Maintenance Bacille Calmette-Guérin Research Articles

The impact of the social construct of race on outcomes among bacille Calmette-Guérin-treated patients with high-risk non-muscle-invasive bladder cancer in an equal-access setting.

The objective of this study was to describe bladder cancer outcomes as a function of race among patients with high-risk non-muscle-invasive bladder cancer (NMIBC) in an equal-access setting. A total of 412 patients with high-risk NMIBC who received bacille Calmette-Guérin (BCG) from January 1, 2010, to December 31, 2015, were assessed. The authors used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, disease-specific, and overall survival outcomes. A total of 372 patients who had complete data were included in the analysis; 48 (13%) and 324 (87%) were Black and White, respectively. There was no difference in age, sex, smoking status, or Charlson Comorbidity Index by race. White patients had a higher socioeconomic status with a greater percentage of patients living above the poverty level in comparison with Black patients (median, 85% vs 77%; P < .001). A total of 360 patients (97%) received adequate induction BCG, and 145 patients (39%) received adequate maintenance BCG therapy. There was no significant difference in rates of adequate induction or maintenance BCG therapy according to race. There was no significant difference in recurrence (hazard ratio [HR], 1.53; 95% confidence interval [CI], 0.64-3.63), progression (HR, 0.77; 95% CI, 0.33-1.82), bladder cancer-specific survival (HR, 1.01; 95% CI, 0.30-3.46), or overall survival (HR, 0.97; 95% CI, 0.56-1.66) according to Black race versus White race. In this small study from an equal-access setting, there was no difference in the receipt of BCG or any differences in bladder cancer outcomes according to race.

Retrospective study of various conservative treatment options with bacille Calmette-Guérin in bladder urothelial carcinoma T1G3: Maintenance therapy

ObjectiveTo compare various conservative treatment options for high-grade T1 nonmuscle-invasive bladder cancer (NMIBC). Bacille Calmette-Guérin (BCG) is the preferred intravesical treatment for high-grade T1 tumors; however, a number of experts still question the need for maintenance BCG. Material and methodsWe retrospectively analyzed data from 1039 patients with primary and recurrent T1G3 NMIBC. All patients underwent complete transurethral resection of the bladder tumor (TURBT), with muscle in the sample and multiple bladder biopsies. The patients were treated with the following: only one initial TURBT (n=108), re-TURBT (n=153), induction with 27mg of BCG (Connaught strain) (n=87), induction with 81mg of BCG (n=489) or induction with 81mg of BCG+maintenance (n=202). The time to first recurrence, progression (to T2 or greater or to metastatic disease) and specific mortality of the disease was assessed using the Kaplan–Meier survival function and were compared using the log-rank test and the Cox multivariate regression model of proportional risks. ResultsThe mean follow-up was 62±39 months. The risk of recurrence was significantly lower for the patients treated with maintenance therapy of 81mg of BCG than in the other treatment groups (p<0.001). The risk of tumor progression was also significantly lower for the patients treated with maintenance BCG than for the patients treated only with one TURBT, re-TURBT and with induction therapy with 27mg of BCG (p=0.0003). The specific disease mortality was significantly lower with BCG maintenance (9.4%) than with only one TURBT (27.8%; p=0.003). ConclusionsIn the case of T1G3 NMIBC, a complete dose of BCG with maintenance is associated with better recurrence results than are other conservative treatment modalities. The results of progression and survival specific to the disease were also better with induction BCG, with or without maintenance.

Increasing age is not associated with toxicity leading to discontinuation of treatment in patients with urothelial non-muscle-invasive bladder cancer randomised to receive 3 years of maintenance bacille Calmette-Guérin: results from European Organisation for Research and Treatment of Cancer Genito-Urinary Group study 30911.

To determine the relationship of age to side-effects leading to discontinuation of treatment in patients with stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with maintenance bacille Calmette-Guérin (BCG). We evaluated toxicity for 487 eligible patients with intermediate- or high-risk Ta-T1 (without carcinoma in situ) NMIBC randomised to receive 3 years of maintenance BCG therapy (247 BCG alone and 240 BCG + isoniazid) in European Organisation for Research and Treatment of Cancer Genito-Urinary Group trial 30911. The percentage of patients who stopped for toxicity and the number of treatment cycles that they received were compared in four age groups, ≤60, 61-70, 71-75 and >75 years, using the Mantel-Haenszel chi-square test for trend. The percentage of patients stopping BCG for toxicity was 17.9% in patients aged ≤60 years, 21.9% in patients aged 61-70 years, 22.9% in patients aged 71-75 years, and 16.4% in patients aged >75 years (P = 0.90). For both systemic and local side-effects, there was likewise no significant difference. In patients with intermediate- and high-risk Ta-T1 NMIBC treated with BCG, no differences in toxicity as a reason for stopping treatment were detected based on patient age.

Estudio retrospectivo de diferentes opciones de tratamiento conservador con Bacilo de Calmette-Guèrin en el carcinoma urotelial vesical T1G3: terapia de mantenimiento

ObjectiveTo compare various conservative treatment options for high-grade T1 nonmuscle-invasive bladder cancer (NMIBC). Bacille Calmette-Guérin (BCG) is the preferred intravesical treatment for high-grade T1 tumours; however, a number of experts still question the need for maintenance BCG. Material and methodsWe retrospectively analysed data from 1039 patients with primary and recurrent T1G3 NMIBC. All patients underwent complete transurethral resection of the bladder tumour (TURBT), with muscle in the sample and multiple bladder biopsies. The patients were treated with the following: only one initial TURBT (n=108), re-TURBT (n=153), induction with 27mg of BCG (Connaught strain) (n=87), induction with 81mg of BCG (n=489) or induction with 81mg of BCG+maintenance (n=202). The time to first recurrence, progression (to T2 or greater or to metastatic disease) and specific mortality of the disease was assessed using the Kaplan-Meier survival function and were compared using the log-rank test and the Cox multivariate regression model of proportional risks. ResultsThe mean follow-up was 62±39 months. The risk of recurrence was significantly lower for the patients treated with maintenance therapy of 81mg of BCG than in the other treatment groups (P<.001). The risk of tumour progression was also significantly lower for the patients treated with maintenance BCG than for the patients treated only with one TURBT, re-TURBT and with induction therapy with 27mg of BCG (P=.0003). The specific disease mortality was significantly lower with BCG maintenance (9.4%) than with only one TURBT (27.8%; P=.003). ConclusionsIn the case of T1G3 NMIBC, a complete dose of BCG with maintenance is associated with better recurrence results than are other conservative treatment modalities. The results of progression and survival specific to the disease were also better with induction BCG, with or without maintenance.

Intravesical chemotherapy plus bacille Calmette‐Guérin in non‐muscle invasive bladder cancer: a systematic review with meta‐analysis

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Non-muscle-invasive bladder cancer has a significant recurrence and progression rate despite transurethral resection. The current standard of care to lower the risk of recurrence and progression is adjuvant BCG followed by maintenance BCG. Despite this, a significant number of patients experience recurrence and progress to invasive cancer. Several randomized trials have studied combination therapy (BCG with chemotherapy) to try to reduce the recurrence and progression rate. We performed a systematic review with meta-analysis and found that adjuvant BCG followed by maintenance therapy is the appropriate standard of care when compared with combination therapy. We conclude that further trials are warranted to test the effects of adding chemotherapy to BCG in patients with Ta or T1 disease, but not in those with Tis alone. To determine if the combination of intravesical chemotherapy and maintenance bacille Calmette-Guérin (BCG), used in sequence, is superior to maintenance BCG alone in the treatment of non-muscle-invasive bladder cancer (NMIBC). We searched biomedical literature databases for randomized controlled trials that compared sequential, intravesical chemotherapy added to maintenance BCG with maintenance BCG alone. Studies that did not use maintenance BCG were excluded. The meta-analysis was performed using the fixed effects model. Four trials were identified, including 801 patients. Adding chemotherapy to maintenance BCG did not result in a significant reduction in recurrence (relative risk [RR] 0.92; 95% confidence interval [CI] 0.79-1.09; P = 0.32) or progression (RR 0.88; 95% CI 0.61-1.27; P = 0.5). The risk of recurrence (RR 0.75; 95% CI 0.61-0.92; P = 0.006) and progression (RR 0.45; 95% CI 0.25-0.81; P = 0.007) were reduced when the single trial that included isolated Tis was excluded. Toxicity was similar for both groups. Adjuvant therapy with induction BCG followed by maintenance BCG is the appropriate standard of care for patients with resected NMIBC at high risk of recurrence. Further trials are warranted to test the effects of adding chemotherapy to BCG in patients with Ta or T1 disease, but not in those with Tis alone.

Bladder Cancer: A Review of Non-Muscle Invasive Disease

Bladder cancer is one of the most common cancers affecting men and women and thus has a profound impact on health care. The majority of patients (75%) with newly diagnosed urothelial tumors have non-muscle invasive disease confined to the bladder mucosa or the lamina propria. The authors review the literature as well as recently published clinical guidelines regarding the bladder cancer risk and causative factors, diagnostic and pathologic evaluation, prognostic variables, and management strategies for patients with non-muscle invasive bladder cancer. Recurrence and progression remain problematic for many patients and are dependent on multiple clinical and pathological features, the most important of which are tumor stage, grade, multifocality, size, recurrence patterns, and the association with carcinoma in situ. Accurate assessment of clinical stage and tumor grade is critical in determining management and surveillance strategies. Intravesical therapies positively influence tumor recurrence rates. Disease progression rates may be impacted in high-risk patients who receive both induction bacille Calmette-Guérin (BCG) and a maintenance BCG regimen. Cystectomy still plays a pivotal role in patients with high-risk tumors and in patients who fail more conservative attempts to eradicate non-muscle invasive disease. Non-muscle invasive bladder cancers represent a broad group of tumors with varying biologic potential. Successful treatment depends on the careful integration of diagnostic and surveillance tests, macroablation through transurethral resection, accurate assessment of clinical stage, and the timely and appropriate delivery of intravesical chemotherapeutic and immunomodulatory agents.

Reduced bladder cancer recurrence rate with cardioprotective aspirin after intravesical bacille Calmette‐Guérin

To evaluate the recurrence-free survival (RFS) rate of patients taking cardioprotective aspirin after intravesical bacille Calmette-Guérin (BCG) for high-grade noninvasive urothelial carcinoma of the bladder, as preventing the recurrence of superficial bladder cancer might decrease patient morbidity and mortality from this disease, and nonsteroidal anti-inflammatory agents (NSAIDs) have shown promise in preclinical prevention through inhibition of the prostaglandin pathway and other mechanisms. In all, 43 patients with carcinoma in situ (CIS) and/or high-grade papillary bladder cancer were treated with intravesical BCG. Patients were stratified according to whether they took cardioprotective aspirin after treatment, and Kaplan-Meier curves of RFS were compared by log-rank analysis. Multivariable analysis was used for potentially confounding factors, including maintenance BCG, the presence of CIS, and smoking status. Of patients taking cardioprotective aspirin, the 5-year RFS rate was 64.3%, compared with 26.9% for patients not taking aspirin, with a significantly higher RFS by univariable log rank analysis (P = 0.03). Even after adjusting for the other factors by multivariable analysis, aspirin seems to affect recurrence (hazard ratio 0.179, P = 0.001). Maintenance BCG (hazard ratio 0.233, P = 0.02) and smoking history (hazard ratio 3.199, P = 0.05) also significantly affected recurrence. There was a significantly higher RFS rate in patients taking cardioprotective aspirin after intravesical BCG therapy for bladder cancer. The results of this study support the further investigation of aspirin and other NSAIDs as preventive agents in patients being treated for superficial bladder cancer.

Immunothérapie par Bacille de Calmette-Guérin : quel protocole ?

Several meta-analyses have reviewed the efficacy of bacille Calmette-Guérin (BCG) immunotherapy in treating nonmuscle-invasive bladder cancer (NMIBC). First, it was shown that BCG therapy was better than endoscopic resection alone in reducing the tumor progression rate, as long as a maintenance protocol was used. Moreover, BCG seems to be superior to mitomycin C in preventing recurrence. BCG has also proven its superiority over mitomycin C in terms of the risk for tumor progression when maintenance treatment is used. BCG maintenance treatment therefore seems to be the choice option to reduce the risk of both recurrence and tumor progression. The modalities for this treatment have not been clearly defined. Several protocols have been tested. Since its efficacy has been proven on a large cohort with randomized analysis, the SWOG protocol is currently the most widely used. It comprises six weekly instillations for the induction treatment, followed by three weekly instillations at 3, 6, 12, 18, 24, 30 and 36 months. It has been shown that BCG therapy toxicity was frequently the reason for interrupting maintenance therapy. In these patients with poor tolerance to the standard BCG dose, reducing the dose seems to be a useful option to improve BCG tolerance while preserving it efficacy. Finally, recent studies have shown that it would be preferable to adapt the dose and frequency of instillations of maintenance BCG to each patient. This individualized approach is undoubtedly BCG therapy's future.

Long-term follow-up of g 3t 1 transitional cell carcinoma of the bladder treated with intravesical bacille calmette-guérin: 18-year experience. : Urology 2002;59:227–231.

Objectives: Immunotherapy with bacille Calmette–Guérin (BCG) has been proposed in the past decade as first-line treatment for high-grade superficial bladder cancer (G 3T 1). We report our 18-year experience in the treatment of patients with G 3T 1 bladder cancer. Methods: From January 1989 to July 1997, 670 patients underwent transurethral resection for superficial bladder cancer. Eighty-one patients (12%) had G 3T 1 tumors. All of these patients were treated with an innovative schedule of Pasteur strain BCG followed by maintenance BCG therapy. Treatment consisted of four cycles of 6 instillations per cycle of BCG. The first cycle was administered weekly × 6, the second was given every 2 weeks × 6, the third cycle was given monthly × 6, and the fourth was given every 3 months × 6 instillations. Results: Sixty-nine patients (84%) completed at least the first two cycles. At a median follow-up of 76 months (range 30 to 197), the overall recurrence rate was 33% (27 of 81). The median time to recurrence was 20 months (range 5 to 128). Of these patients, 12 (15%) had progression at a median follow-up of 16 months (range 8 to 58). Cystectomy was required in seven patients (8%). Death from disease occurred in five (6%) of 81 patients. One patient died of adenocarcinoma at the ureterosigmoidostomy site. Sixty patients (74%) were alive at a median follow-up of 79+ months (range 15 to 182). Of these, 56 (69%) were alive with a functioning bladder. Conclusions: Conservative treatment with BCG is a reasonable approach for patients with primary G 3T 1 transitional cell carcinoma of the bladder. The long-term results of BCG therapy are good. Cystectomy may not be justified as the therapy of choice in first- line treatment of high-grade superficial carcinoma of the bladder.

Long-term maintenance bacille Calmette-Guérin therapy in high-grade superficial bladder cancer

Objectives. To assess the long-term results of intravesical bacille Calmette-Guérin (BCG) induction plus long-term maintenance treatment for high-grade superficial bladder cancer.Methods. Between 1994 and 2000, 41 patients who presented to our clinic with superficial urothelial carcinoma of the bladder (T1G3, T1G3 plus carcinoma in situ, or recurrent TaG2-3) were treated by transurethral resection of all visible tumor and an induction cycle of BCG plus a long-term maintenance BCG course consisting of 11 monthly instillations followed by 4 quarterly instillations and then by 6 six-monthly instillations. The median follow-up was 40 months.Results. Thirty patients remained tumor free throughout the follow-up period. Ten patients had a recurrence of superficial tumor, 9 patients during the monthly instillation course and 1 patient during the quarterly instillation course. One patient presented with progression.Conclusions. Adjuvant immunotherapy with BCG after complete transurethral resection of bladder tumor represents a highly effective primary treatment for high-grade superficial bladder cancer. Our maintenance course of BCG seemed to improve the worldwide accepted effectiveness of the BCG induction course without any important side effects.

Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille Calmette-Guérin: 18-year experience

Objectives. Immunotherapy with bacille Calmette-Guérin (BCG) has been proposed in the past decade as first-line treatment for high-grade superficial bladder cancer (G3T1). We report our 18-year experience in the treatment of patients with G3T1 bladder cancer. Methods. From January 1989 to July 1997, 670 patients underwent transurethral resection for superficial bladder cancer. Eighty-one patients (12%) had G3T1 tumors. All of these patients were treated with an innovative schedule of Pasteur strain BCG followed by maintenance BCG therapy. Treatment consisted of four cycles of 6 instillations per cycle of BCG. The first cycle was administered weekly × 6, the second was given every 2 weeks × 6, the third cycle was given monthly × 6, and the fourth was given every 3 months × 6 instillations. Results. Sixty-nine patients (84%) completed at least the first two cycles. At a median follow-up of 76 months (range 30 to 197), the overall recurrence rate was 33% (27 of 81). The median time to recurrence was 20 months (range 5 to 128). Of these patients, 12 (15%) had progression at a median follow-up of 16 months (range 8 to 58). Cystectomy was required in 7 patients (8%). Death from disease occurred in 5 (6%) of 81 patients. One patient died of adenocarcinoma at the ureterosigmoidostomy site. Sixty patients (74%) were alive at a median follow-up of 79+ months (range 15 to 182). Of these, 56 (69%) were alive with a functioning bladder. Conclusions. Conservative treatment with BCG is a reasonable approach for patients with primary G3T1 transitional cell carcinoma of the bladder. The long-term results of BCG therapy are good. Cystectomy may not be justified as the therapy of choice in first-line treatment of high-grade superficial carcinoma of the bladder.

Diagnosis and management of superficial bladder cancer

Bladder cancer is the fourth leading cause of cancer in American men, accounting for more than 12,000 deaths annually. It was one of the first malignancies in which carcinogens were recognized as an important factor in its cause. Currently, cigarette smoking is by far the most common cause of bladder cancer, although occupational exposure to arylamines has been implicated in the past. Gross or microscopic hematuria is the most common sign at presentation. Initial radiologic evaluation usually includes the excretory urography (intravenous pyelography), although further evaluation of the renal parenchyma with ultrasound or computed tomography scanning has been advocated by some. These radiologic studies are unable to provide adequate bladder imaging, and thus cystoscopy is required for the diagnosis of bladder cancer. Most bladder cancers present as ″superficial” disease, confined to the bladder mucosa or submucosal layer, without muscle invasion. Superficial tumors consist of papillary tumors that are mucosally confined (Ta), papillary or sessile tumors extending into the lamina propria (T1), and carcinoma in situ, which occurs as ″flat” mucosal dysplasia, which can be focal, diffuse, or associated with a papillary or sessile tumor. The natural history of these pathologic subtypes differ significantly. Most superficial tumors (60% to 70%) have a propensity for recurrence after transurethral resection. Some (15% to 25%) are at high risk for progression to muscle invasion. Most superficial tumors can be stratified into high- or low-risk groups depending on tumor stage, grade, size, number, and recurrence pattern. It is important to identify those tumors at risk for recurrence or progression so that adjuvant intravesical therapies can be instituted. Many intravesical chemotherapeutic agents have been shown to reduce tumor recurrence when used in conjunction with transurethral tumor resection. Unfortunately, however, none of these agents have proved to be of benefit in preventing disease progression. Most are given intravesically on a weekly basis, although many studies suggest that a single instillation immediately after transurethral resection may be as good as a longer course of therapy. Although all of these drugs have toxicity, they usually are well tolerated. Intravesical bacille Calmette-Guérin (BCG) is an immunotherapeutic agent that when given intravesically is very effective in the treatment of superficial transitional cell carcinoma. Compared with controls, BCG has a 43% advantage in preventing tumor recurrence, a significantly better rate than the 16% to 21% advantage of intravesical chemotherapy. In addition, BCG is particularly effective in the treatment of carcinoma in situ, eradicating it in more than 80% of cases. In contrast to intravesical chemotherapy, BCG has also been shown to decrease the risk of tumor progression. The optimal course of BCG appears to be a 6-week course of weekly instillations, followed by a 3-week course at 3 months in those tumors that do not respond. In high-risk cancers, maintenance BCG administered for 3 weeks every 6 months may be optimal in limiting recurrence and preventing progression. Unfortunately, adverse effects associated with this prolonged therapy may limit its widespread applicability. In those patients at high risk in whom BCG therapy fails, intravesical interferon-α with or without BCG may be beneficial in some. Photodynamic therapy has also been used but is limited by its toxicity. In patients who progress or do not respond to intravesical therapies, cystectomy should be considered. With the development of orthotopic lower urinary tract reconstruction to the native urethra, the quality of life impact of radical cystectomy has been lessened. (Curr Probl Cancer 2001;25:217-80.)

Intravesical bacille Calmette-Guérin in stage T1 grade 3 bladder cancer therapy: a 7-year follow-up

Objectives. To assess the long-term results of intravesical bacille Calmette-Guérin (BCG) treatment for Stage T1 grade 3 (T1G3) transitional cell carcinoma (TCC) of the bladder. Methods. Fifty-one patients with T1G3 TCC were treated with induction plus maintenance BCG courses after transurethral resection and followed up for at least 5 years or until death. Results. The median follow-up of progression-free patients was 85 months (range 64 to 108). During this period 32 (62.7%) of 51 patients remained progression free, 9 (17.6%) progressed, 8 (15.7%) died of other causes, and 2 (3.9%) were lost to follow-up. Seven patients had extravesical involvement: 5 (9.8%) of 51 had an upper urinary tract tumor and 3 (7.9%) of 38 had prostatic involvement (1 of the 7 had both). The risk of disease progression was significantly higher for patients with a tumor measuring 3 cm or more and those with tumor associated with carcinoma in situ (CIS) in multivariate analyses and for patients with recurrent tumors, solid tumors, or early T1G3 recurrence after BCG in univariate analyses. At last follow-up, 34 patients (66.7%) were alive; 8 (15.7%) had died of causes unrelated to the disease, 7 (13.7%) had died of bladder cancer, and 2 (3.9%) had been lost to follow-up. Disease-specific survival was 86.3%. Conclusions. Intravesical BCG is an effective conservative treatment for T1G3 bladder cancer. Patients with negative prognostic factors such as coexisting CIS or large, solid, or recurrent tumor should be followed up closely and if T1G3 recurs early after the BCG induction course, immediate cystectomy should be performed.

Intravesical bacille calmette-guérin induces the antiangiogenic chemokine interferon-inducible protein 10

Objectives. Intravesical bacille Calmette-Guérin (BCG) induces a variety of cytokines into the urine of patients with superficial transitional cell carcinoma (TCC) of the bladder. Recent data have shown that some cytokines have antiangiogenic activity. We sought to determine whether the potently antiangiogenic chemokine interferon-inducible protein 10 (IP-10) and its inducing antiangiogenic cytokines, interferon-gamma (IFN-γ) and interleukin-12 (IL-12), are increased during intravesical BCG immunotherapy of bladder TCC. Methods. Voided urine samples were collected sequentially from 8 patients before and after each weekly intravesical BCG treatment and from 4 patients receiving maintenance BCG treatments. The urinary output of IP-10, IFN-γ, and IL-12 over 12 post-treatment hours was assessed by enzyme-linked immunosorbent assay. In vitro BCG and cytokine stimulations of human TCC and primary endothelial cell lines were also performed, and their supernatants were studied for IP-10. Results. In all cases after intravesical BCG, patient urine was found to contain significant elevations of IP-10. Urinary IFN-γ and IL-12 levels also increased in similar patterns after intravesical BCG. The peak weekly cytokine response per patient usually occurred between the fourth and sixth treatment for IFN-γ and IP-10, but was less predictable for IL-12. Human TCC and endothelial cell lines were able to secrete IP-10 in response to BCG or interferon stimulation in vitro. Conclusions. Our small series demonstrates that IP-10 and its inducing cytokines are elevated in response to intravesical BCG. These data suggest that, in addition to a cellular immune response, BCG may induce a cytokine-mediated antiangiogenic environment that aids in inhibiting future tumor growth and progression.