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.     

Pharmacokinetic study of intravesical gemcitabine in carcinoma in situ of the bladder refractory to bacillus Calmette-Guérin therapy

INTRODUCTION: Gemcitabine, a chemotherapeutic agent, has been shown to be active against transitional cell cancer of the bladder. The aim of the study was to determine the pharmacokinetic profile of gemcitabine, administered intravesically in patients with carcinoma in situ(CIS). MATERIAL AND METHODS: Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin (BCG) therapy were enrolled. Gemcitabine was given in 50 ml 0.9% NaCl by catheterization and held in the bladder for 1 h, once weekly for 6 consecutive weeks. The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum. Dose levels were: 1,000, 1,250, and 1,500 mg. Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months. RESULTS: Grade-1 neutropenia was observed only in 1 patient. Grade-1 urinary frequency and hematuria were observed in 1 and 3 patients, respectively. No grade 2-4 toxicity or clinically relevant myelosuppression were observed. Gemcitabine was detectable in serum, but with an irrelevant pharmacological effect, in only 1 patient treated with 1,500 mg of gemcitabine. With regard to activity, after 6 instillations of this drug, 4 complete responses were observed. CONCLUSION: Intravesical gemcitabine is well tolerated and safe. No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed. These results warrant further investigation in phase-II trials.     

Vesicoureteral reflux after intravesical instillation of bacillus Calmette-Guérin against carcinoma in situ of the bladder

We report a case of vesicoureteral reflux (VUR) 3 years after intravesical instillation of bacillus Calmette-Guérin (BCG, Tokyo 172 strain) against carcinoma in situ of the bladder. The present case suggests that a long-term careful follow-up is needed to detect not only tumor recurrences but also VUR as a late complication after intravesical BCG instillation.     

Bacillus Calmette-Guérin perfusion therapy for the treatment of transitional cell carcinoma in situ of the upper urinary tract

OBJECTIVES: The aim of this study is to evaluate the efficacy and safety of intrarenal bacillus Calmette-Guérin (BCG) instillation as a treatment for transitional cell carcinoma in situ (CIS) of the upper urinary tract. METHODS: Diagnostic criteria of upper urinary tract CIS were (1) positive urinary cytology, (2) negative multiple random biopsy of the bladder and prostatic urethra, (3) negative radiographic findings in the upper urinary tract and (4) two serial positive cytologies in selective ipsilateral urine sampling from the pyeloureteral system. Eleven patients diagnosed as having upper urinary tract CIS were enrolled in this study. Thus, 11 renal units were treated with BCG instillation. After placing a 6-french Double-J stent, BCG (80 mg) in 40 ml saline was instilled into the bladder weekly, 6 times in total as one course. RESULTS: At the end of one course, 9 cases showed negative urinary cytology. Among these 9 cases, 2 showed recurrence in the upper urinary tract after 4 months and 8 months of disease-free interval, respectively. These 2 cases have received an additional course of BCG instillation, but the urinary cytology did not normalize. Mean recurrence-free time was 19.6 months. Of the other 7 cases who responded to the first course of instillation, 6 cases were alive with no evidence of the disease. The remaining patient died of rectal cancer with no evidence of transitional cell carcinoma (TCC). Of the 2 cases who showed positive urinary cytology even after the first course, 1 underwent nephroureterectomy. The other case was diagnosed as having malignant lymphoma 3 months after the end of this instillation therapy, and he died of malignant lymphoma. As side effects, 8 cases (72.7%) showed bladder irritability, and 4 presented fever higher than 38 degrees C. However, no patient needed antitubercular treatment. CONCLUSION: As for the short-term response, BCG instillation for the treatment of upper urinary tract CIS is considered to be effective and safe. Longer follow-up and further experience with this treatment are required.     

Intravesical bacille Calmette-Guérin in the treatment of carcinoma in situ or high-grade superficial bladder carcinoma after radiotherapy for bladder carcinoma

OBJECTIVE: To evaluate the effectiveness and tolerance of endovesical bacille Calmette-Guérin (BCG) after pelvic radiation therapy for bladder cancer in patients with recurrence as carcinoma in situ (CIS) and/or high-grade superficial bladder cancer. PATIENTS AND METHODS: In a prospective study, 13 patients were treated with weekly instillations of 81 mg BCG Connaught for 6 weeks. for CIS and/or high-grade superficial bladder carcinoma. All had been treated previously with radical radiation therapy for bladder carcinoma. RESULTS: Five patients had no recurrences and six patients retained their bladders, within a median follow-up of 74.5 months. Five patients progressed; two underwent radical surgery and are alive after 75 months of follow-up, and three died from the disease (two were high-risk surgical patients and one had metastatic disease). Another two patients died from intercurrent disease without bladder cancer. Eight patients were alive at a mean (SD range) follow-up of 85 (12, 65-97) months. CONCLUSION: Intravesical BCG is useful for controlling CIS and/or high-grade superficial bladder carcinoma in irradiated bladders and has an acceptable local tolerance: more than a third of patients were free of disease and preserved their bladders. This proportion is acceptable in patients currently scheduled for cystectomy.     

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.     

Isolated renal tuberculosis following intravesical Bacillus Calmette-Guérin therapy for bladder cancer

We present a case of isolated renal tuberculosis following bacillus Calmette-Guérin (BCG) therapy for bladder cancer. In the presurgical radiographic examination, we suspected an atypical renal cell carcinoma. According to the diagnosis of renal cell carcinoma, we performed a radical nephrectomy. The histological findings were tuberculosis-specific inflammatory changes and the patient received an antituberculous multiple drug therapy for a year. It is concluded that we should pay attention to the possibility of a renal tuberculosis granuloma in any patient who presented with subacute formed renal masses following BCG treatment before deciding on the strategy of the treatment of the renal masses, especially in patients who had received such a treatment which induced an immunocompromised state.     

A case of tuberculous epididymitis after Bacillus Calmette-Guérin intravesical instillation therapy for bladder cancer

A 65-year-old male had undergone transurethral resection of bladder tumor (TUR-Bt) four times for recurrent bladder cancer, and each histopathological examination revealed non-invasive urothelial carcinoma, pTa, G2. To prevent further recurrence, he received eight weekly intravesical instillations of Bacillus Calmette-Guérin (BCG). Four months after the BCG therapy, he underwent cystoscopy. One week after the cystoscopy, he developed a painful and swollen left scrotum. Treatment with levofloxacin for acute epididymitis reduced the scrotal pain initially, but the pain increased and 3 months later, a fistula with suppurative discharge appeared at the bottom of the scrotum. A smear of the discharge revealed Gaffky 2, and a culture showed tubercle bacillus. Incisional drainage of the abscess and anti-tuberculosis chemotherapy for 2 months to treat tuberculous epididymitis was not completely effective. We performed a left orchiectomy with resection of the infected scrotal skin. Histopathological examination showed tuberculous epididymitis consisting of a caseating granuloma with epithelioid cells and Langhans giant cells. He received anti-tuberculosis chemotherapy for 4 months postoperatively and had no sign of recurrence 1 year postoperatively.     

Possible factors affecting response to intravesical bacillus Calmette-Guérin (Tokyo 172 Strain) therapy for carcinoma in situ of the bladder: A multivariate analysis

To evaluate clinicopathological factors affecting response to intravesical instillation therapy with the bacillus Calmette-Guérin (BCG) Tokyo 172 strain for carcinoma in situ (CIS) of the bladder, we reviewed data for 84 patients treated between 1985 and 1996. Median follow-up was 56 months. The patients comprised three groups: primary (only the in situ lesion, 31 patients), subsequent (found after treatment of a gross neoplasm, 20), and concomitant (found together with a gross neoplasm, 33). A complete response was found in 62 (74%) of the 84 patients. Intravesical BCG therapy eradicated tumour cells in 74% of the primary group, 70% of the subsequent group, and 76% of the concomitant group. Multivariate logistic regression analysis revealed that the presence of gross haematuria and patient age were significantly associated with a complete response to the intravesical BCG therapy (p<0.05). On the other hand, gender, irritative bladder symptoms, type of extent of CIS, histological grade of CIS, BCG dose, and number of times BCG was given did not exert any significant influence. The 5-year recurrence rate was 33% for the 62 patients for whom a complete response was once achieved. Patients aged 60 or older had a higher probability of recurrence than those less than 60 years of age (p<0.05). Disease progression was found in 13% of the 84 patients and total cystectomy was performed in 19%. The present finding that patient age is related to the response to intravesical BCG therapy may point to a role for the reduced host immunocompetence in elderly individuals.     

Bacillus Calmette-Guérin instillation treatment for carcinoma in situ of the upper urinary tract

OBJECTIVE: To analyse the efficacy and safety of bacillus Calmette-Guérin (BCG) perfusion treatment forcarcinoma in situ (CIS) of the upper urinary tract. PATIENTS AND METHODS: Six patients with cytologically diagnosed CIS of the upper urinary tract were treated by BCG instillation via retrograde catheterization using a 6 F ureteric catheter or an 8 F indwelling JJ ureteric stent between the ureter and bladder. BCG (Tokyo 172 strain, 80 mg in 100 mL normal saline) was instilled weekly for 4 or 8 weeks. The efficacy and safety of the treatment was assessed. RESULTS: The mean (range) follow-up was 22 (9-38) months; none of the patients died, and all were negative for cytology in urine collected from the upper urinary tracts. However, one patient had recurrent CIS in the prostatic urethra; the patient was treated by intravesical BCG instillation. In all patients, positive cytology became negative after one or two instillations of BCG. The ureter became stenotic in two patients. Although irritative symptoms occurred in all patients, such side-effects disappeared in a few months and were not clinically significant. CONCLUSION: In these six patients retrograde BCG instillation for CIS of the upper urinary tract was effective and safe. Based on the cytology results after only two BCG treatments, the dose or number of BCG instillations could possibly be reduced, but further study is needed.     

Is modified in situ vaginal wall sling operation the treatment of choice for recurrent genuine stress incontinence?

PURPOSE: We evaluate objectively the results of a modified in situ vaginal wall sling operation for recurrent genuine stress incontinence and whether it is a substitute for the traditional sling procedure. MATERIALS AND METHODS: A total of 23 patients with urodynamically proved recurrent genuine stress urinary incontinence were recruited in this study. Patients were treated with a modified needle urethropexy technique using an island of in situ vaginal skin as a sling to support the bladder neck and urethra. Surgical outcome was evaluated subjectively and objectively at a median of 15 months. A total of 42 patients who underwent a traditional polytetrafluoroethylene sling operation served as controls. RESULTS: The cure rate of the vaginal wall sling operation was 34.8% by objective assessment, which was lower than that of the traditional sling procedure (88.1%, p <0.05). The subjective success rate demonstrated the same results (vaginal sling 60.9% versus traditional sling 92.9%, p <0.05). The risk factors for operation failure were lower maximal urethral pressure, lower urethral closing pressure, narrow vaginal capacity and previous anterior colporrhaphy or a Stamey operation (all p <0.05). In 3 cases suburethral epithelial inclusion cysts were specific complications of the operation. There was no prolonged urinary retention or urethral erosion. CONCLUSIONS: Based on our results, we do not believe that the vaginal wall sling operation should be recommended for all recurrent genuine stress urinary incontinence cases and especially not for those with factors predictive of surgical failure. Further studies are needed to investigate and clarify the possible causes of failure.     

Late occurrence of bilateral tuberculous-like epididymo-orchitis after intravesical bacille Calmette-Guérin therapy for superficial bladder carcinoma

We report a case of bilateral tuberculous-like epididymo-orchitis occurring 3 years after intravesical bacille Calmette-Guérin instillation therapy in an 83-year-old patient with proven superficial bladder carcinoma. The patient had no previous history of tuberculosis. Because of persistent inflammation and painful swelling of the epididymides and testes, the patient underwent bilateral orchiectomy. This case demonstrates the late adverse effects that can occur after intravesical BCG therapy, which in our patient ended in surgical removal of both gonads.     

Intrarenal bacillus Calmette-Guérin therapy for carcinoma in situ of the upper urinary tract: long-term follow-up and natural course in cases of failure

OBJECTIVE: To assess the long-term efficacy of intrarenal bacillus Calmette-Guérin (BCG) therapy for the treatment of cytologically diagnosed upper tract carcinoma in situ (CIS) and report the time course in cases of failure. PATIENTS AND METHODS: Fourteen renal units in 11 patients cytologically diagnosed as having upper urinary tract (UUT) CIS were treated with intrarenal BCG instillation. The BCG solution was administered by retrograde ureteric catheterization weekly for 6 weeks. RESULTS: Seven units were radiologically and cytologically free of disease at a median follow-up of 60 months. Two units which showed an initial response had recurrence with ipsilateral UUT CIS. The remaining five units did not respond to BCG. Of seven units with an initial negative response or recurrent UUT CIS, nephroureterectomy was undertaken in one because of coincidental renal cell carcinoma. In four of the remaining six units, invasive pelvic tumour developed at a mean follow-up of 20.5 months after the final instillation. Computed tomography showed wall thickening of the renal pelvis in two and mass-forming tumour in the renal parenchyma mimicking renal cell carcinoma in two. In three of these four cases, retrograde pyelography did not show typical findings of renal pelvic tumour, e.g. filling defect, infundibular obstruction or stenosis. CONCLUSIONS: Intrarenal BCG is effective in the treatment of UUT CIS in a long-term follow-up. In cases with a poor response or ipsilateral recurrence of CIS, there is a high risk of developing invasive tumour. Close follow-up using computed tomography is recommended because of the atypical radiographic findings of such tumours.     

Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer?

Single modality bladder sparing therapy for muscle-invasive bladder cancer, including transurethral resection, systemic chemotherapy or radiotherapy have been demonstrated to result in insufficient local control of the primary tumor as well as decreased long-term survival of the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitize tumor tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder preserving approaches are costly, and require close co-operation between different clinical specialists as well as very close follow-up. The good long-term results obtained after cystectomy and creation of an orthotopic neobladder make the possible advantage of a bladder preservation strategy questionable in consideration of quality of life issues. Additionally, side effects related to bladder sparing therapy may result in an increased morbidity and mortality in those patients who in fact need to undergo surgery due to recurrent or progressive disease. Multimodality bladder sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder tumors.     

A phase II clinical trial of oral bropirimine in combination with intravesical bacillus Calmette-Guérin for carcinoma in situ of the bladder: a Southwest Oncology Group Study

OBJECTIVES: To estimate the probability of response when intravesical bacille Calmette-Guérin (BCG) is given in combination with oral bropirimine for bladder carcinoma in situ, and to evaluate toxicity when the 2 agents are combined. METHODS: A total of 51 patients with histologic evidence of carcinoma in situ and no prior treatment with BCG or bropirimine were enrolled in a cooperative group multicenter phase II trial. Initial treatment included Tice BCG 50 mg weekly for 6 weeks and oral bropirimine 3.0 g/day for 3 consecutive days each week for 12 weeks. Response was assessed after 12 weeks by cystoscopy, biopsy, and barbotage cytology. Most patients received a second course followed by an identical assessment. Toxicity was recorded according to the Southwest Oncology Group toxicity criteria. RESULTS: A total of 51 patients were enrolled and treated. There were 42 patients who were eligible and valuable for response and toxicity. There were 28 complete responders (67%, 50% to 80% 95% confidence interval). The 5-year progression-free survival estimate is 53%, and the 5-year survival estimate is 80%. There were no deaths, 2 patients had grade 4 toxicity, 14 grade 3 toxicity, 17 grade 2 toxicity, 6 grade 1 toxicity, and only 3 had no toxicity reported as their worst toxicity grade. CONCLUSIONS: The combination failed to show an estimated response higher than 80%. It is not recommended that further evaluation of this combination be conducted.