Long-term effect of intravesical bacillus Calmette-Guerin on flat carcinoma in situ of the bladder

Intravesical bacillus Calmette-Guerin is effective therapy for multifocal carcinoma in situ of the bladder. The duration of this favorable response and its effect on disease progression are the subject of this report. Between March 1978 and July 1981, 47 patients with diffuse, often symptomatic, carcinoma in situ were treated with intravesical bacillus Calmette-Guerin and followed every 3 to 4 months with cystoendoscopy, biopsy and urine cytology for 3 to 6 years. All patients had had prior or concurrent superficial papillary tumors controlled initially by transurethral resection and fulguration 2 to 3 weeks before bacillus Calmette-Guerin treatment. Of the 47 patients 23 were entered into a randomized study, and received intravesical and percutaneous bacillus Calmette-Guerin. Another 24 patients with carcinoma in situ were treated with intravesical bacillus Calmette-Guerin alone. Bacillus Calmette-Guerin (Pasteur strain) was given intravesically (120 mg. in 50 ml. saline) weekly for 6 weeks. Of the 47 patients 32 (68 per cent) are free of disease (negative urine cytology, cystoendoscopy and biopsy): 15 (65 per cent) after combined bacillus Calmette-Guerin for a median duration of 51 months (range 37 to 75 months) and 17 (71 per cent) after intravesical bacillus Calmette-Guerin alone for a median of 45 months (range 36 to 53 months). Of the 23 patients in the randomized study 4 (17 per cent) have required cystectomy for local progression of disease compared to 17 of 26 controls (65 per cent) who were randomized to transurethral resection and fulguration alone. Cystectomy was performed 3 to 27 months after bacillus Calmette-Guerin treatment and in 3 patients tumor was localized to the prostate gland (no tumor found within the bladder). These data indicate that intravesical bacillus Calmette-Guerin is capable of producing long-term remissions of carcinoma in situ in high risk patients and may prevent or delay progression of disease necessitating cystectomy.     

Intravesical bacillus Calmette-Guerin therapy for in situ transitional cell carcinoma involving the prostatic urethra

A total of 23 patients presenting with multifocal superficial bladder cancer and concomitant in situ transitional cell carcinoma of the prostatic urethra (mucosal in 19 and ductal in 4) underwent transurethral resection and intravesical bacillus Calmette-Guerin therapy. Median followup was 51.6 months (range 6 to 105 months). Of the 23 patients 13 (48 per cent) had a complete response with a median followup of 43.7 months without recurrence. Progression of some type (local, muscle invasion or metastasis) occurred in 10 patients (44 per cent); none occurred in the prostatic urethra. Median interval free of progression was 55.7 months; 7 of 10 patients required cystectomy for progression or refractory disease in the bladder (prostate negative for transitional cell carcinoma). A trial of complete transurethral resection plus intravesical bacillus Calmette-Guerin is a viable alternative to immediate radical cystectomy for patients with mucosal and/or ductal involvement of the prostatic urethra with in situ transitional cell carcinoma.     

Intravesical doxorubicin for prophylaxis in the management of recurrent superficial bladder carcinoma

Intermittent intravesical doxorubicin chemotherapy was given to 27 patients with multiple recurrent superficial transitional cell carcinoma of the bladder, including 12 who had become refractory to intravesical thiotepa. The starting dose was 60 mg. doxorubicin diluted in 40 to 50 ml. normal saline solution and doses were increased to 90 mg. The duration of instillation was 60 minutes. Treatments were administered every 3 weeks for a total of 8 doses, then every 6 weeks for 2 doses and then every 12 weeks for 2 doses. Therapy then ended for patients who were rendered free of disease. Cystoscopy and urinary cytology studies were performed every 3 months throughout the study. Of the patients 30 per cent had intermittent episodes of dysuria, 26 per cent had urinary frequency, 41 per cent had hematuria and 15 per cent had bladder spasms. None of these toxicities required discontinuation of the drug. Analysis of plasma samples for doxorubicin and metabolites revealed no systemic absorption and there was no myelosuppression. Of the 27 patients 15 (56 per cent) have maintained complete eradication of bladder cancer without any evidence of residual carcinoma detected endoscopically or with urinary cytology. Recurrent disease developed in 9 patients (33 per cent) while on therapy, including 3 with muscle invasion. Cystoscopy has remained grossly negative in 3 patients who have had positive class 5 cytology studies. The median duration of followup in all patients has been 12 months, with a range of 6 to 24 months. We conclude that intravesical doxorubicin is tolerated well and is effective in the management of multiple recurrent superficial transitional cell carcinoma of the bladder.     

Retrospective study of efficacy of intravesical BCG alone in treatment of superficial bladder cancer

This is a review of 100 patients at our institution who were treated for superficial bladder cancer. In those patients with carcinoma in situ of the bladder who were treated with conventional therapy (resection and/or fulguration) and intravesical bacillus Calmette-Guerin (BCG) without intradermal BCG, and those patients who were treated with conventional therapy alone, we found a response rate of 60 per cent versus 40 per cent at the end of three months. In comparing those patients with superficial papillary cancer, we found a response of 39 per cent after conventional therapy and 63 per cent after conventional therapy and intravesical BCG. This suggests that intravesical BCG without intradermal BCG can be an important adjunct to the conventional therapy of bladder tumors.     

Does intravesical chemotherapy prevent invasive bladder cancer?

Intravesical chemotherapy has been shown to prolong the interval free of disease and to reduce the tumor recurrence rates in patients with superficial bladder cancer. These observations led us to consider whether a course of intravesical chemotherapy might provide a long-term decrease in the recurrent tumor rate or reduce the incidence of progression to invasive carcinoma. The records of 123 patients entered into a randomized multicenter protocol between 1975 and 1978 were examined. Patients had received a 1-year course of thiotepa or VM26, or transurethral resection alone. Mean followup was 47 months. Patients receiving thiotepa or VM26 had a lower rate of tumor recurrence, expressed as recurrences per 100 patient-months, than those undergoing transurethral resection only (5.25 versus 5.71 versus 7.98) but this was not statistically significant. However, 28 per cent of the controls required therapy besides transurethral resection to control the bladder cancer and 19 per cent died of advanced bladder cancer during followup. Only 15 per cent of the patients undergoing intravesical chemotherapy required therapy other than transurethral resection and only 3 per cent died of advanced carcinoma of the bladder. This finding suggests that intravesical chemotherapy given for 1 year is associated with a significant decrease in the incidence of tumor progression, and provides the justification to conduct future trials with extended followup.     

Results of 6 weekly intravesical bacillus Calmette-Guerin instillations on the treatment of superficial bladder tumors

We evaluated 104 patients with superficial bladder tumors for response to intravesical bacillus Calmett-Guerin therapy. Patients received 6 weekly intravesical bacillus Calmette-Guerin instillations and they were followed for response every 3 months with urinary cytology, cystoscopy and bladder biopsy. Patients were considered treatment failures if either the cytology studies or biopsies were positive for tumor. Of 65 patients who failed the initial treatment course 57 were given an additional 6-week course of therapy. One 6-week course of bacillus Calmette-Guerin was successful in 20 of 55 patients (36 per cent) treated for prophylaxis, 12 of 32 (37 per cent) treated for carcinoma in situ and 7 of 17 (41 per cent) treated for residual tumor. The response rate for the total patient population treated with 1, 6-week course was 37.5 per cent (39 of 104). A second 6-week course was successful in 19 of 29 patients (65 per cent) treated for prophylaxis, 11 of 18 (71 per cent) treated for carcinoma in situ and 4 of 10 (40 per cent) treated for residual tumor. The response rate for all patients receiving a second course of bacillus Calmette-Guerin was 59.6 per cent (34 of 57). Of 6 patients who refused another 6-week course of bacillus Calmette-Guerin 4 had additional recurrences and 3 of these 4 suffered invasive disease. The over-all therapeutic response rate for patients treated with either 6 or 12 weeks of therapy was 70 per cent. These results suggest that 6 weeks of intravesical bacillus Calmette-Guerin do not provide optimal therapy for superficial bladder tumors. The data further suggest that more intensive regimens may increase therapeutic efficacy.     

Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer

Specimens from 84 radical cystectomies for bladder carcinoma performed between January 1984 and July 1986 were reviewed to characterize the involvement of the prostate with transitional cell carcinoma. Whole-mount sectioning of the prostate was performed at 4 mm. intervals and processed in the same manner as radical prostatectomy specimens. A total of 36 patients (43 per cent) had transitional cell carcinoma of the prostate: 94 per cent of these had prostatic urethra involvement and 6 per cent had a normal prostatic urethra but transitional cell carcinoma was present in the periurethral structures. In situ prostatic duct or acini, ejaculatory duct and seminal vesicle involvement occurred, respectively, in 67, 8 and 17 per cent of the patients with prostatic involvement. Of the patients with prostatic involvement 39 per cent had stromal invasion (22 per cent focal and 17 per cent diffuse invasion). The incidence of carcinoma in situ of the bladder neck or trigone (59 per cent), previous intravesical chemotherapy (59 per cent) and ureteral carcinoma (79 per cent) was significantly increased in patients with prostatic involvement. In patients with carcinoma in situ of the trigone or bladder neck, or in whom previous intravesical chemotherapy treatments have failed prostatic involvement should be suspected so that this disease can be detected before stromal invasion occurs.     

Clinical outcome of conservative therapy for stage T1, grade 3 transitional cell carcinoma of the bladder

BACKGROUND: The objective of this study was to retrospectively investigate the effectiveness of transurethral resection of bladder tumor (TURBT) and intravesical instillation therapy for stage T1, grade 3 (T1G3) transitional cell carcinoma (TCC) of the urinary bladder. METHODS: Between January 1995 and December 1997, 97 patients with T1G3 TCC of the urinary bladder were treated by TURBT and adjuvant intravesical instillation with bacillus Calmette-Guérin (BCG) or other anticancer agents. The recurrence-free survival rates were evaluated according to several clinicopathological factors. The cases that progressed to muscle invasive disease were also analysed. RESULTS: In this series, the median follow-up period was 25 months (range, 5- 41) after the initial TURBT. Intravesical recurrence was noted in 44 patients (45%), and the 1, 2, and 3 year recurrence-free survival rates were 72%, 58%, and 42%, respectively. Multivariate analyses revealed that the risk of intravesical recurrence was significantly higher for patients who did not receive BCG therapy, irrespective of age, gender, tumor size, multiplicity, pathological stage, concomitant carcinoma in situ, and lymphovascular involvement. Moreover, after a median of 10 months, disease progression occurred in seven patients (7%), of which only one patient was treated by BCG therapy after initial TURBT. CONCLUSION: These findings suggest that intravesical instillation with BCG combined with TURBT is an effective conservative treatment for T1G3 TCC of the bladder. Patients with negative prognostic factors should be treated by BCG rather than other anticancer agents after TURBT.     

Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression

A multivariate analysis was performed on data from 221 patients with superficial bladder tumors (papilloma in 30, grade II to III stage Ta in 51, grade II to III stage Tis in 111 and grade II to III stage T1 in 29) who were treated with intravesical bacillus Calmette-Guerin and followed for a minimum of 24 months or until progression. The purpose of this analysis was to identify prognostic variables predictive of tumor progression defined as muscle invasion, metastasis or endoscopically uncontrolled superficial bladder carcinoma involving the bladder and/or prostatic urethra. Variables examined before bacillus Calmette-Guerin, and at 3 and 6 months after bacillus Calmette-Guerin included age, sex, race, purified protein derivative reaction, duration of disease, tumor category, tumor grade, multifocality, results of cytology, flow cytometry, cystoscopy, biopsy, prior chemotherapy and bacillus Calmette-Guerin treatment regimen. Significant variables (Cox regression analysis, p less than 0.07) for tumor progression were before bacillus Calmette-Guerin--stage T1 tumors and duration of disease less than 1 year, at 3 months after bacillus Calmette-Guerin--stage T1 tumor, duration of disease less than 1 year, positive cytology studies and multifocality, and at 6 months after bacillus Calmette-Guerin--stage T1 tumor, positive cytology and positive biopsy other than stage T1 tumors. Prognostic risk groups were best defined at 6 months after bacillus Calmette-Guerin, the probability of tumor progression thereafter being at 1, 3 and 5 years, respectively, as follows: for risk group 1 (T1 tumor)--71, 100 and 100 per cent, for risk group 2 (positive biopsy other than T1 plus positive cytology)--25, 79 and 100 per cent, for risk group 3 (either positive biopsy other than stage T1 or positive cytology studies)--18, 40 and greater than 81 per cent, and for risk group 4 (negative biopsy and negative cytology studies)--2, 11 and 26 per cent, respectively. Evaluation of patients with superficial bladder carcinoma at 6 months after intravesical bacillus Calmette-Guerin therapy identifies the probability of tumor progression. Patients at high risk for tumor progression require alternative treatment strategies, whereas low risk patients can be observed for further therapy if necessary.     

Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results

We treated 40 patients with superficial bladder cancer via intravesical bacillus Calmette-Guerin for 1) prophylaxis against tumor recurrence, 2) residual carcinoma or 3) flat carcinoma in situ. A single course of intravesical bacillus Calmette-Guerin therapy was successful in 6 of 11 patients (55 per cent) treated for residual carcinoma and 6 of 12 (50 per cent) treated for carcinoma in situ. Of 17 patients receiving a single course of bacillus Calmette-Guerin for prophylaxis 11 remained free of tumor during short-term followup. A second course of therapy was administered to failures in each treatment category, which resulted in favorable responses in 5 of 6 patients treated for prophylaxis, 2 of 5 treated for residual tumor and 3 of 6 treated for carcinoma in situ. Over-all complete responses were achieved in 16 of 17 patients (94 per cent) treated for prophylaxis, 8 of 11 (73 per cent) for residual carcinoma and 8 of 12 (66 per cent) for carcinoma in situ, with a mean followup from the final treatment of 9.3, 12.3 and 7.9 months, respectively. Favorable results occurred more frequently among patients who exhibited a granulomatous inflammatory response in the bladder and delayed hypersensitivity skin test response to purified protein derivative. Marked variability in viability of bacillus Calmette-Guerin organisms was observed among different lots of bacillus Calmette-Guerin, and a direct relationship was observed between bacillus Calmette-Guerin vaccine viability and therapeutic efficacy. Most patients who failed initial therapy with a low viability lot of bacillus Calmette-Guerin responded favorably to re-treatment with a higher viability lot. The results suggest that the level of viability of each lot of bacillus Calmette-Guerin vaccine should be verified before clinical use.     

Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tumors: incidence, possible pathogenesis and management

A total of 66 patients with multifocal, progressive, flat carcinoma in situ of the bladder responded completely to intravesical bacillus Calmette-Guerin therapy for more than 1 year. Of the patients 19 (29 per cent) had clinical evidence of distal ureteral carcinoma in situ between 13 and 30 months (median 15 months) after bacillus Calmette-Guerin treatment. After evaluation of a positive urinary cytology study failed to reveal recurrent urothelial tumor of the bladder or prostatic urethral mucosa 6 patients underwent distal ureterectomy, 2 underwent nephroureterectomy, and 11 were managed by ureteroscopic resection and fulguration. In patients with carcinoma in situ of the bladder treated successfully with topical therapy the ureters represent a potential site of in situ carcinoma.     

The limits of bacillus Calmette-Guerin for carcinoma in situ of the bladder

PURPOSE: Historically carcinoma in situ of the bladder has been treated with radical cystectomy based on the aggressive and potentially invasive nature of this disease. The introduction in the late 1970s of intravesical bacillus Calmette-Guerin (BCG) has made this therapy the gold standard in the management of carcinoma in situ. Cases that are refractory or resistant to BCG therapy are a management dilemma with various available treatment options. MATERIALS AND METHODS: A comprehensive literature review of the current management of carcinoma in situ of the bladder was performed using MEDLINE, a review of current urology journals and abstracts from recent urology meetings. Data focused on BCG resistant carcinoma in situ of the bladder and current approaches in use for refractory disease. RESULTS: Complete and durable response rates have been reported in more than 70% of patients with carcinoma in situ who are treated with intravesical BCG. To our knowledge the optimal therapeutic regimen has not been established, although extended periods of treatment beyond the originally described 6-week course have not been shown to improve complete response rates. Prolonged administration of BCG is associated with adverse side effects. Various prognostic indicators of recurrence and progression exist that may identify a subset of cases unlikely to respond favorably to a conservative approach, including carcinoma in situ with associated stage T1 bladder lesions, diffuse and multifocal carcinoma in situ, multiple recurrences with intravesical therapy and extravesical involvement. Current molecular markers may also predict the response of carcinoma in situ to therapy. Treatment options available for BCG refractory carcinoma in situ of the bladder include intravesical chemotherapy, combined immuno-chemotherapy and radical cystectomy. Intravesical valrubicin and oral bropirimine have been shown to induce a complete response rate of 21% to 50%, although data on long-term followup are forthcoming. Radical cystectomy remains effective therapy for aggressive carcinoma in situ of the bladder. CONCLUSIONS: The current management of carcinoma in situ of the bladder is ill defined due to the variable natural history and unpredictable response of this disease to therapy. Controversy exists as to the optimal treatment of carcinoma in situ of the bladder since different forms of carcinoma in situ may exist that complicate therapeutic decisions for appropriate therapy. Some tumor characteristics are associated with more aggressive behavior and may be predictive of treatment outcome.     

Bacillus Calmette-Guerin for treatment of superficial transitional cell carcinoma of the bladder in patients who have failed thiotepa and/or mitomycin C

Thirty patients with stage Ta carcinoma in situ or T1 superficial bladder cancer received 6 weeks of intravesical bacillus Calmette-Guerin. All patients had persistent or recurrent tumor despite thiotepa and/or mitomycin C. Response was determined by the results of endoscopy, bladder wash cytology and biopsy performed 4 weeks after the last dose of bacillus Calmette-Guerin. Of the 30 patients 15 (50 per cent) had a complete response. The likelihood of a complete response was better for those with initial Ta lesions (62 per cent) and carcinoma in situ (56 per cent) than for patients with an initial T1 lesion (25 per cent). Although the longest followup is only 36 months (mean 16 months) patients with a complete response have a much better prognosis in terms of subsequent tumor, need for cystectomy and death of bladder cancer.     

Intravesical instillations with bacillus calmette-guérin for the treatment of carcinoma in situ involving prostatic ducts

OBJECTIVES: Bacillus Calmette-Guérin (BCG) has proven its efficacy in the treatment of carcinoma in situ (CIS) of the prostatic urethra. We performed a retrospective study to evaluate the use of intravesical instillations of BCG in patients with carcinoma in situ involving prostatic ducts after complete transurethral resection (TUR). MATERIAL AND METHODS: Eligibility for the study was CIS of the prostatic urethra involving prostatic ducts. Previous instillation with BCG was an exclusion criterion. Patients were treated with intravesical BCG Connaught (81 mg) administered once a week, over a 6-wk period. TUR loop biopsies of the prostate were performed only when a macroscopic tumor was present. RESULTS: In this retrospective study of 11 patients, 8 (73%) presented with macroscopic tumor in the prostatic urethra. Ten patients (91%) had a simultaneous superficial bladder carcinoma. Eight patients (73%) had tumoral involvement of the bladder neck region. After a median follow-up of 27 mo (n=10 patients), the response in the prostatic urethra was 82%, and the response in the bladder due to superficial tumor recurrence was 64%. Two patients with residual ductal disease in the prostatic urethra were subsequently treated with cystoprostatectomy and are currently free of disease. In one of those patients, the cystoprostatectomy specimen did show prostatic stromal invasion. Another patient developed distant metastatic disease and died a few months after diagnosis. Thus, progression was encountered in two patients (18%). Currently, 90% of patients are alive without evidence of disease and 72.7% have benefitted from this bladder preservation strategy. CONCLUSION: Intravesical BCG is a feasible treatment option for patients with CIS involving prostatic ducts. In this retrospective study, bladder preservation was successful in 8 of 11 patients (70%) and there was only one oncologic death. Obviously, these patients need a careful follow-up with cystoscopy and cytology to detect either recurrence or progression and in those with persistent disease after the initial BCG induction therapy, prompt cystectomy is indicated.     

Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer

Between January 1978 and February 1984, 120 patients with superficial bladder tumors and/or carcinoma in situ were enrolled in previously reported therapeutic trials of bacillus Calmette-Guerin. Of all treated patients 78 per cent responded to initial therapy, with a followup of 13 to 120 months (median 67 months). Of the 18 patients who failed 10 were treated with repeat, intensified courses. Nine patients who had recurrent tumors within 3 to 30 months after initiation of bacillus Calmette-Guerin therapy (median 6 months) eventually ceased having recurrence. Status free of disease in the 9 patients ranged from 25 to 90 months since the last recurrence (median 64 months). With retreatment of some of the early failures, the initial success rate of 78 per cent was increased to 89 per cent. These data support the concept that intravesical immunotherapy with bacillus Calmette-Guerin should be repeated in patients who initially appear not to respond. The data also suggest that bacillus Calmette-Guerin induces a durable beneficial response rather than simply delays eventual tumor recurrence.     

The management of superficial bladder tumors and carcinoma in situ with intravesical bacillus Calmette-Guerin

A phase II study was performed to assess the role of bacillus Calmette-Guerin as a prophylaxis against recurrent stages O and A bladder tumors, and in the treatment of existing superficial bladder tumors and carcinoma in situ. Tice strain bacillus Calmette-Guerin (1 vial, 2 to 8 times 10(8) organisms in 60 cc saline) was instilled intravesically without cutaneous inoculation. Instillations were given weekly for 6 weeks and then monthly or until recurrence in 22 patients with a history of recurrent tumors, while 22 with existing stages O and A transitional cell carcinoma, and 19 with carcinoma in situ were treated weekly for 8 weeks and then monthly for 12 months or until failure. Complications included cystitis in 88 per cent of the patients (severe in 20 per cent), fever in 15 per cent, a flu-like syndrome in 13 per cent, edema and pruritus in 1.5 per cent, and ureteral stenosis in 1.5 per cent. Twelve patients (19 per cent) did not complete the study owing to toxicity. Of the patients in the prophylaxis group 67 per cent have had no tumor recurrence 10 to 26 months (mean 15 months) after therapy. Of the patients with existing tumors 36 per cent had complete regression following bacillus Calmette-Guerin therapy and 23 per cent had a partial response. Among the patients with carcinoma in situ 13 (68 per cent) had reversal to normal urothelium and 3 (16 per cent) had marked improvement. None of the patients had recurrence at 11 to 20 months. Intravesical Tice strain bacillus Calmette-Guerin is effective as a prophylaxis against recurrent superficial bladder tumors and in the treatment of carcinoma in situ.     

Long-term followup of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor

We report our long-term experience with 104 patients treated for recurrent superficial bladder tumors followed for a mean of 48 +/- 2 months (range 6 to 83 months). Patients received 6 weekly intravesical bacillus Calmette-Guerin instillations, and were followed for response with urinary cytology, cystoscopy and bladder biopsy. Patients were considered treatment failures if either urinary cytology or biopsy results were positive for tumor. Of 69 patients who failed the initial treatment course 60 were given an additional 6-week course of therapy. A 6-week course of bacillus Calmette-Guerin was successful in 19 of 55 patients (35%) treated for prophylaxis, 10 of 32 (31%) treated for carcinoma in situ and 6 of 17 (35%) treated for residual tumor. The response rate for the total patient population treated with 1, 6-week course was 34% (35 of 104). Another 6-week course was successful in 32 of 60 patients (53%). The over-all response rate free of tumor for patients treated with either 6 or 12 weeks of therapy was 64%. The mean interval free of tumor was 48 months. We evaluated tumor type, stage and grade in conjunction with muscle invasion to assess potential indicators of response to a second course of bacillus Calmette-Guerin. Of 13 patients with carcinoma in situ and 45 with papillary disease 5 (38%) and 26 (58%), respectively, responded to a second course of bacillus Calmette-Guerin (not significantly different). In contrast, 5 of 8 carcinoma in situ failures (63%) had muscle invasive disease, compared to only 3 of 19 papillary nonresponders (16%) (p less than 0.02). These results suggest that intravesical bacillus Calmette-Guerin for the treatment of superficial bladder tumors is an effective long-term therapy. One 6-week course may be ineffective for some patients and another 6-week course provides long-term survival free of tumor for many course 1 failures. Patients who present with carcinoma in situ after a single 6-week course of intravesical bacillus Calmette-Guerin have a significantly higher risk for muscle invasive disease than those with recurrent papillary tumors.     

Intensive intravesical chemotherapy in the treatment of flat carcinoma in situ: is it safe?

Recent enthusiasm for the use of intensive regimens of intravesical chemotherapy in the management of various forms of superficial transitional cell carcinoma of the bladder prompted us to examine retrospectively a group of patients with carcinoma in situ treated by such regimens who failed with progressive and metastatic cancer. Of 8 patients with flat carcinoma in situ treated with thiotepa 5 presented initially with concomitant solitary stage T1 papillary tumors that were resected successfully at initial presentation. Six patients had diffuse or multifocal carcinoma in situ, while 2 others had only a solitary focus of in situ disease. All patients had persistently positive urinary cytology studies during treatment, prompting 3 of them to receive intravesical mitomycin C following their course of thiotepa. Involvement of the prostatic urethra developed during therapy in 3 patients and 3 had muscle-infiltrative disease. At cystectomy 3 of 7 patients had positive pelvic lymph nodes and 4 died of distant metastases at an average of 8 months after cystectomy. These results suggest that despite the apparent advances that have been made in the control of recurrent superficial transitional cell bladder cancer, the intrinsic behavior of some forms of the disease may determine cancer progression. Identification of such patients is indicated for the institution of early aggressive treatment, which in the end may actually be the more conservative therapeutic approach.     

Intravesical combination chemotherapy with mitomycin C and doxorubicin for carcinoma in situ of the bladder

We treated 30 patients with carcinoma in situ of the bladder via intravesical combination chemotherapy. As an induction therapy 20 mg. mitomycin C on day 1 and 40 mg. doxorubicin on day 2 were instilled into the bladder once a week for 5 consecutive weeks. Patients who achieved complete response were assigned a maintenance instillation of mitomycin C alone every 2 to 4 weeks for 1 year. A total of 19 patients achieved complete response following an initial course of induction therapy and 2 partial responders to initial therapy also achieved complete response after repeated induction therapy, resulting in a 70 per cent over-all complete response rate. Toxicity was considerable with moderate to severe bladder irritation occurring in 20 patients but it was tolerable in the majority. Of 21 complete responses 13 remained free of disease for 6 to 43 months (average of 23 months), 5 had recurrent carcinoma in situ and 1 had invasive urethral cancer. In contrast, of 9 nonresponders 2 and 1 had invasive cancer of the bladder and ureter, respectively.     

Equivalent efficacy of mitomycin C plus doxorubicin instillation to bacillus Calmette-Guerin therapy for carcinoma in situ of the bladder

BACKGROUND: To elucidate the most efficient topical therapy for carcinoma in situ of the bladder, the efficacy of intravesical mitomycin C plus doxorubicin therapy was compared with bacillus Calmette-Guerin (BCG) therapy. The clinical behavior of the tumor was analysed according to the histological grade. METHODS: Forty-two patients with carcinoma in situ of the bladder were randomized to intravesical BCG (21 patients) or mitomycin C plus doxorubicin sequential therapy (21 patients) as first line treatment. The non-responders underwent the subsequent instillation of the other intravesical therapy alternately. Of the patients, 27 had grade 2 and 15 had grade 3 cancer. RESULTS: Both topical therapies were equally effective with initial response rates of 86% (18/21) for BCG and 81% (17/21) for mitomycin C plus doxorubicin, irrespective of the tumor grade. Of seven initial non-responders, five patients achieved a complete response by subsequent instillation, resulting in a total response rate of 95%. After a mean follow-up of 47 months, five patients (12%) developed disease progression. The progression rates were not different between the topical therapies, but were significantly higher in grade 3 than in grade 2 cases. CONCLUSION: It appears likely that mitomycin C plus doxorubicin instillation has an equivalent efficacy to BCG as the initial therapy of carcinoma in situ and the combination of them would be the most efficient treatment for the disease. Moreover, histological grading would be clinically useful in defining the tumor characteristics and behavior of carcinoma in situ of the bladder.