The efficacy of intravesical BCG in the treatment of patients with high risk superficial bladder cancer

Sixty-two patients with superficial bladder cancer stage T1 with or without dysplasia or carcinoma in situ and 34 patients with stage TA associated with dysplasia or carcinoma in situ were treated by TUR and TUR+BCG, respectively, and were followed up for an average of 46 months (6–192) and 32 months (6–72), respectively, after therapy. The recurrence rate (61%), progression (37%) and tumour death (19%) were unfavourably high in the group of patients treated by TUR only. On the contrary, the effect of intravesical BCG therapy was excellent. Recurrence rate was as low as 20.5%, and progression and tumour death were not detected in any patient. Intravesical BCG seems to be the best choice for treatment of high risk superficial bladder cancer. The authors recommend their effective modified treatment schedules.     

Leukocytes in the urine after intravesical BCG treatment for superficial bladder cancer

Summary Cellular immunologic reactions occurring in the bladder after intravesical treatment with bacillus Calmette-Guérin (BCG) were investigated by flow cytofluorometric analysis of leukocytes present in the urine. Urine specimens from 11 superficial bladder cancer patients were collected before and 5, 24, 48 and 72 h after repeated BCG instillations. Monoclonal antibodies specific for granulocytes, monocytes/macrophages, and T-and B-lymphocytes were used to characterize and quantify leukocyte subpopulations. The total number of cells in urine was found to be 2- to 485-fold increased 24 h after BCG administration. The predominant cell type present was the polymorphonuclear granulocyte, probably representing a defense mechanism against mycobacteria. The main mononuclear leukocytes in urine specimens were monocytes/macrophages and T-lymphocytes, indicating an ongoing immune response in the bladder wall. Although percentages of lymphocytes were low, T- and B-cells could be identified using a selective cell measurement procedure. In conclusion, a clear increase in the numbers of granulocytes, monocytes/macrophages and T-lymphocytes in urine after intravesical BCG administration was demonstrated, indicating local activation of the immune system.     

Effect mechanism of intravesical BCG immunotherapy of superficial bladder cancer

Immunotherapy for treatment of solid cancer mostly is an experimental treatment. In contrast, intravesical immunotherapy of superficial bladder cancer with bacille Calmette-Guérin (BCG) is clinically well established and accepted worldwide because of better results compared to topical chemotherapy. BCG is currently regarded as the most successful immunotherapy of cancer. Unfortunately the mechanism of action has not yet been fully clarified. This article gives an overview on the complex research on the mechanisms of actionhighly successful therapy.     

Role of fibronectin in intravesical BCG therapy for superficial bladder cancer

Intravesical bacillus Calmette-Guerin (BCG) has been demonstrated to be effective both for prophylaxis and treatment of superficial bladder cancer. In order to identify the progression of events that result in BCG-mediated antitumor activity, studies were performed to evaluate the mechanism of binding of BCG within the bladder. Histological and quantitative studies in a mouse model revealed that BCG attached to the bladder wall only in areas of urothelial damage. Preliminary in vitro data showed that BCG attached to surfaces coated with extracellular matrix proteins. Further studies were then performed using purified extracellular matrix proteins to identify the proteins responsible for attachment. BCG were observed to attach to surfaces coated only with purified fibronectin (FN) but not to other purified proteins including laminin, collagen or fibrinogen. The attachment of BCG to purified FN in vitro was dose dependent and was inhibited by anti-FN antibodies. Moreover, BCG attachment in vivo to bladders with damaged urothelial surfaces was inhibited more than 95% by anti-FN antibodies, but binding was not affected by anti-laminin antibodies or preimmune serum. A survey of commercially available BCG vaccines (Pasteur, Tice, Glaxo, Connaught) showed that only Glaxo BCG did not attach to FN-coated surfaces. Glaxo BCG also was shown to express inferior antitumor activity suggesting that the absence of FN binding by Glaxo may have been associated with the absence of antitumor activity of the vaccine.     

Management of hepatic granulomatous tuberculosis complicating intravesical BCG for superficial bladder cancer

Intravesical bacille Calmette-Guérin (BCG) therapy is the most effective treatment for high-risk superficial bladder cancer. Severe systemic complications are rare, but may occur in approximately 1% of cases. We report a severe complication of intravesical BCG: a disseminated Mycobacterium bovis infection with biopsy-proven granulomatous hepatitis in a patient with bladder cancer. We also elaborate on the different management alternatives.     

Automated flow cytometry to monitor intravesical BCG therapy of superficial bladder cancer

The automated flow cytometry system (FCM) at Memorial Sloan-Kettering Cancer Center has been used to monitor the effect of intravesical BCG in the therapy of superficial bladder cancer. Analysis of saline bladder washings prior to therapy, weekly during the six weeks of therapy, and at follow-up examination in 2 patients, 1 responder and 1 nonresponder, provides the basis for some projections regarding the potential value of this technique.     

Failure of intravesical interferon-alfa-2b for the treatment of patients with superficial bladder cancer previously failing intravesical BCG Therapy

Twelve patients with superficial bladder cancer who had failed one or two 6-week courses of intravesical bacillus Calmette-Guérin (BCG) therapy were treated with recombinant interferon-alfa-2b (rIFN-alfa-2b). Patients received 12 weekly instillations of rIFN-alfa-2b (100 MU) in 50 cc of normal saline. Those with an initial tumor-free response at the 3-month follow-up received maintenance rIFN-alfa-2b instillations (100 MU) monthly for an additional 9 months. Prior to rIFN-alfa-2b treatment, 6 patients had carcinoma in situ (CIS) with concurrent papillary tumor (pTa or pT I), and 6 had grades I or 2 pTa tumors. Patients were monitored every 3 months with urinary cytologies, cystoscopies, and biopsies when indicated. Median follow-up was 18 months (range 12 to 26 months). At the 3-month follow-up tumor recurrence was noted in 8 (66%) of 12 patients. An additional 3 (25%) patients had tumor recurrence at the 6-month follow-up period, and 3 (25%) patients also developed upper tract tumors during follow-up. Only 1 (8%) patient has maintained a continuous tumor-free response for 24 months. We are unable to demonstrate that rIFN-alfa-2b is likely to induce a tumor-free response in superficial bladder tumor patients who have failed intravesical BCG therapy, including those with CIS.     

Clinical value of pathologic changes after intravesical BCG therapy of superficial bladder cancer.

Bladder pathologic features related to intravesical bacillus Calmette-Guerin (BCG) therapy in superficial bladder cancer (Ta, T1, Tis) were evaluated and related to clinical outcome. A total of 105 patients were treated with 75 mg Pasteur BCG weekly for six consecutive weeks. When tumor was not demonstrated a maintenance course was given. An additional six-week course was given when tumor recurrence or persistence, without progression, was observed after the induction course. An inflammatory change in the bladder was the most common pathologic finding. Granuloma was the only specific BCG-related feature and did not appear to be a prognostic factor because of low incidence (24%) and lack of correlation with clinical course. Dysplasia occurred more frequently (57%) in nonresponder patients and (26%) in responder patients, often heralding recurrence of tumor. All patients showing concurrent squamous and/or glandular metaplasia were unresponsive to BCG therapy. Histology and cytology did not correlate perfectly: cytology was ineffective in low-grade tumors and improved diagnostic accuracy, particularly when dysplasia was histologically evident.     

BCG vaccine therapy for treatment of superficial bladder cancer

A total of 42 patients were involved in the study of the effectiveness of BCG vaccine on superficial bladder tumours. The new Bulgarian vaccine CALGEVAX was administered intravesically in consecutive instillations once weekly and then once monthly for a period of 11 months. For intradermal application the F-70 subcellular preparation was used. On the grounds of their initial experience in the treatment of superficial bladder tumours with unspecific immunotherapy the authors would like to express their confidence in the effectiveness of the intravesical application of BCG vaccine.     

BCG细胞壁骨架膀胱灌注防治浅表膀胱癌复发的研究

为了提高膀胱癌的治疗效果，采用ＢＣＧＣＷＳ（细胞壁骨架）行膀胱内灌注，防治浅表膀胱癌复发。５３例膀胱癌患者手术后分为ＢＣＧＣＷＳ组和ＢＣＧ组。ＢＣＧＣＷＳ组（２５例）５ｍｇＢＣＧＣＷＳ加无菌生理盐水５０ｍｌ注入膀胱，ＢＣＧ组（２８例）７５ｍｇＢＣＧ加生理盐水５０ｍｌ注入膀胱。每周１次，连续６周，以后每月一次连续两年。随访６～３２个月，中位数２６个月。两组比较肿瘤复发率无显著性差异，ＢＣＧＣＷＳ组毒副反应比ＢＣＧ组明显减少。结论：ＢＣＧＣＷＳ能有效地防治浅表膀胱癌复发，毒副反应低，并具有保存期长，使用方便的特点。     

Granulomatous prostatitis after intravesical BCG immunotherapy of superficial bladder cancer: a case report

We report a case of granulomatous prostatitis after intravesical BCG immunotherapy for superficial bladder cancer. A 58-year-old man presented with gross hematuria. Cystoscopic examination revealed multiple tumors at the posterior wall of the bladder. The patient underwent transurethral resection of the tumor. Intravesical BCG immunotherapy was postoperatively followed and it eradicated the disease. Digital examination revealed that the prostate became stony-hard and larger 10 weeks after the initial BCG immunotherapy. A needle aspiration cytology and biopsy of the prostate revealed the granulomatous prostatitis due to BCG immunotherapy.     

BCG in management of superficial bladder cancer

Superficial bladder cancer and particularly carcinoma in situ has the potential for invasiveness for which the treatment is cystectomy with a resultant disappointing 50 per cent five-year survival and urinary diversion with a certain diminished quality of life. BCG therapy is a new method of treating aggressive superficial bladder cancer with better response rates than conventional chemotherapy. It may be immunologically mediated and, if so, may be the first major success of a therapeutic modality that offers less morbidity than the currently standard options of surgery, radiotherapy, or chemotherapy.     

Immunophenotypic characterization of the bladder mucosa infiltrating lymphocytes after intravesical BCG treatment for superficial bladder carcinoma.

The lymphocytes infiltrating the bladder mucosa of 28 patients treated with bacillus Calmette-Guérin (BCG) for superficial bladder carcinoma were characterized using an immunohistochemical technique on frozen sections of biopsy specimens obtained during cystoscopy. The inflammatory response induced by BCG consisted mainly of T lymphocytes (CD3+), most of which had the helper/inducer phenotype (CD4+), with a CD4/CD8 ratio greater than 1. A minor subset of lymphocytes were of B phenotype (CD22+). These findings persisted for the whole follow-up period (6-12 months) in spite of a progressive decrease of the inflammatory infiltrate. No difference in the lymphocyte phenotype was observed between nonresponding patients and those who responded to BCG in the short term. It is concluded that, although intravesical BCG therapy does affect the immunocompetent cells of the bladder wall, the BCG-induced antitumor activity is unlikely to depend exclusively on a local immune mechanism.     

Bladder wall fibrosis following intravesical mitomycin treatment for superficial bladder cancer

Mitomycin is used extensively for the prevention of recurrence of superficial bladder cancer. Most treatment regimens of mitomycin are long term, since this seems more effective in preventing recurrence. During treatment some patients develop cystitis of variable severity, which may lead to mucosal ulcerations and cessation of treatment. We report a case in which long-term treatment with mitomycin, following a single episode of transitional cell bladder cancer, has led to bladder fibrosis and loss of its function, without evidence of tumor recurrence.     

Immunotherapy of superficial bladder cancer with BCG

Summary Bacillus Calmette-Guérin (BCG) has achieved an important role in the prophylaxis and treatment of superficial bladder cancer. It has been found effective in the prevention of recurrences after endoscopic surgery as well as in the treatment of residual tumors. The most dramatic responses have been consistently demonstrated in the treatment of carcinoma in situ. Recent experience suggests that prolongation of treatment beyond the 6 weeks advocated in early protocols, significantly increases the anti-tumor activity of BCG. The side effects of intravesical administration of the vaccine are, in the vast majority of patients, well-tolerated, minimal and self-limiting. No permanent functional or structural damage of the bladder has been observed. The effectiveness of BCG is primarily dependent on the strain used as well as the dose, duration and frequency of its administration.     

New agents in intravesical chemotherapy of superficial bladder cancer

Although intravesical chemotherapy has been used in the management of superficial bladder cancer for some decades, until recently there has been little or no progress in the search for new agents. However, in the past few years there have been developments of investigational drugs that may play a future role in this indication. This review highlights the mode of action, indications, dose and administration, efficacy, safety and significance of new chemotherapeutic agents such as intravesical valrubicin, gemcitabine, suramin, gamma-linolenic acid, eflornithine (DFMO), tipifarnib (R115777), fenritinide and celecoxib. Although the initial results achieved with these agents in clinical development seem encouraging, long-term data on the prevention of recurrence, disease progression and survival have yet to be obtained.     

Prospective randomized comparison of intravesical BCG therapy with standard dose versus low doses in superficial bladder cancer

In this study, we evaluated low dose intravesical bacillus Calmette-Guerin (BCG) therapy following transurethral resection (TUR) in 80 patients with superficial bladder cancer. The patients were divided into two groups. Of the Connaught BCG strain 81 mg was given to 40 patients in Group 1 and 54 mg to the remainder of 40 patients in Group 2. BCG was introduced once a week for 6 weeks. Tumour recurrence was seen in 6 patients in Group 1 and in 10 patients in Group 2. Recurrence rates per month were 0.71 and 1.49, respectively. There was no significant difference in complication rates. These data suggest that while the standard dose (81 mg) intravesical therapy of BCG is more effective than the low dose, there was no significant difference in side effects between the two groups.