Intravesical gemcitabine for treatment of superficial bladder cancer not responding to Bacillus Calmette-Guérin vaccine

Objectives  

Intravesical Bacillus Calmette-Guérin (BCG) vaccine is the mainstay of treatment and prophylaxis in superficial bladder cancer (SBC) as it reduces tumor recurrence and disease progression. About one-third of patients do not respond to BCG. The aim of this study was to determine the efficacy of intravesical gemcitabine in patients with BCG-refractory SBC.     

Bacillus Calmette-Guérin without maintenance therapy for high-risk non-muscle-invasive bladder cancer

Background

Bacillus Calmette-Guérin (BCG) is the standard intravesical treatment of high-risk noninvasive (Ta, T1, Tis) bladder cancer. Maintenance BCG is recommended for maximum efficacy.

Objective

We compared our results in a large cohort of high-risk bladder cancer patients who received BCG without maintenance with published results from randomized maintenance BCG trials.

Design, setting, and participants

A cohort of 1021 patients underwent restaging transurethral resection for high-risk (Ta, T1, Tis) bladder cancer.

Intervention

Patients received a 6-wk induction course of BCG therapy. Responding patients did not receive maintenance BCG. Relapsing patients were eligible for retreatment with BCG. All patients were followed for a minimum of 5 yr.

Measurements

End points were 5-yr tumor- and progression-free survival rates.

Results and limitations

Of 816 complete responders to induction BCG, 2- and 5-yr recurrence-free survival rates were 73% and 46%, respectively. The progression-free survival rate was 89%. Progression-free survival time was 56 mo (95% confidence interval, 55-58 mo). Thirty-two percent of the patients required another course of BCG therapy. We cannot exclude that maintenance BCG may benefit patients beyond 5 yr over induction BCG alone and selective BCG retreatments.

Conclusions

Our results with BCG treatment without maintenance of patients with high-risk non-muscle-invasive bladder cancer compare favorably with trials in which comparable patients received maintenance BCG.     

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.     

Treatment of high-risk superficial bladder cancer with maintenance bacille Calmette-Guérin therapy: preliminary results

OBJECTIVE: To evaluate, in a prospective study, the effects and results of maintenance therapy with bacille Calmette-Guérin (BCG) in treating patients with high-risk superficial bladder cancer. PATIENTS AND METHODS: In all, 155 patients were enrolled in a randomized study of transurethral resection alone (53) or combined with intravesical BCG (102) as a treatment for superficial bladder cancer. BCG was administered for six consecutive weeks followed by three weekly instillations in months 3, 6, 12, 18, 24, 30 and 36 after resection. Recurrence, progression, prognostic factors and side-effects were assessed and analysed. RESULTS: After a median (range) follow-up of 23 (6-42) months, 83 of the 102 patients treated with BCG (81%) were disease-free, compared with 24 of the 53 treated with resection alone (45%). There was also a significant difference in tumour progression and time to progression between the trial arms. The disease progressed in eight patients (8%) treated with BCG and in 12 (23%) of those treated by resection alone. Independent risk factors for progression were DNA ploidy status and stage. Only the completion of treatment was predictive of outcome (risk of recurrence) for patients treated with BCG. CONCLUSION: Maintenance BCG therapy was better than resection alone in reducing the incidence of recurrence and progression in patients with high-risk superficial bladder cancer.     

Analysis of sex-based differences to Bacillus Calmette-Guérin for non-muscle invasive bladder cancer

Objective: To evaluate whether differences exist between men and women in response to intravesical BCG treatments. The incidence of urothelial carcinoma of the bladder is lower in women but they tend to present with more aggressive and advanced disease. Some prior studies also suggest there are sex-based differences in response to treatment for non-muscle invasive bladder tumors.Methods: In this retrospective study, we reviewed all consecutive patients who received BCG at the CHU de Québec – Laval University from 2009–2019. Men and women were treated with intravesical BCG therapy following pathologic confirmation of urothelial carcinoma. Outcomes evaluated include recurrence, progression, and treatment tolerability. Recurrence was defined as a pathology confirmed cancer whereas progression was the new development of high-grade (recurrence) pathology or an increase of stage. Tolerability was defined according to the proportion of prescribed BCG received. All clinical details were obtained through review of the medical records, collaborated by pharmacy records for BCG administration. Competing-risk analysis was used to compare outcomes.Results: Among 613 patients who received BCG at our institution between 2009–2019, 472 (77.0%) were men and 141 (23.0%) were women. The recurrence rate was not different between sexes, with a 5-year recurrence risk of 52% (95% CI: 36.93–65.4) among women compared to 57.5% (CI 95%: 51.9–62.6) among men. The overall non-progression rate at 1,3 and 5 years was 97.3% (95% CI: 95.6%–98.3%), 93.6% (95% CI: 91.2%–95.4%), and 91.7% (95% CI: 88.4%–94.1%), respectively. The completion of ≥5 induction BCG instillations and maintenance BCG use was similar in both genders.Conclusions: We report a contemporary NMIBC cohort treated with BCG and find no clear evidence for sex-based differences in response to BCG treatment in regard of progression, recurrence, and tolerability.     

Increased urinary albumin indicating urothelial leakage following intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer

Summary This study on the increase in albumin in the urine of patients with superficial bladder cancer after intravesical bacillus Calmette-Guérin (BCG) treatment was initiated on the basis of two facts. First, extravasation of serum albumin could be expected as a result of the BCG-induced delayed-type hypersensitivity reaction in the bladder wall. Second, appearance of albumin in the urine was a possibility as cytokines also appear in the urine, although probably after being produced suburothelially by infiltrating leukocytes. Albumin and the cytokines interleukin (IL) 1, IL2, IL6, and tumor necrosis factor alpha (TNF) were determined in urine from 20 patients treated with 6 weekly intravesical BCG instillations, collected prior to each instillation and 2, 4, 6, 8, 12, and 24h thereafter. The mean concentration of albumin in pre-therapy specimens was 112±118 (range 2–432) g albumin/ml urine, approximating 14±14 g/ mol creatinine (creat) (n=15), which was comparable to the mean pre-instillation value of 16±32 g/mol creat (n=96). A significant increase in urinary albumin during the 6 weeks of BCG treatment was observed (P<0.001). However, a large variation existed between individual patients and in some patients no reaction was seen. Maximum albumin concentrations were observed after instillations 3–6. A significant correlation between albumin and concentration of the cytokines IL1, IL2, IL6, and TNF was found (P<0.01), correlation coefficients (r) being 0.56, 0.56, 0.67, and 0.71 (n=418), respectively. During the first 24h after instillation cytokines and albumin peaked in the following order: TNFIL2albuminIL6IL1. TNF peaked most frequently after 2–4h and IL1 after 6h, while IL2, albumin, and IL6 peaked between these time points. In conclusion, the presence of albumin in urine indicates a leakiness of the bladder wall after repeated BCG instillations. Since albumin was shown to be stable in urine and the assay is relatively simple and cheap, it may be performed in most hospitals. This will allow largescale investigations of the correlation between elevation of urinary albumin and (tumor) response on BCG therapy.     

Intravesical bacillus Calmette-Guèrin for the treatment of superficial bladder cancer in renal transplant patients

BACKGROUND: Intravesical instillations with bacillus Calmette-Guérin (BCG) is considered the treatment of choice in the prophylaxis of high-grade superficial bladder carcinoma and in the treatment of carcinoma in situ (CIS) of the bladder. METHODS: There is no previous experience with BCG treatment in patients with renal transplantation. Theoretically, immunosuppression is a contraindication because of the risk of severe morbidity and sepsis. We present our experience with endovesical BCG in three renal transplant patients, under immunosuppressive treatment, with high-grade superficial bladder cancer and CIS. RESULTS: Two patients are free of disease at 17 and 60 months. One patient developed disease recurrence and underwent a radical cystectomy. There was neither change in renal function nor any clinical evidence of tuberculous infection. CONCLUSIONS: Intravesical BCG in superficial bladder cancer and/or CIS is a valid option, with no added morbidity to renal transplant patients.     

Cytological changes induced by intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer

To evaluate cytological changes of urothelial cells with intravesical instillation therapy of the bacillus Calmette-Guérin (BCG), cytological specimens of voided urine from patients with superficial bladder cancer (pTa and pT1) treated with intravesical BCG therapy were examined. The following three groups of patients who had no evidence of recurrence more than 2 years after the treatment were studied: groups 1 and 2, patients who were treated with BCG (n = 22) and epirubicin, a derivative of doxorubicin (n = 22), respectively, for prophylaxis of intravesical recurrence after transurethral resection (TUR); and group 3, patients receiving no intravesical therapy after TUR (n = 12). Sixteen cytological characteristics were studied before and after the treatment in each group. In group 1 patients translucent nuclei and prominent nucleoli, vacuolization of cytoplasm, and eosinophilic cytoplasmic inclusions were frequently observed in urothelial cells as well as an increase in granulocytes, especially within 3 months after BCG instillation therapy. In group 2 patients an increased nuclear/cytoplasmic ratio, hyperchromatic nuclei and prominent nucleoli of urothelial cells were transiently found within 1-2 months after intravesical epirubicin therapy. In group 3, translucent nuclei and prominent nucleoli of urothelial cells were found within 1-2 months after TUR. In conclusion, cytological changes induced by BCG therapy are nonspecific and reactive in nature, different from those due to chemotherapeutic agents and distinguishable from malignant changes of urothelial cells.     

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.     

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.     

Urinary fibronectin levels in patients treated with intravesical bacillus Calmette-Guérin for superficial bladder cancer

Intravesical bacillus Calmette-Guérin (BCG) has been shown to be an effective treatment for superficial transitional cell carcinoma (TCC) of the bladder, but the precise mechanism of action of BCG remains poorly understood. Fibronectin (FN), an important component of the extracellular matrix, has been found to play a role in BCG therapy. Some studies have shown that the soluble form of FN can compete efficiently with the matrix form of binding to the specific receptors on the bacteria and could consequently diminish the effect of BCG treatment. To evaluate a possible correlation between the urinary levels of FN and the efficacy of BCG therapy, we determined prospectively the urinary FN levels in 38 patients with TCC of the bladder and in 25 control subjects without malignancy matched for age and sex. All TCC patients were treated with transurethral tumor resection plus 6 weekly intravesical BCG instillations. After an average follow-up of 30 months, 8 patients (21.1%) had recurrent tumors, while 30 (78.9%) were free of tumor after intravesical BCG therapy. Urinary levels of FN in cancer patients have been shown to be significantly higher than controls (p < 0.001). These elevated levels were not decreased significantly after the operation (p > 0. 05). It was also found that the mean urinary FN levels were not statistically significant between patients with recurrence and complete remission. The data suggest that BCG-bladder tumor cell binding is not influenced by soluble fibronectin and urinary FN may not be a ideal marker for selecting patients to BCG therapy.     

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.