Randomized intergroup comparison of bacillus calmette-guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder a southwest oncology group study

To compare the toxicity and efficacy of intravesical bacillus Calmette-Guérin (BCG) immunotherapy and mitomycin C (MMC) chemotherapy in the prophylaxis of recurrent transitional cell carcinoma, 469 patients with completely resected stage Ta or TI transitional cell carcinoma were enrolled in a randomized Southwest Oncology Group Phase III study. All patients were judged to be at increased risk for tumor recurrence due to having had two occurrences of tumor within 56 weeks, stage T I tumor or three or more tumors within 16 weeks, or concurrent carcinoma in situ. Three hundred and seventy-seven evaluable patients received either 50 mg of Tice BCG in 50 cc saline or 20 mg MMC in 20 cc water weekly for 6 weeks and then monthly to one year. Local and systemic grade I and 2 toxicity was seen significantly more frequently following BCG treatment (P = 0.003), but no life threatening toxicity was seen with either treatment. Recurrence-free survival was significantly prolonged (P = 0.017, proportional hazard regression) in patients randomized to the BCG arm compared to the MMC arm, but there were no statistically significant differences at this analysis for worsening-free survival and overall survival, although the number of these events is too low for a definitive analysis of these long-term outcomes. Therefore, when compared to MMC chemotherapy, BCG immunotherapy is associated with a significantly higher frequency of grade 1 and 2 adverse reactions and a significantly lower first recurrence hazard rate.     

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.     

Bacillus Calmette-Guerin: Is monthly maintenance an option for transitional cell carcinoma of the bladder?

Purpose: Recently, a Southwest Oncology Group study (SWOG 8507) demonstrated increased efficacy for a bacillus Calmette-Guerin (BCG) maintenance (mtce) program (3 weekly treatments at 3 months, 6 months, and every 6 months thereafter for 3 years) following 6 weekly instillations with BCG as compared to no mtce (“6+3” protocol). The remarkable results from the mtce arm were unfortunately accompanied by grade 3 or 4 toxicity in 26%. In fact; only 16% of the patients in the maintenance arm received BCG at each of the 7 prescribed courses. Herein, we report on a series of 37 patients with high risk (rapidly recurring grade 2 or 3) Ta, T1 transitional cell carcinoma (TCC) or carcinoma in situ (TIS) of the bladder who received 6 weekly BCG treatments followed by monthly mtce for one year. Patients and Methods: This was a prospective, non-randomized trial of 37 patients with high risk superficial transitional cell carcinoma (TCC) who received one or two 6-week induction courses of intravesical Tice BCG, followed by monthly mtce for 12 months. Entry criteria were identical to those of SWOG 8507. The mean follow-up interval was 40.7 months. Results: Twenty eight of thirty-seven patients (75.7%) remained free of disease recurrence at a median of 40.7 (range 13–101) months. Only one patient progressed to muscle invasive disease. Only 1 of 37 (2.7%) patient experienced grade 3/4 toxicity. Conclusion: In this single institution, monthly maintenance protocol, freedom from recurrence was significant with dramatically less grade 3 or 4 toxicity than reported in SWOG 8507.     

Bacillus Calmette-Guerin. Is monthly maintenance an option for transitional cell carcinoma of the bladder?

Purpose: Recently, a Southwest Oncology Group study (SWOG 8507) demonstrated increased efficacy for a bacillus Calmette-Guerin (BCG) maintenance (mtce) program (3 weekly treatments at 3 months, 6 months, and every 6 months thereafter for 3 years) following 6 weekly instillations with BCG as compared to no mtce ("6+3" protocol). The remarkable results from the mtce arm were unfortunately accompanied by grade 3 or 4 toxicity in 26%. In fact; only 16% of the patients in the maintenance arm received BCG at each of the 7 prescribed courses. Herein, we report on a series of 37 patients with high risk (rapidly recurring grade 2 or 3) Ta, T1 transitional cell carcinoma (TCC) or carcinoma in situ (TIS) of the bladder who received 6 weekly BCG treatments followed by monthly mtce for one year. Patients and Methods: This was a prospective, non-randomized trial of 37 patients with high risk superficial transitional cell carcinoma (TCC) who received one or two 6-week induction courses of intravesical Tice BCG, followed by monthly mtce for 12 months. Entry criteria were identical to those of SWOG 8507. The mean follow-up interval was 40.7 months. Results: Twenty eight of thirty-seven patients (75.7%) remained free of disease recurrence at a median of 40.7 (range 13-101) months. Only one patient progressed to muscle invasive disease. Only 1 of 37 (2.7%) patient experienced grade 3/4 toxicity. Conclusion: In this single institution, monthly maintenance protocol, freedom from recurrence was significant with dramatically less grade 3 or 4 toxicity than reported in SWOG 8507.     

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

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

Failure to achieve a complete response to induction BCG therapy is associated with increased risk of disease worsening and death in patients with high risk non-muscle invasive bladder cancer

PurposeThe Southwest Oncology Group conducted a randomized trial of induction bacillus Calmette-Guérin (BCG) with or without maintenance BCG. In these additional retrospective analyses, our goal was to evaluate the association of a complete response (CR) or remaining with no evidence of disease (NED) vs. no CR during induction therapy with subsequent survival after adjusting for other potential confounders. Among all patients randomized to maintenance treatment, we also wanted to identify combinations of baseline covariates in order to define prognostic groups for subsequent worsening-free survival.MethodsOutcome measures of worsening-free and overall survival were assessed using Kaplan Meier estimates and proportional hazards regression models. For the classification and regression tree (CART) analysis, 434 patients randomized to maintenance vs. no therapy with complete covariate information were included.ResultsOf the 593 evaluable patients, 341 were not randomized to maintenance BCG. Patients who achieved a prior complete response during induction BCG had a 5-year survival probability of 77% compared with 62% for patients who did not [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.44, 0.81; P = 0.0008]. Prior CR retained significance when adjusted for age, gender, prior intravesical chemotherapy, and papillary disease versus CIS (HR = 0.63; 95% CI: 0.46, 0.86; P = 0.003). CART analysis identified 4 prognostic groups. Older patients (≥62 years old) previously treated with intravesical chemotherapy who failed to achieve a CR had a 5-fold higher risk of a worsening event relative to those who are younger (<67 years old) and achieve a CR (HR = 5.09; 95% CI: 3.37, 7.68; P < 0.0001).ConclusionFailure to achieve a complete response after induction BCG is associated with a significant risk of a worsening event and death for patients with CIS or Ta or T1 bladder cancer at increased risk of recurrence.     

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.     

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.     

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

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

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.     

Intravesical gemcitabine in BCG-refractory T1G3 transitional cell carcinoma of the bladder: a pilot study

OBJECTIVE: The aim of this pilot study is to analyze the safety and short-term efficacy of gemcitabine (GEM) as salvage intravesical therapy in a very selected population of bacille Calmette-Guérin (BCG)-resistant T1G3 patients. METHODS: 9 recurrent BCG-refractory pT1G3 patients, unsuitable for radical treatment, were treated with GEM, and compared with 10 pT1G3 patients previously treated with at least two courses of transurethral resection plus BGC, with further conservative endovesical BCG administration. RESULTS: Both intravesical administrations of GEM and BCG were generally well tolerated: no severe adverse events were reported. Of the 9 patients treated with GEM, 3 were recurrence-free after 13, 17 and 21 months and 7 kept an intact bladder, with an overall survival rate of 9 of 9. Among 10 patients treated with BCG instillation, 1 was recurrence-free after 27 months and 6 kept their bladders, with a survival rate of 8 of 10. CONCLUSIONS: Our experience confirms the high risk of tumor recurrence and progression of BCG-refractory pT1G3 transitional cell carcinoma. In this case, further BCG courses seem to be unsuitable, resulting in a high risk of tumor progression and mortality. The use of GEM in BCG-refractory pT1G3 patients has to be considered experimental until multicentric randomized studies with adequate follow-up are able to confirm the preliminary results of this pilot study.     

表浅性膀胱肿瘤的预后

从１９８０年１月至１９９１年１２月，对１２１例表浅性膀胱肿瘤进行回顾性研究，首次手术采用经尿道肿瘤电灼术，电切术或膀胱部分切除术，术后配合膀胱内灌药辅助治疗。其中６０例术后复发（４９．６％），术后１、２、３和５年的无瘤率分别为８６．８％、７６．８％、７３．５％和６８．６％。资料表明，初诊时呈多发者、直径大于１ｃｍ和细胞恶性分级高的肿瘤术后无瘤率分别低于单发者、直径小于１ｃｍ和细胞恶性分级低的肿瘤，有显著性差异（Ｐ＜０．０５）。术后６个月内肿瘤复发者经治疗后肿瘤再次复发的机会高。术后膀胱内灌药可以预防肿瘤复发，以灌注丝裂霉素和卡介苗效果好。     

Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette-Guerin therapy.

We reviewed our results with 86 patients who had a pretreatment history of a stage T1 tumor. All patients were treated with transurethral resection of all visible tumor followed by intravesical bacillus Calmette-Guerin (BCG) and many patients received additional maintenance therapy. Local recurrences were treated with repeat transurethral resection followed by additional BCG. Median followup was 59 months, with a range of 9 to 149 months. Overall, 78 of 86 patients (91%) were free of tumor recurrence with BCG therapy. This result includes 69% of the patients who responded to the initial transurethral resection and intravesical BCG, and 22% who ceased having tumors after additional treatments for local recurrences. Only 7% of the patients had progression to stage T2 tumors after BCG therapy. Grade of the stage T1 tumor, concurrent carcinoma in situ and tumor multiplicity before BCG did not predict tumor recurrence or progression. Of patients with recurrences after BCG therapy, those with stage T1 tumors had a higher rate of progression compared to those with stage Ta tumors but the difference was not statistically significant (p = 0.086). These data clearly support the efficacy of transurethral resection plus intravesical BCG immunotherapy in the treatment of stage T1 tumors as well as in the prevention of disease progression.     

A single‐institution experience with induction and maintenance intravesical docetaxel in the management of non‐muscle‐invasive bladder cancer refractory to bacille Calmette‐Guérin therapy

OBJECTIVE

To analyse the durability of response for patients with non‐muscle‐invasive bladder cancer (NMIBC) refractory to bacille Calmette‐Guérin (BCG) therapy and treated with intravesical docetaxel in a combined induction and maintenance regimen.

PATIENTS AND METHODS

A previous phase I trial showed docetaxel to be safe for intravesical therapy, with no systemic absorption and minimal toxicity after six weekly instillations for patients with BCG‐refractory NMIBC. In that trial, docetaxel gave a 56% complete response (CR) rate at 12 weeks, but the durability was only 22%. Thus a second group of patients was treated with a 6‐week induction and then given monthly maintenance therapy with intravesical docetaxel. Thirteen patients with BCG‐refractory Ta, T1, or Tis transitional cell carcinoma were treated. Induction therapy was administered as six weekly intravesical instillations of 75 mg followed by single‐dose monthly maintenance therapy for nine additional instillations in patients who had a CR. The initial response at 12 weeks from the start of induction therapy was evaluated by cystoscopy with biopsy, and urine cytology. The follow‐up consisted of quarterly cystoscopy with biopsy and cytology, and periodic imaging.

RESULTS

The median follow‐up was 13 months; 10 of 13 patients had a CR after induction, and six have remained disease‐free during the follow‐up. Of those in who the treatment failed, six had transurethral resection of the tumour and one a cystectomy. All 10 initial responders completed at least three instillations of maintenance therapy to date (median nine instillations), of whom six have remained recurrence‐free.

CONCLUSION

Monthly maintenance therapy with intravesical docetaxel appears to extend the durability of response to induction treatment for a selected group of patients with BCG‐refractory NMIBC, and might decrease the overall risk of recurrence in high‐risk NMIBC.     

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.     

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

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

Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group

PURPOSE: We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who otherwise would have undergone cystectomy. Total anthracycline recovery in urine samples obtained within 24 hours of valrubicin administration was assessed in a subset of patients. MATERIALS AND METHODS: A total of 90 patients with recurrent carcinoma in situ after failed multiple prior courses of intravesical therapy, including at least 1 course of BCG, participated in this open label, noncomparative study. Each patient received 6 weekly instillations of 800 mg. intravesical valrubicin. Disease evaluations were made at baseline and 3-month intervals following treatment. Evaluations included cystoscopy with biopsy and urine cytology. Toxicity was noted throughout treatment and followup. No evidence of disease recurrence for 6 months or greater was considered a complete response. RESULTS: Of 90 patients 19 (21%) had a complete response, including 7 who remained disease-free at the last evaluation, with a median followup of 30 months. Additionally, 14 patients who did not meet the strict protocol definition of complete response had superficial Ta disease only. Median time to failure and/or last followup for complete responders was greater than 18 months. Recurrence has been noted in 79 patients to date, including only 2 with clinically advanced disease (stage T2). Of these 79 patients 44 (56%, 4 responders and 40 nonresponders) underwent radical cystectomy. Of the 41 patients with known pathological stage 6 (15%) had stage pT3 or greater at cystectomy. Four patients died of bladder cancer during the median followup of 30 months, none of whom was a complete responder or underwent cystectomy following valrubicin. The main side effects of valrubicin therapy were reversible local bladder symptoms. CONCLUSIONS: Valrubicin was effective and well tolerated in patients with carcinoma in situ of the bladder refractory to BCG therapy. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an undue risk to most patients.     

Conservative treatment of diffuse carcinoma in situ of the bladder with repeated courses of intravesical therapy

We present a series of 13 patients with diffuse carcinoma in situ (CIS) of the bladder who failed an initial induction course of intravesical therapy with Mitomycin C, thiotepa, doxorubicin or Bacillus Calmette Guérin (BCG). Cystectomy, although indicated, was, for various reasons, not performed after the first failure of intravesical therapy and all patients were subsequently treated topically with the same or different agents. Of the 7 patients treated with 2 induction courses, 6 showed a complete response during a follow-up period of 24 to 42 months. Although 1 patient initially responded completely, he developed invasive transitional cell carcinoma (TCC) Grade IV 30 months later. Among the 3 patients who underwent 3 induction courses, 2 had a complete response at 42 and 60 months of follow-up and 1 developed TCC Grade IV with muscle invasion 18 months later. Two of the 3 patients treated with 4 induction courses are free of disease at 48 and 57 months; the third developed low grade, low stage TCC. This experience suggests that the majority of patients with CIS who fail initial treatment usually respond to further treatment with the same or a different drug. The question as to whether a second course of intravesical therapy, subsequent to failure of the first course, should be given before cystectomy requires further investigation.     

Bacillus Calmete-Guérin plus interferon-alpha2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity

Bacillus Calmette-Guérin (BCG) and interferon-alpha2B (IFN-alpha2B) have both been individually used for the intravesical treatment of superficial bladder cancer. We report our experience on the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-alpha2B for treating superficial bladder cancer, including patients failing previous BCG therapy. Thirty-two patients with superficial bladder cancer underwent 6 weekly treatments with full-, one-third, or one-tenth-dose of BCG plus 50 or 100 MU of IFN-alpha2B based on prior BCG exposure and tolerance. Patients with no evidence of disease proceeded onto maintenance therapy of 3 weekly treatments at 3 months followed by 2 additional maintenance cycles given 6 months apart. Response was assessed by cystoscopy/biopsy every 3 months after treatment. Before BCG plus IFN-alpha2B treatment, 20 patients (63%) had previously failed intravesical BCG therapy, 27 (84%) had aggressive disease (stage T1, grade 3, or carcinoma in situ), 27 (84%) had recurrent disease, 14 (44%) had multifocal disease, and 6 (19%) had disease of over 4 years duration. At median follow-up of 22 months, 21 patients (66%) remain disease-free and 11 patients (34%) had disease-recurrence. Nineteen of 32 patients (59%) were disease-free after the initial induction cycle. Six of 11 patients 55% ultimately failing combination therapy did so at the first 3 to 4 month evaluation. Four of 7 patients (57%) benefited from salvage re-induction therapy. Of the 20 patients previously treated with BCG, 12 patients (60%) remain disease-free. Combination BCG plus IFN-alpha2B intravesical therapy was well tolerated. Combination intravesical BCG plus IFN-alpha2B is an effective and tolerable alternative for patients with superficial bladder cancer, including those patients in whom intravesical BCG therapy had previously failed. Benefits of this combination therapy may include potentially less morbidity, improved clinical efficacy, and in the long term, fewer patients undergoing radical therapy. However, radical treatment options should be pursued for early failures of this combination regimen in those patients with risk factors for recurrence and progression.     

Bacillus Calmette-Guérin Failure in Patients with Non–Muscle-invasive Urothelial Carcinoma of the Bladder May Be Due to the Urologist's Failure to Detect Urothelial Carcinoma of the Upper Urinary Tract and Urethra

BackgroundVarious reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non–muscle-invasive urothelial bladder carcinoma (NMIBC).ObjectiveTo explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure.Design, setting, and participantsRetrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr.InterventionTwo or more intravesical BCG induction courses without maintenance.Outcome measurements and statistical analysisPrimary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics.Results and limitationsOf the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis.ConclusionsIn our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.