Bacillus Calmette-Guerin and bladder cancer

Bladder cancer is the second most common cancer of the urinary tract, and overall it is among the top 10 cancers in men. Transitional cell carcinoma (TCC) is the most common type, with the majority being superficial disease, i.e. the tumour has not gone beyond the lamina propria. The main problem with superficial TCC is the high recurrence rate. Various forms of treatment methods have been attempted to reduce the recurrence rate, with intravesical bacillus Calmette-Guerin (BCG) being the most successful to date. In fact, intravesical BCG is one of the most successful forms of immunotherapy in the treatment of any form of cancer. This article is a general review of BCG in bladder cancer with an emphasis on the indication and mechanism of action in reducing recurrence and progression.     

Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer

PURPOSE: Of all medical disciplines it is exclusively in urology in which immunotherapy for cancer has an established position today with intravesical bacillus Calmette-Guerin (BCG) against superficial bladder carcinoma recurrences. BCG is regarded as the most successful immunotherapy to date. However, the mode of action has not yet been fully elucidated. We provide a thorough overview of this complex field of research. MATERIALS AND METHODS: Rather than simply reporting all experimental data available for better understanding the involved immune mechanisms, we chose to provide comprehensively only information supported by several independent pathways of evidence. RESULTS: Major findings made during the last few years include systematic analyses of patient material, detailed in vitro studies and investigations in animal models, which have led to a substantially greater understanding of the mechanisms involved. CONCLUSIONS: The efficacy of BCG is based on a complex and long lasting local immune activation. The bladder as a confined compartment, in which high local concentrations of the immunotherapy agent and effective recruitment of immune cells can be achieved, serves as an ideal target organ for this type of immunotherapy approach.     

Granulomatous prostatitis following bacillus Calmette-Guerin immunotherapy of bladder cancer

Granulomatous prostatitis is a recognized complication of intravesical bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. Of 32 patients receiving such therapy 13 underwent prostatic core biopsy and/or fine needle aspiration for clinical indications. Prostatic induration or nodularity developed in 12 patients and 1 underwent biopsy for staging of known prostatic carcinoma. Granulomatous prostatitis was found in 100 per cent of those patients who underwent biopsy or aspiration, indicating that the incidence of this finding is at least 41 per cent following bacillus Calmette-Guerin immunotherapy. Acid-fast bacilli were demonstrated within the prostate of 3 patients with granulomatous prostatitis. The mean interval between the initiation of therapy and diagnosis of granulomatous prostatitis was 11.5 months. Bacillus Calmette-Guerin related granulomas of the prostate may be differentiated histologically from nonspecific granulomatous prostatitis, allergic prostatitis and postoperative granulomas. The clinical implications of these findings are discussed.     

Bacillus Calmette-Guerin and interleukin-2 for treatment of superficial bladder cancer

A total of 22 patients with bladder cancer received bacillus Calmette-Guerin (BCG) and interleukin-2. Significant bladder tumor remissions were noted in 15 of 17 patients (88%). Of 5 patients with carcinoma in situ 1 was noncompliant and he died of carcinoma in situ. The other 4 patients are in remission. BCG alone was instilled in 22 additional patients with superficial bladder cancer. The remission rates were encouraging. Of the 22 patients 13 (59%) had remission of the bladder tumor. A half dose of BCG (60 mg.) is adequate when given weekly for 6 weeks. Maintenance therapy is important as noted in both of our clinical arms. BCG and interleukin-2 therapy results in a higher remission rate.     

Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer

Our series of 195 patients, plus 134 reported on in the literature and 949 reviewed by various physicians provide 1,278 patients for review of bacillus Calmette-Guerin therapy complications. Cystitis occurred in 91 per cent of the patients. Complications identified included fever more than 103F in 50 patients (3.9 per cent), granulomatous prostatitis in 17 (1.3 per cent), bacillus Calmette-Guerin pneumonitis or hepatitis in 12 (0.9 per cent), arthritis or arthralgia in 6 (0.5 per cent), hematuria requiring catheterization or transfusion in 6 (0.5 per cent), skin rash in 5 (0.4 per cent), skin abscess in 5 (0.4 per cent), ureteral obstruction in 4 (0.3 per cent), epididymo-orchitis in 2 (0.2 per cent), bladder contracture in 2 (0.2 per cent), hypotension in 1 (0.1 per cent) and cytopenia in 1 (0.1 per cent). Most of the severe irritative side effects and subsequent systemic complications can be prevented with prophylactic isoniazid given for 3 days, beginning the morning of treatment. Patients with life-threatening systemic bacillus Calmette-Guerin infection or anaphylaxis should receive 500 mg. cycloserine twice daily for 3 days in addition to combination antituberculous therapy because the rapid action of this drug may be life-saving. Direct intralesional bacillus Calmette-Guerin immunotherapy can produce sepsis and death, and should be avoided but intravesical bacillus Calmette-Guerin generally is well tolerated and has produced no complication in more than 95 per cent of the patients treated.     

Intravesical bacillus Calmette-Guerin immunotherapy after previous prostate radiotherapy for high-grade non-muscle-invasive bladder cancer

ObjectivesIntravesical bacillus Calmette-Guerin (BCG) immunotherapy is a standard treatment for high-grade non-muscle-invasive bladder cancer (NMIBC). We evaluated outcomes of BCG therapy for NMIBC in patients with a previous history of prostate cancer (CaP) radiotherapy (RT).Materials and methodsA retrospective review of patients with a history of CaP RT who subsequently underwent treatment with intravesical BCG for high-grade NMIBC was performed. Patients were categorized as “BCG success” or “BCG failure” (defined as stage progression or recurrent/persistent disease). We evaluated factors related to the radiotherapy (type, interval to BCG), bladder cancer (clinical stage, immunotherapy type, and course), and patient comorbidities, to identify factors associated with BCG failure.ResultsFrom 1996 to 2008, 26 patients with high-grade NMIBC received intravesical BCG immunotherapy after CaP RT. At a mean follow-up of nearly 5 years, 13 patients (50%) were successfully managed with one or more induction courses of BCG with or without the addition of interferon alpha. Twelve (46%) eventually required cystectomy for disease recurrence or progression, of which half had pathologically advanced disease (≥pT3). Clinical stage was similar between BCG success and failure patients (P = 0.40). Those who failed immunotherapy were more likely to have had a longer interval between RT and BCG induction (5.8 vs. 2.4 years, P = 0.02).ConclusionApproximately 50% of patients with NMIBC who were previously exposed to prostate radiation had a durable response to intravesical BCG. For non-responders, extravesical progression was common.     

Intravesical Bacillus Calmette-Guerin for treatment of bladder tumor

The patients with bladder tumor (11 tumor) were given intravesical Bacillus Calmette-Guerin (BCG) therapy. The concentration of BCG solution varied from 80 to 240 mg in 40 ml of normal saline. The intravesical instillation therapy with this solution was repeated 6 times at a week interval. Seven of the tumors showed excellent response and had completely disappeared upon endoscopic examination. All of the highly responded tumors were small papillary lesions of low grade and low stage of malignancy. Regarding side effects, irritable bladder occurred in 70%, elevation of body temperature of over 37 degrees C in 40% and gross hematuria in 30% of the patients. Among them, one patient was treated with INH (0.3 g/day) for 2 weeks with satisfactory remission of the symptoms. Though the number of cases and follow up period are not satisfactory enough, topical therapy with BCG can be said to be an effective therapeutic measure against early stage urotherial tumors.     

Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup.

We report the outcome of 61 patients with superficial bladder tumors who received bacillus Calmette-Guerin (BCG) therapy and were followed for at least 10 years (range 10 to 13 years). A total of 19 patients (31%) remains free of tumor and progression, 17 (28%) had interval superficial recurrences but no progression and 25 (41%) had progression, first identified as muscle invasion in 12, prostatic involvement in 8 or metastasis in 5. Most tumors recurred or progressed within the first 5 years. Of the 61 patients 33 (54%) are disease-free and with an intact bladder, 13 (21%) are alive after cystectomy, 2 (3%) died of other causes, 1 (2%) is alive with metastasis and 12 (20%) died of metastatic urothelial cancer (11 from the bladder or prostate and 1 from an upper tract tumor).     

Bacillus Calmette-Guerin therapy for high risk stage T1 superficial bladder cancer.

Numerous studies have shown bacillus Calmette-Guerin (BCG) to be an effective prophylactic and therapeutic agent for superficial transitional cell carcinoma of the bladder. The high grade stage T1 lesion treated by transurethral resection alone is reported to progress to muscle invasion in 30 to 50% of the patients. Therefore, some have recommended treatment with cystectomy. To evaluate BCG treatment of the stage T1 lesion we reviewed our results with a single or repeated 6-week course of the Armand-Frappier Pasteur strain BCG and compared them with those in the literature. We also compared these results with those of treatment of the stage TA lesion. We treated 30 stage T1 cancer patients who were described as at high risk based on the criteria of histology grade 3 in 24 and grade 2 in 6, carcinoma in situ present in 14 and positive urine cytology results 2 to 3 weeks after transurethral resection in 26. Followup ranged from 12 to 78 months, with a mean of 39 months. After a single 6-week course of BCG 14 patients (47%) had negative cytology and biopsy findings at 6 months. Also, 6 patients had conversion to negative cytology and biopsy results after a second 6-week course of treatment, for an over-all complete response rate of 66%. After the initial course of BCG 4 patients had progression to cystectomy: 1 for muscle invasion and 3 for a persistent stage T1 lesion. They had no evidence of disease 12 to 60 months postoperatively. One patient had progression to metastasis after a second course of BCG. Therefore, the over-all progression rate to cystectomy or metastasis was 17% (5 of 30 patients). All 5 patients were among the 16 who failed to achieve a complete response after the initial course of BCG. In conclusion, our experience and that of others demonstrate that BCG therapy is an effective initial treatment of stage T1 disease to prevent progression and recurrence, and to preserve bladder function. Close monitoring will identify those nonresponders who require surgical intervention.     

Bacillus Calmette-Guerin immunotherapy of the cancer-contaminated wound.

A model has been developed to study the usefulness of immunologically active irrigating solutions in the prevention of implantation of cancer cells in surgical wounds. A poorly differentiated transitional cell carcinoma of the bladder (MBT₂) was used in serial transplants. Tumor suspensions were instilled into 1-cm-long, 0.3-cm-deep incisions in the lateral thigh and irrigated with test or control solutions. Levamisole, Glaxo strain Bacillus Calmette-Guerin (BCG), and Tice strain BCG were compared with distilled water and saline controls. Effects of preimmunization with BCG were also studied. Significant improvements were found only in animals treated with Tice strain BCG. Seventy percent of Tice strain BCG-treated animals were long-term survivors. Overall, BCG-preimmunized animals showed slightly slower tumor growth rates, but only the Tice strain BCG animals showed lower tumor incidence and higher long-term survival (40%). BCG dosage and route of administration are discussed. The current study supports the proposition that BCG may be useful in decreasing the local postoperative recurrence of tumor in patients with bladder carcinoma.     

Treatment of Bacillus Calmette-Guerin refractory superficial bladder cancer: further intravesical therapy

We here report our clinical experience with salvage therapy for patients with bacillus Calmette-Guerin (BCG)-refractory superficial bladder cancer and discuss current approaches to the disease, especially focusing on bladder preservation. First, we evaluated the efficacy of an initial 6-week course of intravesical BCG in 93 patients with carcinoma in situ (CIS) of the bladder. Of these, 91% achieved a complete response (CR) at the evaluation at 3 months. The 2- and 5-year recurrence-free rates were 71 and 67%, respectively (mean follow-up 39 months). These results support the intravesical BCG as a first-line therapy for CIS. Next, we assessed the efficacy of a second course of intravesical BCG for 16 patients who failed the initial induction course for CIS. Of these, 94% achieved CR at the evaluation at 3-month, and the 2- and 5-year recurrence-free rates were 62 and 46%, respectively (mean follow-up 28 months). None of the patients who received a second course had disease progression. Thus, a second course of BCG therapy seems to be a reasonable option for CIS patients failing the initial course. We also report our initial experience with intravesical gemcitabine therapy for 3 patients with BCG-refractory CIS of the bladder and 1 patient with recurrent multiple tumors. Gemcitabine (1500 mg in 100 ml saline) was given in the bladder for 1 hour twice weekly for a total of 12 treatments. The treatment was associated with minimal bladder irritation and systemic absorption, and was well tolerated except in a 90-year-old man who discontinued therapy because of grade 2 toxicity. Two patients achieved CR and maintained a tumor-free status beyond 14 months, suggesting that the intravesical gemcitabine is a promising salvage therapy for BCG-refractory superficial bladder cancer.     

Bacillus Calmette-Guerin for superficial transitional cell carcinoma of the bladder

Pasteur strain bacillus Calmette-Guerin was used to treat superficial transitional cell carcinoma of the bladder in 28 patients. Patients selected for treatment had an incomplete resection, positive selected site biopsies and/or post-resection positive cytology findings. Complete response required negative histology and cytology findings at cystoscopic followup 4 to 8 weeks after completion of treatment. Of the patients 20 (71 per cent) demonstrated a complete response, including all 6 with carcinoma in situ. Results converted to negative in 16 of 17 patients with positive urine cytology findings and 4 with positive prostatic urethral biopsies. Of the responders 8 had received prior treatment with thiotepa. The treatment regimen of 120 mg. Pasteur strain bacillus Calmette-Guerin weekly for 6 weeks was well tolerated. It was necessary to limit the number of treatments to 5 because of local irritative effects in only 3 patients. No chronic bladder disability has been noted during followup of 3 to 30 months. This experience supports the efficacy of bacillus Calmette-Guerin as a cost-effective, well tolerated treatment modality for patients with superficial transitional cell carcinoma of the bladder.     

Perioperative immunotherapy for muscle-invasive bladder cancer

Radical cystectomy is the standard of care treatment for patients with localized muscle-invasive bladder cancer (MIBC). However, patients with MIBC experience high rates of relapse despite primary therapy, and perioperative strategy is an important treatment option. Cisplatin-based neoadjuvant chemotherapy was associated with improved prognosis, and adjuvant chemotherapy is also an important option for selected patients. However, perioperative chemotherapy is not effective in some patients. Moreover, the currently recommended perioperative treatment is cisplatin-based chemotherapy; approximately 50% of the patients are ineligilble for cisplatin treatment owing to various reasons such as medical comorbidities, poor performance status, and renal insufficiency. The recent success of treatment with immune checkpoint inhibitors (ICIs) suggests that ICIs is the new standard therapy for patients with metastatic bladder cancer. Furthermore, ICIs showed more favorable toxicity profiles than conventional cytotoxic chemotherapy. These results indicate that ICIs may play a role in the treatment of muscle-invasive disease, and many recent studies have been conducted in a perioperative setting. The present review aims to summarize and discuss the current perioperative strategy of immunotherapy focused on ICIs based on recent ongoing clinical trials.     

卡介苗灌注治疗肾移植继发膀胱癌患者的初步经验

目的:总结卡介苗膀胱灌注治疗肾移植继发膀胱癌患者的经验。方法:回顾性分析2015年1月至2019年12月天津市第一中心医院5例肾移植后继发膀胱癌行卡介苗膀胱灌注患者的临床资料。男1例,女4例;移植后应用免疫抑制剂期间1例(例1)继发高级别非肌层浸润性膀胱癌(NMIBC),3例(例2、3、5)继发低级别NMIBC,1例(...     

Polymorphisms of the human NRAMP1 gene are associated with response to bacillus Calmette-Guerin immunotherapy for superficial bladder cancer

PURPOSE: Superficial bladder tumors have a high recurrence rate and 10% to 20% of recurrences progress to invasive cancer. Recurrence and progression can best be prevented by nonspecific immunotherapy using intravesical BCG instillations. The NRAMP1 gene has been implicated in susceptibility to infectious and autoimmune diseases, and in response to BCG in murine models. We evaluated the association of 5 NRAMP1 gene polymorphisms with the risk of superficial bladder cancer recurrence and response to immunotherapy. MATERIALS AND METHODS: The (GT)n, 274 C/T, 469 + 14 G/C, 1465-85 G/A and D534N polymorphisms were tested on peripheral blood DNA of individuals from three cohorts: 37 bladder tumor patients treated by transurethral resection and without recurrence after up to eight years, 67 patients at high risk of recurrence of their bladder tumors and treated with BCG and 109 controls, using restriction fragment length polymorphisms or microsatellite analysis following PCR amplification. RESULTS: The D543N G:A genotype was found more frequently in patients at high risk of recurrence (8 of 67 or 12%) than in controls (2 of 109 or 2%) (p = 0.007). Patients with nonrecurrent tumors showed no difference with controls (1 of 37 or 3%) (p = 1.0). Moreover, in multivariate and survival analyses, both D543N and (GT)n polymorphisms showed association with recurrence-free survival in the cohort of patients at high risk of recurrence, following BCG treatment. CONCLUSIONS: These data suggest the implication of the NRAMP1 gene in bladder cancer recurrence and response to BCG immunotherapy.     

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.