) received intravesical instillation of BCG after transurethral resection of the bladder tumor (BCG group and CIS-BCG group). The Tokyo 172 strain BCG was given for 8 weeks, as a rule, in a dose of 80 mg in 40 ml of saline instilled into the bladder. As a control, 15 patients with grade 3 superficial bladder cancer who did not receive BCG therapy after TUR were compared (non-BCG group). Of the BCG group (n=19), 4 patients (21.1%) had recurrent tumor and 3 had invasive progression after BCG therapy and died as a result of tumor progression, while in the non-BCG group (n=15), 8 cases (53.3%) developed recurrence, only one case had progression and died of cancer. In the CIS-BCG group (n=5), 3 patients (60.0%) had recurrent tumor and 2 had invasive progression. Univariate analysis (Logrank test) demonstrated that tumor size and adjuvant instillation of BCG were associated with tumor recurrence except for carcinoma in situ, but tumor progression and survival did not differ significantly. Our results suggest that BCG therapy prevents grade 3 superficial bladder cancer (pT1, pTa) recurrence.     

The ablative effect of quarter dose bacillus Calmette-Guerin on a papillary marker lesion of the bladder

PURPOSE: Low dose bacillus Calmette-Guerin (BCG) for stage TaT1 transitional cell carcinoma of the bladder has been given in various studies with the aim of decreasing side effects while maintaining the same efficacy as full dose bacillus Calmette-Guerin. However, its application in clinical practice remains controversial. We examined the ablative activity and incidence of side effects of intravesical quarter dose BCG given for a papillary marker lesion of the bladder. MATERIALS AND METHODS: Included in our study were 44 patients with primary or recurrent, multiple but no more than 10 lesions of stage pTaT1, grades 1 to 2 transitional cell carcinoma of the bladder. Intravesical treatment begun 14 days after the complete transurethral resection of all visible tumors except 1 marker lesion no larger than 1 cm. consisted of instillations of 30 mg. Connaught strain BCG diluted in 50 ml. saline once weekly for 6 consecutive weeks. Two weeks after the last instillation any residual tumor was completely resected. In cases of complete disappearance of the marker lesion deep biopsy of the tumor area was done. Urine cytology was also performed. RESULTS: There was a complete response in 27 of the 44 patients (61%), no response in 12 (27%) and progression to carcinoma in situ in 1 (2%), while the response was not evaluable in 4. Local side effects included dysuria in 54% of cases and macroscopic hematuria in 39%. Neither BCG induced infection nor BCG sepsis was observed. CONCLUSIONS: Quarter dose BCG has a clear ablative effect on superficial bladder cancer with a 61% response rate. Phase III trials are now required to compare its efficacy and toxicity to those of full dose BCG.     

Oral or intravesical bacillus Calmette-Guerin immunoprophylaxis in bladder carcinoma

A total of 71 patients with superficial transitional cell carcinoma underwent transurethral resection of bladder tumor. All patients had stage pTa or pT1 transitional cell carcinoma or carcinoma in situ without other concurrent malignancies. The patients were assigned to 3 treatment groups: control group--transurethral resection discontinued within the study, oral bacillus Calmette-Guerin (BCG) group--transurethral resection of bladder tumor plus BCG (Moreau) and intravesical BCG group--transurethral resection of bladder tumor plus BCG. Of 9 patients in the control group 8 (89%) experienced tumor recurrence during a mean followup of 20 months. Of the 28 patients in the oral BCG group 11 (39.3%) had recurrence during a mean followup of 36 months. Of the 34 patients in the intravesical group 6 (18%) had recurrence in a 24-month mean followup. The incidence of complications was higher in the intravesical (41.2%) than in the oral BCG group (28.5%). These results show that intravesical BCG is a more effective immunotherapy; however, oral BCG can be used in patients who do not accept intravesical BCG administration.     

Cyclooxygenase-2 is highly expressed in carcinoma in situ and T1 transitional cell carcinoma of the bladder

PURPOSE: We describe cyclooxygenase-2 (COX-2) expression patterns in patients with carcinoma in situ and/or stage T1 transitional cell carcinoma. We determined whether expression is associated with clinical outcome in these patients. MATERIALS AND METHODS: Immunostaining for COX-2 was performed on paraffin embedded bladder biopsy specimens from 2 independent groups of patients without muscle invasive carcinoma, including 39 with carcinoma in situ and 34 with stage T1 tumors. Immunoreactivity was scored as the percent of carcinoma in situ cells with cytoplasmic staining for COX-2 in the carcinoma in situ group and as the percent of stage T1 cells expressing COX-2 in the stage T1 transitional cell carcinoma group. We evaluated other molecular alterations, including E-cadherin, p21 and p53, because evidence suggests a biological association of COX-2 with alterations in these molecular markers. RESULTS: In the carcinoma in situ group 5 patients (13%) had no immunoreactivity, while 2 (5%), 5 (13%) and 27 (69%) had 10%, 20% and 30% or greater carcinoma in situ cells positive for COX-2, respectively. In the transitional cell carcinoma group 1 (3%), 4 (12%) and 29 (85%) patients had 10%, 20% and 30% or greater positive cells, respectively. COX-2 expression was not associated with any clinical or pathological parameters, or with molecular markers regardless of the cutoff used. It was also not associated with clinical outcomes in the stage T1 transitional cell carcinoma group. In the carcinoma in situ group COX-2 expression was significantly associated with disease recurrence using cutoffs of 0% and greater than 10% positive cells, and with disease progression using a greater than 20% cutoff. However, it was not associated with bladder cancer related survival. CONCLUSIONS: COX-2 is expressed in a high percent of patients with carcinoma in situ and stage T1 transitional cell carcinoma, supporting the rationale for chemoprevention studies with selective COX-2. We could not substantiate a role for COX-2 immunohistochemistry for the staging and prognosis of carcinoma in situ and/or stage T1 transitional cell carcinoma.     

Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor

PURPOSE: To review understaging and outcome of patients who underwent radical cystectomy (RC) for high risk superficial bladder cancer after bacillus Calmette-Guérin (BCG) failure. PATIENTS AND METHODS: We carried out a retrospective study of 62 cases in which RC was indicated for clinical stage Tis, Ta, T1 transitional cell bladder tumors that failed transurethral resection (TUR) and BCG treatment. We used BCG (81 mg/Connaught BCG) in patients with superficial grade 3 tumors and CIS. We considered BCG failure a high-grade recurrence at 3 months of the first BCG course or after 2 courses. RC indications, correlation between their clinical and pathological stage and the ensuing progress were analyzed. We assessed the existence of any pre-cystectomy clinical or pathological factor related to understaging and survival. RESULTS: RC was performed in 22 patients with carcinoma in situ (CIS) (35%), 7 with Ta (11,2%), 31 with T1 (50%), and 2 with Tx tumors (3%). All 62 but one were high-grade tumors (grade 3 and/or CIS). Tumor was clinically understaged with stages pT2 or greater on the RC specimen in 17 patients (27%). The presence of tumor in the prostatic urethra at the moment of endoscopic staging before RC was the only factor associated with clinical understaging (p=0.003) and shorter survival (p<0.0002). Five-year disease-specific survival rate was significantly lower in understaged (38%) as compared with not-understaged patients (90%) after a median follow-up of 40-months (range 1-142) (p=0.006). Overall five-year disease-specific survival was 79%. CONCLUSIONS: RC should be performed prior to progression in high risk superficial tumors that fail after TUR and BCG. In patients with clinical and pathological nonmuscle invasive disease, RC provides an excellent disease-free survival. One third of patients with HRSBT who underwent RC after BCG failure were understaged and had a shorter survival. Tumor in the prostatic urethra at endoscopic staging was the only factor associated to understaging and shorter survival.     

Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer

OBJECTIVES: To examine in a prospective study the incidence of recurrence and progression in patients with Stage T1 bladder carcinoma after complete transurethral resection of the bladder tumor and adjuvant immunotherapy with bacillus Calmette-Guérin (BCG). METHODS: Between July 1987 and April 1999, 126 patients presenting to our clinic with a superficial urothelial carcinoma of the bladder (Stage pT1, grade 1-3) received adjuvant intravesical immunotherapy with BCG after complete transurethral resection of the bladder tumor. In the case of recurrence of superficial tumor (pTa, pT1, or carcinoma in situ), patients received a second cycle of BCG. For muscle-invasive tumor progression (pT2, pT3, or pT4), radical cystectomy was recommended. Six of the patients (5%) presented with Stage pT1,G1 tumor, 74 (59%) with Stage pT1,G2 tumor, and 46 patients (36%) with Stage pT1,G3 tumor. Median follow-up was 53 months (range 3 to 144). RESULTS: One hundred eight patients (86%) remained tumor-free with a retained bladder during the follow-up after one or two 6-week cycles of BCG. Twenty-four patients (19%) had a recurrence of superficial tumor, 13 (10%) had muscle-invasive progression after the first BCG cycle, and an additional 4 (3%) had progression after the second BCG cycle. Six patients (5%) underwent radical cystectomy, and 9 patients (7%) died as a result of tumor progression. The tumor-free survival rate of all patients was 89% (112 of 126). CONCLUSIONS: Adjuvant immunotherapy with BCG after complete transurethral resection of the bladder tumor represents a highly effective primary treatment for Stage T1 carcinoma of the bladder. Even in Stage pT1,G3 tumor, immediate radical cystectomy does not appear necessary.     

Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy

PURPOSE: This study was an evaluation of whether restaging transurethral resection (TUR) of superficial bladder cancer improves the early response to bacillus Calmette-Guerin (BCG) therapy. MATERIALS AND METHODS: A total of 347 patients with high risk superficial bladder cancer (high grade Ta and T1 tumors associated with carcinoma in situ) underwent a single transurethral resection (TUR, 132 patients) or restaging TUR (215 patients) before receiving 6 weekly intravesical BCG treatments. The patients were evaluated for response (presence or absence of tumor) at first followup cystoscopy, at 6 and 12 months after treatment, and evaluated for disease stage progression within 3 years of followup. RESULTS: Of the 132 patients who underwent a single TUR before BCG therapy, 75 (57%) had residual or recurrent tumor at the first cystoscopy and 45 (34%) later had progression, compared with 62 of 215 patients (29%) who had residual or recurrent tumors and 16 (7%) who had progression after undergoing restaging TUR (p = 0.001). CONCLUSIONS: Restaging TUR of high risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency of subsequent tumor recurrence and appears to delay early tumor progression.     

Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials

PURPOSE: We determine if intravesical bacillus Calmette-Guerin (BCG) reduces the risk of progression after transurethral resection to stage T2 disease or higher in patients with superficial (stage Ta, T1 or carcinoma in situ) bladder cancer. MATERIALS AND METHODS: A meta-analysis was performed of the published results of randomized clinical trials comparing transurethral resection plus intravesical BCG to either resection alone or resection plus another treatment other than BCG. RESULTS: We identified 24 trials with progression information on 4,863 patients. Based on a median followup of 2.5 years and a maximum of 15 years, 260 of 2,658 patients on BCG (9.8%) had progression compared to 304 of 2,205 patients in the control groups (13.8%), a reduction of 27% in the odds of progression on BCG (OR 0.73, p = 0.001). The percent of patients with progression was low (6.4% of 2,880 patients with papillary tumors and 13.9% of 403 patients with carcinoma in situ, reflecting the short followup and relatively low risk patients entered in many of the trials. The size of the treatment effect was similar in patients with papillary tumors and in those with carcinoma in situ. However, only patients receiving maintenance BCG benefited. There was no statistically significant difference in treatment effect for either overall survival or death due to bladder cancer. CONCLUSIONS: Intravesical BCG significantly reduces the risk of progression after transurethral resection in patients with superficial bladder cancer who receive maintenance treatment. Thus, it is the agent of choice for patients with intermediate and high risk papillary tumors and those with carcinoma in situ.     

Pretreatment p53 nuclear overexpression as a prognostic marker in superficial bladder cancer treated with Bacillus Calmette-Guérin (BCG)

INTRODUCTION: Altered p53 gene product correlates with the stage and grade of bladder tumor, but its value as a predictor of BCG response has been disappointing. In order to revisit the prognostic value of pretreatment p53 nuclear overexpression for the BCG response, we studied a large cohort of consecutive patients with superficial bladder cancer treated with BCG. METHODS: From 1988 to 2001, 102 patients with a history of multifocal, recurrent, and/or high-risk papillary transitional cell carcinoma or carcinoma in situ, were treated for the first time with BCG. p53 immunostaining was performed on paraffin-embedded tissues using monoclonal antibody DO7 and an automated immunostainer. Special attention was paid to the conditions of tumor fixation. p53 overexpression was defined as more than 20% tumor cells with p53-stained nuclei. RESULTS: Immunostaining was significantly higher for Ta/T1 G3 +/- Cis (p < 0.001), tumoral substage T1b (p = 0.001), grade 3 (p = 0.0001), and Cis (p = 0.002). Times to recurrence, progression and cancer death were shorter among patients with p53 overexpression (p = 0.03; p < 0.0001; p = 0.0003). In multivariate analysis, p53 overexpression was an independent predictor of recurrence (p = 0.0003) [RR = 0.15; 95%CI, 0.06 to 0.42]. CONCLUSION: Pretreatment p53 nuclear overexpression in superficial bladder tumors is associated with a high risk of disease recurrence, progression and cancer death after BCG therapy. Applying antibody DO7 with an automated immunostainer and stringent fixative conditions, p53 nuclear immunostaining yields clinically relevant information and may be a useful tool for selecting patients with superficial bladder cancer who might be resistant to BCG.     

Total cystectomy after intravesical bacillus Calmette-Guérin (Tokyo strain) therapy for superficial bladder cancer: Experience in Japan

To clarify which patients might most require total cystectomy after intravesical bacillus Calmette-Guérin (BCG) therapy, we reviewed data for 111 individuals with superficial bladder cancer. Of the 111 patients, 73 received the BCG treatment for prophylaxis of intravesical recurrence after transurethral resection (group 1), 24 therapeutically for Ta or T1 tumours (group 2), and 14 for eradicating carcinomas in situ (CIS, group 3). Although the BCG therapy significantly reduced frequencies of recurrence in group 1, 27 patients (37%) did develop tumours again. Tumours disappeared in 18 of 24 patients (75%) in group 2, and in 11 of 14 (79%) in group 3. The rate of disease progression was 6% for all 111 patients: 3% (2/73) for group 1, 17% (4/24) for group 2, and 7% (1/14) for group 3. A total of 16 of the 111 patients (14%) underwent total cystectomy, the respective figures being 7% in group 1, 29% in group 2, and 29% in group 3. Indications for total cystectomy were progression in 7, recurrent multiple tumours in 5, persistent CIS in 2, a contracted bladder in 1, and occurrence of bilateral renal pelvic cancer in 1. Thus, 4 of 6 patients (67%) who had tumours unresponsive to BCG therapy in group 2 demonstrated progression and necessitated total cystectomy. Because tumours persisting after BCG therapy are frequently of the muscle-invasive type, such cases should be regarded as candidates for immediate total cystectomy.     

Intravesical bacillus Calmette-Guerin for patients with high-risk superficial bladder cancer

Intravesical bacillus Calmette-Guérin (BCG) was employed in the treatment of 55 patients with aggressive superficial transitional cell carcinoma of the bladder (cTa, cT1, cTis). All of the patients had a previous history of recurrent superficial disease, and 41 (75%) were treatment failures following other intravesical therapy. Thirty-six (66%) patients responded to treatment, and 19 (34%) were treatment failures. Twenty-seven (66%) of 41 patients with cTa-cT1 tumors and 9 (64%) of 14 patients with cTis responded, with a mean follow-up period of 30.5 months. Disease progression was noted in 8 (15%) of the patients and muscle invasive disease in 6. Patients with a history of three or more previous events of tumor recurrence, positive urinary cytology, and multicentric disease, all fared worse than patients without these characteristics (p less than 0.05). BCG is an effective agent in controlling superficial transitional cell carcinoma of the bladder, even in a high-risk group of patients who failed previous intravesical therapy. BCG should be employed in this group of patients prior to radical surgery.     

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.     

Long-term followup of initial Ta grade 1 transitional cell carcinoma of the bladder

PURPOSE: We evaluate the long-term outcome of initial Ta grade 1 transitional cell carcinoma. MATERIALS AND METHODS: A total of 152 patients with initial Ta grade 1 bladder tumor were followed for a mean of 76 months (range 6 to 241). Recurrence was defined as positive findings on cystoscopy or biopsy. Progression was defined as an increase in tumor grade or stage. RESULTS: Tumor recurrence in 83 of 152 patients (55%) was noted within 12 months of followup in 38 patients (46%), between 12 and 24 in 11 (13%), and between 24 and 60 in 22 (27%). A significant number of recurrences (12, 14%) were diagnosed more than 60 months after the first tumor. Of 83 patients with recurrence 31 (37%) had progression, including 21 to grade 2 and 2 to grade 3 disease. Carcinoma in situ was diagnosed in 3 patients and 5 had muscle invasive disease. Progression occurred more than 24 months after initial diagnosis in 20 patients and more than 60 months after first tumor event (2 had carcinoma in situ and 2 had muscle invasive disease) in 12. CONCLUSIONS: Ta grade 1 bladder transitional cell carcinomas have a high recurrence rate and progression is not uncommon. These findings warrant close long-term followup, even when in some settings the trend is to discontinue followup after 5 years without any abnormal findings.