Therapy For Superficial Bladder Cancer Research Articles

Does Isoniazid Reduce Side Effects of Intravesical Bacillus Calmette-Guerin Therapy in Superficial Bladder Cancer? Interim Results of European Organization for Research and Treatment of Cancer Protocol 30911

We analyzed the influence of the tuberculostatic agent isoniazid on the incidence and severity of adverse effects of intravesical bacillus Calmette-Guerin (BCG) therapy in patients with superficial bladder cancer. In a prospective randomized multicenter study the side effects of intravesical instillations with Tice strain BCG with and without isoniazid were compared in patients with stages pTa and pT1 bladder tumors. Isoniazid was given orally at a dose of 300 mg. daily at every instillation in an attempt to decrease the side effects of BCG. No differences in local or systemic adverse reactions after intravesical immune therapy with BCG could be observed between patients treated with or without prophylactic isoniazid therapy. However, analysis of liver function tests after BCG with isoniazid showed slightly more liver toxicity compared to BCG alone. Prophylactic administration of isoniazid during BCG instillations provides no decrease in any known side effect of BCG. In contrast, transient liver function disturbances are encountered slightly more frequently when isoniazid is administered. The use of prophylactic isoniazid in patients treated with BCG is not recommended.

Does Isoniazid Reduce Side Effects of Intravesical Bacillus Calmette-Guerin Therapy in Superficial Bladder Cancer? Interim Results of European Organization for Research and Treatment of Cancer Protocol 30911

Does Isoniazid Reduce Side Effects of Intravesical Bacillus Calmette-Guerin Therapy in Superficial Bladder Cancer? Interim Results of European Organization for Research and Treatment of Cancer Protocol 30911

Evolution and Clinical Significance of the T Cell Proliferative and Cytokine Response Directed Against the Fibronectin Binding Antigen 85 Complex of Bacillus Calmette-Guerin During Intravesical Treatment of Superficial Bladder Cancer

The antitumorigenic effect of intravesical bacillus Calmette-Guerin (BCG) in superficial bladder cancer was reported to be initiated by the attachment of BCG to the bladder wall via fibronectin. The antigen 85 complex secreted in BCG culture filtrate binds specifically to fibronectin and is a powerful T cell stimulus. Therefore, we investigated the evolution and clinical significance of the cellular proliferative response and cytokine production during intravesical BCG therapy against this purified antigen 85 complex. Evolution of the lymphoproliferation, interleukin-2 and interferon-gamma production of peripheral blood lymphocytes against tuberculin (purified protein derivative), purified antigen 85, BCG culture filtrate, whole BCG bacilli and pokeweed mitogen was tested before and after 6 weekly intravesical BCG instillations in 29 patients with superficial bladder cancer at intermediate or high risk for recurrence. A major increase in the lymphoproliferative response against purified protein derivative, antigen 85, BCG culture filtrate, whole BCG and pokeweed mitogen was observed in 69.0, 65.5, 79.3, 48.3 and 65.3% of the patients, respectively, analyzed after BCG therapy. Reactivity returned to baseline values at 6 months of followup. Of the patients who received a second BCG course because of tumor recurrence 66% had a novel increase in lymphoproliferation against antigen 85. An increase in the production of interleukin-2 and interferon-gamma by peripheral lymphocytes against antigen 85 was noted in 42.1 and 50% of the treated patients, respectively, after a single BCG course. During a mean followup of 23.11 months 48.5% of the patients remained tumor-free. No correlation could be found between the immunological response against any of the BCG antigens and the clinical evolution of the response. Intravesical BCG instillations induce a transient (less than 6 months) peripheral immune activation against several purified BCG antigens and among them the fibronectin binding antigen 85 complex. Reactivation is observed in most cases after additional BCG courses. The absence of long lasting immune activation after a single 6-week course of BCG could be related to the increased clinical efficacy observed with BCG maintenance instillations.

Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer

In intravesical therapy for superficial bladder carcinoma urothelial cells may, through the production of cytokines, contribute to the bacillus Calmette-Guerin (BCG)-induced local immunological reaction and associated antitumor efficacy. The aim of this study was to investigate such a role for the neutrophil-attracting cytokine interleukin-8 (IL-8). The appearance of IL-8 in patients urine after BCG therapy was compared with BCG-induced IL-6 and IL-2 and the stability of IL-8 in urine was tested. Compared to IL-6 and IL-2, a rapid induction of IL-8 was observed, occurring after the first BCG instillation. Urinary IL-8 was highly stable, even after 24 h incubation at 37 degrees C. The IL-8 concentration after the first instillation seemed to be associated with subsequent development of an immune response. Consequently, IL-8 seems an attractive candidate for investigation of its prognostic value for a clinical response to BCG therapy.

Photodynamic Therapy in the Management of Bladder Cancer

Photodynamic therapy (PDT) is primarily suggested for the therapy of papillary transitional cell carcinoma (TCC) and refractory carcinoma in situ (CIS), and prophylaxis of recurrent superficial TCC in those patients who have failed intravesical chemotherapy or immunotherapy. We reviewed our 13-year experience to assess the long-term role of PDT in the management of superficial bladder cancer, and propose a standard protocol. Fifty eight patients underwent a single PDT treatment with 1.5-2.0 mg/kg of Photofrin and 10-25 J/cm2 of light (630 nm). This single PDT treatment produced overall response rates of 84.2% in 19 patients with recurrent superficial papillary TCC, 80% in 20 patients with refractory CIS, and 89.5% in 19 patients receiving prophylaxis. The PDT dose of 2.0 mg/kg and 15-25 J/cm2 produced the most durable tumor response at the expense of severe local morbidity. However, the PDT dose of 1.5 mg/kg and 10-15 J/cm2 yielded variable tumor responses, with minimal local morbidity. Overall our data confirm that PDT is an effective therapy for superficial bladder cancer. We recommend PDT as a second line or immediate therapy for BCG or chemotherapy failures using a standard PDT dose of 1.5 mg/kg of Photofrin and 15 J/cm2 (630 nm) and a scheduled repeat treatment with 1.5 mg/kg and 10 J/cm2 at 6 and 12 months.

A Randomized Multicenter Trial of Adjuvant Therapy in Superficial Bladder Cancer

A Randomized Multicenter Trial of Adjuvant Therapy in Superficial Bladder Cancer

Quality of life in patients undergoing bacille Calmette-Guérin therapy for superficial bladder cancer.

To determine the impact of post-operative education about bladder cancer and topical immunotherapy on the physical, psychological and social well-being of patients with superficial bladder cancer. Eighty-five patients (mean age 59 years, range 26-85, 64 men and 21 women) receiving topical immunotherapy were questioned during the initial cycle of treatment and during maintenance therapy with bacille Calmette-Guérin (BCG). Patients completed a questionnaire on their quality of life when they commenced treatment and twice more during maintenance therapy. Psychological distress and physical symptoms were intense when the diagnosis of bladder cancer was revealed to the patients, despite the knowledge that this cancer is usually curable. The overall quality of life, condition of health and sexual activity were mostly only moderate, were poor during initial therapy and better during 3-monthly maintenance therapy. In general, the quality of life of these patients is characterized by the disruption of their lifestyle and marked by change in their circumstances. It is the responsibility of the urologist to take the necessary time to educate, comfort and motivate such patients with superficial bladder cancer.

Early clinical experience with 5‐aminolevulinic acid for the photodynamic therapy of superficial bladder cancer

To report clinical experience with intravesical instillations of 5-aminolevulinic acid (ALA) for the photodynamic therapy of superficial bladder cancer and to assess any side-effects of the treatment. Ten patients (six men and four women, mean age 62.3 years, range 42-73) with refractory superficial bladder cancer were treated with photodynamic therapy using 5 g of ALA dissolved in 30 mL sodium bicarbonate instilled intravesically. After a mean retention of 5.1 h, the bladder interior was illuminated transurethrally at radiation integrals of 15, 30 or 60 J/cm2. At integrals of 15 or 30 J/cm2 red light (635 nm) was used and at 60 J/cm2, green light (514 nm, 40 J/cm2) was combined with a subsequent application of red light (635 nm, 20 J/cm2). After 10-12 weeks, four patients had a complete remission, two a partial remission, there was no change in three and one had progressive disease. Of those patients responding, the bladder was preserved in five after a mean follow-up of 15 months (range 6-27). There were no photodermatoses or bladder shrinkage in any patient. Photodynamic therapy with intravesically applied ALA is effective in destroying superficial urothelial carcinomas of the bladder. There were no serious side-effects which could preclude further clinical testing.

Urinary Cytokines During Intravesical Bacillus Calmetteguerin Therapy for Superficial Bladder Cancer: Processing, Stability and Prognostic Value

Purpose An accurate prognostic indicator to identify nonresponding patients with superficial transitional cell carcinoma of the bladder at an early stage of intravesical bacillus Calmette-Guerin (BCG) therapy is urgently needed. Materials and Methods The processing conditions and stability of several BCG induced urinary cytokines were analyzed, as was the possible correlation between these cytokines (indicating immune responsiveness to BCG) and bladder tumor recurrence. We studied 23 patients with superficial transitional cell carcinoma of the bladder. Monitoring was performed by serial collection of urine during the first 24 hours after each of the 6 consecutive weekly intravesical BCG instillations. Baseline pre-therapy cytokine levels were 3.9 plus/minus 4.7 pg./micromole creatinine for interleukin-1 beta, 0.0 plus/minus 0.0 units per micromole creatinine for interleukin-2, 8.9 plus/minus 12.9 pg./micromole creatinine for interleukin-6 and 0.1 plus/minus 0.2 pg./micromole creatinine for tumor necrosis factor-alpha (all measured by enzyme-linked immunosorbent assay). To investigate the correlation between interleukin-2 and bladder tumor recurrence, patients were stratified into 2 groups based on an early (6 months or less) or late (greater than 6 months) recurrent tumor. For each patient the highest cytokine value measured during the 6-week BCG treatment course was evaluated. Results The results were positive if the level in urine exceeded 0.34 units interleukin-2 per micromole creatinine. A significant correlation between urinary interleukin-2 and tumor recurrence was found (p = 0.003, 23 patients). Of the studied cytokines obtained from BCG treated patients, interleukin-1 beta, 2 and 6 but not tumor necrosis factor-alpha were stable in urine at 4C and 20C. At 37C all cytokines were unstable. Interferon-gamma could only be detected in immediately dialyzed urine and its occurrence correlated most with that of interleukin-2. Processing of urine by centrifugation to remove leukocytes immediately after collection was not required for reliable measurements of interleukins-2 and 6. Based on these results interleukins-2 and 6 were preferred for extensive monitoring of the BCG induced immune reaction. Conclusions Our study provides significant evidence for a correlation between urinary cytokine induction and clinical response following intravesical BCG therapy. Particularly, monitoring of interleukin-2 may have the potential for prognostic value provided that strict precautions regarding urine collection, such as maximal 2-hour sampling and immediate cooling, are taken.

Urinary Cytokines During Intravesical Bacillus Calmetteguerin Therapy for Superficial Bladder Cancer

Urinary Cytokines During Intravesical Bacillus Calmetteguerin Therapy for Superficial Bladder Cancer

153 O - In vitro electromotive administration of mitomycin C in human bladder wall

Adjuvant intravesical mitomycin C (MMC) therapy for superficial bladder cancer has been shown to decrease the one-year recurrence rate by 2–43% and Ta tumours appear to respond more favorably than T1 (Herr, J. Urol., 1987). Experimental studies showed that inhibitory MMC concentrations are achieved in the urothelium (Ta tumours) in 100% of cases, in the lamina propria (TI tumours) in 20% and in the muscle layer (T2 tumours) in about 17% (Wientjes, Cancer Res., 1991). The aim of these investigations is to establish the tissue concentrations of MMC following passive diffusion (PD) and electromotive administration (EMDA) into human bladder wall samples. Sections of human bladder were inserted into a two chamber diffusion cell. The urothelium was exposed to the donor compartment (MMC 10 mg in 100 ml 0.24% saline) containing an anode and the serosa to the receptor compartment (100 ml 0.9% saline) containing a cathode. EMDA experiments were performed with pulsed current of 5 mA for 15 min. No electric current was applied in PD control experiments. MMC in samples was measured by HPLC analysis. The concentrations of MMC were determined in 15 paired experiments (30 bladder samples). The total (71,075 ng) and the mean (4,738 ng) quantities of MMC transported into tissue samples by EMDA significantly exceed the respective amounts (30,763 ng and 2,051 ng) administered by PD and similarly with wet tissue concentrations (22,923 ng/g and 1,528 ng/g versus 9,271 ng/g and 618 ng/g). In conclusion, EMDA enhances MMC penetration into the bladder wall and the method can be utilized generally for intravescical pharmacological studies. Adjuvant intravesical mitomycin C (MMC) therapy for superficial bladder cancer has been shown to decrease the one-year recurrence rate by 2–43% and Ta tumours appear to respond more favorably than T1 (Herr, J. Urol., 1987). Experimental studies showed that inhibitory MMC concentrations are achieved in the urothelium (Ta tumours) in 100% of cases, in the lamina propria (TI tumours) in 20% and in the muscle layer (T2 tumours) in about 17% (Wientjes, Cancer Res., 1991). The aim of these investigations is to establish the tissue concentrations of MMC following passive diffusion (PD) and electromotive administration (EMDA) into human bladder wall samples. Sections of human bladder were inserted into a two chamber diffusion cell. The urothelium was exposed to the donor compartment (MMC 10 mg in 100 ml 0.24% saline) containing an anode and the serosa to the receptor compartment (100 ml 0.9% saline) containing a cathode. EMDA experiments were performed with pulsed current of 5 mA for 15 min. No electric current was applied in PD control experiments. MMC in samples was measured by HPLC analysis. The concentrations of MMC were determined in 15 paired experiments (30 bladder samples). The total (71,075 ng) and the mean (4,738 ng) quantities of MMC transported into tissue samples by EMDA significantly exceed the respective amounts (30,763 ng and 2,051 ng) administered by PD and similarly with wet tissue concentrations (22,923 ng/g and 1,528 ng/g versus 9,271 ng/g and 618 ng/g). In conclusion, EMDA enhances MMC penetration into the bladder wall and the method can be utilized generally for intravescical pharmacological studies.

Early Disease Progression after Intravesical Bacillus Calmette‐Guérin (BCG) Therapy for Superficial Bladder Cancer

Disease progression after Bacillus Calmette-Guérin (BCG) instillation therapy for bladder cancer is not rare. The purpose of this study was to evaluate the outcome of patients treated with BCG for superficial bladder cancer, focusing on the patients who developed invasive disease during follow-up. The possible mechanism and risk factors for early progression after BCG therapy are discussed. A total of 25 patients with superficial bladder cancer (pTa, pT1 and/or pTis) were treated with intravesical BCG instillation (80 mg in 80 ml saline) once a week for eight weeks. Four of the 25 patients received maintenance therapy with BCG (once a month for 3 to 10 months). Patients were followed every three months and underwent cystoscopy, biopsy, and urinary cytology at these intervals. Disease progression was defined as invasion to muscle or prostate, or development of metastatic disease. Clinicopathological features of the patients, especially those with progression, were analyzed. Progression was observed in six of the 25 patients, (including four of 19 patients with carcinoma in situ and two of five patients treated prophylactically with BCG). The average time to progression was 8.7 months. Four patients died of cancer despite intensive treatment. Two patients are alive: one without evidence of disease after cystectomy and the other with metastatic disease. Proper patient selection, careful follow-up, and immediate aggressive therapy in case of progression were considered to be important factors to obtain satisfactory results with BCG therapy for bladder cancer.

Original Articles: Bladder Cancer: Keyhole-Limpet Hemocyanin Immunotherapy in the Bilharzial Bladder: A New Treatment Modality? Phase II Trial: Superficial Bladder Cancer

The efficacy of immunotherapy with keyhole-limpet hemocyanin or bacillus Calmette-Guerin for superficial bladder cancer is well known. A strong similarity has been noted between keyhole-limpet hemocyanin antigen and schistosomal antigen. In regard to this finding, we investigated the mechanisms of specific immunotherapy with keyhole-limpet hemocyanin in schistosomal associated transitional cell carcinoma. Keyhole-limpet hemocyanin was used for its ability to prevent tumor recurrence and because of its similarity to schistosomal antigen for intravesical specific immunotherapy in 13 patients with superficial transitional cell bladder tumors (Ta, Tis, T1) associated with urinary schistosomiasis. Keyhole-limpet hemocyanin immunotherapy reduced the recurrence rate of superficial bladder tumors to 15.4% compared to 76.9% before therapy.

Therapy of superficial bladder cancer

Intravesical therapy is used in the management of superficial transitional cell carcinoma of the urinary bladder (i.e. Ta, T1, and carcinoma in situ) with specific objectives, including treating existing or residual tumor, preventing recurrence of tumor, preventing progression of disease, and prolonging survival. The initial clinical stage and grade remain the main determinant factors in survival, irrespective of the treatment. Involvement of prostatic urethral mucosa with bladder cancer can be effectively treated with bacillus Calmette-Guerin intravesical immunotherapy. Results of current investigations suggest that biologic and molecular markers might be useful in monitoring the outcome of intravesical therapy. Intravesical chemotherapy has demonstrated a reduction in short-term tumor recurrence rates, but has had no positive impact on disease progression or prolongation of survival. Bacillus Calmette-Guerin immunotherapy remains the most effective treatment and prophylaxis for transitional cell carcinoma, with a positive impact on tumor recurrence rate, disease progression, and prolongation of survival. Interferons, keyhole limpet hemocyanin and Photofrin-mediated photodynamic therapy are under investigation in the management of transitional cell carcinoma and the efficacy results are encouraging. This review summarizes the recent advances in intravesical therapy and prophylaxis of transitional cell carcinoma and the important role of intravesical immunotherapy.

Selection of patients for intravesical therapy for superficial bladder cancer.

In a nonrandomized retrospective study, 133 patients with superficial transitional cell carcinoma of the bladder were evaluated to identify any clinical prognostic features which indicate the necessity of intravesical therapy (IVT). The risk factors taken into account were stage, grade and multiplicity of the tumour. All patients were treated initially by complete transurethral resection (TUR); 27 patients received no further treatment after resection of the tumour, 106 patients received adjuvant IVT over a period of 6 weeks. The mean follow-up was 23 and 18.8 months in the TUR-only group and TUR+IVT group, respectively. In the TUR-only group 7 and in the TUR+IVT group 29 recurrences were encountered. Patient group with no risk factors (Ta, GI, solitary tumour) or with only one risk factor revealed no statistical difference in terms of the recurrence rate from the identical control group. So it does not seem worthwhile to give additional therapy in the low-risk group. Another notable outcome of this study was that the higher the potential risk factors, the higher the likelihood of recurrence. The results suggest that T1 tumours, multifocal tumours, and high-grade tumours have poor prognosis, making additional treatment necessary.

Positive Urinary Cytology Following a Complete Response to Intravesical Bacillus Calmette-Guerin Therapy: Pattern of Recurrence

The pattern of disease recurrence was examined in 75 patients with clinically undetectable positive urinary cytology results following a complete response to intravesical bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer. A complete response was defined as negative cystoscopy and biopsy findings, urine cytology and flow cytometry (when available) for at least 1 year following therapy. Urinary cytology was positive in the absence of clinical disease at a median of 25 months (range 12 to 96) after BCG administration. Clinically recognizable disease (defined by a positive biopsy or visible papillary tumor) developed at a median of 6 months (range 2 to 60) after positive cytology was detected in 62 patients (83%), while 13 (17%) had persistently positive cytology results without an obvious source at a median of 6 months (range 2 to 29).The bladder was the single most common site of recurrence, with 39 recurrences developing in 36 patients (58%, 3 of whom had recurrent cancer after a complete response to each of 2 separate courses of BCG): 30 (77%) were superficial (stages Ta in 2, Tis in 25, Tis/T1 in 2 and T1 in 1) and 9 (23%) were invasive (stage T2+). Median interval to the detection of bladder recurrence following a positive cytology result was 6 months (range 2 to 50). Upper urinary tract disease developed at a median of 7 months (range 2 to 41) in 11 patients (18%), while 7 (11%) had a prostatic recurrence at a median of 5 months (range 2 to 60). There were 9 synchronous bladder and prostate (5) or upper tract (4) recurrences in 8 patients (13%) at a median of 22 months (range 2 to 40) in the former group and 15.5 months (range 3 to 20) in the latter group. Overall, of 75 sites of recurrence in 62 patients 48 (64%) were in the bladder, 15 (20%) in the upper urinary tract and 12 (16%) in the prostate.High risk patients with superficial bladder cancer who have clinically unconfirmed positive urinary cytology results following a complete response to intravesical BCG therapy require aggressive evaluation of intravesical and extravesical sites to detect the presence of persistent or progressive in situ or invasive disease.

Effects of isoniazid (INH) on the BCG-induced local immune response after intravesical BCG therapy for superficial bladder cancer.

Because recent investigations showed that the use of isoniazid (INH) severely impaired the local immune reaction to intravesical bacillus Calmette-Guérin (BCG) in the bladder of guinea pigs, in this study the effect of INH in man has been investigated. Patients were treated with BCG with or without oral INH. The concentration of free INH in most urine samples of patients treated with BCG/INH was much higher (mean 38.0 +/- 60.9 micrograms INH/ml) than the minimal inhibitory concentration (MIC; 0.1 microgram INH/ml), suggesting at least a bacteriostatic potential of the INH present. However, in vitro studies showed that these urinary concentrations of INH did not kill BCG organisms effectively, even at a concentration of 150 micrograms/ml for 24 h. After the fifth and sixth BCG instillations a significant increase in the concentration of cytokines (IL2, IL6, IL8 and TNFa), IgG and IgA antibodies to BCG and the number of leukocytes in urine was observed. The leukocytes mainly consisted of granulocytes, besides monocytes/macrophages and, in lower amounts, T- and B-lymphocytes and natural killer (NK) cells. The absolute number of granulocytes and the concentration of IgG antibodies after BCG instillation were significantly suppressed by INH, whereas INH appeared to have no effect on the urinary cytokine and IgA antibody concentrations or the total number and phenotype of the leukocytes present. In conclusion, the results of this study indicate that INH does not impair the local immunological stimulation after BCG instillation in man as severely as was observed in the guinea pig and it may be expected that INH does not impair the antitumor efficacy of BCG.

Intravesical BCG therapy of superficial bladder cancer: study of adverse effects.

Immunotherapy with intravesical bacillus Calmette-Guérin (BCG) has proved to be more effective than most chemotherapeutic agents in the prophylaxis and treatment of superficial bladder tumours. Side-effects, both local and systemic, are the main limitations against its use. With the aim of lowering the incidence and severity of side-effects, we started to use two vials of BCG, Connaught type, per instillation, instead of three vials, as recommended by the manufacturer. We prospectively reviewed adverse effects of BCG treatment at the lower dosage in 92 patients. Compared with other series, we found a similar incidence of adverse effects except for some local effects as haematuria which showed a higher incidence, but we also found a lower rate of tumour relapse. Four primary tumours were recorded during the study period. In our open study, a lower BCG intravesical dosage is not followed by a reduction in side-effects.

Intravesical therapy in superficial bladder cancer

Objective. To identify the appropriate characteristics of superficial bladder cancer that allow the physician to predict tumor behavior. Methods. We analyzed 1,745 patients with primary superficial bladder cancer with regard to disease and patient characteristics. Results. With the characteristics we found, the population can be described and prognostic factors can be found. Moreover, with the use of these factors, it appears to be possible to predict tumor behavior on a group level. Prediction on an individual level, however, remains far from ideal. Conclusions. Three treatment options can be chosen: follow-up after initial transurethral resection, additional instillations with intravesical chemotherapy, or instillations with bacillus Calmette-Guerin (BCG). In case instillations are indicated, most (but not all) superficial bladder cancer trials show superiority of BCG over intravesical chemotherapy, although at the cost of more side effects. However, with intravesical BCG, it seems possible to influence the natural history of superficial bladder cancer, which means that we can delay progression and improve survival.

Total cystectomy after intravesical bacillus Calmette-Guérin (Tokyo strain) therapy for superficial bladder cancer: Experience in Japan

To clarify which patients might most require total cystectomy after intravesical bacillus Calmette-Guérin (BCG) therapy, we reviewed data for 111 individuals with superficial bladder cancer. Of the 111 patients, 73 received the BCG treatment for prophylaxis of intravesical recurrence after transurethral resection (group 1), 24 therapeutically for Ta or T1 tumours (group 2), and 14 for eradicating carcinomas in situ (CIS, group 3). Although the BCG therapy significantly reduced frequencies of recurrence in group 1, 27 patients (37%) did develop tumours again. Tumours disappeared in 18 of 24 patients (75%) in group 2, and in 11 of 14 (79%) in group 3. The rate of disease progression was 6% for all 111 patients: 3% (2/73) for group 1, 17% (4/24) for group 2, and 7% (1/14) for group 3. A total of 16 of the 111 patients (14%) underwent total cystectomy, the respective figures being 7% in group 1, 29% in group 2, and 29% in group 3. Indications for total cystectomy were progression in 7, recurrent multiple tumours in 5, persistent CIS in 2, a contracted bladder in 1, and occurrence of bilateral renal pelvic cancer in 1. Thus, 4 of 6 patients (67%) who had tumours unresponsive to BCG therapy in group 2 demonstrated progression and necessitated total cystectomy. Because tumours persisting after BCG therapy are frequently of the muscle-invasive type, such cases should be regarded as candidates for immediate total cystectomy.